Arashdeep Singh

Title of Research: Unravelling underlying mechanisms of Bardet-Biedl syndrome (BBS) phenotype

Additional Authors: N. Haq; S. Luckey; S.Mansouri; H.Gogoi; M. Yang; K. Rourk; L. Jin; S. Christou-Savina; G. de Lartigue

Abstract:

Bardet-Biedl syndrome (BBS) is a ciliopathic genetic disorder characterized by obesity, diabetes, and cognitive impairment. BBS genes are critical for receptor transport, therefore, we hypothesize that mutations in these genes cause dysregulated endocrine hormone signalling that may explain the symptomatic mechanisms.
We developed a new BBS5 knockout mouse (BBS5-/-) and discovered that it exhibits all the classic symptoms observed in BBS patients, including rampant hyperphagia, cognitive impairments, dysregulated glucose control, and 3-4 fold increased fat mass on chow diet compared to wildtype littermates. We observed increased proinflammatory macrophages and decreased regulatory T-cells in the adipocytes leading to chronic inflammation implicated in obesity pathogenesis. Unbiased transcriptomic analysis of the hypothalamus, a key brain region for energy homeostasis, revealed disruption of many critical endocrine receptors in BBS5-/- mice. Feeding experiments revealed resistance to both satiety peptides leptin and cholecystokinin, in-part explaining overeating and confirming the predicted neuroendocrine pathway dysfunction in BBS5-/- mice. The receptor for the satiety peptide glucagon-like-peptide-1 (GLP1) was uniquely found to be upregulated in the hypothalamus of BBS5-/- mice. Pharmacological administration of FDA-approved GLP1 receptor agonist effectively reduced food intake and body weight and thus could have a potential therapeutic.
Overall, BBS5-/- mice are a valuable new translational tool that has revealed a new putative therapeutic strategy for Bardet-Biedl syndrome.

 

About the author

Arashdeep SinghDr. Arashdeep Singh is a Postdoctoral Associate at the Department of Pharmacodynamics, University of Florida, USA. When What and Why we eat, and how that affects our metabolism define Dr. Singh’s scientific work. His research aims at studying the Neurobiology of the Vagal Gut-Brain Axis in regulating body weight and feeding behaviors in Dr. Guillaume de Lartigue’s lab. Dr. Singh loves multidisciplinary collaborations, and his research expertise is in the fields of Endocrinology, Gut Physiology, Gut Microbiota, and Metabolic Diseases.