Leptin Resistance

Goldilocks: “like porridge, leptin needs to be juuuuust right.”

Leptin is a hormone secreted primarily in white adipose fat cells and plays a role in regulating energy balance by curbing or stimulating hunger. Often referred to as the “satiety hormone,” leptin works by signaling the need to start or stop eating. In the short term, as fat supplies are reduced, leptin levels drop to signal when enough food has been consumed per meal.

Leptin levels vary exponentially, not linearly, with fat mass.1,2” White fat, or white adipose tissue, is traditionally linked to the development of obesity, heart disease and diabetes, because it stores up calories, in contrast to brown fat which burns calories to generate heat.

Leptin also works on a more seasonal basis. Leptin is released from the body’s fat base and is a longer term signaling mechanism to indicate when it is time to build more fat supplies to ensure survival. If fat supplies are adequate, then leptin levels will be high. If fat supplies are low, then the corresponding lower leptin levels will signal that it is time to eat carbohydrates to rebuild fat supplies. This is a natural metabolic feedback mechanism that plays out for multiple species.

It is possible however for the body to become leptin resistant, just as it is possible to become insulin resistant. High circulating levels of leptin can result in downregulation of leptin receptors. As a result, the elevated levels of leptin fail to signal the need to stop eating. Over eating and the associated incremental weight gain is common with leptin resistance.

The SH2B adapter protein 1 (SH2B1) has been identified as a positive regulator of insulin, IGF–1 and leptin action.4-7 It is well known that insulin’s primary role is to regulate glucose and lipid metabolism. SH2B1 deletion results in marked insulin and leptin resistance, obesity, and type 2 diabetes in mice as well as humans, indicating that SH2B1is required for the maintenance of normal body weight, insulin sensitivity, and glucose metabolism.7-12 In addition, it has been consistently demonstrated that SNPs in the SH2B1 gene are associated with obesity and/or BMI. The rs7498665 SNP of the SH2B1 gene, which is included in the Kashi Health Weight Management Genetic Panel, results in the non-synonymous amino acid exchange Thr484Ala in a splice variant-independent position with low conservation. The association of increased BMI with SH2B1 SNP (rs7498665 and/or rs7359397) risk alleles has been robustly replicated in a study of 249,796 individuals of European ancestry,13 and in 34,416 subjects of various ethnicities14. Another study, conducted in 1,700 Dutch women, 15 demonstrated that the risk allele at rs7498665 was associated with increased intake of total fat (per allele effect: 1.08 g/d), saturated fat (per allele effect: 0.60 g/d) and monounsaturated fat (per allele effect: 0.37 g/d). These results suggest that consumption of a diet high in fat, and particularly a diet high in saturated fat, places people who possess the SH2B1 risk allele at a greater risk of obesity.

The Kashi Health Weight Management Panel provides valuable genetic data so you can offer the best guidance to each of your patients on their ideal diet approaches for individualized weight loss goals. The lifestyle recommendations support the work you are doing by identifying key eating and exercise strategies. Call 877-879-1815 to order the free Weight Management Poster, request patient education brochures, and begin using this informative tool in your practice.

References

  1. Lönnqvist F, Arner P, Nordfors L, Schalling M (1995). “Overexpression of the obese (ob) gene in adipose tissue of human obese subjects”. Nat. Med. 1 (9): 950–3. doi:10.1038/nm0995-950. PMID 7585223.
  2. Madej T (1998). “Considerations in the use of lipid-based drug products”. J Intraven Nurs. 21 (6): 326. PMID 10392096.
  3. J Clin Endocrinol Metab. 2000 Aug;85(8):2685-91. Twenty-four-hour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake. Chin-Chance C1, Polonsky KS, Schoeller DA.
  4. Kotani K et al. SH2-B alpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase. Biochem. J. 1998;335:103–109
  5. Maures TJ et al. SH2B1(SH2–B) and JAK2: a multifunctional adaptor protein and kinase made for each other. Trends Endocrinol Metab. 2007;18: 38–45
  6. Morris DL et al. SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins. Diabetes. 2009;58:2039-2047
  7. Ren D et al. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. J Clin Invest 2007;117:397–406
  8. Duan C et al. Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. Mol Cell Biol 2004;24:7435–7443
  9. Ren D et al. Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metabolism. 2005;2:95–104
  10. Li M et al. Differential role of SH2-B and APS in regulating energy and glucose homeostasis. Endocrinology. 2006;147: 2163–2170
  11. Bochukova EG et al. Large, rare chromosomal deletions associated with severe early onset obesity. Nature. 2010;463:666–670
  12. Walters RG et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature. 2010;463:671–675
  13. Speliotes EK et al. Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nat Genet. 2010;42:937–948
  14. Thorleifsson G et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet. 2009;41:18–24
  15. Bauer F et al. Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference. Am J Clin Nutr. 2009;90:951–959