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Masterclass With Masterjohn Pro

MWM Pro is your tool for getting the most out of my MWM classes as quickly and easily as possible. It helps you tailor the classes to your own needs, find anything in a pinch, and access an expansive world of knowledge using MWM as your foundation.

  Home       About Me      Contact Me

Masterclass With Masterjohn Pro

MWM Pro is your tool for getting the most out of my MWM classes as quickly and easily as possible. It helps you tailor the classes to your own needs, find anything in a pinch, and access an expansive world of knowledge using MWM as your foundation.

Why This Class Is For You

Do you love health and wellness so much that you just want to read everything you can about it, but often find yourself understanding only half (or even less) of what you read? MWM Pro will give you the foundation you need to take your understanding to the next level.

Do you need to learn biochemistry for school but wish you could learn the material in a more relevant, lively, or entertaining way? That’s exactly what I’ve done with these classes: hit the science hard, but take the time to explain why it’s relevant and what you can do with it; let my natural passion and enthusiasm shine through in my teaching, and sprinkle just the right amount of humor to make it feel fun

Do you already have a good foundation, but want my unique out-of-the-box perspective that I’ve synthesized from my deep dive into the scientific literature? Perfect. In these classes I fuse the fundamentals with the latest research (and the timeless but often neglected research of bygone eras!). I top it all off by sprinkling in my own novel ideas. 

If any of these apply, MWM Pro is for you. 

Why This Class Is For You

Do you love health and wellness so much that you just want to read everything you can about it, but often find yourself understanding only half (or even less) of what you read? MWM Pro will give you the foundation you need to take your understanding to the next level.

Do you need to learn biochemistry for school but wish you could learn the material in a more relevant, lively, or entertaining way? That’s exactly what I’ve done with these classes: hit the science hard, but take the time to explain why it’s relevant and what you can do with it; let my natural passion and enthusiasm shine through in my teaching, and sprinkle just the right amount of humor to make it feel fun

Do you already have a good foundation, but want my unique out-of-the-box perspective that I’ve synthesized from my deep dive into the scientific literature? Perfect. In these classes I fuse the fundamentals with the latest research (and the timeless but often neglected research of bygone eras!). I top it all off by sprinkling in my own novel ideas. 

If any of these apply, MWM Pro is for you. 

MWM Energy Metabolism: What the Class Covers

This class is all about how we handle energy from the food we eat. The energy we derive from food supports every other system in the body, making energy metabolism the foundation of every question about health and disease. 

We begin with basic concepts about the nature of energy. If you have a science background, these lessons serve as a review. If you don’t, they serve as a foundation. We then move into the pathways of cellular respiration, which all of our macronutrients (protein, carbs, fat) share in common. After an overview, we cover the biochemistry of the citric acid cycle in exhaustive detail, slowing down at each step to explain how the step fits into the overall system and how the information is relevant and practically useful to matters of health and disease. 

Once we finish discussing the pathways shared in common, we move on to discussing the differences between the metabolism of different macronutrients. We start with the consequences of using different pathways, and then layer on the different effects these nutrients have on hormones that control energy metabolism. We do this first for how we break down food to use its energy, and then we finish with how we store energy as glycogen and fat.

Throughout the entire class, we go through the material more slowly than a typical academic course would so we can discuss key questions that make the material relevant:

  • Why does it matter whether we eat protein, carbs, or fat?
  • What are the vitamins and minerals we need, and how do these requirements change when we make different choices about macronutrients?
  • How can we use the biochemistry to understand how to interpret blood and urine tests of health, disease, and nutritional status?
  • How can we leverage our understanding of the biochemistry to help prevent or reverse common diseases?
  • How can we leverage our understanding of the biochemistry to maximize our performance in whatever domains of life we care most about?

MWM Energy Metabolism: What the Class Covers

This class is all about how we handle energy from the food we eat. The energy we derive from food supports every other system in the body, making energy metabolism the foundation of every question about health and disease. 

We begin with basic concepts about the nature of energy. If you have a science background, these lessons serve as a review. If you don’t, they serve as a foundation. We then move into the pathways of cellular respiration, which all of our macronutrients (protein, carbs, fat) share in common. After an overview, we cover the biochemistry of the citric acid cycle in exhaustive detail, slowing down at each step to explain how the step fits into the overall system and how the information is relevant and practically useful to matters of health and disease. 

Once we finish discussing the pathways shared in common, we move on to discussing the differences between the metabolism of different macronutrients. We start with the consequences of using different pathways, and then layer on the different effects these nutrients have on hormones that control energy metabolism. We do this first for how we break down food to use its energy, and then we finish with how we store energy as glycogen and fat.

Throughout the entire class, we go through the material more slowly than a typical academic course would so we can discuss key questions that make the material relevant:

  • Why does it matter whether we eat protein, carbs, or fat?
  • What are the vitamins and minerals we need, and how do these requirements change when we make different choices about macronutrients?
  • How can we use the biochemistry to understand how to interpret blood and urine tests of health, disease, and nutritional status?
  • How can we leverage our understanding of the biochemistry to help prevent or reverse common diseases?
  • How can we leverage our understanding of the biochemistry to maximize our performance in whatever domains of life we care most about?

What You’re Paying For

Masterclass With Masterjohn is free. It always has been, and it always will be. If all you want to do is sit back and enjoy the show, you can watch the videos on YouTube or Facebook. 

But MWM Pro gives you an incredible ability to use the classes to get exactly what you need out of them:

  • Early access to the content before it launches on YouTube and Facebook.
  • Keyword search all the lessons at once to quickly find the lessons you need.
  • Keyword search the videos themselves and instantaneously arrive at the point where I discuss what you’re looking for. 
  • Speed up and slow down the videos with the click of a button to learn at your desired pace.
  • Trouble understanding a particular point? Pick any segment of the video you want and set it to repeat until you understand it.
  • Access the transcripts and slides as web pages or downloadable PDFs.
  • Timestamps in the transcripts make it easy to alternate between the transcripts and videos.
  • Download the audio of each lesson to listen when you’re on the go.
  • Expand your knowledge with suggestions for further reading (including both free material and specific page numbers in related textbooks) and access reading material quickly with direct links to related content.
  • Ask questions and discuss the lessons with other MWM Pro users in dedicated forums.


What You’re Paying For

Masterclass With Masterjohn is free. It always has been, and it always will be. If all you want to do is sit back and enjoy the show, you can watch the videos on YouTube or Facebook. 

But MWM Pro gives you an incredible ability to use the classes to get exactly what you need out of them:

  • Early access to the content before it launches on YouTube and Facebook.
  • Keyword search all the lessons at once to quickly find the lessons you need.
  • Keyword search the videos themselves and instantaneously arrive at the point where I discuss what you’re looking for. 
  • Speed up and slow down the videos with the click of a button to learn at your desired pace.
  • Trouble understanding a particular point? Pick any segment of the video you want and set it to repeat until you understand it.
  • Access the transcripts and slides as web pages or downloadable PDFs.
  • Timestamps in the transcripts make it easy to alternate between the transcripts and videos.
  • Download the audio of each lesson to listen when you’re on the go.
  • Expand your knowledge with suggestions for further reading (including both free material and specific page numbers in related textbooks) and access reading material quickly with direct links to related content.
  • Ask questions and discuss the lessons with other MWM Pro users in dedicated forums.


How It Works and What It Costs

I offer two ways to sign up for MWM Pro: the monthly plan and the yearly plan. The features you get in each plan are the same, but the monthly plan offers lower upfront costs while the yearly plan saves you money in the long run and gives you early access to a larger amount of content. After purchasing your membership, you’ll log in to this site and have all the MWM Pro features right at your fingertips.

Watch this video to learn more.

The table below compares and contrasts the two plans:

How It Works and What It Costs

I offer two ways to sign up for MWM Pro: the monthly plan and the yearly plan. The features you get in each plan are the same, but the monthly plan offers lower upfront costs while the yearly plan saves you money in the long run and gives you early access to a larger amount of content. After purchasing your membership, you’ll log in to this site and have all the MWM Pro features right at your fingertips. 

Watch this video to learn more. 

The table below compares and contrasts the two plans:

Frequently Asked Questions

  • Am I guaranteed new content every month? 

No. You are guaranteed access to all MWM Pro features for the entire period for which you pay. Most MWM classes are likely to be 3-4 months long, with two lessons per week ranging from 25 to 45 minutes long. When a class ends, there will likely be a break of approximately one month before the beginning of a new class. I make no guarantee of new classes, however. 

  • Do I pay for each class?

No. Paying for MWM Pro entitles you to Pro features for all MWM classes. Currently, this only entitles you to the energy metabolism class. However, Pro features will soon be added to the antioxidant class, and as soon as they are, all paying Pro members will receive immediate access. If and when new MWM classes are added, you will immediately receive access to them providing your membership is active at that time.

  • Is the content in this course the same as in a biochemistry course?

Not exactly. This class is about breaking down, using, and storing energy. A biochemistry class may cover the synthesis of the many molecules in the cell, but this class covers biosynthesis only in the limited context of where it intersects with energy metabolism. On the other hand, this class covers energy metabolism itself in more detail than many biochemistry classes would, and covers many special topics of nutrition, health, and disease that would not be given much if any attention in the average biochemistry class.

  • Are there quizzes and exams? 

Not in this class. The fact that I am focusing exclusively on content production is what allows me to make so much high-quality content. It’s also what allows me to offer these Pro features at ridiculously low prices. The yearly plan, for example, costs less than a typical science textbook! And it’s what allows me to offer them to an unlimited number of people. I may eventually offer higher-priced courses with limited seating that have more individualized guidance, evaluation and feedback, but this will not be integrated into MWM Pro.  

  • Do you answer questions in the forums?

I will do my best to check in on the forums at least once per week, and I will try to answer the questions that are best answered by me. But the forums are primarily for you. I hope an active community evolves within them where you can help other MWM Pro members with the material and other MWM Pro members can help you.  

  • Can you add ____________?

Maybe! Once you’re an MWM Pro member, you’ll have access to the “feature requests” thread in the forums. If the feature falls within my vision for MWM Pro and can be implemented affordably without excessive hassle, I will consider adding it.  

  • Do you have an affiliate program?

You bet! You can sign up here and earn a 20% commission on any new memberships you generate. Refer five people and you’ve paid for your annual plan. Refer more, and suddenly you’re making money. I ask only that you promote the program in an honest manner. Get a membership because you expect to love it, and promote it because you do love it.  

