Specifically, the group found that suppressing O-linked β-N-acetylglucosamine (O-GlcNAc) signaling over a short period of time may serve as a strategy to selectively target obesity.

Previous research has demonstrated that intra-abdominal visceral fat is strongly correlated to obesity-related diseases. However, the molecular and cellular mechanisms underlying the regulation of visceral fat are poorly understood.

Moreover, dysregulation of O-GlcNAc as part of the hexosamine biosynthetic pathway (branch of glycolysis) is linked to perturbed fat storage. O-GlcNAc signaling is controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase. Therefore, the researchers wanted to explore the role of O-GlcNAc signaling in regulating adipose tissue dynamics in response to nutrient availability.

Perilipins are a family of proteins that associate with the surface of lipid droplets (lipid-rich cellular organelles) in fat cells. These "doormen" act as a natural barrier to protect against lipolysis. The phosphorylation of perilipins exposes stored lipids for breakdown. In obese individuals, perilipin expression is elevated.

Understanding the role of OGT

Using the inducible deletion system, the researchers found that the primary role of OGT in adipose tissue is blocking lipolysis in visceral fat. They provided evidence using knockout mice that in the absence of OGT, rapid loss of visceral fat occurs and the cells are sensitized to lipolytic stimulation. Alternatively, overexpression of OGT in adipose tissues inhibited lipolysis and promoted the accumulation of fat.

Therefore, the team suggests that suppressing O-GlcNAc signaling over a short period of time may serve as a strategy to selectively target obesity.

Restoring healthy balance

A gene therapy approach was also explored in this study. O-GlcNAcylation sites on lipid droplet-associated perilipin 1 (PLIN1) related to the regulation of lipolysis were identified using computational prediction programs. Measuring gene expression levels of lipolysis regulators showed that the S492A/S517A mutation decreased overall PLIN1 O-GlcNAcylation by approximately 60%. Overall, the research supports a model where OGT inhibition stimulates lipolysis by catalyzing PLIN1 O-GlcNAcylation at S492 and S517 and suppressing PLIN1 phosphorylation.

These results make "OGT a very attractive target to pharmaceutically treat obesity," said senior author Xiaoyong Yang, PhD, an associate professor at Yale University School of Medicine.

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