Cellular Aging Contributes to Failure of Cold-Induced Beige Adipocyte Formation in Old Mice and Humans

Daniel C. Berry, Yuwei Jiang, Robert W. Arpke, Elizabeth L. Close, Aki Uchida, David Reading, Eric D. Berglund, Michael Kyba, Jonathan M. Graff

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Cold temperatures induce progenitor cells within white adipose tissue to form beige adipocytes that burn energy and generate heat; this is a potential anti-diabesity therapy. However, the potential to form cold-induced beige adipocytes declines with age. This creates a clinical roadblock to potential therapeutic use in older individuals, who constitute a large percentage of the obesity epidemic. Here we show that aging murine and human beige progenitor cells display a cellular aging, senescence-like phenotype that accounts for their age-dependent failure. Activating the senescence pathway, either genetically or pharmacologically, in young beige progenitors induces premature cellular senescence and blocks their potential to form cold-induced beige adipocytes. Conversely, genetically or pharmacologically reversing cellular aging by targeting the p38/MAPK-p16Ink4a pathway in aged mouse or human beige progenitor cells rejuvenates cold-induced beiging. This in turn increases glucose sensitivity. Collectively, these data indicate that anti-aging or senescence modalities could be a strategy to induce beiging, thereby improving metabolic health in aging humans.

Original languageEnglish (US)
Pages (from-to)166-181
Number of pages16
JournalCell Metabolism
Volume25
Issue number1
DOIs
StatePublished - Jan 10 2017

Bibliographical note

Funding Information:
This study was supported by grants to J.M.G. from the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Disease ( R01 DK066556 , R01 DK064261 , and R01 DK088220 ). D.C.B. is supported by the National Institute of Diabetes and Digestive and Kidney Disease grant K01 DK109027 . Correspondence and requests for materials should be addressed to D.C.B. and J.M.G. J.M.G. is a co-founder and shareholder of Reata Pharmaceuticals.

Keywords

  • Ink4a/Arf
  • adipose
  • beige adipocytes
  • cellular aging
  • cold exposure
  • mural cells
  • senescence
  • thermogenesis

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