  • Do you offer certification?

At the present time, I do not. In the future, I may offer specific courses that provide evaluation, feedback, guidance, and certification. If I do, they will be a much higher priced item than MWM Pro. MWM Pro provides you with incredible tools to self-pace your own learning independently, without direct oversight by me, which helps me keep the price low and helps me focus on creating high-quality content.  

  • Can I pause my subscription access in the middle of a payment period?

Unfortunately, no. To “pause” your MWM Pro membership means to stop future payments temporarily while keeping your account history and login credentials intact. For example, if you purchase a monthly subscription on May 4 and pause it on May 10, you will have access until June 4, after which you lose access until you resume payments. If you purchase a yearly subscription on May 4, 2017 and pause it on May 10, 2017, you will have access until May 4, 2018, after which you will lose access until you resume payments. In either case, you log in to the same account page, view your account history if desired, and resume your subscription with one click. By contrast, if you “canceled” your account, everything would be the same as if you “paused,” except you’d have to create a new account when you want to resume access and payment. While I wish I could offer a pause to your subscription access in the middle of a payment period so you can save your access for a later time, the membership software I use does not currently offer that feature. I will see if they can add it in the future.  

  • Can I watch the MWM Pro videos on Apple TV?

You can watch them this way when they come out publicly on YouTube, but you cannot presently watch them in the MWM Pro membership portal this way. I am working behind the scenes to make this a feature, but I cannot promise to implement it within a specific timeframe.  

  • How long can I access the material after I purchase the course?

You aren’t technically purchasing a course. MWM Pro will eventually encompass many courses and you are paying for a subscription to the premium features of all courses. Since you are paying for a feature subscription, your access only lasts as long as you keep up your payments. For example, if you purchase the monthly subscription, each monthly payment earns you access for one month, and if you purchase the yearly subscription, each yearly payment earns you access for one year. But, for the life of the program, the content you have access to increases indefinitely over time. If two years from now there are six courses, you pay the same subscription price and have automatic access to premium features for all of them.  

  • Do you offer student discounts?

I do not offer student discounts, but consider this. The main biochemistry textbook I use for the energy metabolism class sells on Amazon for $179.51. The average cost of a 3-credit college course is $1782.48. Most online courses that are offered by individuals rather than accredited higher education institutions cost between $300 and $400. MWM Pro is a fusion of textbook and class, designed with features to make it infinitely easier to extract the value you need from it. At $120/year, I am practically giving it away, and doing so very happily.  

  • Can I see a syllabus or a complete list of lessons?

As I produce the content, I am continually finding new connections and new topics that need to be explored, making the classes multiply. Therefore, I don’t feel comfortable releasing a list of individual lessons for the entire class. However, if you sign up now, you get immediate access to the following lessons: 

1. Thermodynamics, Energy, and Order This lesson provides an overview of the concept of energy at the microscopic level. If you’ve taken general chemistry, you will recognize it as a light review of the unit on thermodynamics. If you have not, it will provide you with the foundational concepts needed to make sense of the rest of the lessons. It does this through the lens of answering the following question: why do we have to eat such an enormous amount of food?  

2. Activation Energy and Enzymes This lesson provides an overview of the concept of activation energy and how enzymes lower it, thereby providing the means for exquisite control over what happens in our bodies. It covers the basic mechanisms of enzyme regulation with a few examples and explains the strengths and limitations of each mode of regulation. It does this through the lens of answering the following question: given the second law of thermodynamics, why does any order remain in the universe? Why don’t we and everything else fall apart?  

3. Cellular Respiration This lesson provides an overview of the basic objectives of using the citric acid cycle and the electron transport chain to make ATP. We start here because, no matter whether we burn protein, carbs, or fat, these two interrelated systems are what is shared in common.  

4. Aconitase and ROS This lesson explores the first two steps of the citric acid cycle and explains how the rate of ATP production is regulated according to the abilities of the electron transport chain. Together with lesson five, it explains how cells regulate their ATP production according to their needs and abilities. In the course of exploring this theme, we examine the role of reactive oxygen species in diabetes.  

5. Isocitrate & α-Ketoglutarate Dehydrogenases and AMPK This lesson explores the third and fourth steps of the citric acid cycle and explains how the rate of ATP production is regulated according to the cell’s need for ATP. Together with lesson four, it explains how cells regulate their ATP production according to their needs and abilities. In the course of exploring this theme, we look at the role of AMP kinase (AMPK) in promoting energy uptake during exercise. We consider how AMPK and reactive oxygen species, so often at odds with one another, work together to produce fitness in response to exercise.  

6. How Isocitrate Dehydrogenase Makes Oxalosuccinate Decarboxylate Itself This lesson looks at the third step of the citric acid cycle in much more detail, digging into the organic chemistry concepts involved in the conversion of isocitrate to α-ketoglutarate. We dive deep into this because it’s the only way to explain why this step parts ways with most other decarboxylation reactions in that it does not require thiamin (vitamin B1). This, in turn, provides a basis for understanding why burning carbohydrate for fuel requires twice as much thiamin than burning fat, and why high-fat, low-carbohydrate, ketogenic diets can be used to overcome problems with thiamin deficiency or defects in thiamin-dependent enzymes. We conclude by looking at how this step allows the interconversion of amino acids and citric acid cycle intermediates, the role of vitamin B6 in this process, and the use of enzymes known as transaminases to diagnose B6 deficiency and liver dysfunction.  

7. α-Ketoglutarate Dehydrogenase, A Massive Enzymatic Factory This lesson looks at the mechanisms of fourth step of the citric acid in much more detail, looking at the roles of thiamin, niacin (vitamin B3), riboflavin (vitamin B2), and lipoic acid. This lays the basis for considering the seven unforgettable things covered in lesson eight.  

8. 7 Unforgettable Things About α-Ketoglutarate Dehydrogenase This complex is so rich in biochemical concepts and relevance to health and disease. Having done the dirty work of looking at its organic chemistry mechanisms in the last lesson, here we explore broadly applicable biochemistry principles like energetic coupling and substrate channeling. We look at how thiamin deficiency, oxidative stress, arsenic, and heavy metal poisoning can affect metabolism, and how to recognize markers of these processes in blood or urine. We make the subtle yet critical distinction between oxidative stress and oxidative damage. We look at the role of this complex in Alzheimer’s disease. We then turn to the product of this complex, succinyl CoA, to examine how it provides an entry into the cycle for odd-chain fatty acids and certain amino acids and an exit out of the cycle for the synthesis of heme. In doing so, we look at the roles of vitamins B12 and B6 in these processes, the use of methylmalonic acid to diagnose B12 deficiency, and the ability of B6 deficiency to cause sideroblastic anemia.  

9. Why Does CoA Come Back to the TCA Cycle? This lesson addresses the curious case of why CoA makes a brief cameo in the citric acid cycle during the formation of succinyl CoA only to leave again in the next step. We dig into the chemistry underlying the high-energy thioester bond that CoA forms with acyl groups, which explains more broadly one of the key roles of sulfur in energy metabolism. We conclude by looking at how the appearance of CoA allows us to harness energy released during the decarboxylation of alpha-ketoglutarate to form ATP directly during “substrate-level phosphorylation,” or, alternatively, to use energy from ATP to invest in the synthesis of heme.  

10. That Moment You Rip Apart Water to Get Your Oxygen In this lesson we look at the final three steps in the citric acid cycle with three goals in mind: 1) we need to invest another oxygen atom to allow the continued release of carbon dioxide in future turns of the cycle, 2) we need to reconstitute the alpha-keto group we lost during the formation of succinyl CoA to allow continued exchange with amino acids, and 3) we need to create an electron-deficient portion of the molecule that is able to accept the incoming acetyl group in the next turn of the cycle. In doing so, we look at the broader concept that water is the source of oxygen whenever we lack the oxygen we need to release carbons as carbon dioxide. This concept is critical to master to understand one of the most important differences between fat and carbohydrate: because of their different oxygen contents, they consume different amounts of water and generate different amounts of carbon dioxide in their metabolism. This impacts the functions of vitamin K and biotin, the stress we place on our lungs, and the delivery of oxygen to our muscles during exercise. We also look at the role of phosphate in “borrowing” oxygen from water, which will help us understand later why glycolysis is a source of water in the cell.  

11. How to Interpret Urinary Tests of TCA Cycle Intermediates Here we revew what we’ve learned so far and introduce a quantitative evaluation of the flow of energy through the cycle through the lens of a clinical application: how to interpret the citric acid metabolite section of a urinary organic acids test. We begin with an explanation of the curious absence of oxaloacetate on these tests, which takes us back to the basic principles of chemical bonding. Ultimately, we identify patterns reflecting three conditions: energy overload, oxidative stress, and thiamin deficiency.  

12. Carbs, Fat, and Carbon Dioxide While the tenth lesson’s look at water as the source of oxygen needed to release carbon dioxide in the citric acid cycle may have seemed a bit tedious, the twelfth lesson brings the exact same principle to life with striking dietary relevance. Because carbohydrate is richer in oxygen than fat, it consumes less water during its metabolism and releases more carbon dioxide. Carbon dioxide puts stress on the lungs and its generation should be restricted in the case of lung injury to allow healing. This calls for a low-carbohydrate, high-fat diet. On the other hand, carbon dioxide is needed to support the action of vitamin K and biotin, and to promote delivery of oxygen to tissues during exercise. Thus, many other situations may call for more carbohydrate. The fact that carbs and fat generate different amounts of carbon dioxide is also the basis for the respiratory quotient (RQ), an index of carbon dioxide generated per oxygen consumed. Exercise scientists use the RQ to estimate how different conditions affect the relative utilization of different macronutrients for fuel.  

13. Pyruvate Dehydrogenase: Why Carbs Leave Your Thiamin Working Overtime The pyruvate dehydrogenase complex catalyzes the one decarboxylation step that carbohydrate undergoes to generate acetyl CoA, which accounts for the one carbon dioxide molecule produced in carbohydrate metabolism that is not produced during the metabolism of fat. It also accounts for why burning carbs requires twice as much thiamin as fat. In fact, the pyruvate dehydrogenase complex is remarkably analogous to the alpha-ketoglutarate dehydrogenase complex, sharing all the same cofactors and catalyzing virtually the same reactions. In this lesson, we look at why this has to be true and how it works. This provides the foundation for our deeply practical look at thiamin in the next lesson.  

