Article thumbnail

Hyperleptinemia Is Required for the Development of Leptin Resistance

By Zachary A. Knight, K. Schot Hannan, Matthew L. Greenberg and Jeffrey M. Friedman


Leptin regulates body weight by signaling to the brain the availability of energy stored as fat. This negative feedback loop becomes disrupted in most obese individuals, resulting in a state known as leptin resistance. The physiological causes of leptin resistance remain poorly understood. Here we test the hypothesis that hyperleptinemia is required for the development of leptin resistance in diet-induced obese mice. We show that mice whose plasma leptin has been clamped to lean levels develop obesity in response to a high-fat diet, and the magnitude of this obesity is indistinguishable from wild-type controls. Yet these obese animals with constant low levels of plasma leptin remain highly sensitive to exogenous leptin even after long-term exposure to a high fat diet. This shows that dietary fats alone are insufficient to block the response to leptin. The data also suggest that hyperleptinemia itself can contribute to leptin resistance by downregulating cellular response to leptin as has been shown for other hormones

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (2008). A translational profiling approach for the molecular characterization of CNS cell types.
  2. (1997). Acute stimulation of glucose metabolism in mice by leptin treatment.
  3. (2010). Antidiabetic effects of IGFBP2, a leptin-regulated gene.
  4. (2009). Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin.
  5. (1996). Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans.
  6. (1997). Congenital leptin deficiency is associated with severe early-onset obesity in humans.
  7. (2006). Control of energy homeostasis: role of enzymes and intermediates of fatty acid metabolism in the central nervous system.
  8. (2000). Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice.
  9. (2006). Dietinduced obesity alters AMP kinase activity in hypothalamus and skeletal muscle.
  10. (2007). Dietinduced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons.
  11. (2009). Does hypothalamic inflammation cause obesity?
  12. (1999). Effects of recombinant leptin therapy in a child with congenital leptin deficiency.
  13. (1995). Effects of the obese gene product on body weight regulation in ob/ob mice.
  14. (2008). Endoplasmic reticulum stress induces leptin resistance.
  15. (2009). Endoplasmic reticulum stress plays a central role in development of leptin resistance.
  16. (2004). Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3.
  17. (2006). Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells.
  18. (2009). Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity.
  19. (2004). Genetic vulnerability to diet-induced obesity in the C57BL/6J mouse: physiological and molecular characteristics.
  20. (2009). HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptindependent and -independent mechanisms.
  21. (2008). High-fat diet-induced changes in body mass and hypothalamic gene expression in wild-type and leptindeficient mice.
  22. (2008). Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity.
  23. (2010). Hypothalamic inflammation and energy homeostasis: resolving the paradox.
  24. (2009). Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet.
  25. (2005). Hypothalamic sensing of fatty acids.
  26. (1998). Identification of SOCS-3 as a potential mediator of central leptin resistance.
  27. (2010). Interaction of leptin and amylin in the long-term maintenance of weight loss in diet-induced obese rats.
  28. (1996). Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/ db mice.
  29. (1995). Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects.
  30. (1995). Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action.
  31. (2005). Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats.
  32. (2008). Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies.
  33. (2010). Leptin therapy in insulin-deficient type I diabetes.
  34. (2008). Making insulindeficient type 1 diabetic rodents thrive without insulin.
  35. (2010). Mechanism of attenuation of leptin signaling under chronic ligand stimulation.
  36. (2007). Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function.
  37. (2009). MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity.
  38. (1997). Physiological response to long-term peripheral and central leptin infusion in lean and obese mice.
  39. (1994). Positional cloning of the mouse obese gene and its human homologue.
  40. (2004). Rapid rewiring of arcuate nucleus feeding circuits by leptin.
  41. (2004). Region-specific leptin resistance within the hypothalamus of diet-induced obese mice.
  42. (2006). Regulating insulin signaling and beta-cell function through IRS proteins.
  43. (2009). Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity.
  44. (2005). Skeletal muscle AMP-activated protein kinase phosphorylation parallels metabolic phenotype in leptin transgenic mice under dietary modification.
  45. (2004). Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to dietinduced obesity.
  46. (2000). SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985.
  47. (2007). The hormonal control of food intake.
  48. (1995). The role of neuropeptide Y in the antiobesity action of the obese gene product.
  49. (2000). Transient effects of longterm leptin supplementation in the prevention of diet-induced obesity in mice.
  50. (2004). Trophic action of leptin on hypothalamic neurons that regulate feeding.
  51. (2000). Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.
  52. (1995). Weightreducing effects of the plasma protein encoded by the obese gene.