Stop Resisting! Leptin Resistance and Fat

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

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

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

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!

References

[1] Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114(12):1752-61.

[2] Swinburn BA, Sacks G, Hall KD, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet. 2011;378(9793):804-14.

[3] Catenacci VA, Hill JO, Wyatt HR. The obesity epidemic. Clin Chest Med. 2009;30(3):415-44, vii.

[4] Roth J, Qiang X, Marbán SL, Redelt H, Lowell BC. The obesity pandemic: where have we been and where are we going?. Obes Res. 2004;12 Suppl 2:88S-101S.

[5] Greenberg AS, Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr. 2006;83(2):461S-465S.

[6] Keller KB, Lemberg L. Obesity and the metabolic syndrome. Am J Crit Care. 2003;12(2):167-70.

[7] Misra A, Khurana L. Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab. 2008;93(11 Suppl 1):S9-30.

[8] Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106(4):473-81.

[9] Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 2004;25(1):4-7.

[10] Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007;8(1):21-34.

[11] Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395(6704):763-70.

[12] Ahima RS. Revisiting leptin's role in obesity and weight loss. J Clin Invest. 2008;118(7):2380-3.

[13] Enriori PJ, Evans AE, Sinnayah P, et al. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab. 2007;5(3):181-94.

[14] Jéquier E. Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci. 2002;967:379-88.

[15] Huang KC, Lin RC, Kormas N, et al. Plasma leptin is associated with insulin resistance independent of age, body mass index, fat mass, lipids, and pubertal development in nondiabetic adolescents. Int J Obes Relat Metab Disord. 2004;28(4):470-5.

[16] Bravo PE, Morse S, Borne DM, Aguilar EA, Reisin E. Leptin and hypertension in obesity. Vasc Health Risk Manag. 2006;2(2):163-9.

[17] Carter S, Caron A, Richard D, Picard F. Role of leptin resistance in the development of obesity in older patients. Clin Interv Aging. 2013;8:829-44.

[18] Shah NR, Braverman ER. Measuring adiposity in patients: the utility of body mass index (BMI), percent body fat, and leptin. PLoS ONE. 2012;7(4):e33308.

[19] Myers MG, Leibel RL, Seeley RJ, Schwartz MW. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab. 2010;21(11):643-51.

[20] Kalra SP. Circumventing leptin resistance for weight control. Proc Natl Acad Sci USA. 2001;98(8):4279-81.

[21] Carter S, Caron A, Richard D, Picard F. Role of leptin resistance in the development of obesity in older patients. Clin Interv Aging. 2013;8:829-44.

[22] Mark AL, Correia ML, Rahmouni K, Haynes WG. Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications. J Hypertens. 2002;20(7):1245-50.

[23] Friedman JM. The function of leptin in nutrition, weight, and physiology. Nutr Rev. 2002;60(10 Pt 2):S1-14.

[24] Jönsson T, Olsson S, Ahrén B, Bøg-hansen TC, Dole A, Lindeberg S. Agrarian diet and diseases of affluence--do evolutionary novel dietary lectins cause leptin resistance?. BMC Endocr Disord. 2005;5(1):10.

[25] Air EL, Benoit SC, Clegg DJ, Seeley RJ, Woods SC. Insulin and leptin combine additively to reduce food intake and body weight in rats. Endocrinology. 2002;143(6):2449-52.

[26] Huang L, Li C. Leptin: a multifunctional hormone. Cell Res. 2000;10(2):81-92.

[27] Friedman JM. The function of leptin in nutrition, weight, and physiology. Nutr Rev. 2002;60(10 Pt 2):S1-14.

[28] Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord. 2002;26(11):1407-33.

[29] Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382(6588):250-2.

[30] Guagnano MT, Romano M, Falco A, et al. Leptin increase is associated with markers of the hemostatic system in obese healthy women. J Thromb Haemost. 2003;1(11):2330-4.