14. Thiamin, Carbs, Ketogenic Diets, and Microbes Did you realize that thiamin deficiency can be caused by your environment? In the old days, beriberi was associated with the consumption of white rice. Nowadays, refined foods are an unlikely cause of thiamin deficiency because they are fortified. We associate deficiency syndromes such as Wernicke’s encephalopathy and Korsakoff’s psychosis primarily with chronic alcoholism. Yet there are regional outbreaks of thiamin deficiency among wildlife attributed to poorly characterized thiamin antagonists in the environment. Thiamin-destroying amoebas can pollute water, thiamin-destroying bacteria have been isolated from human feces, and thiamin-destroying fungi have also been identified. Could toxic indoor molds and systemic infections play a role as well?  

Thiamin deficiency is overwhelmingly neurological in nature and hurts the metabolism of carbohydrate much more than fat. Indeed, preliminary evidence suggests thiamin supplementation can help mitigate glucose intolerance. Ketogenic diets are the diets that maximally spare thiamin and are best characterized as treatments for neurological disorders. Anecdotally, ketogenic diet-responsive neurological problems sometimes arise as a result of infection. Could ketogenic diets be treating problems with thiamin or thiamin-dependent enzymes? One must exercise caution here: fat contains little thiamin, and ketogenic diets can actually cause thiamin deficiency if they don’t contain added B vitamins. The relationships between thiamin, glucose metabolism, and neurological health are remarkable and desperately need our attention.  

15. Lactate: Rescuing NAD+ and Generating ATP From Glycolysis One of the advantages of carbohydrate over fat is the ability to support the production of lactate. This is so important that carbohydrate is physiologically essential to red blood cells and certain brain cells known as astrocytes. For the same reason, it plays an important role in supporting the energy requirements of the lens and cornea, kidney medulla, and testes, and supports the quick boosts of peak energy needed during stressful situations that include high-intensity exercise. The biochemical role of lactate is to rescue NAD+ during times when NAD+ becomes limiting for glycolysis and glycolysis becomes a meaningful source of ATP. Through the Cori cycle, lactate can extract energy from the liver’s supply of ATP and deliver it to other tissues such as skeletal muscle in the form of glucose. This lesson fleshes out the physiological and biochemical roles of lactate and serves as a foundation for the next lesson, which explores the role of carbohydrate in supporting sports performance.  

16. Anaplerosis: Why Carbs Spare Protein in Ways That Fat Can’t “Anaplerosis” means “to fill up” and refers to substrates and reactions that fill up a metabolic pathway as its own substrates leak out for other purposes. The citric acid cycle is a central example of this because its intermediates are often used to synthesize other components the cell needs. On a mixed diet where carbohydrate provides much of the energy, pyruvate serves as the main anaplerotic substrate. During carbohydrate restriction, protein takes over. Fat is the least anaplerotic of the macronutrients because the main product of fatty acid metabolism, acetyl CoA, is not directly anaplerotic. There are several very minor pathways that allow some anaplerosis from fat, but they are unlikely to eclipse the need for protein to support this purpose during carbohydrate restriction. Thus, carbs and protein are the two primary sources of anaplerosis. This means carbs can spare the need for protein, and that protein requirements rise on a carb-restricted diet.  

17. Carbs and Sports Performance: The Principles Can athletes fat-adapt their workouts? This lesson lays down the principles of exercise biochemistry and physiology needed to understand the importance of the three energy systems supporting energy metabolism in skeletal muscle: the phosphagen system (ATP and creatine), anaerobic glycolysis (dependent on carbs), and oxidative phosphorylation (dependent on carbs, fat, or protein). We discuss why maximal intensity always depends on carbs if the intensity and duration are sufficient to deplete phosphocreatine concentrations, and clarify the window of time and intensity that can be fat-adapted. This sets the foundation for the next lesson, which looks at the evidence of how carbohydrate restriction and ketogenic diets impact sports performance.  

18. Carbs and Sports Performance: The Evidence Can fat fuel intensity in a competitive athlete? This lesson takes a critical look at the commonly cited evidence in favor of a neutral or beneficial effect of low-carbohydrate or ketogenic diets on sports performance, as well as key pieces of conflicting evidence. Bottom line? Fat can fuel duration, but probably can never fuel your peak intensity, just as the physiology would predict.  

19. Glycolysis: The Miracle of Turning Phosphate Into Water In this lesson, we examine the entire glycolytic pathway. We use as our theme the transfer of oxygen from phosphate to newly generated water. This explains why the standard stoichiometry of glycolysis found in textbooks show it generating two water molecules, and ties the information together with the analogous principles from substrate-level phosphorylation in the citric acid cycle and the relative differences in water consumption and carbon dioxide generation between fat and carbohydrate. As with our discussion of the citric acid cycle, we also reveal why the standard stoichiometry of glycolysis is misleading and why, when we account for atoms rather than molecules, we find glycolysis to be net water-neutral.  

20. Beta-Oxidation: When Fat and Water Mix In this lesson, we examine the beta-oxidation in its simplest form: the breakdown of a long-chain, saturated fatty acid. We see once again the principle that the oxygen content of a molecule determines how much water its metabolism consumes and how much carbon dioxide its metabolism releases. In beta-oxidation, we consume one water per round and release no carbon dioxide. This reflects the fact that fatty acids are not hydrates of carbons like sugars are, which is where the name carbohydrate comes from.  

21. What Shuts Down Glycolysis? Too Much Energy. This lesson covers the regulation of glycolysis. The principle regulation occurs at phosphofructokinase, which guards the gate to the first irreversible, committed step to burn glucose for energy. What governs it? Energy. If you need more ATP, you burn more glucose; if you don’t, you don’t. If the cell has glucose beyond its needs for energy, it uses it for the pentose phosphate pathway, which allows the production of 5-carbon sugars and antioxidant defense if needed, or stores it as glycogen if there is room. If not, glucose-6-phosphate accumulates and shuts down hexokinase. This, together with low AMPK levels, causes glucose to get left in the blood. The other key regulated step of glycolysis is pyruvate kinase, where the primary purpose of regulation is to prevent futile cycling between steps of glycolysis and gluconeogenesis. On the whole, glycolysis and glucose uptake are regulated primarily by energy status and secondarily by glucose-specific decisions about the need for glycogen or for the pentose phosphate pathway. Since we mostly use glucose for energy under most circumstances, the key regulation of the pathway is the regulation of phosphofructokinase by energy status. This means glucose uptake is largely driven by energy status, and our decisions about preventing hyperglycemia should center on total energy balance.  

22. What Shuts Down Fat Burning? Too Much Energy. This lesson covers the regulation of beta-oxidation. The primary regulation of beta-oxidation occurs at the mitochondrial membrane, where fatty acids are transported into the mitochondrion. Acetyl CoA carboxylase governs both the formation of fatty acids from non-carbohydrate precursors and the transport of fatty acids into the mitochondrion. Its product, malonyl CoA, is a substrate for fatty acid synthesis in the cytosol but a regulator of fatty acid transport in the mitochondrion. Thus, there are two isoforms of acetyl CoA carboxylase that are regulated similarly. The cytosolic isoform plays a direct role in fatty acid synthesis and the mitochondrial isoform regulates beta-oxidation. This ensures that the two processes are regulated reciprocally, so that one is shut down to the extent the other is activated, thereby preventing wasteful futile cycling. The primary regulator of acetyl CoA carboxylase activity is, as you might expect by this point, energy status. When a cell needs more energy, it lets fatty acids into the mitochondrion. When it has too much, it shuts down fat-burning.  

23. Is Insulin Really a Response to Carbohydrate or Just a Gauge of Energy Status? Insulin secretion. Remarkably, we know from dietary studies that we get the most insulin from eating carbohydrate, yet we know from molecular and cellular studies that insulin secretion is primarily triggered by the ratio of ATP to ADP inside the pancreatic beta-cell. The former implies that insulin is a response to glucose, while the latter implies that insulin is a response to total energy availability. What can explain this discrepancy? In this lesson, we explore the possibility that it is the anatomy and physiology that drive the dietary effect of carbohydrate rather than the biochemistry. Carbs are wired to get soaked up by the pancreas when blood sugar rises above the normal fasting level once the liver has taken its share to replete hepatic glycogen, whereas fats are wired to go primarily to the heart and muscle when those organs need energy and to go primarily to adipose tissue otherwise. The combination of circulatory routes and the relative expression of glucose transporters and lipoprotein lipase by different tissues likely directs fat to the pancreatic beta-cell as a source of ATP only during extreme hyperglycemia or when it exceeds adipose storage capacity due to obesity, insulin resistance, or very high-fat meals. The pancreatic beta-cell does have a diversity of complicated and often controversial secondary biochemical mechanisms that “amplify” the insulin-triggering effect of ATP, and carbs are more versatile at supporting these mechanism than fat. These likely make a contribution to the dietary effect, but they strike me as unlikely to be the primary driver of the dietary effect. Thus, insulin is a response mainly to carbohydrate availability but also to total energy availability, and this driven mainly by the anatomy and physiology but also by the biochemistry. Seeing insulin as a response to cellular energy status will eventually help us broaden our view of insulin as a key governor of what to do with that energy that goes far, far beyond regulating blood glucose levels.  

24. How Insulin Makes You Burn Carbs for Energy Most people interested in health and nutrition know that insulin clears glucose from the blood into cells, but it is much less widely appreciated that insulin also makes you burn that glucose for energy. Insulin stimulates the translocation of GLUT4 to the membrane of skeletal muscle, heart, and adipose cells, and activates hexokinase 2. GLUT 4 increases the rate of glucose transport across the cell membrane and hexokinase 2 locks the glucose into the cell, making sure that glucose travels inward rather than outward. Insulin stimulates glycogen synthase, causing you to store glucose as glycogen, but it also stimulates pyruvate dehydrogenase, causing you to burn pyruvate for energy. The key determinant of which one of these you do is the energy status of the cell. Glucose 6-phosphate is needed to activate glycogen synthase, and it only accumulates if high energy status is inhibiting phosphofructokinase. If low energy status is stimulating phosphofructokinase, the net effect of insulin is to irreversibly commit glucose to glycolysis, and then to stimulate the conversion of pyruvate to acetyl CoA, which then enters the citric acid cycle to allow the full combustion of the carbons and maximal synthesis of ATP. Thus, if you need the energy, the net effect of insulin is to make you burn glucose to get that energy.  

