Tag Archives: leptin

Leptin Resistance | The Paleo Diet

What’s all the buzz about leptin? With over half the American population trying desperately to lose weight,1 it’s no wonder we’ve become fascinated with a hormone that prompts us to think obesity or starvation.

Robert H. Lustig, MD, professor of pediatrics at UCSF and a member of the Endocrine Society’s Obesity Task Force explains “Leptin is a protein that’s made in the fat cells, circulates in the bloodstream, and goes to the brain; it’s the way your fat cells tell your brain that your energy thermostat is set right…and you have enough energy stored in your fat cells to engage in normal, relatively expensive metabolic processes.” Dr. Lustig goes on to discuss that levels are likely genetically set for each person. When an unbalance occurs exceeding your leptin threshold, the brain responds to the energy sufficiency, allowing you to “burn energy at a normal rate, eat food at a normal amount, engage in exercise at a normal rate, and you can engage in expensive processes, like puberty and pregnancy.”2

When the body doesn’t respond to the signal, it cannot stimulate your metabolism or suppress your appetite, inducing leptin resistance. This can make losing weight difficult if not impossible. With insulin resistance, pre-diabetes, and ultimately a diagnosis of Type II Diabetes on the rise, so too are the number of individuals diagnosed with leptin resistance.

The Standard American Diet (SAD), leading a predominantly sedentary lifestyle, too much stress, and not enough sleep all contribute to leptin resistance.3 Assessing whether leptin resistance is contributing to shedding stubborn pounds once and for all, shouldn’t start with the notion of a magic bullet, but an overhaul of lifestyle.

Sure, it’s easy to find leptin supplements online that promise the oomph you need to kickstart your new weight loss regime. But are they effective? Not according to research.

Because leptin is a digestible protein that doesn’t enter the bloodstream, the body just breaks it up. Further, leptin supplements sold online don’t actually contain leptin, but rather ingredients that are purported to help improve leptin functioning or feelings of fullness.4

So what’s the answer? As always, we need to go back to basics and look at the problem, rather than the symptom.

Leptin and insulin communicate and work in conjunction with other hormones to control our energy balance and as insulin levels rise, so do leptin levels. If we start by following a balanced, Paleo eating plan, which prevents blood sugar spike to begin with, we regulate our blood sugar and leptin release, reducing our chances of developing leptin and insulin resistance.

The takeaway: stop doing your body a disservice. Ask yourself:

  1. Am I eating right?
  2. Are my macronutrients balanced?
  3. Is my food timing in check?
  4. Am I exercising regularly?

If you answered ‘No’ to any of these questions, you may be hindering your weight loss and setting yourself up for additional adverse effects, like increasing your risk for cardiovascular disease (CVD) and other metabolic diseases.

“With obesity, leptin cannot tell our brain to stop eating, but it can still tell our brain to increase the activity of the cardiovascular system,” said Dr. Eric Belin de Chantemele, physiologist in the Department of Physiology at the Medical College of Georgia at Georgia Regents University. 5

Researchers have also shown that fat-derived leptin directly activates aldosterone synthase expression in the adrenal glands, resulting in production of more of the steroid hormone aldosterone. Increased aldosterone directly effects blood pressure by regulating salt-water balance in the body, contributes to widespread inflammation, blood vessel stiffness and scarring, enlargement and stiffness of the heart, and impaired insulin sensitivity. High levels of aldosterone are an obesity hallmark and a leading cause of metabolic and cardiovascular problems6

Avoid widespread inflammation. Stop insulin resistance in its tracks. Keep blood sugar low. These three key health tenants fit the bill and are easily achieved by following a Paleo diet. Add a little patience into the mix and avoid the urge for ‘get results fast!’ and Viola! We give our bodies the time to calm inflammation, shed the extra weight, and reset its hormonal cascade.

Take action now, before you need medical intervention!


