Withaferin A exerts an anti-obesity effect by increasing energy expenditure through thermogenic gene expression in high-fat diet-fed obese mice

Phytomedicine. 2021 Feb;82:153457. doi: 10.1016/j.phymed.2020.153457. Epub 2020 Dec 30.


Background: The enhancement of energy expenditure has attracted attention as a therapeutic target for the management of body weight. Withaferin A (WFA), a major constituent of Withania somnifera extract, has been reported to possess anti-obesity properties, however the underlying mechanism remains unknown.

Purpose: To investigate whether WFA exerts anti-obesity effects via increased energy expenditure, and if so, to characterize the underlying pathway.

Methods: C57BL/6 J mice were fed a high-fat diet (HFD) for 10 weeks, and WFA was orally administered for 7 days. The oxygen consumption rate of mice was measured at 9 weeks using an OxyletPro™ system. Hematoxylin and eosin (H&E), immunohistochemistry, immunoblotting, and real-time PCR methods were used.

Results: Treatment with WFA ameliorated HFD-induced obesity by increasing energy expenditure by improving of mitochondrial activity in brown adipose tissue (BAT) and promotion of subcutaneous white adipose tissue (scWAT) browning via increasing uncoupling protein 1 levels. WFA administration also significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the BAT of obese mice. Additionally, WFA activated mitogen-activated protein kinase (MAPK) signaling, including p38/extracellular signal-regulated kinase MAPK, in both BAT and scWAT.

Conclusion: WFA enhances energy expenditure and ameliorates obesity via the induction of AMPK and activating p38/extracellular signal-regulated kinase MAPK, which triggers mitochondrial biogenesis and browning-related gene expression.

Keywords: AMP-activated protein kinase; Adipose tissue browning; Energy expenditure; Mitochondrial activity; Mitogen-activated protein kinase; Withaferin A.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adipose Tissue, Brown / drug effects
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Animals
  • Anti-Obesity Agents / pharmacology*
  • Body Weight / drug effects
  • Diet, High-Fat*
  • Energy Metabolism / drug effects*
  • Gene Expression / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Mitochondria / metabolism
  • Obesity / drug therapy*
  • Thermogenesis / drug effects*
  • Thermogenesis / genetics
  • Uncoupling Protein 1 / metabolism
  • Withania / chemistry
  • Withanolides / pharmacology
  • Withanolides / therapeutic use*


  • Anti-Obesity Agents
  • Uncoupling Protein 1
  • Withanolides
  • AMP-Activated Protein Kinases
  • withaferin A