25. How Insulin Stops Fat-Burning Insulin prevents fat-burning in part by locking fat in adipose tissue and in part by shutting down transport of fatty acids into the mitochondrion inside cells. By downregulating lipoprotein lipase (LPL) at heart and skeletal muscle and upregulating it at adipose tissue, insulin shifts dietary fat away from heart and muscle and toward adipose tissue. By downregulating hormone-sensitive lipase in adipose tissue, it prevents the release of free fatty acids from adipose tissue into the blood. At the cellular level, insulin leads to the phosphorylation and deactivation of AMPK. Since AMPK inhibits acetyl CoA carboxylase, insulin-mediated deactivation of AMPK leads to activation of acetyl CoA carboxylase and the conversion of acetyl CoA to malonyl CoA. Malonyl CoA inhibits carnitine palmitoyl transferase-1 (CPT-1) and thus blocks the transport of fatty acids into the mitochondrion. Nevertheless, all of these steps are also regulated at the most fundamental level by energy status, as covered in lesson 22. Further, insulin stimulates the burning of carbohydrate for energy, as covered in lesson 24. So, is insulin’s blockade of fat-burning sufficient to cause net fat storage, or does this critically depend on energy balance? This question will be answered in the next lesson.  

26. Why Insulin Doesn’t Make Us Fat Although insulin promotes storage of fat in adipose tissue, this occurs in the context of multiple layers of regulation where energy balance is the final determinant of how much fat we store. In a caloric deficit, the low energy status of muscle and heart will lead them to take up fat rather than adipose tissue, even in the presence of insulin. Insulin combined with low energy status will promote the uptake of glucose in skeletal muscle over adipose tissue and will promote the oxidation of glucose rather than its incorporation into fat. Some advocates of the carbohydrate hypothesis of obesity have argued that glucose is needed to form the glycerol backbone of triglycerides within adipose tissue. Although glucose can serve this role, it isn’t necessary because adipose glyceroneogenesis and hepatic gluconeogenesis can both provide the needed glycerol phosphate. Further, low energy status promotes the use of glycerol as fuel and high energy status is needed to promote the formation of glycerol from glucose. Finally, fatty acids are needed to store fat in adipose tissue and they overwhelmingly come from dietary fat in almost any circumstance. Insulin can only promote de novo lipogenesis, the synthesis of fatty acids from other precursors such as carbohydrate, in the context of excess energy, and this pathway is minor in conditions of caloric deficit, caloric balance, or moderate caloric excess. Thus, although insulin does promote storage of fat in adipose tissue, it doesn’t directly affect energy balance, and energy balance is the determinant of how much fat you store overall.  

27. The Pentose Phosphate Pathway: The Many Essential Roles of Glucose The pentose phosphate pathway provides a deep look into a stunning array of essential roles for glucose. In it, glucose becomes the source of NADPH, used for antioxidant defense, detoxification, recycling of nutrients like vitamin K and folate, and the anabolic synthesis of fatty acids, cholesterol, neurotransmitters, and nucleotides. At the same time, glucose also becomes the source of 5-carbon sugars, used structurally in DNA, RNA, and energy carriers like ATP, coenzyme A, NADH, NADPH, and FADH2. DNA is needed for growth, reproduction, and cellular repair; RNA is needed to translate genetic information from DNA into all of the structures in our bodies; the energy carriers constitute the very infrastructure of the entire system of energy metabolism. This lesson covers the details of the pentose phosphate pathway, how it operates in multiple modes according to the relative needs of the cell for ATP, NADPH, and 5-carbon sugars, the role of glucose 6-phosphate dehydrogenase deficiency and thiamin deficiency in its dysfunction, and what it means for the importance of glucose to human health.

28. Insulin as a Gauge of Short-Term Energy Supply and Energetic Versatility Insulin is commonly seen as a response to blood glucose whose primary role is to keep blood glucose within a narrow range. This view of insulin fails to account for its many roles outside of energy metabolism that govern long-term investments in health. The biochemistry and physiology of insulin secretion suggest, rather, that insulin is a gauge of short-term energy status and energetic versatility. Since glucose can only be stored in small amounts and since it is the most versatile of the macronutrients in its ability to support specialized pathways of energy metabolism, it makes sense that it would be wired to the pancreas as the primary signal of short-term energy status and energetic versatility. In this lesson, we review the unique uses of glucose and the mechanisms of insulin signaling to synthesize them into a more nuanced view of the role of insulin than is typically presented.  

29. Gluconeogenesis: Expensive, but Essential Gluconeogenesis is extremely expensive. Three steps of glycolysis are so energetically favorable that they are irreversible. Getting around them requires four gluconeogenesis-specific enzymes and the investment of a much larger amount of energy. Overall, six ATP worth of energy are invested to yield glucose, a molecule that only yields 2 ATP when broken down in glycolysis. This lesson covers the details of the reactions as well as the rationale for investing so much energy. One of the most pervasive themes in biology is the drive to conserve energy. That we will spend this much energy synthesizing glucose is a testament to how essential it is to our life and well being.  

30. Gluconeogenesis Occurs When the Liver is Rich in Energy and the Body is Deprived of Glucose Since gluconeogenesis is extremely expensive, it has to be tightly regulated so that it only occurs when both of two conditions are met: 1) the liver has enough energy to invest a portion into synthesizing glucose, and 2) the rest of the body is in need of that glucose.  

Since the liver is the metabolic hub of the body that also plays a major role in anabolic synthesis and nitrogen disposal, it also regulates glycolysis and gluconeogenesis according to whether amino acids are available to supply energy in place of glucose and whether there is sufficient citrate and associated energy for biosynthesis. This lesson covers how insulin, glucagon, alanine, citrate, fructose 2-6-bisphosphate, ATP, ADP, and AMP regulate the flux between glycolysis and gluconeogenesis.  

31. Gluconeogenesis as a Stress Response: Regulation by Cortisol The last lesson covered how insulin, glucagon, and allosteric regulators from within the liver ensure that the liver only engages in gluconeogenesis when it can and when it needs to. This lesson focuses on an additional layer of regulation: cortisol. Cortisol is the principal glucocorticoid in humans. Glucocorticoids are steroid hormones produced by the adrenal cortex that increase blood glucose. Cortisol has multiple actions on the liver, muscle, adipose, and pancreas that all converge on making glucose more available to the brain. Among them, it increases movement of fatty acids from adipose to the liver, which provide the energy for gluconeogenesis, and the movement of amino acids from skeletal muscle to the liver, which provide the building blocks for gluconeogenesis. Cortisol serves both to antagonize insulin, thereby acutely increasing gluconeogenesis, and to increase the synthesis of gluconeogenic enzymes, which amplifies all other pro-gluconeogenic signaling and increases the total capacity for gluconeogenesis. In fact, even the day-to-day regulation of gluconeogenesis by glucagon is strongly dependent on normal healthy levels of cortisol in the background. Since gluconeogenesis is an extremely expensive investment with a negative return, it makes sense that the body would regulate it as a stress response, and thus place it under control by cortisol. This raises the question of whether carbohydrate restriction increases cortisol. Several studies are reviewed in this lesson that indicate that 1) there may be an extreme level of carbohydrate restriction that always increases cortisol, and 2) carbohydrate restriction definitely increases cortisol in some people. It may be the case that other stressors in a person’s “stress bucket” determine whether and how strongly the person reacts to carbohydrate restriction with elevated cortisol.  

32. This is How Ketogenesis Works In conditions of glucose deprivation, such as fasting or carbohydrate restriction, ketogenesis serves to reduce our needs for glucose. This reduces the need to engage in the energetically wasteful process of gluconeogenesis, which would otherwise be extremely taxing on our skeletal muscle if dietary protein were inadequate. Ketogenesis mainly occurs in the liver. The biochemical event that leads to ketogenesis is an accumulation of acetyl CoA that cannot enter the citric acid cycle because it exceeds the supply of oxaloacetate. The set of physiological conditions that provoke this biochemical event are as follows: free fatty acids from adipose tissue reach the liver, providing the energy needed for gluconeogenesis as well as a large excess of acetyl CoA. Oxaloacetate, with the help of the energy provided by free fatty acids, leaves the citric acid cycle for gluconeogenesis. These events increase the ratio of acetyl CoA to oxaloacetate, which leads to the accumulation of acetyl CoA that cannot enter the citric acid cycle and therefore enter the ketogenic pathway. This pathway results in the production of acetoacetate, a ketoacid. Acetoacetate can then be reduced to beta-hydroxybutyrate, a hydroxyacid, in a manner analogous to the reduction of pyruvate, a ketoacid, to lactate, a hydroxyacid. Acetoacetate is an unstable beta-ketoacid just like oxalosuccinate (covered in lesson 6) and can also spontaneously decarboxylate to form acetone, a simple ketone that is extremely volatile and can evaporate through the lungs, causing ketone breath. This lesson covers the basic mechanisms of ketogenesis and sets the ground for the forthcoming lesson on the benefits and drawbacks of ketogenesis in various contexts.  

33. This is How We Burn Ketones for Energy The production of ketones in the liver frees up coenzyme A (CoA) that would otherwise be captured in the accumulating acetyl CoA, and the conversion of acetoacetate to beta-hydroxybutyrate frees up NAD+ that would otherwise be trapped as NADH as the production of NADH in beta-oxidation exceeds that oxidized in the electron transport chain. This allows free CoA and NAD+ to keep beta-oxidation running rapidly. The ketone bodies then traverse through the inner mitochondrial and plasma membranes through the monocarboxylate transporter 1 (MCT1), and possibly through the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane. They travel through the blood to ketone-utilizing tissues, where they get into the mitochondria through the same transporters that allowed them to exit the liver. Beta-hydroxybutyrate must be converted to acetoacetate to undergo further metabolism in the ketone-utilizing tissue. Acetoacetate is converted to acetoacetyl CoA using the CoA from succinyl CoA. It is then split to two acetyl CoA by beta-ketothiolase, the same exact enzyme that catalyzes the opposite conversion during ketogenesis. The acetyl CoA then enters the citric acid cycle. The use of succinyl CoA causes the loss of one ATP that would otherwise have been synthesized in the substrate-level phosphorylation step of the citric acid cycle. Nevertheless, most ATP energy is conserved and ketones represent an efficient means of transporting energy between tissues.  

