Control of molecular 'doormen' in fat cells offers potential new obesity treatment

By Samantha Black, PhD, ScienceBoard editor in chief

January 10, 2020 -- New treatment options for obesity could emerge from a study published in Nature Communications on January 10. Researchers from Yale University School of Medicine utilized cellular and molecular approaches to identify pathways to restore the healthy balance of fat cells.

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.


Do you have a unique perspective on your research related to metabolism or obesity research? Contact the editor today to learn more.

---

Join The Science Advisory Board today!


Precision medicine and molecular understanding of illness
The current era of scientific research is seen by many as a golden age of discovery in genetics, due to rapid progress in numerous areas of science and...
Researchers use drug repurposing to identify new treatment for Metabolic Syndrome
A research team from the University of Trento find a novel method for using old drugs in new ways, specifically for Metabolic Syndrome. This revolutionary...
Global Collaboration Launched for Large-Scale DNA Study Exploring Connection Between Genetics and Disease
A new partnership was announced between Intermountain Healthcare and deCODE Genetics to collaborate on the largest DNA mapping effort undertaken in the...

Copyright © 2020 scienceboard.net


Conferences
Connect
Science Advisory Board on LinkedIn
Science Advisory Board on Facebook
Science Advisory Board on Twitter