O-GlcNAc transferase inhibits visceral fat lipolysis and promotes diet-induced obesity

Yunfan Yang,Min-Dian Li,Simeng Wang,Yuyang Liu,Qunxiang Ong,Jia Mi,Kaisi Zhang,Minnie Fu,Weiming Ni,Xiaoyong Yang,Bichen Zhang

doi:10.1038/s41467-019-13914-8

Abstract

Excessive visceral fat accumulation is a primary risk factor for metabolically unhealthy obesity and related diseases. The visceral fat is highly susceptible to the availability of external nutrients. Nutrient flux into the hexosamine biosynthetic pathway leads to protein posttranslational modification by O-linked β-N-acetylglucosamine (O-GlcNAc) moieties. O-GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Here, we report that inducible deletion of adipose OGT causes a rapid visceral fat loss by specifically promoting lipolysis in visceral fat. Mechanistically, visceral fat maintains a high level of O-GlcNAcylation during fasting. Loss of OGT decreases O-GlcNAcylation of lipid droplet-associated perilipin 1 (PLIN1), which leads to elevated PLIN1 phosphorylation and enhanced lipolysis. Moreover, adipose OGT overexpression inhibits lipolysis and promotes diet-induced obesity. These findings establish an essential role for OGT in adipose tissue homeostasis and indicate a unique potential for targeting O-GlcNAc signaling in the treatment of obesity.

Highlights

Excessive visceral fat accumulation is a primary risk factor for metabolically unhealthy obesity and related diseases
To determine the role of O-GlcNAc transferase (OGT) in adult adipose tissue homeostasis, we generated OGT adipose-specific knockout (AKO) mice by crossing a strain of mice harboring floxed alleles of Ogt with another strain in which the expression CreER, a tamoxifeninducible Cre recombinase, is under the control of the adiponectin promoter (Fig. 1a). This model allowed for the depletion of OGT in various adipose depots, including interscapular brown adipose tissue (BAT), subcutaneous inguinal white adipose tissue, and visceral epididymal white adipose tissue in adult mice (Fig. 1b)
The knockout efficiency of Ogt in BAT, inguinal white adipose tissue (iWAT), and epididymal white adipose tissue (eWAT) after tamoxifen administration was determined by quantitative real-time PCR (RT-PCR) analysis and Western blot analysis (Supplementary Fig. 1a, b and Fig. 1c)

Summary

Introduction

Excessive visceral fat accumulation is a primary risk factor for metabolically unhealthy obesity and related diseases. Once considered a passive lipid storage depot, adipose tissue is known to have enormous plasticity and is capable of adapting its size, phenotype, and metabolic functions to nutrient availability[11,12,13,14] These dynamics enable adipose tissue to store excess nutrients as fat and to provide energy by releasing fat through lipolysis. Loss of adipose OGT promotes lipolysis in visceral fat by decreasing O-GlcNAcylation and promoting phosphorylation of lipid droplet-associated PLIN1, while overexpression of adipose OGT inhibits adipose tissue lipolysis and promotes diet-induced obesity and wholebody insulin resistance. Our analyses suggest that enhanced adipose O-GlcNAc signaling is a molecular signature for obesity and diabetes in humans These data reveal an essential role for OGT in lipolysis regulation and indicate a unique potential for targeting O-GlcNAc signaling to combat metabolically unhealthy obesity

Methods

Results

Conclusion