Lipid kinase PIK3C3 maintains healthy brown and white adipose tissues to prevent metabolic diseases

Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2214874120. doi: 10.1073/pnas.2214874120. Epub 2022 Dec 27.

Abstract

Adequate mass and function of adipose tissues (ATs) play essential roles in preventing metabolic perturbations. The pathological reduction of ATs in lipodystrophy leads to an array of metabolic diseases. Understanding the underlying mechanisms may benefit the development of effective therapies. Several cellular processes, including autophagy and vesicle trafficking, function collectively to maintain AT homeostasis. Here, we investigated the impact of adipocyte-specific deletion of the lipid kinase phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) on AT homeostasis and systemic metabolism in mice. We report that PIK3C3 functions in all ATs and that its absence disturbs adipocyte autophagy and hinders adipocyte differentiation, survival, and function with differential effects on brown and white ATs. These abnormalities cause loss of white ATs, whitening followed by loss of brown ATs, and impaired "browning" of white ATs. Consequently, mice exhibit compromised thermogenic capacity and develop dyslipidemia, hepatic steatosis, insulin resistance, and type 2 diabetes. While these effects of PIK3C3 largely contrast previous findings with the autophagy-related (ATG) protein ATG7 in adipocytes, mice with a combined deficiency in both factors reveal a dominant role of the PIK3C3-deficient phenotype. We have also found that dietary lipid excess exacerbates AT pathologies caused by PIK3C3 deficiency. Surprisingly, glucose tolerance is spared in adipocyte-specific PIK3C3-deficient mice, a phenotype that is more evident during dietary lipid excess. These findings reveal a crucial yet complex role for PIK3C3 in ATs, with potential therapeutic implications.

Keywords: PIK3C3/VPS34; adipocyte; autophagy; lipodystrophy; metabolic disease.

MeSH terms

  • Adipocytes / metabolism
  • Adipocytes, Brown / metabolism
  • Adipose Tissue, Brown / metabolism
  • Animals
  • Class III Phosphatidylinositol 3-Kinases / genetics
  • Class III Phosphatidylinositol 3-Kinases / metabolism
  • Diabetes Mellitus, Type 2* / metabolism
  • Insulin Resistance*
  • Lipids
  • Mice

Substances

  • Class III Phosphatidylinositol 3-Kinases
  • Lipids
  • PIK3C3 protein, mouse