Leptin resistance in mouse models of hyperphagia

By: Rachel Wevrick, Ph.D.

Department of Medical Genetics, University of Alberta 

Hypothesis: They hypothesize that leptin receptor (LepR) signaling defects cause congenital leptin  resistance in PWS hypothalamic neurons, preceding obesity and contributing to hyperphagia and obesity in PWS and similar genetic disorders such as Bardet-Biedl syndrome. The insensitivity to multiple hormones signaling energy needs (e.g. ghrelin) and broader phenotypes of PWS suggests

that more complex processes are additionally affected in PWS, also because of defective intracellular signaling pathways that may overlap with the leptin response pathways in the brain. 

Aim: To examine leptin sensitivity in murine models of PWS and related disorders, including mice carrying targeted inactivation of the Snord116/MBII-85, necdin, and Magel2 PWS candidate genes, the Smith Magenis gene Rai1, and BBS genes. The long-term goal is to determine whether defective LepR signaling is responsible for hyperphagia in PWS and related genetic disorders, and

possibly contributes to hyperphagia in the general population. 

Expected Significance: Congenital leptin resistance secondary to LepR mutations has been identified in rare individuals, in the db/db mouse and in the Zucker rat. Varying degrees of leptin resistance are found in most obese individuals, although there is no formal test for leptin resistance

in humans. Decreasing leptin resistance is a major goal in pharmaceutical obesity research, and exenatide and pramlintide acetate have shown some promise in this area. Dietary restriction and weight loss are partially effective in the obese population, although rebound weight gain is attributed mainly to continued leptin resistance. Finding that one of the PWS genes, for example

loss of MBII-85, specifically confers congenital and pre-obese leptin resistance in genetically hyperphagic mice would allow therapies directed at minimizing leptin resistance in the mice, for example targeting the snoRNA pathway. The knowledge that individuals with PWS are congenitally leptin resistant would draw attention to this disorder as a model for other forms of leptin resistance, and would provide a sound and logical explanation for the severe post-weaning hyperphagia that is so characteristic of PWS.