PR001450 (Project)

Description:Adequate mass and function of adipose tissues (ATs) play an essential role in preventing metabolic perturbations. 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, function collectively to maintain AT homeostasis. Here, we investigated the impact of adipocyte-specific deletion of the autophagy-related lipid kinase 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 caused loss of white ATs, whitening followed by loss of brown ATs, and impaired browning of white ATs. Consequently, mice exhibited compromised thermogenic capacity and developed dyslipidemia, hepatic steatosis, insulin resistance and type 2 diabetes. While these effects of PIK3C3 contrast previous findings with the autophagy-related protein ATG7 in adipocytes, mice with a combined deficiency in both factors revealed a dominant role of the PIK3C3-deficient phenotype. We also found that dietary lipid excess exacerbates AT pathologies caused by PIK3C3 deficiency. Surprisingly, glucose tolerance was spared in adipocyte-specific PIK3C3-deficient mice, a phenotype that was more evident during dietary lipid excess. These findings reveal a crucial yet complex role for PIK3C3 in ATs and suggest the potential of targeting this factor for therapeutic intervention in metabolic diseases.