Researchers: less fat due to insulin receptor defect

Geschatte leestijd: 6 minuten Mice with an insulin receptor defect have 50-70 percent less body fat, regardless of how much they eat. Moreover, they live almost 20% longer. When will people start benefiting from this knowledge?

Insulin Receptor Defect

It’s 2002 when a group of researchers in Boston captures the hopes of the world of the obese. A group of special mice lifts a corner of the veil and shows a future where gyms are merely relics of the past. A future where the difference between a Big Mac with a large cola and a salad with spring water is just a matter of taste. A future where you can eat more, be leaner, and even live longer. Book burnings are taking place all over the world. Not political or religious burnings, but bonfires of former obese people throwing all their diet and weight loss books onto the pyre. It may sound like (poorly written) science fiction, but those who benefit from this have been walking this earth for more than a decade. Although, that’s a bit grandiose for a group of special laboratory mice spending their (longer) lives in a cage.

Evolution Lags Behind

Let’s take a step back to explain once again the process that causes unwanted weight for so many. For this, we need to go back to the time of hunters and gatherers. Since the emergence of modern humans some 150,000 to 200,000 years ago, survival has been mainly through hunting and gathering [1-3]. Sometimes a feast when you’ve successfully hunted, then days with little to no food available if that stupid animal was too fast. It wasn’t until about 6000 years ago that agriculture became a significant source of food. Fast forward to the current consumer society, and you see a huge change in the availability of food. Especially in the last century, the cost of food in the West has drastically decreased. In 1930, for example, the average American spent 25% of their income on food, while now it’s only about 10% [4]. The availability of food has increased during the same time, and it takes less effort to get food. You don’t have to travel as far (everything in one supermarket), spend less time cooking, etc.

Insulin and Fat Storage “for a rainy day”

So, our bodies have had to survive on irregular food intake for about 150,000 to 200,000 years. This has taught the body, among other things, to store fatty acids in fat cells as reserve fuel for times when food is scarce. Insulin plays a crucial role in this. Insulin rises when you consume carbohydrates or sugars, thereby increasing the amount of glucose in your blood. Some of this is stored as glycogen in the muscles due to the action of insulin. However, this storage is limited. In fat cells, insulin sends a signal to allow fatty acids inside. Once inside, they are converted into triglycerides, effectively locking them in the fat cell. This way, much more energy can be stored. A beautiful system if you don’t know when in the week you’ll have food and when you won’t. However, in a time when food is excessively available, it’s a recipe for obesity. This fat storage action occurs with the help of cell receptors in the fat cells that specifically respond to the presence of insulin. You need insulin to keep your blood sugar low, not only by increasing fat storage but also by storing glycogen in the muscles and by making muscles grow by producing proteins. People whose cells do not or poorly respond to the presence of insulin (insulin resistance) therefore have all kinds of problems. But what happens if you specifically disable the receptors in the fat cells? What happens if the fat cells can’t “see” the insulin while insulin can still do its job elsewhere in the body?

“FIRKO Mice”

Researchers from the Joslin Diabetes Center and Department of Medicine at Harvard Medical School in Boston have the answer. At least, in mice. In 2002, they published the data from their study [5]. They developed mice in whom the insulin receptors in the fat cells of mice were disabled; the so-called fat-specific insulin receptor knockout (or FIRKO) mice. The insulin receptors in the muscles still work, so they can store glycogen and convert amino acids into protein. However, when it comes to the fat cells, insulin has no effect. The receptors that should come into action in the FIRKO mice are disabled. The result: The FIRKO mice had 50-70 percent less fat than the control mice, regardless of how much they ate. Moreover, they lived almost 18% longer. Interestingly, the chance of developing diabetes at a later age (where insulin receptors elsewhere such as in the liver and muscles don’t work well either) was also lower in the FIRKO mice.

Using the Cre-loxP system, we created mice with fat-specific disruption of the insulin receptor gene (FIRKO mice). These mice have low fat mass, loss of the normal relationship between plasma leptin and body weight, and are protected against age-related and hypothalamic lesion-induced obesity, and obesity-related glucose intolerance.

“FAT10 Mice”

More recently, in 2013, researchers at Yale achieved somewhat similar results through a different route [6]. They disabled the gene HLA-F adjacent transcript 10 (“FAT10”). This gene is known to be involved in the immune system and is activated during inflammation, but much remains unclear about its function. The Yale researchers discovered a few remarkable things in mice with a defective FAT10 gene.

