An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination

Cell Rep. 2018 Jun 19;23(12):3607-3620. doi: 10.1016/j.celrep.2018.05.065.


Exposure to cold temperature is well known to upregulate heat shock protein (Hsp) expression and recruit and/or activate brown adipose tissue and beige adipocytes in humans and animals. However, whether and how Hsps regulate adipocyte function for energy homeostatic responses is poorly understood. Here, we demonstrate a critical role of Hsp20 as a negative regulator of adipocyte function. Deletion of Hsp20 enhances non-shivering thermogenesis and suppresses inflammatory responses, leading to improvement of glucose and lipid metabolism under both chow diet and high-fat diet conditions. Mechanistically, Hsp20 controls adipocyte function by interacting with the subunit of the ubiquitin ligase complex, F-box only protein 4 (FBXO4), and regulating the ubiquitin-dependent degradation of peroxisome proliferation activated receptor gamma (PPARγ). Indeed, Hsp20 deficiency mimics and enhances the pharmacological effects of the PPARγ agonist rosiglitazone. Together, our findings suggest a role of Hsp20 in mediating adipocyte function by linking β-adrenergic signaling to PPARγ activity.

Keywords: FBXO4; Hsp20; PPARγ; lipogenesis; thermogenesis; ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Adipose Tissue, White / metabolism
  • Adiposity / drug effects
  • Animals
  • Cold Temperature
  • Energy Metabolism / drug effects
  • F-Box Proteins / metabolism*
  • Glucose / metabolism
  • HSP20 Heat-Shock Proteins / deficiency
  • HSP20 Heat-Shock Proteins / genetics
  • HSP20 Heat-Shock Proteins / metabolism*
  • Inflammation / pathology
  • Insulin Resistance
  • Lipid Metabolism / drug effects
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / pathology
  • PPAR gamma / metabolism*
  • Protein Stability / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rosiglitazone / pharmacology
  • Ubiquitination* / drug effects


  • F-Box Proteins
  • Fbx4 protein, mouse
  • HSP20 Heat-Shock Proteins
  • PPAR gamma
  • RNA, Messenger
  • Rosiglitazone
  • Glucose