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.
Bibliographical noteFunding 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.
© 2017 Elsevier Inc.
- beige adipocytes
- cellular aging
- cold exposure
- mural cells