Directors' Report

January 2024 

A Human Syndrome Provides Clues on Obesity

Bardet-Biedl syndrome (BBS for short) is a human genetic disorder that affect many parts of the body. Obesity is one of the major features of BBS. Excess fat accumulation typically begins in early childhood and continues to be an issue throughout life. Consequently, BBS patients suffer from complications of obesity that include type 2 diabetes.

Dr. Kamal Rahmouni, FOEDRC co-director, and his laboratory have been at the forefront of research aimed at understanding why do BBS patients develop obesity and diabetes. His work has led to the identification of an important role for the genes and proteins that underlie Bardet-Biedl syndrome.  A recent publication from his lab showed that selective deletion of one of the BBS genes (BBS1) in very small number of neurons of a tiny region in the brain called the hypothalamus leads to an increase in body weight and fat accumulation in mice. These mice also developed hallmarks of type 2 diabetes such as insulin resistance and inability to clear glucose from the blood. To understand the molecular causes of these metabolic alterations, the team combined various molecular techniques to reveal an important role for the proteins encoded by BBS genes in helping other proteins to get where they belong within cells. In particular, BBS proteins were found to be necessary to equip neurons with sensors that detect signals about energy status. Thus, absence of BBS proteins makes the neurons blind to what is happening in the body because these cells become unable to detect signals about energy status that emanate from the blood or other cells around them. This could be thought as similar to a car losing its fuel gage. As a consequence, these neurons think that the body is out of energy. As a consequence, the neurons activate biological processes that promote hunger, food intake and reduces energy expenditure to increase energy reserves in the form of fat. This defect explain why Bardet-Biedl syndrome patients develop severe obesity and why it manifests in early childhood. The molecular mechanism uncovered by Dr. Rahmouni and his team represent a new way by which obesity can develop. Ongoing research in his lab is aimed at understanding the relevance of these findings to common obesity and associated diseases including type 2 diabetes.

It should be noted that the work reported in the recent publication from the Rahmouni lab represent a teamwork involving many trainees including Dr. Paul Williams who is funded by the FOEDRC NIH T32 diabetes research training grant.