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Cell Metab. 2017 Jan 10;25(1):166-181. doi: 10.1016/j.cmet.2016.10.023. Epub 2016 Nov 23.

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

Author information

1
Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: daniel.berry@utsouthwestern.edu.
2
Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA.
3
Lillehei Heart Institute, University Minnesota, Minneapolis, MN 55455, USA; Department of Medicine, University Minnesota, Minneapolis, MN 55455, USA.
4
Division of Metabolic Mechanisms of Disease in the Advanced Imaging Research Center and Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
5
Department of Radiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
6
Lillehei Heart Institute, University Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University Minnesota, Minneapolis, MN 55455, USA.
7
Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jon.graff@utsouthwestern.edu.

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.

KEYWORDS:

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

PMID:
27889388
PMCID:
PMC5226893
DOI:
10.1016/j.cmet.2016.10.023
[Indexed for MEDLINE]
Free PMC Article

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