Medical College of Wisconsin
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Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers. Genes Dev 2015 Jan 01;29(1):7-22

Date

12/17/2014

Pubmed ID

25504365

Pubmed Central ID

PMC4281566

DOI

10.1101/gad.250829.114

Scopus ID

2-s2.0-84920403959 (requires institutional sign-in at Scopus site)   132 Citations

Abstract

Long-term exposure to peroxisome proliferator-activated receptor γ (PPARγ) agonists such as rosiglitazone induces browning of rodent and human adipocytes; however, the transcriptional mechanisms governing this phenotypic switch in adipocytes are largely unknown. Here we show that rosiglitazone-induced browning of human adipocytes activates a comprehensive gene program that leads to increased mitochondrial oxidative capacity. Once induced, this gene program and oxidative capacity are maintained independently of rosiglitazone, suggesting that additional browning factors are activated. Browning triggers reprogramming of PPARγ binding, leading to the formation of PPARγ "superenhancers" that are selective for brown-in-white (brite) adipocytes. These are highly associated with key brite-selective genes. Based on such an association, we identified an evolutionarily conserved metabolic regulator, Kruppel-like factor 11 (KLF11), as a novel browning transcription factor in human adipocytes that is required for rosiglitazone-induced browning, including the increase in mitochondrial oxidative capacity. KLF11 is directly induced by PPARγ and appears to cooperate with PPARγ in a feed-forward manner to activate and maintain the brite-selective gene program.

Author List

Loft A, Forss I, Siersbæk MS, Schmidt SF, Larsen AS, Madsen JG, Pisani DF, Nielsen R, Aagaard MM, Mathison A, Neville MJ, Urrutia R, Karpe F, Amri EZ, Mandrup S

Author

Angela Mathison PhD Associate Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adipocytes
Adipocytes, Brown
Apoptosis Regulatory Proteins
Cell Cycle Proteins
Cellular Reprogramming
Chromatin
Gene Expression Regulation
Humans
Hypoglycemic Agents
Mitochondria
Oxidation-Reduction
PPAR gamma
Protein Binding
Repressor Proteins
Thiazolidinediones
Transcriptional Activation