PPARγ agonists Induce a White-to-Brown Fat Conversion through Stabilization of PRDM16 Protein

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 brow...

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Bibliographic Details
Published in:Cell metabolism 2012-03, Vol.15 (3), p.395-404
Main Authors: Ohno, Haruya, Shinoda, Kosaku, Spiegelman, Bruce M., Kajimura, Shingo
Format: Article
Language:English
Subjects:
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
Sulfides - pharmacology
Thiazolidinediones - pharmacology
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary: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. [Display omitted] ► PPARγ full agonists induce a brown fat phenotype in subcutaneous WAT ► PRDM16 is required for the development of PPARγ agonist-inducible brow adipocytes ► PRDM16 and PPARγ agonists synergistically activate the brown fat gene program ► Browning effect is mediated through the enhanced stability of the PRDM16 protein
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2012.01.019