Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers

Anne Loft, Isabel Forss, Majken Storm Siersbæk, Søren Fisker Schmidt, Ann-Sofie Bøgh Larsen, Jesper Grud Skat Madsen, Didier F Pisani, Ronni Nielsen, Mads Malik Aagaard, Angela Mathison, Matt J Neville, Raul Urrutia, Fredrik Karpe, Ez-Zoubir Amri, Susanne Mandrup

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Abstract

Long-term exposure to peroxisome proliferator-activated receptor g (PPARg) 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 PPARg binding, leading to the formation of PPARg ‘‘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 PPARg and appears to cooperate with PPARg in a feed-forward manner to activate and maintain the brite-selective gene program.

Original languageEnglish
JournalGenes & Development
Volume29
Issue number1
Pages (from-to)7-22
ISSN0890-9369
DOIs
Publication statusPublished - 2015

Keywords

  • Browning of human adipocytes
  • Genomic reprogramming
  • KLF11
  • PPARγ
  • Rosiglitazone
  • Superenhancer

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