PPARγ Agonists Induce a White-To-Brown Fat Conversion Through Stabilization of PRDM16 Protein

Cell Metab. 2012 Mar 7;15(3):395-404. doi: 10.1016/j.cmet.2012.01.019.

Abstract

Brown adipose tissue dissipates energy through heat and functions as a defense against cold and obesity. PPARγ ligands have been shown to induce the browning of white adipocytes; however, the underlying mechanisms remain unclear. Here, we show that PPARγ ligands require full agonism to induce a brown fat gene program preferentially in subcutaneous white adipose. These effects require expression of PRDM16, a factor that controls the development of classical brown fat. Depletion of PRDM16 blunts the effects of the PPARγ agonist rosiglitazone on the induced brown fat gene program. Conversely, PRDM16 and rosiglitazone synergistically activate the brown fat gene program in vivo. This synergy is tightly associated with an increased accumulation of PRDM16 protein, due in large measure to an increase in the half-life of the protein in agonist treated cells. Identifying compounds that stabilize PRDM16 protein may represent a plausible therapeutic pathway for the treatment of obesity and diabetes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue, Brown / drug effects
  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism*
  • Animals
  • Blotting, Western
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Indoles / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxygen Consumption / drug effects
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism*
  • Protein Stability / drug effects
  • Rosiglitazone
  • Sulfides / pharmacology
  • Thiazolidinediones / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • 5-chloro-1-(4-chlorobenzyl)-3-(phenylthio)indole-2-carboxylic acid
  • DNA-Binding Proteins
  • Indoles
  • PPAR gamma
  • Prdm16 protein, mouse
  • Sulfides
  • Thiazolidinediones
  • Transcription Factors
  • Rosiglitazone

Associated data

  • GEO/GSE35011