Researchers have found that a specific molecule regulates stress-induced inflammatory responses in obese visceral fat — the type of fat that wraps around internal organs.
This key finding could offer new potential therapeutic targets against obesity. The study, “The obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation,” was published in the journal Nature Communications.
While it has long been known that visceral fat is associated with metabolic syndromes, insulin resistance, and increased risk of death when compared to subcutaneous fat (which lies just beneath the skin), the molecular mechanism underlying the damaging effect of visceral fat has been largely unknown.
Now, a team of researchers at the College of Medicine at University of Illinois in Chicago identified the responsible molecule, called TRIP-Br2. In a previous study, the team, led by Chong Wee Liew, assistant professor of physiology and biophysics in the College of Medicine, University of Illinois, discovered that TRIP-Br2 expression was up-regulated specifically in the visceral fat of obese individuals.
To understand the biological relevance of TRIP-Br2, researchers engineered TRIP-Br2 knock-out mice (mice deleted for the TRIP-Br2 gene). When fed a high-fat diet, TRIP-Br2 knock-out mice maintained normal weight, and were free of insulin resistance and inflammation.
“TRIP-Br2 appears to block or prevent normal lipolysis,” Liew said in a press release. Lipolysis is the breakdown of fat stored in cells’ lipid droplets.
“Without TRIP-Br2, lipolysis and oxidative metabolism take place at an increased rate, so fat is broken down and quickly used as energy and does not have a chance to build up in organs like the liver,” Liew said.
The team discovered why TRIP-Br2 is up-regulated specifically in visceral fat and not in subcutaneous fat. In obese people, a key organelle called endoplasmic reticulum (ER) becomes stressed with overeating – an excess of flux of nutrients enters cells, which poses a huge effort on the ER, leading to accumulation of damaging proteins inside it, a condition known as ER stress.
In obese visceral fat cells, a stressed ER leads to the production of inflammatory cytokines. However, in TRIP-Br2 knock-out mice, the stressed ER is blocked from triggering inflammatory cytokine production.
Researchers also found that the transcription factor GATA3 is responsible for the ER stress-induced TRIP-Br2 expression in visceral fat.
“Together, our findings indicate that these molecular regulators, TRIP-Br2 and GATA3, could be viable targets for small drug molecules that could serve as potential therapeutic agents against obesity,” Liew said.