34. This is Why We Make Ketones The physiological purpose of ketogenesis is to spare the loss of lean mass that would otherwise occur during prolonged fasting. Meeting the glucose requirement of the brain entirely by gluconeogenesis from amino acids would cause us to lose 2.2 pounds of lean mass every day. This would cause us to die much more quickly from starvation than we actually do. Ketones can fuel 75% of the brain’s energy requirement. Glycerol from triglyceride hydrolysis and acetone derived from ketogenesis can together spare 55% of the amino acids that would otherwise be used to sustain the brain’s remaining glucose requirement. The acidity of ketones requires the kidney to hydrolyze glutamine to neutralize it with ammonia, however, and this attenuates the sparing of lean mass. In fact, it doubles the amount of protein breakdown over that used to synthesize glucose alone. When considering all this, ketogenesis cuts down the amount of lean mass lost during fasting 5-fold, allowing us to survive for a much longer time during fasting than we would be able to without ketones.  

35. Ketone Homeostasis During Fasting Ketone homeostasis has two central objectives: 1) keep ketone levels high enough to feed the brain, and 2) keep ketone levels low enough to avoid the serious and life-threatening condition of ketoacidosis. While proportion of circulating ketones taken up by skeletal muscle, heart, and other tissues during fasting is initially high, these tissues limit their absolute uptake of ketones and may even lower their uptake in response to increased availability of free fatty acids. As a result, ketone concentrations rapidly outpace production rates, and this is exactly what allows them to reach high enough concentrations to feed the brain. To outcompete glucose for transport across the blood brain barrier, they also act on the liver to suppress glucose output, causing blood glucose to lower. While high ketones and low glucose favor maximal penetration of ketones into the brain, the threat of ketoacidosis requires a negative feedback loop. Thus, ketones suppress adipose tissue lipolysis, restraining their own production so that blood concentrations stay in the sweet spot to safely nourish the brain.  

36. Ketoacidosis: The Dark Side of Ketones Ketones have a dark side: ketoacidosis. And it does NOT only happen in diabetes. Ketoacidosis is a serious and life-threatening medical condition wherein ketones accumulate to such high levels that they overwhelm the body’s natural buffering capacity and sink the pH of the blood to dangerous and possibly fatal levels. Ketoacidosis is most often associated with poorly controlled diabetes. Contrary to many popular claims, however, it is not limited to diabetes. Alcohol abuse with malnourishment, fasting during pregnancy or lactation, and in rare cases low-carbohydrate diets can be causes of ketoacidosis. This lesson covers the science behind ketoacidosis and reviews several case reports to illustrate what it looks like in practice.  

37. Inuit Genetics Show Us Why Evolution Does Not Want Us In Constant Ketosis Why were the Inuit never in ketosis, despite their traditional high-fat diet? That question is answered in this lesson. The answer provides a stunning example of human evolution and makes it clear that evolution does not “want” us in a constant state of ketosis. CPT-1a deficiency is a genetic disorder in the ability to make ketones and to derive energy from fatty acids needed to make glucose during fasting. In its severe form, it is extremely rare, dangerous, and fatal if not treated with frequent feeding and often a high-carbohydrate, low-fat diet. A much more mild form of CPT-1a deficiency known as “the Arctic variant” is only found in the Arctic and it is nearly universal in the Arctic. It causes a serious impairment in the ability to make ketones, dramatically raises the risk of developing hypoglycemia while fasting, and causes a three-fold increase in infant mortality. Yet virtually everyone native to the Arctic has it and it is usually asymptomatic. What is utterly stunning about this is that this variant took hold of the Arctic in one of the strongest selective sweeps ever documented in humans. This means that evolution judged this variant as better suited to the Arctic environment than almost any human gene has ever been suited to any environment. How on earth can an impairment in fat metabolism be well suited to an environment that forces a high-fat diet on its inhabitants? Watch the full video to find out.

Frequently Asked Questions

  • Am I guaranteed new content every month?

No. You are guaranteed access to all MWM Pro features for the entire period for which you pay. Most MWM classes are likely to be 3-4 months long, with two lessons per week ranging from 25 to 45 minutes long. When a class ends, there will likely be a break of approximately one month before the beginning of a new class. I make no guarantee of new classes, however. 

  • Do I pay for each class?

No. Paying for MWM Pro entitles you to Pro features for all MWM classes. Currently, this only entitles you to the energy metabolism class. However, Pro features will soon be added to the antioxidant class, and as soon as they are, all paying Pro members will receive immediate access. If and when new MWM classes are added, you will immediately receive access to them providing your membership is active at that time.

  • Is the content in this course the same as in a biochemistry course?

Not exactly. This class is about breaking down, using, and storing energy. A biochemistry class may cover the synthesis of the many molecules in the cell, but this class covers biosynthesis only in the limited context of where it intersects with energy metabolism. On the other hand, this class covers energy metabolism itself in more detail than many biochemistry classes would, and covers many special topics of nutrition, health, and disease that would not be given much if any attention in the average biochemistry class.

  • Are there quizzes and exams? 

Not in this class. The fact that I am focusing exclusively on content production is what allows me to make so much high-quality content. It’s also what allows me to offer these Pro features at ridiculously low prices. The yearly plan, for example, costs less than a typical science textbook! And it’s what allows me to offer them to an unlimited number of people. I may eventually offer higher-priced courses with limited seating that have more individualized guidance, evaluation and feedback, but this will not be integrated into MWM Pro.  

  • Do you answer questions in the forums?

I will do my best to check in on the forums at least once per week, and I will try to answer the questions that are best answered by me. But the forums are primarily for you. I hope an active community evolves within them where you can help other MWM Pro members with the material and other MWM Pro members can help you.  

  • Can you add ____________?

Maybe! Once you’re an MWM Pro member, you’ll have access to the “feature requests” thread in the forums. If the feature falls within my vision for MWM Pro and can be implemented affordably without excessive hassle, I will consider adding it.  

  • Do you have an affiliate program?

You bet! You can sign up here and earn a 20% commission on any new memberships you generate. Refer five people and you’ve paid for your annual plan. Refer more, and suddenly you’re making money. I ask only that you promote the program in an honest manner. Get a membership because you expect to love it, and promote it because you do love it.  

  • Do you offer certification?

At the present time, I do not. In the future, I may offer specific courses that provide evaluation, feedback, guidance, and certification. If I do, they will be a much higher priced item than MWM Pro. MWM Pro provides you with incredible tools to self-pace your own learning independently, without direct oversight by me, which helps me keep the price low and helps me focus on creating high-quality content.  

  • Can I pause my subscription access in the middle of a payment period?

Unfortunately, no. To “pause” your MWM Pro membership means to stop future payments temporarily while keeping your account history and login credentials intact. For example, if you purchase a monthly subscription on May 4 and pause it on May 10, you will have access until June 4, after which you lose access until you resume payments. If you purchase a yearly subscription on May 4, 2017 and pause it on May 10, 2017, you will have access until May 4, 2018, after which you will lose access until you resume payments. In either case, you log in to the same account page, view your account history if desired, and resume your subscription with one click. By contrast, if you “canceled” your account, everything would be the same as if you “paused,” except you’d have to create a new account when you want to resume access and payment. While I wish I could offer a pause to your subscription access in the middle of a payment period so you can save your access for a later time, the membership software I use does not currently offer that feature. I will see if they can add it in the future.  

  • Can I watch the MWM Pro videos on Apple TV?

You can watch them this way when they come out publicly on YouTube, but you cannot presently watch them in the MWM Pro membership portal this way. I am working behind the scenes to make this a feature, but I cannot promise to implement it within a specific timeframe.  

  • How long can I access the material after I purchase the course?

You aren’t technically purchasing a course. MWM Pro will eventually encompass many courses and you are paying for a subscription to the premium features of all courses. Since you are paying for a feature subscription, your access only lasts as long as you keep up your payments. For example, if you purchase the monthly subscription, each monthly payment earns you access for one month, and if you purchase the yearly subscription, each yearly payment earns you access for one year. But, for the life of the program, the content you have access to increases indefinitely over time. If two years from now there are six courses, you pay the same subscription price and have automatic access to premium features for all of them.  

  • Do you offer student discounts?

I do not offer student discounts, but consider this. The main biochemistry textbook I use for the energy metabolism class sells on Amazon for $179.51. The average cost of a 3-credit college course is $1782.48. Most online courses that are offered by individuals rather than accredited higher education institutions cost between $300 and $400. MWM Pro is a fusion of textbook and class, designed with features to make it infinitely easier to extract the value you need from it. At $120/year, I am practically giving it away, and doing so very happily. 

  • Can I see a syllabus or a complete list of lessons?

As I produce the content, I am continually finding new connections and new topics that need to be explored, making the classes multiply. Therefore, I don’t feel comfortable releasing a list of individual lessons for the entire class. However, if you sign up for the yearly membership, you get immediate access to the following lessons: 

1. Thermodynamics, Energy, and Order This lesson provides an overview of the concept of energy at the microscopic level. If you’ve taken general chemistry, you will recognize it as a light review of the unit on thermodynamics. If you have not, it will provide you with the foundational concepts needed to make sense of the rest of the lessons. It does this through the lens of answering the following question: why do we have to eat such an enormous amount of food?  

2. Activation Energy and Enzymes This lesson provides an overview of the concept of activation energy and how enzymes lower it, thereby providing the means for exquisite control over what happens in our bodies. It covers the basic mechanisms of enzyme regulation with a few examples and explains the strengths and limitations of each mode of regulation. It does this through the lens of answering the following question: given the second law of thermodynamics, why does any order remain in the universe? Why don’t we and everything else fall apart?  

3. Cellular Respiration This lesson provides an overview of the basic objectives of using the citric acid cycle and the electron transport chain to make ATP. We start here because, no matter whether we burn protein, carbs, or fat, these two interrelated systems are what is shared in common.  

4. Aconitase and ROS This lesson explores the first two steps of the citric acid cycle and explains how the rate of ATP production is regulated according to the abilities of the electron transport chain. Together with lesson five, it explains how cells regulate their ATP production according to their needs and abilities. In the course of exploring this theme, we examine the role of reactive oxygen species in diabetes.  

