The Dysfunctional MDM2-p53 Axis in Adipocytes Contributes to Ageing Related Metabolic Complications by Induction of Lipodystrophy

Zhuohao Liu, Leigang Jin, Jin-Kui Yang, Baile Wang, Kelvin Kl Wu, Philip Hallenborg, Aimin Xu, Kenneth Ky Cheng

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Profound loss and senescence of adipose tissues are hallmarks of advanced age, but the underlying cause and their metabolic consequences remain obscure. Proper function of the murine double minute 2 (MDM2)-p53 axis is known to prevent tumorigenesis and several metabolic diseases, yet its role in regulation of adipose tissue aging is still poorly understood. In this study, we show that the proximal p53 inhibitor MDM2 is markedly downregulated in subcutaneous white and brown adipose tissues of mice during aging. Genetic disruption of MDM2 in adipocytes triggers canonical p53-mediated apoptotic and senescent programs, leading to age-dependent lipodystrophy and its associated metabolic disorders, including type 2 diabetes, nonalcoholic fatty liver disease, hyperlipidemia, and energy imbalance. Surprisingly, this lipodystrophy mouse model also displays premature loss of physiological integrity, including impaired exercise capacity, multiple organ senescence, and shorter life span. Transplantation of subcutaneous fat rejuvenates the metabolic health of this aging-like lipodystrophy mouse model. Furthermore, senescence-associated secretory factors from MDM2-null adipocytes impede adipocyte progenitor differentiation via a non-cell-autonomous manner. Our findings suggest that tight regulation of the MDM2-p53 axis in adipocytes is required for adipose tissue dynamics and metabolic health during the aging process.

Original languageEnglish
JournalDiabetes
Volume67
Issue number11
Pages (from-to)2397-2409
ISSN0046-0192
DOIs
Publication statusPublished - Nov 2018

Keywords

  • Adipocytes/metabolism
  • Aging/metabolism
  • Animals
  • Calorimetry, Indirect
  • Down-Regulation
  • Energy Metabolism/genetics
  • Glucose Tolerance Test
  • Lipodystrophy/metabolism
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-mdm2/genetics
  • Tumor Suppressor Protein p53/genetics

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