Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

KyeongJin Kim (), Jin Ku Kang, Young Hoon Jung, Sang Bae Lee, Raffaela Rametta, Paola Dongiovanni, Luca Valenti and Utpal B. Pajvani ()
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KyeongJin Kim: Columbia University
Jin Ku Kang: Columbia University
Young Hoon Jung: Inha University
Sang Bae Lee: Jeonbuk National University
Raffaela Rametta: Università degli Studi di Milano
Paola Dongiovanni: Università degli Studi di Milano
Luca Valenti: Università degli Studi di Milano
Utpal B. Pajvani: Columbia University

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

Date: 2021
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DOI: 10.1038/s41467-021-22106-2

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