5. Isocitrate & α-Ketoglutarate Dehydrogenases and AMPK This lesson explores the third and fourth steps of the citric acid cycle and explains how the rate of ATP production is regulated according to the cell’s need for ATP. Together with lesson four, it explains how cells regulate their ATP production according to their needs and abilities. In the course of exploring this theme, we look at the role of AMP kinase (AMPK) in promoting energy uptake during exercise. We consider how AMPK and reactive oxygen species, so often at odds with one another, work together to produce fitness in response to exercise.  

6. How Isocitrate Dehydrogenase Makes Oxalosuccinate Decarboxylate Itself This lesson looks at the third step of the citric acid cycle in much more detail, digging into the organic chemistry concepts involved in the conversion of isocitrate to α-ketoglutarate. We dive deep into this because it’s the only way to explain why this step parts ways with most other decarboxylation reactions in that it does not require thiamin (vitamin B1). This, in turn, provides a basis for understanding why burning carbohydrate for fuel requires twice as much thiamin than burning fat, and why high-fat, low-carbohydrate, ketogenic diets can be used to overcome problems with thiamin deficiency or defects in thiamin-dependent enzymes. We conclude by looking at how this step allows the interconversion of amino acids and citric acid cycle intermediates, the role of vitamin B6 in this process, and the use of enzymes known as transaminases to diagnose B6 deficiency and liver dysfunction.  

7. α-Ketoglutarate Dehydrogenase, A Massive Enzymatic Factory This lesson looks at the mechanisms of fourth step of the citric acid in much more detail, looking at the roles of thiamin, niacin (vitamin B3), riboflavin (vitamin B2), and lipoic acid. This lays the basis for considering the seven unforgettable things covered in lesson eight.  

8. 7 Unforgettable Things About α-Ketoglutarate Dehydrogenase This complex is so rich in biochemical concepts and relevance to health and disease. Having done the dirty work of looking at its organic chemistry mechanisms in the last lesson, here we explore broadly applicable biochemistry principles like energetic coupling and substrate channeling. We look at how thiamin deficiency, oxidative stress, arsenic, and heavy metal poisoning can affect metabolism, and how to recognize markers of these processes in blood or urine. We make the subtle yet critical distinction between oxidative stress and oxidative damage. We look at the role of this complex in Alzheimer’s disease. We then turn to the product of this complex, succinyl CoA, to examine how it provides an entry into the cycle for odd-chain fatty acids and certain amino acids and an exit out of the cycle for the synthesis of heme. In doing so, we look at the roles of vitamins B12 and B6 in these processes, the use of methylmalonic acid to diagnose B12 deficiency, and the ability of B6 deficiency to cause sideroblastic anemia.  

9. Why Does CoA Come Back to the TCA Cycle? This lesson addresses the curious case of why CoA makes a brief cameo in the citric acid cycle during the formation of succinyl CoA only to leave again in the next step. We dig into the chemistry underlying the high-energy thioester bond that CoA forms with acyl groups, which explains more broadly one of the key roles of sulfur in energy metabolism. We conclude by looking at how the appearance of CoA allows us to harness energy released during the decarboxylation of alpha-ketoglutarate to form ATP directly during “substrate-level phosphorylation,” or, alternatively, to use energy from ATP to invest in the synthesis of heme.  

10. That Moment You Rip Apart Water to Get Your Oxygen In this lesson we look at the final three steps in the citric acid cycle with three goals in mind: 1) we need to invest another oxygen atom to allow the continued release of carbon dioxide in future turns of the cycle, 2) we need to reconstitute the alpha-keto group we lost during the formation of succinyl CoA to allow continued exchange with amino acids, and 3) we need to create an electron-deficient portion of the molecule that is able to accept the incoming acetyl group in the next turn of the cycle. In doing so, we look at the broader concept that water is the source of oxygen whenever we lack the oxygen we need to release carbons as carbon dioxide. This concept is critical to master to understand one of the most important differences between fat and carbohydrate: because of their different oxygen contents, they consume different amounts of water and generate different amounts of carbon dioxide in their metabolism. This impacts the functions of vitamin K and biotin, the stress we place on our lungs, and the delivery of oxygen to our muscles during exercise. We also look at the role of phosphate in “borrowing” oxygen from water, which will help us understand later why glycolysis is a source of water in the cell.  

11. How to Interpret Urinary Tests of TCA Cycle Intermediates Here we revew what we’ve learned so far and introduce a quantitative evaluation of the flow of energy through the cycle through the lens of a clinical application: how to interpret the citric acid metabolite section of a urinary organic acids test. We begin with an explanation of the curious absence of oxaloacetate on these tests, which takes us back to the basic principles of chemical bonding. Ultimately, we identify patterns reflecting three conditions: energy overload, oxidative stress, and thiamin deficiency.  

12. Carbs, Fat, and Carbon Dioxide While the tenth lesson’s look at water as the source of oxygen needed to release carbon dioxide in the citric acid cycle may have seemed a bit tedious, the twelfth lesson brings the exact same principle to life with striking dietary relevance. Because carbohydrate is richer in oxygen than fat, it consumes less water during its metabolism and releases more carbon dioxide. Carbon dioxide puts stress on the lungs and its generation should be restricted in the case of lung injury to allow healing. This calls for a low-carbohydrate, high-fat diet. On the other hand, carbon dioxide is needed to support the action of vitamin K and biotin, and to promote delivery of oxygen to tissues during exercise. Thus, many other situations may call for more carbohydrate. The fact that carbs and fat generate different amounts of carbon dioxide is also the basis for the respiratory quotient (RQ), an index of carbon dioxide generated per oxygen consumed. Exercise scientists use the RQ to estimate how different conditions affect the relative utilization of different macronutrients for fuel.  

13. Pyruvate Dehydrogenase: Why Carbs Leave Your Thiamin Working Overtime The pyruvate dehydrogenase complex catalyzes the one decarboxylation step that carbohydrate undergoes to generate acetyl CoA, which accounts for the one carbon dioxide molecule produced in carbohydrate metabolism that is not produced during the metabolism of fat. It also accounts for why burning carbs requires twice as much thiamin as fat. In fact, the pyruvate dehydrogenase complex is remarkably analogous to the alpha-ketoglutarate dehydrogenase complex, sharing all the same cofactors and catalyzing virtually the same reactions. In this lesson, we look at why this has to be true and how it works. This provides the foundation for our deeply practical look at thiamin in the next lesson.  

14. Thiamin, Carbs, Ketogenic Diets, and Microbes Did you realize that thiamin deficiency can be caused by your environment? In the old days, beriberi was associated with the consumption of white rice. Nowadays, refined foods are an unlikely cause of thiamin deficiency because they are fortified. We associate deficiency syndromes such as Wernicke’s encephalopathy and Korsakoff’s psychosis primarily with chronic alcoholism. Yet there are regional outbreaks of thiamin deficiency among wildlife attributed to poorly characterized thiamin antagonists in the environment. Thiamin-destroying amoebas can pollute water, thiamin-destroying bacteria have been isolated from human feces, and thiamin-destroying fungi have also been identified. Could toxic indoor molds and systemic infections play a role as well?  

Thiamin deficiency is overwhelmingly neurological in nature and hurts the metabolism of carbohydrate much more than fat. Indeed, preliminary evidence suggests thiamin supplementation can help mitigate glucose intolerance. Ketogenic diets are the diets that maximally spare thiamin and are best characterized as treatments for neurological disorders. Anecdotally, ketogenic diet-responsive neurological problems sometimes arise as a result of infection. Could ketogenic diets be treating problems with thiamin or thiamin-dependent enzymes? One must exercise caution here: fat contains little thiamin, and ketogenic diets can actually cause thiamin deficiency if they don’t contain added B vitamins. The relationships between thiamin, glucose metabolism, and neurological health are remarkable and desperately need our attention.  

15. Lactate: Rescuing NAD+ and Generating ATP From Glycolysis One of the advantages of carbohydrate over fat is the ability to support the production of lactate. This is so important that carbohydrate is physiologically essential to red blood cells and certain brain cells known as astrocytes. For the same reason, it plays an important role in supporting the energy requirements of the lens and cornea, kidney medulla, and testes, and supports the quick boosts of peak energy needed during stressful situations that include high-intensity exercise. The biochemical role of lactate is to rescue NAD+ during times when NAD+ becomes limiting for glycolysis and glycolysis becomes a meaningful source of ATP. Through the Cori cycle, lactate can extract energy from the liver’s supply of ATP and deliver it to other tissues such as skeletal muscle in the form of glucose. This lesson fleshes out the physiological and biochemical roles of lactate and serves as a foundation for the next lesson, which explores the role of carbohydrate in supporting sports performance.

16. Anaplerosis: Why Carbs Spare Protein in Ways That Fat Can’t “Anaplerosis” means “to fill up” and refers to substrates and reactions that fill up a metabolic pathway as its own substrates leak out for other purposes. The citric acid cycle is a central example of this because its intermediates are often used to synthesize other components the cell needs. On a mixed diet where carbohydrate provides much of the energy, pyruvate serves as the main anaplerotic substrate. During carbohydrate restriction, protein takes over. Fat is the least anaplerotic of the macronutrients because the main product of fatty acid metabolism, acetyl CoA, is not directly anaplerotic. There are several very minor pathways that allow some anaplerosis from fat, but they are unlikely to eclipse the need for protein to support this purpose during carbohydrate restriction. Thus, carbs and protein are the two primary sources of anaplerosis. This means carbs can spare the need for protein, and that protein requirements rise on a carb-restricted diet.  

17. Carbs and Sports Performance: The Principles Can athletes fat-adapt their workouts? This lesson lays down the principles of exercise biochemistry and physiology needed to understand the importance of the three energy systems supporting energy metabolism in skeletal muscle: the phosphagen system (ATP and creatine), anaerobic glycolysis (dependent on carbs), and oxidative phosphorylation (dependent on carbs, fat, or protein). We discuss why maximal intensity always depends on carbs if the intensity and duration are sufficient to deplete phosphocreatine concentrations, and clarify the window of time and intensity that can be fat-adapted. This sets the foundation for the next lesson, which looks at the evidence of how carbohydrate restriction and ketogenic diets impact sports performance.

18. Carbs and Sports Performance: The Evidence Can fat fuel intensity in a competitive athlete? This lesson takes a critical look at the commonly cited evidence in favor of a neutral or beneficial effect of low-carbohydrate or ketogenic diets on sports performance, as well as key pieces of conflicting evidence. Bottom line? Fat can fuel duration, but probably can never fuel your peak intensity, just as the physiology would predict.  

