Rapamycin Normalizes Serum Leptin by Alleviating Obesity and Reducing Leptin Synthesis in Aged Rats

J Gerontol A Biol Sci Med Sci. 2016 Jul;71(7):891-9. doi: 10.1093/gerona/glu230. Epub 2015 Jan 23.


This investigation examines whether a low intermittent dose of rapamycin will avoid the hyperlipidemia and diabetes-like syndrome associated with rapamycin while still decreasing body weight and adiposity in aged obese rats. Furthermore, we examined if the rapamycin-mediated decrease in serum leptin was a reflection of decreased adiposity, diminished leptin synthesis, or both. To these ends, rapamycin (1mg/kg) was administered three times a week to 3 and 24-month old rats. Body weight, food intake, body composition, mTORC1 signaling, markers of metabolism, as well as serum leptin levels and leptin synthesis in adipose tissue were examined and compared to that following a central infusion of rapamycin. Our data suggest that the dosing schedule of rapamycin acts on peripheral targets to inhibit mTORC1 signaling, preferentially reducing adiposity and sparing lean mass in an aged model of obesity resulting in favorable outcomes on blood triglycerides, increasing lean/fat ratio, and normalizing elevated serum leptin with age. The initial mechanism underlying the rapamycin responses appears to have a peripheral action and not central. The peripheral rapamycin responses may communicate an excessive nutrients signal to the hypothalamus that triggers an anorexic response to reduce food consumption. This coupled with potential peripheral mechanism serves to decrease adiposity and synthesis of leptin.

Keywords: Leptin synthesis; Rapamycin; mTORC1.

MeSH terms

  • Adiposity / drug effects
  • Adiposity / physiology
  • Aging* / drug effects
  • Aging* / physiology
  • Animals
  • Body Weight* / drug effects
  • Body Weight* / physiology
  • Dose-Response Relationship, Drug
  • Glucose Metabolism Disorders / metabolism
  • Glucose Metabolism Disorders / prevention & control
  • Immunosuppressive Agents / metabolism
  • Immunosuppressive Agents / pharmacology
  • Leptin* / biosynthesis
  • Leptin* / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / metabolism*
  • Obesity / metabolism
  • Rats
  • Signal Transduction / drug effects
  • Sirolimus* / metabolism
  • Sirolimus* / pharmacology
  • TOR Serine-Threonine Kinases / metabolism*
  • Treatment Outcome


  • Immunosuppressive Agents
  • Leptin
  • Multiprotein Complexes
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Sirolimus