1. “Americans’ Desire to Shed Pounds Outweighs Effort.” Gallup.com. N.p., n.d. Web. 19 Oct. 2015

2. “Leptin Hormone & Supplements: Do They Work for Obesity & Weight Loss?” WebMD. WebMD, n.d. Web. 19 Oct. 2015

3. Galland, M.D. Leo. “Leptin: How to Make This Fat-Burning Hormone Work for You.” The Huffington Post. TheHuffingtonPost.com, n.d. Web. 19 Oct. 2015

4. “The Facts on Leptin: FAQ.” WebMD. WebMD, n.d. Web. 19 Oct. 2015

5. “Satiety Hormone Leptin Plays a Direct Role in Cardiovascular Disease in Obesity.” ScienceDaily. ScienceDaily, n.d. Web. 19 Oct. 2015

6. Anne-Cécile Huby, Galina Antonova, Jake Groenendyk, Celso E. Gomez-Sanchez, Wendy B. Bollag, Jessica A. Filosa, Eric J. Belin de Chantemèle. The Adipocyte-Derived Hormone Leptin is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis. Circulation, 2015; CIRCULATIONAHA.115.018226 DOI: 10.1161/CIRCULATIONAHA.115.018226

This Is Your Brain on Paleo | The Paleo Diet
I’ve previously discussed the variety of positive neuronal changes that occur when consuming a healthier, Paleo Diet. This is especially true when you are moving away from a Western diet, filled with inflammatory seed oils, empty calories, and lots of sugar.1, 2 When consuming these foods, your brain literally reprograms itself, to come to crave and long after its next “fix.”3, 4 This is where changing your diet can not only help to change your body, but also your mind.5, 6

Take for example, the Nrf2 transcription factor. Nrf2 is a master regulator of intracellular redox homeostasis.7 Some research has shown that a ketogenic diet may activate the Nrf2 pathway via redox signaling, leading to chronic cellular adaptation, induction of protective proteins, and improvement of the mitochondrial redox state.8 Other research has shown that dietary flavonoids (mainly vegetables and fruits) are neuroprotective via proteins related to Nrf2.9 Nrf2, or nuclear factor erythroid 2-related factor 2, is critical for neuronal protection, through the induction of various cytoprotective genes.10

This Is Your Brain on Paleo | The Paleo Diet

McEwen, Bruce S. “Protective and Damaging Effects of Stress Mediators: Central Role of the Brain.” Dialogues in Clinical Neuroscience 8.4 (2006): 367–381. Print.

With this information in hand (or should I say, in your head) it starts to become clearer how making a simple change in your diet, can have many protective effects, especially when trying to avoid Alzheimer’s, or other debilitating neurological conditions.11 Many chronic diseases are underpinned by chronic inflammation, and yes, this extends to inflammation of the brain, as well.12, 13 As researchers have stated, the Keap1/Nrf2/ARE pathway plays a major role in health resilience and can be made more robust and responsive by certain dietary factors.14

With the damaging amount of free radicals produced by today’s high stress, low sleep and low nutrient lifestyles, it is time to take a serious look at just how much damage you are doing to your brain.15, 16 Do you think it is just a mere coincidence that the New England Journal of Medicine correlated higher average blood sugar (which occurs from consuming a high sugar diet) with an increased risk for dementia?17 I don’t. Our rates of crippling neurological disease have risen exponentially, as, simultaneously, has the rate of type 2 diabetes, which is obtained from, you guessed it, a high sugar diet.18

But it is not simply removing sugar that is the answer to all of our problems. It is also what foods and calories you are consuming, instead of the sugary breakfast cereals, pastries, and donuts. Vegetables have many beneficial compounds, which have been shown to help provide protection against neurological breakdown, and even enhance cell-to-cell signaling.19 This makes perfect sense given the many poor quality foods that can cause an increase in inflammatory chemical production.20 So, the basic hypothesis is simple: remove the foods causing the inflammation and higher rate of glycation (aging process), and replace them with foods that enhance neuronal signaling, and protect your brain from damage.21

This Is Your Brain on Paleo | The Paleo Diet
This Is Your Brain on Paleo | The Paleo Diet

“Result Filters.” National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 05 Jan. 2015.

One element not yet discussed, is BDNF, or brain-derived neurotrophic factor.22 A 2002 neuroscience study sums up this factor, and more specifically, how a poor diet can negatively affect your brain. Researchers concluded that a high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning.23 Unfortunately, the term “high fat,” continues to prevail in the scientific community, when researchers really mean trans fat, poor quality fat, and/or high fat plus high sugar. Nonetheless, this study easily conveys the idea that a poor diet will immediately cause problems in your hippocampus, your ability to learn, and how the brain reorganizes neuronal pathways in the brain. In a word: Bad.