19. Glycolysis: The Miracle of Turning Phosphate Into Water In this lesson, we examine the entire glycolytic pathway. We use as our theme the transfer of oxygen from phosphate to newly generated water. This explains why the standard stoichiometry of glycolysis found in textbooks show it generating two water molecules, and ties the information together with the analogous principles from substrate-level phosphorylation in the citric acid cycle and the relative differences in water consumption and carbon dioxide generation between fat and carbohydrate. As with our discussion of the citric acid cycle, we also reveal why the standard stoichiometry of glycolysis is misleading and why, when we account for atoms rather than molecules, we find glycolysis to be net water-neutral.  

20. Beta-Oxidation: When Fat and Water Mix In this lesson, we examine the beta-oxidation in its simplest form: the breakdown of a long-chain, saturated fatty acid. We see once again the principle that the oxygen content of a molecule determines how much water its metabolism consumes and how much carbon dioxide its metabolism releases. In beta-oxidation, we consume one water per round and release no carbon dioxide. This reflects the fact that fatty acids are not hydrates of carbons like sugars are, which is where the name carbohydrate comes from.

21. What Shuts Down Glycolysis? Too Much Energy. This lesson covers the regulation of glycolysis. The principle regulation occurs at phosphofructokinase, which guards the gate to the first irreversible, committed step to burn glucose for energy. What governs it? Energy. If you need more ATP, you burn more glucose; if you don’t, you don’t. If the cell has glucose beyond its needs for energy, it uses it for the pentose phosphate pathway, which allows the production of 5-carbon sugars and antioxidant defense if needed, or stores it as glycogen if there is room. If not, glucose-6-phosphate accumulates and shuts down hexokinase. This, together with low AMPK levels, causes glucose to get left in the blood. The other key regulated step of glycolysis is pyruvate kinase, where the primary purpose of regulation is to prevent futile cycling between steps of glycolysis and gluconeogenesis. On the whole, glycolysis and glucose uptake are regulated primarily by energy status and secondarily by glucose-specific decisions about the need for glycogen or for the pentose phosphate pathway. Since we mostly use glucose for energy under most circumstances, the key regulation of the pathway is the regulation of phosphofructokinase by energy status. This means glucose uptake is largely driven by energy status, and our decisions about preventing hyperglycemia should center on total energy balance.  

22. What Shuts Down Fat Burning? Too Much Energy. This lesson covers the regulation of beta-oxidation. The primary regulation of beta-oxidation occurs at the mitochondrial membrane, where fatty acids are transported into the mitochondrion. Acetyl CoA carboxylase governs both the formation of fatty acids from non-carbohydrate precursors and the transport of fatty acids into the mitochondrion. Its product, malonyl CoA, is a substrate for fatty acid synthesis in the cytosol but a regulator of fatty acid transport in the mitochondrion. Thus, there are two isoforms of acetyl CoA carboxylase that are regulated similarly. The cytosolic isoform plays a direct role in fatty acid synthesis and the mitochondrial isoform regulates beta-oxidation. This ensures that the two processes are regulated reciprocally, so that one is shut down to the extent the other is activated, thereby preventing wasteful futile cycling. The primary regulator of acetyl CoA carboxylase activity is, as you might expect by this point, energy status. When a cell needs more energy, it lets fatty acids into the mitochondrion. When it has too much, it shuts down fat-burning.  

23. Is Insulin Really a Response to Carbohydrate or Just a Gauge of Energy Status? Insulin secretion. Remarkably, we know from dietary studies that we get the most insulin from eating carbohydrate, yet we know from molecular and cellular studies that insulin secretion is primarily triggered by the ratio of ATP to ADP inside the pancreatic beta-cell. The former implies that insulin is a response to glucose, while the latter implies that insulin is a response to total energy availability. What can explain this discrepancy? In this lesson, we explore the possibility that it is the anatomy and physiology that drive the dietary effect of carbohydrate rather than the biochemistry. Carbs are wired to get soaked up by the pancreas when blood sugar rises above the normal fasting level once the liver has taken its share to replete hepatic glycogen, whereas fats are wired to go primarily to the heart and muscle when those organs need energy and to go primarily to adipose tissue otherwise. The combination of circulatory routes and the relative expression of glucose transporters and lipoprotein lipase by different tissues likely directs fat to the pancreatic beta-cell as a source of ATP only during extreme hyperglycemia or when it exceeds adipose storage capacity due to obesity, insulin resistance, or very high-fat meals. The pancreatic beta-cell does have a diversity of complicated and often controversial secondary biochemical mechanisms that “amplify” the insulin-triggering effect of ATP, and carbs are more versatile at supporting these mechanism than fat. These likely make a contribution to the dietary effect, but they strike me as unlikely to be the primary driver of the dietary effect. Thus, insulin is a response mainly to carbohydrate availability but also to total energy availability, and this driven mainly by the anatomy and physiology but also by the biochemistry. Seeing insulin as a response to cellular energy status will eventually help us broaden our view of insulin as a key governor of what to do with that energy that goes far, far beyond regulating blood glucose levels.

24. How Insulin Makes You Burn Carbs for Energy Most people interested in health and nutrition know that insulin clears glucose from the blood into cells, but it is much less widely appreciated that insulin also makes you burn that glucose for energy. Insulin stimulates the translocation of GLUT4 to the membrane of skeletal muscle, heart, and adipose cells, and activates hexokinase 2. GLUT 4 increases the rate of glucose transport across the cell membrane and hexokinase 2 locks the glucose into the cell, making sure that glucose travels inward rather than outward. Insulin stimulates glycogen synthase, causing you to store glucose as glycogen, but it also stimulates pyruvate dehydrogenase, causing you to burn pyruvate for energy. The key determinant of which one of these you do is the energy status of the cell. Glucose 6-phosphate is needed to activate glycogen synthase, and it only accumulates if high energy status is inhibiting phosphofructokinase. If low energy status is stimulating phosphofructokinase, the net effect of insulin is to irreversibly commit glucose to glycolysis, and then to stimulate the conversion of pyruvate to acetyl CoA, which then enters the citric acid cycle to allow the full combustion of the carbons and maximal synthesis of ATP. Thus, if you need the energy, the net effect of insulin is to make you burn glucose to get that energy.  

25. How Insulin Stops Fat-Burning Insulin prevents fat-burning in part by locking fat in adipose tissue and in part by shutting down transport of fatty acids into the mitochondrion inside cells. By downregulating lipoprotein lipase (LPL) at heart and skeletal muscle and upregulating it at adipose tissue, insulin shifts dietary fat away from heart and muscle and toward adipose tissue. By downregulating hormone-sensitive lipase in adipose tissue, it prevents the release of free fatty acids from adipose tissue into the blood. At the cellular level, insulin leads to the phosphorylation and deactivation of AMPK. Since AMPK inhibits acetyl CoA carboxylase, insulin-mediated deactivation of AMPK leads to activation of acetyl CoA carboxylase and the conversion of acetyl CoA to malonyl CoA. Malonyl CoA inhibits carnitine palmitoyl transferase-1 (CPT-1) and thus blocks the transport of fatty acids into the mitochondrion. Nevertheless, all of these steps are also regulated at the most fundamental level by energy status, as covered in lesson 22. Further, insulin stimulates the burning of carbohydrate for energy, as covered in lesson 24. So, is insulin’s blockade of fat-burning sufficient to cause net fat storage, or does this critically depend on energy balance? This question will be answered in the next lesson.  

26. Why Insulin Doesn’t Make Us Fat Although insulin promotes storage of fat in adipose tissue, this occurs in the context of multiple layers of regulation where energy balance is the final determinant of how much fat we store. In a caloric deficit, the low energy status of muscle and heart will lead them to take up fat rather than adipose tissue, even in the presence of insulin. Insulin combined with low energy status will promote the uptake of glucose in skeletal muscle over adipose tissue and will promote the oxidation of glucose rather than its incorporation into fat. Some advocates of the carbohydrate hypothesis of obesity have argued that glucose is needed to form the glycerol backbone of triglycerides within adipose tissue. Although glucose can serve this role, it isn’t necessary because adipose glyceroneogenesis and hepatic gluconeogenesis can both provide the needed glycerol phosphate. Further, low energy status promotes the use of glycerol as fuel and high energy status is needed to promote the formation of glycerol from glucose. Finally, fatty acids are needed to store fat in adipose tissue and they overwhelmingly come from dietary fat in almost any circumstance. Insulin can only promote de novo lipogenesis, the synthesis of fatty acids from other precursors such as carbohydrate, in the context of excess energy, and this pathway is minor in conditions of caloric deficit, caloric balance, or moderate caloric excess. Thus, although insulin does promote storage of fat in adipose tissue, it doesn’t directly affect energy balance, and energy balance is the determinant of how much fat you store overall.  

27. The Pentose Phosphate Pathway: The Many Essential Roles of Glucose The pentose phosphate pathway provides a deep look into a stunning array of essential roles for glucose. In it, glucose becomes the source of NADPH, used for antioxidant defense, detoxification, recycling of nutrients like vitamin K and folate, and the anabolic synthesis of fatty acids, cholesterol, neurotransmitters, and nucleotides. At the same time, glucose also becomes the source of 5-carbon sugars, used structurally in DNA, RNA, and energy carriers like ATP, coenzyme A, NADH, NADPH, and FADH2. DNA is needed for growth, reproduction, and cellular repair; RNA is needed to translate genetic information from DNA into all of the structures in our bodies; the energy carriers constitute the very infrastructure of the entire system of energy metabolism. This lesson covers the details of the pentose phosphate pathway, how it operates in multiple modes according to the relative needs of the cell for ATP, NADPH, and 5-carbon sugars, the role of glucose 6-phosphate dehydrogenase deficiency and thiamin deficiency in its dysfunction, and what it means for the importance of glucose to human health.  

28. Insulin as a Gauge of Short-Term Energy Supply and Energetic Versatility Insulin is commonly seen as a response to blood glucose whose primary role is to keep blood glucose within a narrow range. This view of insulin fails to account for its many roles outside of energy metabolism that govern long-term investments in health. The biochemistry and physiology of insulin secretion suggest, rather, that insulin is a gauge of short-term energy status and energetic versatility. Since glucose can only be stored in small amounts and since it is the most versatile of the macronutrients in its ability to support specialized pathways of energy metabolism, it makes sense that it would be wired to the pancreas as the primary signal of short-term energy status and energetic versatility. In this lesson, we review the unique uses of glucose and the mechanisms of insulin signaling to synthesize them into a more nuanced view of the role of insulin than is typically presented.  

