Mastering Nutrition Podcast Episode 44, t, Chris Masterjohn, PhD talks about the Biochemistry of Why Insulin Doesn't Make You Fat

The Biochemistry of Why Insulin Doesn’t Make You Fat

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Mastering Nutrition Podcast Episode 44, t, Chris Masterjohn, PhD talks about the Biochemistry of Why Insulin Doesn't Make You Fat

Do carbs and insulin make you fat? The argument centers on the ability of insulin to promote the conversion of carbohydrate to fat and lock fat in adipose tissue, as well as the necessity of glucose to provide the backbone to fat molecules within adipose tissue. But the argument ignores that all of these pathways are fundamentally regulated at a biochemical level by how much energy you need and how much you have. In episode 44 of Mastering Nutrition, we take a deep dive into the details of the biochemistry and physiology and see how insulin serves as a gauge of whole-body energy and glucose availability but simply can't be the thing that makes you fat.

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Show Notes for “The Biochemistry of Why Insulin Doesn't Make You Fat”

In this episode, you'll find all of the following and more:

00:45 Cliff Notes

10:15 The biochemistry and physiology of the carbohydrate/insulin hypothesis of obesity: insulin stimulates de novo lipogenesis (fatty acid synthesis), promoting the conversion of carbohydrate to fat; insulin stimulates lipoprotein lipase (LPL) and inhibits hormone-sensitive lipase (HSL) at adipose tissue, locking fat into fat cells; since adipose tissue lacks glycerol kinase, it cannot reuse the glycerol backbone of fats digested by lipoprotein lipase, and dietary carbohydrate is needed to provide the glycerol 3-phosphate that forms the backbone of newly resynthesized triglycerides.

16:30 All biochemical pathways are regulated by cellular energy status. Key players are ATP, ADP, AMP, AMP kinase (AMPK), NADH/NAD+, FADH2/FAD, Ca2+, CoA and acyl CoAs, and citrate.

30:42 Although insulin promotes storage of fat in fat tissue, this can be overridden by low energy status.

40:10 Although insulin promotes fat storage, it causes a proportionate increase glucose oxidation, so no net change in caloric balance.

46:10 Glucose oxidation in muscle is driven by energy status and that determines the availability of glucose to adipose tissue.

01:00:45 Glucose can act as the source of glycerol 3-P for adipose tissue triglyceride synthesis, but it isn’t necessary because of gluconeogenesis and glyceroneogenesis. Furthermore, while it can serve this role, the degree to which it does so is driven by energy status.

01:05:50 Glucose can act as a source of glycerol 3-P for adipose, but it needs a source of fatty acids, which come mainly from fat as long as energy status is high enough.

01:06:50 Insulin can drive de novo lipogenesis, but only when energy status is high enough.

01:20:05 What happens when we eat carbs alone, fat alone, or both in the context of low and high energy status.

01:32:20 The path to weight loss is the path to a sustainable caloric deficit.

Masterclass Lessons Related to “The Biochemistry of Why Insulin Doesn't Make You Fat”

What Shuts Down Glycolysis and Glucose Uptake? Too Much Energy. | MWM 2.21

What Shuts Down Fat Burning? Too Much Energy. | MWM 2.22

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Other Podcast Episodes and Posts Related to “The Biochemistry of Why Insulin Doesn't Make You Fat”

Ketogenesis Isn't All About Carbs and Insulin | Mastering Nutrition Episode 22

Insulin Resistance Isn’t All About Carbs and Insulin | Mastering Nutrition Episode 25

When Fat People Can’t Get Fat Enough and Lean People Get Fat in All the Wrong Places | Mastering Nutrition Episode 26

Is Insulin Resistance Really Making Us Fat? | November 2010 blog post

Research and Educational Resources Related to “The Biochemistry of Why Insulin Doesn't Make You Fat”

For biochemistry textbooks, I recommend Ferrier, Biochemistry for beginners and Berg, Biochemistry and for intermediate or advanced readers. The Berg book is in its eighth edition (2015), but the fifth edition (2002) is freely available. Huge swaths are the same between them, but many portions are updated and a handful of sections are added new or fundamentally changed. The free version is hard to read straight through because it is searchable but not browsable. The Kindle or hardcover versions are much easier to read.

Tortora, Principles of Anatomy and Physiology: 14th Edition, 2013 is a good resource for understanding the transport routes of fat and carbohydrate from an anatomy and physiology perspective.

Byers et al. Avian and Mammalian Facilitative Glucose Transporters. 2017.

Kersten. Physiological regulation of lipoprotein lipase. 2014.

Winder. Cellular energy sensing and signaling by AMP-activated protein kinase. 2007.

Mitrou et al. Rates of Glucose Uptake in Adipose Tissue and Muscle in Vivo after a Mixed Meal in Women with Morbid Obesity. 2009.

Reshef. Glyceroneogenesis and the triglyceride/fatty acid cycle. 2003.

Hanson. Glyceroneogenesis revisited. 2003.

Hellerstein. De novo lipogenesis in humans: metabolic and regulatory aspects. 1999.

Acheson. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. 1988.