This Is Your Brain on Paleo | The Paleo Diet

“Result Filters.” National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 05 Jan. 2015.

BDNF importance stems from not only helping to support the survival of existing neurons, but encouraging the growth of new neurons and synapses.24 Yes, this means that it, quite literally, can help you get smarter.25 So, if you’re consuming a poor diet, you will likely not be able to improve your intelligence at the same rate as you would, when consuming a healthier, Paleo Diet. BDNF is just one of the many factors that play into the neurological role of consuming healthy fats, high quality sources of protein and lots of vegetables, all key tenets of a Paleo Diet.

This Is Your Brain on Paleo | The Paleo Diet

“Result Filters.” National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 05 Jan. 2015.

Let’s talk about leptin resistance and what impact this condition has on your brain.26 When consuming a poor diet, you are very likely to develop insulin resistance.27 Accompanying that, is usually leptin resistance.28 Leptin is your body’s way of telling your brain that you are full, and you do not need to eat any more food.29 Those born with a leptin deficiency, almost immediately become obese, because their brain simply cannot realize they have consumed enough calories.30

But leptin resistance, rather than leptin deficiency, means you are now resistant to the body’s way of telling your brain to stop eating.31 This leads to a whole host of problems, the least of which, is over consumption and the resulting weight gain.32 Researchers have found that chronically elevated leptin decreases hypothalamic leptin receptor expression and protein levels and impairs leptin signaling.33 This is only the first step in the vicious cycle of weight gain via leptin resistance.34 Since hypothalamic leptin receptor expression has been decreased, your brain actually changes from consuming a poor diet.35, 36, 37

Many people are unaware of all the pathways and details that come from simply changing the food that is on their plate. But the many crucial scientific changes that occur, silently, but steadily, are what really lead to obesity and disease.38, 39 Becoming aware of them, and changing what you put in your mouth, is perhaps the single most important thing you can do, to get healthier and to save yourself from a lifetime of chronic disease and unhappiness.40, 41 A Paleo Diet is brain-friendly, and will be one of the biggest changes you make, to become smarter, happier, leaner, and disease-free!


[1] Gutiérrez-fisac JL, Angel royo-bordonada M, Rodríguez-artalejo F. [Health-risks associated with Western diet and sedentariness: the obesity epidemia]. Gac Sanit. 2006;20 Suppl 1:48-54.

[2] Poti JM, Duffey KJ, Popkin BM. The association of fast food consumption with poor dietary outcomes and obesity among children: is it the fast food or the remainder of the diet?. Am J Clin Nutr. 2014;99(1):162-71.

[3] Heatherton TF. Neuroscience of self and self-regulation. Annu Rev Psychol. 2011;62:363-90.

[4] Berthoud HR. The neurobiology of food intake in an obesogenic environment. Proc Nutr Soc. 2012;71(4):478-87.

[5] Pilot randomized trial demonstrating reversal of obesity-related abnormalities in reward system responsivity to food cues with a behavioral intervention. Nutrition & Diabetes. 2014;4(9):e129.

[6] Available at: //www.ncbi.nlm.nih.gov/pubmedhealth/behindtheheadlines/news/2014-09-02-brain-can-be-retrained-to-prefer-healthy-foods/. Accessed December 30, 2014.

[7] Zhang YK, Wu KC, Liu J, Klaassen CD. Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. Toxicol Appl Pharmacol. 2012;264(3):305-14.

[8] Milder JB, Liang LP, Patel M. Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. Neurobiol Dis. 2010;40(1):238-44.

[9] Leonardo CC, Doré S. Dietary flavonoids are neuroprotective through Nrf2-coordinated induction of endogenous cytoprotective proteins. Nutr Neurosci. 2011;14(5):226-36.

[10] Available at: //www.ncbi.nlm.nih.gov/gene/4780. Accessed December 28, 2014.

[11] Ravona-springer R, Moshier E, Schmeidler J, et al. Changes in glycemic control are associated with changes in cognition in non-diabetic elderly. J Alzheimers Dis. 2012;30(2):299-309.

[12] Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun. 2004;18(5):407-13.

