Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice

Nat Med. 2016 Sep;22(9):1023-32. doi: 10.1038/nm.4145. Epub 2016 Aug 1.


The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules that have mRNA expression profiles similar to that of celastrol, a naturally occurring compound that we previously identified as a leptin sensitizer. Through this process, we identified another naturally occurring compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin-A treatment of mice with diet-induced obesity (DIO) resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities, including hepatic steatosis. Withaferin-A treatment marginally affected the body weight of ob/ob and db/db mice, both of which are deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism that occur independently of its leptin-sensitizing effect. Our results show that the metabolic abnormalities of DIO can be mitigated by sensitizing animals to endogenous leptin, and they indicate that withaferin A is a potential leptin sensitizer with additional antidiabetic actions.

MeSH terms

  • Animals
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Blotting, Western
  • Body Weight / drug effects*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diet, High-Fat*
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Fluorescent Antibody Technique
  • Glucose Tolerance Test
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Immunohistochemistry
  • Leptin / metabolism*
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Obese
  • Obesity / metabolism*
  • Pentacyclic Triterpenes
  • Real-Time Polymerase Chain Reaction
  • STAT3 Transcription Factor / drug effects
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Triterpenes / pharmacology
  • Withanolides / pharmacology*


  • Blood Glucose
  • Leptin
  • Pentacyclic Triterpenes
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Triterpenes
  • Withanolides
  • withaferin A
  • celastrol