A Leptin Resistance Solution?

Leptin is a hormone that signals the very important message, “I am not hungry”. In a culture that has easy access to tempting foods, why would anyone ever want to stop eating? The answer to this question lies in the body’s ability to feel full. Leptin is produced primarily by adipose tissue and, when the systems works the way it should, the body increases leptin levels which triggers a decrease in appetite1. At first glance this may seem like a perfect system, but just as with insulin, when the levels of leptin are high for an extended period of time, resistance to the signal develops 2. The consequence of this is called leptin resistance and it leads to an increased feeling of hunger, decreased feelings of satiety, and more eating action resulting in weight gain. This is an important survival mechanism when there is only seasonal supply of food, and when it is important to build up energy stores to be burned when less food is available. However, in modern times, when food is available all year round, leptin resistance increases the risk of a patient becoming obese.

As incidence of leptin resistance is increasing in the obese population, providers are looking for ways to improve the leptin signaling process and decrease resistance. Since leptin is a key link between nutrition and many physiologic systems, understanding leptin resistance, and possibly finding a way to intervene between insulin and leptin signaling, has become a major goal3,4. Any diet which is high in sugar, particularly fructose,5 leads to excess insulin being secreted by the body 6. Chronically elevated insulin levels help to block leptin’s negative feedback signal.7 The moral of the story here is to significantly reduce carbohydrate, especially refined, simple carbohydrate.

Genetics can also play an important role in the way the hypothalamus processes the signal leptin. Research established a gene called SH2B1 which encodes for a protein that is a positive regulator of both insulin and leptin action8. Deletion of the SH2B1 gene entirely can very easily lead to severe obesity, insulin resistance, and leptin resistance8. Some people possess a single nucleotide polymorphism (SNP) in SH2B1 called rs7498665 which has been associated with an alteration to the protein product. The SNP rs7498665 has also been strongly correlated to an increased BMI in people who possess the variant.9 Because leptin resistance is associated with receptor signaling in the hypothalamus, researchers are starting to look at the connection between this SNP in the gene SH2B1 and obesity. Understanding the influence genes have on patient presentation can help the practitioner to focus their treatment. When treating patients with the SNP rs7498665 it is important to optimize the body’s response to leptin.

As leptin resistance is better understood, treatment of this condition is becoming more important to clinicians. Some research shows that a long-term exercise strategy can be a valuable tool for gradually decreasing leptin resistance by reducing both insulin and leptin levels; however changing diet away from simple carbohydrates and saturated fats and portion control can have the greatest long term effect. Genetic testing can be a valuable tool for identifying patients that maybe at risk for leptin resistance, and can help the practitioner target their treatment protocol to each specific patient.


  1. Kam, Katherine. Reviewed by Martin, Laura MD (01/2010). WebMD. The Facts on Leptin: FAQ. http://www.webmd.com/diet/obesity/features/the-facts-on-leptin-faq#1
  2. Munzberg Heike, Flier Jeffrey, Bjorbaek, Christian. “Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice”. Endocrinology 145 (11) (2004) 4880-4889.
  4. Mancour LV, Daghestani HN, Dutta S, et al. Ligand-induced architecture of the leptin receptor signaling complex. Mol Cell. 2012;48(4):655-61.
  5. 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.
  6. 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.
  7. Amitani M, Asakawa A, Amitani H, Inui A. The role of leptin in the control of insulin-glucose axis. Front Neurosci. 2013;7:51.
  8. Maures Tj. Et al. SH2B1 (SH2-B) and JAK2: a muiltifunctional adaptor protein and kinase made for each other. Trends Endocrinol Metab. 2007; 18: 38-45.
  9. WillerCj et al. Six new loci associated with body mass index highlight a neuronal influence on bodyweight regulation. Nature Genetics. 2009:25-34.