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

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.

Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2

“…This is an interesting finding in light of the hypothesis put forth by Gupta et al (2017) that HFD adaptation in islets is preceded (Hart and Akimoto, 2009), many of which (e.g., Pdx1 and Hnf1a) fall into the lower molecular weight range that was particular sensitive to obesity-precipitated increases in O-GlcNAcylation. In non-islet tissues, O-GlcNAcylation has been increasingly linked to aspects of intracellular lipid metabolism, including the regulation of lipid droplet formation (Keembiyehetty et al, 2011), fatty acid uptake in the heart (Laczy et al, 2011), lipid synthesis and b-oxidation in the liver (Ido-Kitamura et al, 2012;Ruan et al, 2012), and adipocytes (Li et al, 2018;Luo et al, 2007;Yang et al, 2020). The current study supports and extends an emerging role for OGT in lipid sensing and lipid metabolic regulation.…”

Protein O-GlcNAc Modification Links Dietary and Gut Microbial Cues to the Differentiation of Enteroendocrine L Cells

“…To extend these findings in vivo , we then specifically overexpressed OGT in intestinal epithelial cells by crossing Villin-Cre with a mouse line harboring an inducible rat OGT transgene in the Rosa26 locus ( Yang et al, 2020 ; Figure 3C ). qRT-PCR showed that expression of the rat Ogt gene was significantly up-regulated in intestinal tissues ( Figure 3D ).…”

“…Ogt-floxed mice ( Shafi et al, 2000 ) and Rosa26-rOGT-floxed on the C57BL/6 background were kindly provided by Dr. Xiaoyong Yang ( Yang et al, 2020 ). Villin-Cre mice (stock no.…”

Role of O‐linked N‐acetylglucosamine in the homeostasis of metabolic organs, and its potential links with diabetes and its complications

“…The role of O‐GlcNAcylation in the balance between these processes has been shown by studies of adipose tissue‐specific genetic models. An increase in O‐GlcNAcylation, induced by overexpression of Ogt in adipose tissue, inhibits lipolysis and promotes diet‐induced obesity, whereas the disruption O‐GlcNAcylation in adipose tissue by Ogt knockout promotes lipolysis by stimulating perilipin activity by phosphorylation (Figure 2) 27 . In addition, high O‐GlcNAcylation in adipocytes induces hyperphagia by transcriptionally activating genes that mediate de novo lipid desaturation through the accumulation of N‐arachidonoylethanolamine, an appetite‐inducing cannabinoid 28 .…”