[31] Phillips BG, Kato M, Narkiewicz K, Choe I, Somers VK. Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea. Am J Physiol Heart Circ Physiol. 2000;279(1):H234-7.

[32] Hall KD, Heymsfield SB, Kemnitz JW, Klein S, Schoeller DA, Speakman JR. Energy balance and its components: implications for body weight regulation. Am J Clin Nutr. 2012;95(4):989-94.

[33] Lemay V, Drapeau V, Tremblay A, Mathieu ME. Exercise and negative energy balance in males who perform mental work. Pediatr Obes. 2014;9(4):300-9.

[34] Ruhl CE, Everhart JE. Leptin concentrations in the United States: relations with demographic and anthropometric measures. Am J Clin Nutr. 2001;74(3):295-301.

[35] Plasma leptin levels are related to body composition, sex, insulin levels and the A55V polymorphism of the UCP2 gene. International Journal of Obesity. 2007;31(8):1311.

[36] Ozcan L, Ergin AS, Lu A, et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009;9(1):35-51.

[37] Mancour LV, Daghestani HN, Dutta S, et al. Ligand-induced architecture of the leptin receptor signaling complex. Mol Cell. 2012;48(4):655-61.

[38] Merat S, Casanada F, Sutphin M, Palinski W, Reaven PD. Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet. Arterioscler Thromb Vasc Biol. 1999;19(5):1223-30.

[39] Amitani M, Asakawa A, Amitani H, Inui A. The role of leptin in the control of insulin-glucose axis. Front Neurosci. 2013;7:51.

[40] Lustig RH. Childhood obesity: behavioral aberration or biochemical drive? Reinterpreting the First Law of Thermodynamics. Nat Clin Pract Endocrinol Metab. 2006;2(8):447-58.

[41] Isganaitis E, Lustig RH. Fast food, central nervous system insulin resistance, and obesity. Arterioscler Thromb Vasc Biol. 2005;25(12):2451-62.

[42] Hellström L, Wahrenberg H, Hruska K, Reynisdottir S, Arner P. Mechanisms behind gender differences in circulating leptin levels. J Intern Med. 2000;247(4):457-62.

[43] Dirlewanger M, Di vetta V, Guenat E, et al. Effects of short-term carbohydrate or fat overfeeding on energy expenditure and plasma leptin concentrations in healthy female subjects. Int J Obes Relat Metab Disord. 2000;24(11):1413-8.

[44] Bates SH, Kulkarni RN, Seifert M, Myers MG. Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis. Cell Metab. 2005;1(3):169-78.

[45] Banks AS, Davis SM, Bates SH, Myers MG. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem. 2000;275(19):14563-72.

[46] Cowley MA, Smart JL, Rubinstein M, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411(6836):480-4.

[47] Münzberg H, Jobst EE, Bates SH, et al. Appropriate inhibition of orexigenic hypothalamic arcuate nucleus neurons independently of leptin receptor/STAT3 signaling. J Neurosci. 2007;27(1):69-74.

[48] Rahmouni K, Fath MA, Seo S, et al. Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J Clin Invest. 2008;118(4):1458-67.

[49] Vasselli JR. The role of dietary components in leptin resistance. Adv Nutr. 2012;3(5):736-8.

[50] Myers MG, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008;70:537-56.

[51] Håkansson ML, Hulting AL, Meister B. Expression of leptin receptor mRNA in the hypothalamic arcuate nucleus--relationship with NPY neurones. Neuroreport. 1996;7(18):3087-92.

[52] Spiegel K, Leproult R, L'hermite-balériaux M, Copinschi G, Penev PD, Van cauter E. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab. 2004;89(11):5762-71.

[53] Teff KL, Elliott SS, Tschöp M, et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab. 2004;89(6):2963-72.

[54] Aijälä M, Malo E, Ukkola O, et al. Long-term fructose feeding changes the expression of leptin receptors and autophagy genes in the adipose tissue and liver of male rats: a possible link to elevated triglycerides. Genes Nutr. 2013;8(6):623-35.