[13] Calderón-garcidueñas L, Reed W, Maronpot RR, et al. Brain inflammation and Alzheimer’s-like pathology in individuals exposed to severe air pollution. Toxicol Pathol. 2004;32(6):650-8.

[14] Stefanson AL, Bakovic M. Dietary regulation of Keap1/Nrf2/ARE pathway: focus on plant-derived compounds and trace minerals. Nutrients. 2014;6(9):3777-801.

[15] Mcewen BS. Protective and damaging effects of stress mediators: central role of the brain. Dialogues Clin Neurosci. 2006;8(4):367-81.

[16] Cohen JI, Yates KF, Duong M, Convit A. Obesity, orbitofrontal structure and function are associated with food choice: a cross-sectional study. BMJ Open. 2011;1(2):e000175.

[17] Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369(6):540-8.

[18] Moreira PI. High-sugar diets, type 2 diabetes and Alzheimer’s disease. Curr Opin Clin Nutr Metab Care. 2013;16(4):440-5.

[19] Choi HS, Jeon HJ, Lee OH, Lee BY. Indole-3-carbinol, a vegetable phytochemical, inhibits adipogenesis by regulating cell cycle and AMPKα signaling. Biochimie. 2014;104:127-36.

[20] Mattson MP, Chan SL, Duan W. Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. Physiol Rev. 2002;82(3):637-72.

[21] Bredesen DE. Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY). 2014;6(9):707-17.

[22] Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors. 2004;22(3):123-31.

[23] Molteni R, Barnard RJ, Ying Z, Roberts CK, Gómez-pinilla F. A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience. 2002;112(4):803-14.

[24] Song C, Fang S, Lv G, Mei X. Gastrodin promotes the secretion of brain-derived neurotrophic factor in the injured spinal cord. Neural Regen Res. 2013;8(15):1383-9.

[25] Rostami E, Krueger F, Zoubak S, et al. BDNF polymorphism predicts general intelligence after penetrating traumatic brain injury. PLoS ONE. 2011;6(11):e27389.

[26] Eikelis N, Wiesner G, Lambert G, Esler M. Brain leptin resistance in human obesity revisited. Regul Pept. 2007;139(1-3):45-51.

[27] Johnson-down L, Labonte ME, Martin ID, et al. Quality of diet is associated with insulin resistance in the Cree (Eeyouch) indigenous population of northern Québec. Nutr Metab Cardiovasc Dis. 2014;

[28] Lustig RH, Sen S, Soberman JE, Velasquez-mieyer PA. Obesity, leptin resistance, and the effects of insulin reduction. Int J Obes Relat Metab Disord. 2004;28(10):1344-8.

[29] 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.

[30] Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387(6636):903-8.

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

[32] Martin SS, Qasim A, Reilly MP. Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol. 2008;52(15):1201-10.

[33] Leptin and the regulation of body weight in mammals. Nature. 1998;395(6704):763.

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

[35] Mitchell SE, Nogueiras R, Morris A, et al. Leptin receptor gene expression and number in the brain are regulated by leptin level and nutritional status. J Physiol (Lond). 2009;587(Pt 14):3573-85.

[36] Gamber KM, Huo L, Ha S, Hairston JE, Greeley S, Bjørbæk C. Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity. PLoS ONE. 2012;7(1):e30485.

[37] Korner J, Savontaus E, Chua SC, Leibel RL, Wardlaw SL. Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus. J Neuroendocrinol. 2001;13(11):959-66.

[38] Chakraborty S, Zawieja S, Wang W, Zawieja DC, Muthuchamy M. Lymphatic system: a vital link between metabolic syndrome and inflammation. Ann N Y Acad Sci. 2010;1207 Suppl 1:E94-102.

[39] Kolčić I. Double burden of malnutrition: A silent driver of double burden of disease in low- and middle-income countries. J Glob Health. 2012;2(2):020303.

[40] Frassetto LA, Schloetter M, Mietus-synder M, Morris RC, Sebastian A. Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr. 2009;63(8):947-55.

[41] Fujimura KE, Slusher NA, Cabana MD, Lynch SV. Role of the gut microbiota in defining human health. Expert Rev Anti Infect Ther. 2010;8(4):435-54.

Affiliates and Credentials