Obesity resistance and increased energy expenditure by white adipose tissue browning in Oga +/- mice

Abstract

Aims/hypothesis O-GlcNAcylation plays a role as a metabolic sensor regulating cellular signalling, transcription and metabolism. Transcription factors and signalling pathways related to metabolism are modulated by N-acetyl-glucosamine (OGlcNAc) modification. Aberrant regulation of OGlcNAcylation is closely linked to insulin resistance, type 2 diabetes and obesity. Current evidence shows that increased O-GlcNAcylation negatively regulates insulin signalling, which is associated with insulin resistance and type 2 diabetes. Here, we aimed to evaluate the effects of Oga (also known as Mgea5) haploinsufficiency, which causes hyper-OGlcNAcylation, on metabolism. Methods We examined whether Oga +/-mice developed insulin resistance. Metabolic variables were determined including body weight, glucose and insulin tolerance, metabolic rate and thermogenesis. Results Oga deficiency does not affect insulin signalling even at hyper-O-GlcNAc levels. Oga +/-mice are lean with reduced fat mass and improved glucose tolerance. Furthermore, Oga +/-mice resist high-fat diet-induced obesity with ameliorated hepatic steatosis and improved glucose metabolism. Oga haploinsufficiency potentiates energy expenditure through the enhancement of brown adipocyte differentiation from the stromal vascular fraction of subcutaneous white adipose tissue (WAT). Conclusions/interpretation Our observations suggest that O-GlcNAcase (OGA) is essential for energy metabolism via regulation of the thermogenic WAT program.

Memory and synaptic plasticity are impaired by dysregulated hippocampal O-GlcNAcylation

“…The different experimental designs might have resulted in conflicting results. Previously, the discrepancy in the effect of dysregulated O-GlcNAcylation was also observed in other intracellular signaling pathways and physiological functions333438. Despite this discrepancy, earlier studies suggest that dysregulated O-GlcNAcylation can affect synaptic plasticity.…”

Invalidation of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Reduces Diet-Induced Low-Grade Inflammation and Adiposity

“…Recent evidence has demonstrated that WAT can adopt a brown-like adipose tissue phenotype known as browning of WAT. This browning process is a potential new target for treating obesity and explains the resistance of different mice strains to diet-induced obesity ( Wan et al, 2012 ; Schneider et al, 2016 ) by increasing non-shivering thermogenesis and enhancing EE ( Yang et al, 2015 ; Choi et al, 2016 ). Some studies highlighted that PGE2 can activate the trans-differentiation of white adipocytes, into brown adipocytes, in both human and mice ( García-Alonso et al, 2013 ; García-Alonso et al, 2016 ).…”

Mitochondria in White, Brown, and Beige Adipocytes

“…Taken together, although mitochondria in the brown fat are mainly acknowledged as important regulators of thermogenesis and those in the white fat as providers of constituents essential for lipogenesis, recent evidence suggests that mitochondria in adipose tissues might play plentiful roles in the regulation of the whole body energy homeostasis, crosstalk between adipose tissues and striated muscle, or control of insulin sensitivity and glucose metabolism [ 87 – 90 ].…”