Feeding regulation by ASB4

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Project Summary/Abstract The genetic basis of most common forms of obesity is polygenic, highlighting the importance of interactions among different genetic variants in body weight regulation. Indeed, large-scale GWAS studies have identified increasing number of genetic variants that are associated with human obesity. Despite these advances, the metabolic functions of these genetic variants and how they interact with key regulators of energy balance are still poorly understood. We recently identified Ankyrin Repeat and SOCS Box Containing 4 (ASB4), a gene that is linked to human obesity by multiple GWAS studies, as an important regulator of satiety especially after period of food deprivation. Expression of Asb4 is modulated by nutritional status, being responsive to leptin and agouti-related protein in a reciprocal fashion, allowing ASB4 to sense changes of body’s energy reserve. We show that ASB4 deficiency leads to increased meal size and food intake during periods of intense feeding, such as refeeding. We also show that ASB4 is required for the expression of calcitonin receptor (CalcR) and the anorectic effects of salmon calcitonin, a potent ligand for CalcR. Together, these findings strongly indicate that ASB4 is important for metabolic control in humans and mice, and that it is an important regulator of meal size. The goal of this R01 application is to determine the mechanisms by which ASB4 exerts its metabolic effects. We will identify ASB4 neuronal subpopulations that control meal size and food intake. We will evaluate if importance of ASB4 in satiety control manifests under intermittent fasting, a feeding pattern that promotes consumption of large meals. As ASB4 is highly conserved between mice and humans and is linked to obesity by GWAS studies, this study will provide mechanistic insight into how ASB4 may regulate meal size and food intake in humans.