Abstract

Obesity and type 2 diabetes are major global health challenges, affecting millions of individuals. These conditions also frequently occur in rare genetic disorders such as Alström Syndrome, which is caused by mutations in the ALMS1 gene. Like many other obesity-associated genes, ALMS1 encodes a protein that localizes to a vital cellular structure known as the primary cilium—an antenna-like organelle crucial for cellular communication.

Primary cilia are present on many cell types, including neurons, and serve as key hubs for signaling. Recent studies from our lab and others have shown that loss of cilia in specific regions of the hypothalamus leads to overeating and obesity in mice, underscoring the essential role of neuronal cilia in regulating body weight. Intriguingly, several signaling receptors involved in energy homeostasis are concentrated at neuronal cilia. A notable example is the Melanocortin-4 Receptor (MC4R), a ciliary receptor whose mutations are the leading cause of monogenic obesity.

The central aim of my proposed study is to define the molecular function of ALMS1, investigate its contribution to primary cilia in vivo, and uncover the mechanisms by which its dysfunction leads to obesity in Alström Syndrome. To achieve this, I will employ a multidisciplinary approach combining molecular and cell biology techniques with genetically engineered animal models of obesity. My long-term research goal is to advance our understanding of how cells build and maintain their primary cilia, and to define core principles that guide the localization of essential signaling receptors—such as MC4R—to these structures.