Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Adipocytes, Brown / cytology
  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cellular Reprogramming
  • Chromatin / metabolism
  • Gene Expression Regulation
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Mitochondria / drug effects
  • Oxidation-Reduction
  • PPAR gamma / genetics*
  • PPAR gamma / metabolism*
  • Protein Binding
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Rosiglitazone
  • Thiazolidinediones / pharmacology
  • Transcriptional Activation / drug effects

Substances

  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins
  • Chromatin
  • Hypoglycemic Agents
  • KLF11 protein, human
  • PPAR gamma
  • Repressor Proteins
  • Thiazolidinediones
  • Rosiglitazone