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Autophagy-related protein PIK3C3 maintains healthy brown and white adipose tissues to prevent metabolic diseases

ABSTRACT: 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.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Adipose Tissue

DISEASE(S): Diabetes

SUBMITTER: Katrina Leaptrot

PROVIDER: ST002268 | MetabolomicsWorkbench | Fri Aug 26 00:00:00 BST 2022

REPOSITORIES: MetabolomicsWorkbench

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Project description:Purpose: To investigate alterations in subcutaneous white adipose gene expression induced by genetic AMPK activation in vivo, in mice fed a chow or a high-fat diet. Methods: Subcutaneous white adipose tissue mRNA profiles of wild-type transgenic (WT-Tg) mice and mice expressing a gain-of-function AMPK mutant gamma1 subunit (D316A-Tg) were generated by deep sequencing. Results: RNA sequencing revealed over 3000 differentially expressed genes between WT-Tg and D316A-Tg subcutaneous white adipose tissue (WATsc) from mice fed a high fat diet (HFD), of which many were classified as 'skeletal muscle-associated'. Interestingly, uncoupling protein 1 (UCP1), associated with 'beige' adipocyte formation in WATsc, was not differentially expressed. On a chow diet, many differentially expressed genes were also identified, with gene ontology analysis identifiying glycolysis, TCA cycle and brown fat differentiation as highly enriched; key features of brown adipocyte identity. HFD-associated skeletal-muscle associated gene expression was either not significantly altered, or significantly down-regulated on a chow diet, indicating a diet-induced gene signature in D316A-Tg WATsc. Conclusions: Our study revealed gene signatures indicative of brown adipocyte development on a chow diet, where no overt metabolic phenotype was observed in gain-of-function animals. When fed a HFD, WATsc from D316A-Tg mice displayed a muscle-like gene signature, expressing key components of creatine and calcium thermogenic cycles including Ckmt2 (creatine kinase, mitochondrial 2) Atp2a1 (SERCA1-sarco/endoplasmic reticulum ATPase 1) and ryr1 (ryanodine receptor 1). UCP1 expression was not altered between WT-Tg and D316A-Tg mice fed a HFD. Our findings suggest a novel role for AMPK in the regulation of white adipocyte identity and a potentially novel cell population that, when metabolically challenged, preferrentially utilise muscle-like thermogenic futile cycles independent of UCP1 to mediate whole organism energy expenditure.

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Autophagy-related protein PIK3C3 maintains healthy brown and white adipose tissues to prevent metabolic diseases

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