Stop Resisting! Leptin Resistance and Fat

There are undoubtedly many distinct variables, which each play a role, in the development of obesity.^{1, 2, 3, 4, 5} Whether it is too much sugar (usually leading to insulin resistance), too many calories, or simply a lack of exercise – obesity can result from a multitude of causative factors.^{6 7, 8, 9} However, one interesting variable that has come into light in the scientific community, is a hormone called leptin.^{10, 11, 12, 13} The rate of an individual’s leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of the percentage of body fat.^{14, 15} Obese individuals typically have large amounts of leptin,^{16, 17, 18} however, their brain usually cannot “see” their leptin, resulting in a state termed leptin resistance.^{19, 20, 21, 22}

“The Role of Leptin in the Control of Insulin-glucose Axis.” Frontiers. N.p., n.d. Web. 22 Dec. 2014.

“Obesity and Leptin Resistance.” Trends in endocrinology and metabolism: TEM 21.11 (2010)

Leptin is an adipocyte hormone that functions as the afferent signal in a negative feedback loop regulating body weight.^{23, 24, 25, 26} As researchers state, leptin also functions as a key link between nutrition and the function of most, if not all, other physiologic systems.^{27, 28, 29} How does this apply to you, and your quest to stay lean? Well, when an individual gains weight, their level of leptin increases.^{30, 31} The individual is then typically in a state of positive energy balance.³² Weight loss, in turn, typically leads to a state of negative energy balance.³³ Interestingly, human beings appear to be multivariate, both in their sensitivity to leptin, and also how much leptin is produced by the body.^{34, 35}

Paz-Filho G, Mastronardi C, Wong ML, Licinio J. Leptin therapy, insulin sensitivity, and glucose homeostasis. Indian J Endocr Metab 2012;16, Suppl S3:549-55

Since leptin is a key link between nutrition and just about every physiologic system, understanding leptin resistance, and possibly finding a way to intervene between insulin and leptin signaling, has become a major goal, in the science of finding a ‘cure’ for obesity.^{36, 37} A typical Western diet, which is usually extremely high in sugar, leads to excess insulin being secreted by the body.³⁸ Chronically elevated insulin levels, help to block leptin’s negative feedback signal.³⁹ This is how you get fat.

More specifically, researchers have posited that lack of available insulin receptor substrate 2, which is used by the leptin receptor (and can commonly be caused by hyperinsulinemia) may result in defective leptin signal transduction.^{40, 41} Interestingly, gender also plays a role in leptin levels, as women demonstrate markedly higher levels, compared to men.⁴² Even in the short term, changes in dietary carbohydrate intake induce changes in plasma leptin levels, which is also interesting, in regards to causative factors of obesity.⁴³

Nature.com. Nature Publishing Group, n.d. Web. 22 Dec. 2014.

Martínez de Morentin“‘Mens Sana In Corpore Sano’: Exercise and Hypothalamic ER Stress.” PLoS Biology 8.8 (2010): e1000464.

Your hypothalamus contains a receptor for leptin, called LRb.⁴⁴ Once leptin binds to this receptor, a cascade of biochemical signaling takes place.⁴⁵ Orexigenic neuropeptides are downregulated, and anorexigenic neuropeptides are upregulated.⁴⁶ Some of these neuropeptides include: neuropeptide Y, agouti-related peptide, melanin-concentrating hormone, corticotropin-releasing-hormone, and alpha-melanocyte-stimulating hormone, to name but a few.⁴⁷ With basic logic, it would seem to make sense that by injecting leptin, we would be able to induce weight loss in humans. However, this has not been shown to work, further advancing the theory that it is leptin resistance, not lack of leptin, which is causing the problem of widespread obesity, in today’s population.^{48, 49}

Martínez de Morentin“‘Mens Sana In Corpore Sano’: Exercise and Hypothalamic ER Stress.” PLoS Biology 8.8 (2010): e1000464.

“The Role of Leptin in the Control of Insulin-glucose Axis.” Frontiers. N.p., n.d. Web. 22 Dec. 2014.

Leptin-stimulated phosphorylation of Tyr(985) has been shown to promote a cellular leptin resistance, in obese subjects.⁵⁰ Further, a multitude of features of the arcuate nucleus of the hypothalamus, may help to add to the level of cellular leptin resistance.⁵¹ Another factor, which is so overlooked by the general populace, is that circulating levels of leptin are influenced by sleep duration.⁵² Another commonly overlooked element to leptin resistance, is dietary fructose.⁵³

Long term feeding of fructose has been shown to result in leptin resistance.⁵⁴ This is yet another reason to leave fructose largely out of one’s diet. A Paleo Diet, which is rich with nutrients, fiber, protein and healthy fats, will not lead to leptin resistance, and may even help to reverse it. While the science of leptin is ever-evolving and changing, the tenets of a healthy lifestyle are not. Getting plenty of sleep, limiting stress, getting sunshine, and eating well – all tenets of a Paleo lifestyle – will result in a healthier, happier version of yourself!

Casey Thaler, B.A., NASM-CPT, FNS

@EatCleanTClean

Eat Clean Train Clean

http://www.EatCleanTrainClean.com

Casey Thaler, B.A., NASM-CPT, FNS is an NASM® certified personal trainer and NASM® certified fitness nutrition specialist. He writes for Paleo Magazine® and for PaleoHacks. He also runs his own nutrition and fitness consulting company, Eat Clean, Train Clean®. He is pursuing his Ph.D in Nutritional Biochemistry, hopefully from Harvard University.

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