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  1. Hi Chris,
    I really enjoy your podcast in general and look forward to sit in traffic in the morning so I can learn some biochemistry. I think I understood your point pretty about allosteric regulation of key enzymes that govern uptake, storage or utilization based on markers of energy status such as ATP, ADP etc..But I failed to understand why being lean seems to equal low energy status within the cell. What about being lean sends a low energy status signal to the cell?

  2. I’m coming in rather late to the discussion. I thought the podcast had some great points and managed to follow along with most of it (just). But I missed an explanation of the mechanism by which any one of the two eating protocols (high carb low fat or low carb high fat) or both, can get an overweight person to release the stored adipose tissue if they maintained their cellular energy status at a deficit through their meals?

  3. Hi Chris. I think you have a great podcast. I think your science is correct, but we don’t live in a vacuum. It sounded like you were making an argument for the thermodynamic model of calories (calories in vs calories out). I would guess that if you are in metabolic homeostasis and injested 2000 calories of cotton candy vs 2000 calories of fatty spare ribs. The cotton candy would result in a greater insulin spike and more fat storage. You also neglected to talk about insulin’s hormonal effects on hunger. Do you have an agenda against low carb?

    1. As a functional health practitioner and promoter of both the keto diet and a ketone supplement, I am very interested in this topic.

      I’ve come full circle back to CICO: calories in calories out. If I ate 2000 calories of either, I’d gain weight. If I consistently eat more calories than I burn, I will gain weight. I’m no scientist but, anecdotally and in my direct experience, this is what actually happens.

      From all my reading on insulin’s fat storing properties, DNL (de novo lipogenesis which is the carb to fat process) happens very slowly. The excess glucose in your blood doesn’t just get tossed in and stored as fat… Looking forward to hearing more about this from Chris.

      1. Absolutely no one gets fat from DNL. It’s utterly ridiculous as the rates are way too low even on a high carb diet. You are correct. Calories.

    2. No, I have an agenda against nonsense, and low-carb alt-physiology is nonsense. I have no problem with carbohydrate restriction when done carefully with an eye on potential problems.

      If you eat 2000 kcal/d of cotton candy, you will probably throw up and it won’t be too long before you have all sorts of nutritional deficiencies. Do it long enough and I bet you’d lose weight from the nutritional deficiencies.

      Insulin suppresses hunger unless it’s injected to the extent it causes hypoglycemia.

      1. If it’s just calories in. Type 1 Diabetics have symptoms of increased hunger with increased weight loss prior to diagnosis. They are eating plenty of calories, yet they are losing weight. As a study of 1, I find I am hungrier throughout the day, if I start my day with carbs vs fat or intermittent fasting. Oh well, I’m out on this one. Keep up the good work. Thanks Chris.

  4. Because this is a topic near and dear to me, I desperately wish I were educated enough to understand what you write! My head is exploding.

    AFAIK (because it’s all over the internet), too much glucose in the blood leads to too much insulin. Chronic hyperinsulinemia leads to insulin resistance which leads to insulin shoving glucose into fat storage. Or… maybe it’s really just CICO?

  5. Hey Chris,

    Where does the use of protein for fuel come into the picture? Is it only used for fuel during starvation or carbohydrate restriction? I’m assuming that if there is adequate glycogen then protein will be used to for everything other than energy, and when glycogen is depleted, gluconeogenesis will be used to synthesize glucose from amino acides. Is this the case?

    1. It’s normally used to some degree by skeletal muscle and liver. You use more protein for energy when you eat more protein than you need for protein synthesis.

  6. Hi Chris
    I am old school, I like to read, mark, annotate the words rather than listen (these are difficult to do while only listening and make subsequent reviews impossible). Therefore, I would really appreciate a written version.

  7. This is a very good description of Why Insulin Doesn’t Make You Fat, IF Insulin Doesn’t Make You Fat, that is, it is not presenting experimental results but rather a theory based on some aspects of biochemistry primarily from an energetic perspective. An explanation of why Insulin does make you fat, IF it does, rests on kinetics rather than thermodynamics. As you explained well, insulin inhibits HSL. So, re-synthesis of TAG (from fatty acids coming in from the diet or from a previous round of lipolysis) will persist — let’s assume at the usual pace, and HSL is inhibited. What insulin and other hormones do (among other effects) is to modify enzymes. Enzymes control rates, not energy. if you now come in with another meal while the TAG-FA cycle is still biased in the direction of synthesis, you will accumulate fat regardless of the thermodynamics of the reactions. Diagram: Figure 1 in paper on nonequilibrium thermodynamics ( So that is a different theory based on the same biochemical pathways…again, IF insulin does make you fat. So, what makes most of us think it does: 1. The major reason people with diabetes don’t take their insulin is because they think it makes them fat. 2, Those of us who fight fat do not find that most diets are the same and primarily driven by calories. Both are anecdotal and both explanations above are theories, so this is just my perspective.

    1. Richard,

      You are correct, I did not address experimental evidence in humans. I chose to do that because I feel it has been argued over ad nauseum and I wanted to do something different.

      You are interpreting my comments about “energy status” incorrectly. Thermodynamics is indeed relevant here but I hardly invoked it. What I mean by energy status is allosteric regulation of the enzymes by molecules that reflect energy charge and redox status. So, they are modifying the enzymes just like insulin, with slightly different mechanisms but the same result, a change in enzymatic activity.

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