Knockout of the FAT10 Gene Prolongs Lifespan and Reduces Age-Associated Biomarkers.

Aged FAT10ko mice appeared younger than their age- and sex-matched controls, with maintenance of muscle mass (delayed sarcopenia), denser, smoother, and darker fur (Fig. S1), and absence of tumors. To assess impact on lifespan, we conducted Kaplan–Meier analysis (24) on mortality patterns of the two sexes compared with WT mice (Fig. 1). The analysis showed that male and female FAT10ko mice had a 20% increase in both median and overall lifespan. Notably, 42% percent of male KOs and 52% of female KOs remained alive after the death of the last WT mouse. When all normal mice from the study had died, half of the FAT10 mice were still alive. So, they lived longer, looked younger, but were also leaner:

FAT10ko Mice Are Leaner than Their Control Counterparts.

Increased lifespan in KO mice was associated with dramatically reduced adiposity. KO mice, independent of sex, gained significantly less weight than WT mice (Fig. S2A). Differences in weight became more pronounced with age. Whereas WT mice gained weight through their lifespan, the preponderance of weight gain in KO mice occurred by 12 mo of age.

Especially the increase in weight during aging remained limited in the FAT10 mice.

From Mouse to Human

That’s all well and good for the FIRKO and FAT10 mice, but when will we humans benefit from this? It won’t surprise you that a bit more research needs to be done before you can disable certain genes or receptors in humans. In a study in 2011, for example, we saw what happened to mice on a ketogenic diet [7]. The mice received so few carbohydrates that no insulin was produced. As a result, the fat cells also did not receive a signal to store fatty acids in the form of triglycerides. In these mice, the fat content of the liver was found to be increased. This was not the case in the FIRKO and FAT10 mice. The fact that these mice live longer ultimately suggests that the benefits outweigh the potential drawbacks, but it’s still nice if you can rule out certain things. Some things may not affect your lifespan, but they do affect your joy of life. Things that mice cannot articulate and on which researchers have not yet tested. The researchers at the Joslin Diabetes Center are looking for pharmaceutical companies willing to work with them on the development of medication that should make it possible to achieve the FIRKO effect in humans. These and similar developments, where technological breakthroughs free us from certain consequences of certain behaviors (eat without getting fat), or reward us for something we haven’t done (not exercising but being muscular), will increasingly determine our future. So, I dare to make the bold prediction that gyms will no longer exist within the next 15 years. At least not in the current form where much is based on pushing yourself to achieve results that will be much easier to achieve. These technologies are growing exponentially and will be available sooner than most of us probably think. We will therefore pay more and more attention to this on FITsociety.nl.

References

1. Eaton, S.B., S.B.(3rd) Eaton, and M.J. Konner. Paleolithic nutrition revisited: A twelve year retrospective on its nature and implications. Eur. J. Clin. Nutr. 1:207-216, 1997. Issues of Dietary Protein Intake in Humans 147
2. Cordain, L., J. Brand-Miller, S. Eaton, N. Mann, H.A. Holt, and J.D. Speth. World wide hunter gatherer (Plant:Animal) subsistence ratios: relevance for present day macronutrient recommendations. Am. J. Clin. Nutr. 71:682-692, 2000.
3. Mann, N. Dietary lean red meat and human evolution. Eur. J. Nutr. 39:71-79, 2000.
4. Blüher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, Kahn CR. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell. 2002 Jul;3(1):25-38. PubMed PMID:12110165.
5. Canaan A, DeFuria J, Perelman E, et al. Extended lifespan and reduced adiposity in mice lacking the FAT10 gene. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(14):5313-5318. doi:10.1073/pnas.1323426111.
6. Joel R. Garbow, Jason M. Doherty, Rebecca C. Schugar, Sarah Travers, Mary L. Weber, Anna E. Wentz, Nkiruka Ezenwajiaku, David G. Cotter, Elizabeth M. Brunt, Peter A. Crawford. Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet.American Journal of Physiology – Gastrointestinal and Liver Physiology Published 1 June 2011 Vol. 300 no. 6, G956-G967 DOI: 10.1152/ajpgi.00539.2010