Format

Send to

Choose Destination
Genes Dev. 2015 Jan 1;29(1):7-22. doi: 10.1101/gad.250829.114. Epub 2014 Dec 12.

Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers.

Author information

1
Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark;
2
Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark;
3
UMR 7277, Centre National de la Recherche Scientifique, U1091, Institut National de la Santé et de la Recherche Médicale, Institute of Biology Valrose, University Nice Sophia Antipolis, 06100 Nice, France;
4
Laboratory of Epigenetics and Chromatin Dynamics, Mayo Clinic, Rochester, Minnesota 55905, USA;
5
National Institute for Health Research, Oxford Biomedical Research Centre, OX3 7LE Oxford, United Kingdom.
6
Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark; s.mandrup@bmb.sdu.dk.

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.

KEYWORDS:

KLF11; PPARγ; browning of human adipocytes; genomic reprogramming; rosiglitazone; superenhancer

PMID:
25504365
PMCID:
PMC4281566
DOI:
10.1101/gad.250829.114
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center