title: Cellular Aging Contributes to Failure of Cold-Induced Beige Adipocyte Formation in Old Mice and Humans.
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-p16Ink4apathway 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.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: daniel.berry@utsouthwestern.edu.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Berry
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Lillehei Heart Institute, University Minnesota, Minneapolis, MN 55455, USA; Department of Medicine, University Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Arpke
authors.affiliation: Division of Metabolic Mechanisms of Disease in the Advanced Imaging Research Center and Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Close
authors.affiliation: Division of Metabolic Mechanisms of Disease in the Advanced Imaging Research Center and Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Aki
authors.initials: A
authors.lastname: Uchida
authors.affiliation: Department of Radiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: David
authors.initials: D
authors.lastname: Reading
authors.affiliation: Division of Metabolic Mechanisms of Disease in the Advanced Imaging Research Center and Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Berglund
authors.affiliation: Lillehei Heart Institute, University Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.affiliation: 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.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Graff
mesh_terms: D000199:Actins / Q000378:metabolism; D000069797:Adipocytes, Beige / Q000166:cytology* / Q000378:metabolism*; D000375:Aging / Q000502:physiology*; D000818:Animals; D016922:Cellular Senescence; D003080:Cold Temperature; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D010641:Phenotype; D013234:Stem Cells / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C544013:alpha-smooth muscle actin, mouse; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Ink4a/Arf; adipose; beige adipocytes; cellular aging; cold exposure; mural cells; senescence; thermogenesis