29. Gluconeogenesis: Expensive, but Essential Gluconeogenesis is extremely expensive. Three steps of glycolysis are so energetically favorable that they are irreversible. Getting around them requires four gluconeogenesis-specific enzymes and the investment of a much larger amount of energy. Overall, six ATP worth of energy are invested to yield glucose, a molecule that only yields 2 ATP when broken down in glycolysis. This lesson covers the details of the reactions as well as the rationale for investing so much energy. One of the most pervasive themes in biology is the drive to conserve energy. That we will spend this much energy synthesizing glucose is a testament to how essential it is to our life and well being.  

30. Gluconeogenesis Occurs When the Liver is Rich in Energy and the Body is Deprived of Glucose Since gluconeogenesis is extremely expensive, it has to be tightly regulated so that it only occurs when both of two conditions are met: 1) the liver has enough energy to invest a portion into synthesizing glucose, and 2) the rest of the body is in need of that glucose.  

Since the liver is the metabolic hub of the body that also plays a major role in anabolic synthesis and nitrogen disposal. Since gluconeogenesis is extremely expensive, it has to be tightly regulated so that it only occurs when both of two conditions are met: 1) the liver has enough energy to invest a portion into synthesizing glucose, and 2) the rest of the body is in need of that glucose.  

Since the liver is the metabolic hub of the body that also plays a major role in anabolic synthesis and nitrogen disposal, it also regulates glycolysis and gluconeogenesis according to whether amino acids are available to supply energy in place of glucose and whether there is sufficient citrate and associated energy for biosynthesis. This lesson covers how insulin, glucagon, alanine, citrate, fructose 2-6-bisphosphate, ATP, ADP, and AMP regulate the flux between glycolysis and gluconeogenesis.  

31. Gluconeogenesis as a Stress Response: Regulation by Cortisol The last lesson covered how insulin, glucagon, and allosteric regulators from within the liver ensure that the liver only engages in gluconeogenesis when it can and when it needs to. This lesson focuses on an additional layer of regulation: cortisol. Cortisol is the principal glucocorticoid in humans. Glucocorticoids are steroid hormones produced by the adrenal cortex that increase blood glucose. Cortisol has multiple actions on the liver, muscle, adipose, and pancreas that all converge on making glucose more available to the brain. Among them, it increases movement of fatty acids from adipose to the liver, which provide the energy for gluconeogenesis, and the movement of amino acids from skeletal muscle to the liver, which provide the building blocks for gluconeogenesis. Cortisol serves both to antagonize insulin, thereby acutely increasing gluconeogenesis, and to increase the synthesis of gluconeogenic enzymes, which amplifies all other pro-gluconeogenic signaling and increases the total capacity for gluconeogenesis. In fact, even the day-to-day regulation of gluconeogenesis by glucagon is strongly dependent on normal healthy levels of cortisol in the background. Since gluconeogenesis is an extremely expensive investment with a negative return, it makes sense that the body would regulate it as a stress response, and thus place it under control by cortisol. This raises the question of whether carbohydrate restriction increases cortisol. Several studies are reviewed in this lesson that indicate that 1) there may be an extreme level of carbohydrate restriction that always increases cortisol, and 2) carbohydrate restriction definitely increases cortisol in some people. It may be the case that other stressors in a person’s “stress bucket” determine whether and how strongly the person reacts to carbohydrate restriction with elevated cortisol.  

32. This is How Ketogenesis Works In conditions of glucose deprivation, such as fasting or carbohydrate restriction, ketogenesis serves to reduce our needs for glucose. This reduces the need to engage in the energetically wasteful process of gluconeogenesis, which would otherwise be extremely taxing on our skeletal muscle if dietary protein were inadequate. Ketogenesis mainly occurs in the liver. The biochemical event that leads to ketogenesis is an accumulation of acetyl CoA that cannot enter the citric acid cycle because it exceeds the supply of oxaloacetate. The set of physiological conditions that provoke this biochemical event are as follows: free fatty acids from adipose tissue reach the liver, providing the energy needed for gluconeogenesis as well as a large excess of acetyl CoA. Oxaloacetate, with the help of the energy provided by free fatty acids, leaves the citric acid cycle for gluconeogenesis. These events increase the ratio of acetyl CoA to oxaloacetate, which leads to the accumulation of acetyl CoA that cannot enter the citric acid cycle and therefore enter the ketogenic pathway. This pathway results in the production of acetoacetate, a ketoacid. Acetoacetate can then be reduced to beta-hydroxybutyrate, a hydroxyacid, in a manner analogous to the reduction of pyruvate, a ketoacid, to lactate, a hydroxyacid. Acetoacetate is an unstable beta-ketoacid just like oxalosuccinate (covered in lesson 6) and can also spontaneously decarboxylate to form acetone, a simple ketone that is extremely volatile and can evaporate through the lungs, causing ketone breath. This lesson covers the basic mechanisms of ketogenesis and sets the ground for the forthcoming lesson on the benefits and drawbacks of ketogenesis in various contexts.  

33. This is How We Burn Ketones for Energy The production of ketones in the liver frees up coenzyme A (CoA) that would otherwise be captured in the accumulating acetyl CoA, and the conversion of acetoacetate to beta-hydroxybutyrate frees up NAD+ that would otherwise be trapped as NADH as the production of NADH in beta-oxidation exceeds that oxidized in the electron transport chain. This allows free CoA and NAD+ to keep beta-oxidation running rapidly. The ketone bodies then traverse through the inner mitochondrial and plasma membranes through the monocarboxylate transporter 1 (MCT1), and possibly through the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane. They travel through the blood to ketone-utilizing tissues, where they get into the mitochondria through the same transporters that allowed them to exit the liver. Beta-hydroxybutyrate must be converted to acetoacetate to undergo further metabolism in the ketone-utilizing tissue. Acetoacetate is converted to acetoacetyl CoA using the CoA from succinyl CoA. It is then split to two acetyl CoA by beta-ketothiolase, the same exact enzyme that catalyzes the opposite conversion during ketogenesis. The acetyl CoA then enters the citric acid cycle. The use of succinyl CoA causes the loss of one ATP that would otherwise have been synthesized in the substrate-level phosphorylation step of the citric acid cycle. Nevertheless, most ATP energy is conserved and ketones represent an efficient means of transporting energy between tissues.  

34. This is Why We Make Ketones The physiological purpose of ketogenesis is to spare the loss of lean mass that would otherwise occur during prolonged fasting. Meeting the glucose requirement of the brain entirely by gluconeogenesis from amino acids would cause us to lose 2.2 pounds of lean mass every day. This would cause us to die much more quickly from starvation than we actually do. Ketones can fuel 75% of the brain’s energy requirement. Glycerol from triglyceride hydrolysis and acetone derived from ketogenesis can together spare 55% of the amino acids that would otherwise be used to sustain the brain’s remaining glucose requirement. The acidity of ketones requires the kidney to hydrolyze glutamine to neutralize it with ammonia, however, and this attenuates the sparing of lean mass. In fact, it doubles the amount of protein breakdown over that used to synthesize glucose alone. When considering all this, ketogenesis cuts down the amount of lean mass lost during fasting 5-fold, allowing us to survive for a much longer time during fasting than we would be able to without ketones.  

35. Ketone Homeostasis During Fasting Ketone homeostasis has two central objectives: 1) keep ketone levels high enough to feed the brain, and 2) keep ketone levels low enough to avoid the serious and life-threatening condition of ketoacidosis. While proportion of circulating ketones taken up by skeletal muscle, heart, and other tissues during fasting is initially high, these tissues limit their absolute uptake of ketones and may even lower their uptake in response to increased availability of free fatty acids. As a result, ketone concentrations rapidly outpace production rates, and this is exactly what allows them to reach high enough concentrations to feed the brain. To outcompete glucose for transport across the blood brain barrier, they also act on the liver to suppress glucose output, causing blood glucose to lower. While high ketones and low glucose favor maximal penetration of ketones into the brain, the threat of ketoacidosis requires a negative feedback loop. Thus, ketones suppress adipose tissue lipolysis, restraining their own production so that blood concentrations stay in the sweet spot to safely nourish the brain.  

36. Ketoacidosis: The Dark Side of Ketones Ketones have a dark side: ketoacidosis. And it does NOT only happen in diabetes. Ketoacidosis is a serious and life-threatening medical condition wherein ketones accumulate to such high levels that they overwhelm the body’s natural buffering capacity and sink the pH of the blood to dangerous and possibly fatal levels. Ketoacidosis is most often associated with poorly controlled diabetes. Contrary to many popular claims, however, it is not limited to diabetes. Alcohol abuse with malnourishment, fasting during pregnancy or lactation, and in rare cases low-carbohydrate diets can be causes of ketoacidosis. This lesson covers the science behind ketoacidosis and reviews several case reports to illustrate what it looks like in practice.  

37. Inuit Genetics Show Us Why Evolution Does Not Want Us In Constant Ketosis Why were the Inuit never in ketosis, despite their traditional high-fat diet? That question is answered in this lesson. The answer provides a stunning example of human evolution and makes it clear that evolution does not “want” us in a constant state of ketosis. CPT-1a deficiency is a genetic disorder in the ability to make ketones and to derive energy from fatty acids needed to make glucose during fasting. In its severe form, it is extremely rare, dangerous, and fatal if not treated with frequent feeding and often a high-carbohydrate, low-fat diet. A much more mild form of CPT-1a deficiency known as “the Arctic variant” is only found in the Arctic and it is nearly universal in the Arctic. It causes a serious impairment in the ability to make ketones, dramatically raises the risk of developing hypoglycemia while fasting, and causes a three-fold increase in infant mortality. Yet virtually everyone native to the Arctic has it and it is usually asymptomatic. What is utterly stunning about this is that this variant took hold of the Arctic in one of the strongest selective sweeps ever documented in humans. This means that evolution judged this variant as better suited to the Arctic environment than almost any human gene has ever been suited to any environment. How on earth can an impairment in fat metabolism be well suited to an environment that forces a high-fat diet on its inhabitants? Watch the full video to find out.  

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Still have a question? You can contact me using this form. Hope to talk to you soon!