Here are the audio cliff notes for the MWM Energy Metabolism class. You can also find them in the Mastering Nutrition podcast feed (iTunes, Stitcher, RSS). Each “cliff notes” is a roughly ten-minute audio file that you can stream or download giving you the essentials condensed from the full lesson. Below the streaming and download buttons, you'll find the description in case you want to look for the cliff notes that sound most interesting. Nevertheless, I recommend listening to them in order since each one builds upon the lessons before it.
For the complete lessons, see the MWM Free archive, which displays them in reverse chronological order. Or, to go to a specific lesson, use the shortcut chrismasterjohnphd.com/mwm/2/x where “x” is the lesson number. Finally, if you want premium features to help you master the material, you can sign up for MWM Pro.
Without further adieu, behold, the cliff notes!
Thermodynamics | MWM Energy Metabolism Cliff Notes #1
The first MWM Energy Metabolism lesson answers the question, why do we have to eat such an enormous amount of food?
The answer is to comply with the second law of thermodynamics. If you have a chemistry background, you should recognize this as a light review of the thermodynamics unit from a general chemistry class, with its most essential concepts teased out and packed into a half hour lesson. If you don’t, you can use this as a basic foundation for understanding the biochemistry to follow.
The lesson relates the 2nd law to food coloring dispersing in water, how a hydropower plant operates, ATP production, and why we need to eat our bodyweight in food more than once a month. In the process, we have a little fun.
Activation Energy & Enzymes | MWM Energy Metabolism Cliff Notes #2
The second MWM energy metabolism looks at how we use enzymes to exert exquisite control over what happens inside our bodies.
If the second law of thermodynamics holds that entropy is always increasing, why don’t we reach maximum entropy right away? Why do we observe any order at all? The activation energy represents the resistance to change that can be found in any substance. We exploit the concept biologically by maintaining a body temperature that provides insufficient energy for most relevant reactions to go forward without catalysis, and imposing upon this backdrop an expansive repertoire of enzymes that can, in a regulated fashion, lower the energy barriers sufficiently for reactions to go forward.
This lesson looks at how they do that, and how we regulate their activity.
Cellular Respiration| MWM Energy Metabolism Cliff Notes #3
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.
Regulation of ATP Production by Reactive Oxygen Species | MWM Energy Metabolism Cliff Notes #4
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.
Regulation of ATP Production by the Need for ATP | MWM Energy Metabolism Cliff Notes #5
The fifth MWM Energy Metabolism 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 when ATP levels are low.
Isocitrate Dehydrogenase | MWM Energy Metabolism Cliff Notes #6
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.
α-Ketoglutarate Dehydrogenase | MWM Energy Metabolism Cliff Notes #7
The alpha-ketoglutarate dehydrogenase complex is marvelously complex and incredibly rich in details that are relevant to the big picture of metabolism and to many issues of health and disease. Today, we break down what actually happens so that we can spend all of Wednesday’s lesson discussing the rich array of relevant principles it brings to light.
7 Unforgettable Things About α-Ketoglutarate Dehydrogenase | MWM Energy Metabolism Cliff Notes #8
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.
Why Does CoA Come Back to the TCA Cycle? | MWM Energy Metabolism Cliff Notes #9
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.
Why We Consume H2O in the TCA Cycle | MWM Energy Metabolism Cliff Notes #10
This lesson looks at the fundamental principle that atomic oxygen is the limiting factor for the release of carbon dioxide in metabolism, and when we don’t have enough we take it from water. This will become very relevant when we cover fats versus carbohydrates, because they consume different amounts of water and release different amounts of carbon dioxide for this very reason. That, in turn, relates to a number of health endpoints such as the functions of vitamin K and biotin, delivery of oxygen to tissues, and the stress placed on the lungs during breathing.
Here, we look at the principle in the citric acid cycle. In doing so, we see that, while textbooks only point to two water molecules consumed, a third water molecule is irreversibly consumed to donate oxygen to the cycle via phosphate.
Urinary Organic Acid Tests | MWM Energy Metabolism Cliff Notes #11
Now we take it clinical: how do we use what we’ve learned so far to interpret the section of a urinary organic acids test that reports the citric acid cycle metabolites?
We begin by looking at the underlying chemistry to explain the curious absence of oxaloacetate on these tests. We conclude by mastering the ability to spot three unique patterns: energy overload, oxidative stress, and thiamin deficiency.
Carbs, Fat, and Carbon Dioxide | MWM Energy Metabolism Cliff Notes #12
Since carbs are richer in oxygen than fat, they consume less water in their metabolism and release 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.
In our first glimpse into glycolysis and beta-oxidation, we find that understanding the basic chemical makeup of these molecules is deeply relevant to how we would manipulate the diet in many contexts of health and disease.
Pyruvate Dehydrogenase | MWM Energy Metabolism Cliff Notes #13
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.
Thiamin, Ketones, and Microbes | MWM Energy Metabolism Cliff Notes #14
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.
Why We Make Lactic Acid | MWM Energy Metabolism Cliff Notes #15
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.
Carbs Spare Protein In a Way Fat Can't | MWM Energy Metabolism Cliff Notes #16
“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.
Carbs and Sports Performance: The Principles | MWM Energy Metabolism Cliff Notes #17
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.
Carbs and Sports Performance: The Evidence | MWM Energy Metabolism Cliff Notes # 18
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.
Glycolysis | MWM Energy Metabolism Cliff Notes #19
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.
Beta-Oxidation |MWM Energy Metabolism Cliff Notes #20
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.
Energy Status Regulates Glycolysis |MWM Energy Metabolism Cliff Notes #21
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.
Energy Status Regulates Fat Burning | MWM Energy Metabolism Cliff Notes #22
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.
Insulin Isn’t Just About Glucose | MWM Energy Metabolism Cliff Notes #23
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.
Insulin Makes You a Carb Burner | MWM Energy Metabolism Cliff Notes #24
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.
Insulin Shuts Down Fat-Burning | MWM Energy Metabolism Cliff Notes #25
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.
Insulin Doesn’t Make You Fat | MWM Energy Metabolism Cliff Notes #26
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.
The Pentose Phosphate Pathway | MWM Energy Metabolism Cliff Notes #27
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.
Insulin as a Gauge of Energetic Versatility | MWM Energy Metabolism Cliff Notes #28
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.
Gluconeogenesis |MWM Energy Metabolism Cliff Notes #29
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.
Regulation of Gluconeogenesis | MWM Energy Metabolism Cliff Notes #30
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.
Cortisol and Gluconeogenesis |MWM Energy Metabolism Cliff Notes #31
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.