STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure

Nat Metab. 2021 Mar;3(3):428-441. doi: 10.1038/s42255-021-00362-2. Epub 2021 Mar 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism*
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, White / metabolism
  • Animals
  • Cell Line
  • Energy Metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Mitophagy*
  • Obesity / prevention & control
  • Obesity / therapy
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Serine-Threonine Kinase 3
  • Signal Transduction*

Substances

  • Intracellular Signaling Peptides and Proteins
  • STK4 protein, human
  • Protein Serine-Threonine Kinases
  • STK3 protein, human
  • Serine-Threonine Kinase 3