Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

Kyeongjin Kim,Luca Valenti,Jin Ku Kang,Raffaela Rametta,Sang Bae Lee,Young Hoon Jung,Utpal B Pajvani,Paola Dongiovanni

doi:10.1038/s41467-021-22106-2

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.

Highlights

Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood
PHLPP1 and 2 proteins are highly expressed in white adipose tissue (WAT) and brown adipose tissue (BAT) depots[17]
We observed that visceral adipose PHLPP2 was positively associated with BMI in obese patients undergoing bariatric surgery (Supplementary Fig. 1b), with the caveat that there were no “lean” subjects given the nature of the experimental cohort

Summary

Introduction

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 found decreased PHLPP2 levels in the obese liver, which leads to unrestrained insulin action, excess de novo lipogenesis, and fatty liver[17,18] During these studies, we observed far higher expression of PHLPP2 in adipose than the liver or other tissues[17]; here, we find that adipocyte PHLPP2 is further increased in obese mice, suggesting that PHLPP2 may play an important role in adipocyte biology. Excess lipolysis is not detrimental to overall glucose and lipid homeostasis—adipocyte-specific PHLPP2 KO (A-PHLPP2) mice showed mildly improved glucose homeostasis, as well as a significant reduction in hepatic triglycerides, due to increased adipocyte PPARα activity, increased adiponectin secretion and hepatocyte fatty acid oxidation This signaling axis translates to patients as well, as adipose PHLPP2 levels negatively correlate with serum adiponectin. These data suggest that blocking excess adipocyte PHLPP2 may uncouple obesity from its metabolic comorbidities

Methods

Results

Conclusion