STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure

Yoon Keun Cho, Yeonho Son, Abhirup Saha, Doeun Kim, Cheoljun Choi, Minsu Kim, Ji Hyun Park, Hyeonyeong Im, Juhyeong Han, Kyungmin Kim, Young Suk Jung, Jeanho Yun, Eun Ju Bae, Je Kyung Seong, Mi Ock Lee, Sangkyu Lee, James G. Granneman, Yun Hee Lee

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Obesity reduces adipocyte mitochondrial function, and expanding adipocyte oxidative capacity is an emerging strategy to improve systemic metabolism. Here, we report that serine/threonine-protein kinase 3 (STK3) and STK4 are key physiological suppressors of mitochondrial capacity in brown, beige and white adipose tissues. Levels of STK3 and STK4, kinases in the Hippo signalling pathway, are greater in white than brown adipose tissues, and levels in brown adipose tissue are suppressed by cold exposure and greatly elevated by surgical denervation. Genetic inactivation of Stk3 and Stk4 increases mitochondrial mass and function, stabilizes uncoupling protein 1 in beige adipose tissue and confers resistance to metabolic dysfunction induced by high-fat diet feeding. Mechanistically, STK3 and STK4 increase adipocyte mitophagy in part by regulating the phosphorylation and dimerization status of the mitophagy receptor BNIP3. STK3 and STK4 expression levels are elevated in human obesity, and pharmacological inhibition improves metabolic profiles in a mouse model of obesity, suggesting STK3 and STK4 as potential targets for treating obesity-related diseases.

Original languageEnglish
Pages (from-to)428-441
Number of pages14
JournalNature Metabolism
Volume3
Issue number3
DOIs
Publication statusPublished - 2021 Mar

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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