Insulin Resistance Part 2: When Fat People Can't Get Fat Enough and Lean People Get Fat in All the Wrong Places.

When Fat People Can’t Get Fat Enough and Lean People Get Fat in All the Wrong Places

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Insulin Resistance Part 2: When Fat People Can't Get Fat Enough and Lean People Get Fat in All the Wrong Places.

In episode 25, Insulin Resistance Isn't All About Carbs and Insulin, I explained why an individual cell would “decide” to stop taking up energy. Here in episode 26, I explain tissue-level energy overload, focusing on adipose tissue and liver.

At adipose tissue, the problem with fatness isn't the amount of fat. It's that we've reached the point where we can't get any fatter. Well, we can, but we can no longer do so while maintaining a healthy organizational structure within adipose tissue that allows blood, oxygen, and nutrients to get to where they need to go. Surprisingly, some of the things that enable proper expansion, and thus protect our metabolic health, are things that we usually think of as “bad,” such as inflammation. In fact, the pro-inflammatory changes in the gut microbiome in response to an obesogenic diet provide information to adipose tissue that it needs to prepare for healthy expansion.  And adipose expansion is most protective at the site of the “bad” body fat: visceral fat in the abdomen.

At liver, the problem is fat gets trapped in the liver, flattening out everything in the cell and hogging the space needed for glycogen storage, and this can happen even in a lean person.

I conclude with some practical recommendations about body composition and nutrient density.

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Read on for the show notes.

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Show Notes for Episode 26

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

  09:40  Cliff Notes
  13:08   Mechanics of adipose tissue expansion
  15:40   Consequences of poor adipose tissue expansion
  17:12    Internal Stress as a consequence
  19:47   Animal models of limitations to adipose expansion
  24:12   Glycerol availability manipulated by PEPCK expression
  27:20  Carbohydrate could play a role in preventing metabolic dysfunction by    providing glycerol if glyceroneogenesis is limiting
  28:05  Deletion of genes involved in lipid droplet formation
  28:42  Septa organization
  29:02  Deletion of collagen genes
  29:53  Matrix metalloproteinases (MMPs)
  31:11   Hypoxia and HIF1 – alpha
  32:15  Inflammation (tumor necrosis factor alpha or TNF -alpha, interleukins or ILs toll-like receptors or TLRs) is necessary to allow proper extracellular matrix (ECM) reorganization and capillary bed reorganization
  36:58  Visceral abdominal fat expansion is most protective because visceral fat drains directly into the liver via the portal vein, and releases more fat into the liver when it cannot expand further
  41:48  Liver as the metabolic hub of fat and carbohydrate metabolism
  43:45  Fat accumulation in liver likely directly compromises glycogen storage
  48:45  Factors in fatty liver disease
  50:45  Sources of liver fat: adipose, dietary fat, de novo lipogenesis (DNL) from carbohydrate is minor
  57:08  Factors in triglyceride export:  oxidative stress and choline
  59:08 The choline requirement is increased more by fat than other macronutrients and more by long-chain saturated fats than other fats
1:04:54 Practical strategies:  body composition is king and queen, but it might not be the right time to lose fat
1:06:28 A well rounded nutrient-dense diet is low-hanging fruit at any time
1:10:44  Additional strategies require nutritional analysis with the help of a health care professional and data generation

Links and Research Related to Episode 26

Episode 25 on what causes insulin resistance in an individual cell.

The Cell Biology of Fat Expansion

Adipocyte Inflammation Is Essential for Healthy Adipose Tissue Expansion and Remodeling

Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance

Start Here for Fatty Liver Disease (and index of my related posts)

Episode 3 on The Sugar Conspiracy

AJCN Publishes a New PUFA Study That Should Make Us Long for the Old Days

Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease.

Episode 23 on how I lost 30 pounds in four months, how I knew it was time, why it sometimes isn't the right time to lose weight, and how to make it time.

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  1. I heard the podcast but I am a little confused by what exactly you mean with the lean people reference. You said it’s more important to look at the liver for lean people but in some cases people have genetic problems with adipose tissue causing lipodystrophy..So what about the other lean people who don’t have lipodystrophy?

    What happens to the extra calories for lean people who don’t have lipodystrophy but a fatty liver? Why aren’t they getting fatter in the adipose tissue and instead getting fat in the liver? Or will the fat start getting stored in the right places i.e adipocytes once you fix the liver?

    I am asking because i have mild hepatic steaosis and relatively high triglycerides (150-200) for a year or so now..I have very little body fat or muscle..I am a bit IR with fasting insulin at 6.7, fasting glucose 80, A1c 5.3. But I get hungry every 2-3 hours and even during night breaking my sleep, I don’t eat big portions though..I am sure part of it is probably my liver getting loaded with fat and not being able to store glycogen, but the other point is why is the body not storing excess calories/fat in adipose tissue in my case or other lean people’s with IR/hepatic steaosis, if it’s not lipodystrophy since it’s rare?

    Thanks a lot!

  2. Hi Chris,

    Long time no “talk” on the Interwebz. I recently started binge listening to your podcasts and am loving the content. Brings back fond memories of the old Paleo Hack days. I hope to get caught up to the most recent one soon. Your ability to explain complex biochem in such an accessible way is wonderful!

    Anyway, a question related to this episode – If an individual has fatty liver, is there an argument against a rapid weight/fat loss protocol (such as PSMF or the potato hack) given the liver is damaged and unable to export large amounts of visceral fat being liberated? Would this exacerbate the fatty liver condition? If so, is a better strategy to moderate the weight loss to reduce the burden on the liver while focusing on other factors (insulin sensitivity, sleep hygiene, stress, etc) until the liver is healed?


    1. It would, at least temporarily. I always prefer a moderate caloric deficit of 1-2 lb/wk anyway. But, increased fatty liver should reverse itself with time if weight loss is sustained.

      1. And great to hear from you! Also, antioxidant support and choline are a good strategy for assisting clearing the liver fat.

  3. Chris,

    Fabulous job as always. This information is extremely helpful. I do have one question though. I do believe that toxin overload in the blood also contributes to insulin resistance but I do not understand how this mechanism works and what might be the best strategies for mitigating this, particularly for latent infections like Epstein-Barr or Lyme disease, etc. It would be wonderful to get your perspectives on this as well.

    1. Hi Stephanie, I do believe that infection would be relevant, and I believe the best thing to do would be to treat the infection. Of course, that is an entirely different topic than treating insulin resistance, and I’m not prepared to give some sort of comprehensive review of how to treat each infection.

  4. Definitely a complex subject! When someone is said to be insulin resistant, they are usually obese, so on the surface this looks like the adipose tissue has an increase in insulin sensitivity, not decrease.

    But if the body is trying to manage a bad situation, i.e. disposing of more energy than it needs, perhaps the insulin resistance people talk about is localized to the liver and muscles.

    Maybe the only solution is to evolve a much higher BMR, through increased muscle mass? However, while good for building muscle, isn’t high levels of protein/IGF/MTor associated with cancer and cardiovascular disease? Yet high IGF in the brain, appears to be protective of Alzheimer’s?

    So many variables!

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