Obesity is a global epidemic. The underlying premise of this proposal is that the identification of new genetic factors predisposing individuals to unhealthy weight gain may improve risk assessments and reveal novel targets for pharmacological interventions designed to treat obesity.
The goal of the proposed research is to gain a detailed understanding of an adult-onset overweight phenotype manifested in mice lacking one subunit (GIRK4) of a potassium ion channel activated in a G protein-dependent manner by neurotransmitters and hormones such as somatostatin, serotonin, dopamine, y-aminobutyric acid (GABA), and opioids. The tissue distribution of GIRK4 is limited, and thus its conspicuous presence in glucagon-secreting pancreatic a-cells and in feeding-relevant neurons of the ventromedial hypothalamic nucleus suggests likely anatomical loci underlying the adult-onset weight gain phenotype.
A multi-disciplinary effort is proposed that will yield a rigorous characterization of this interesting phenotype while exploring roles for GIRK4 in novel aspects of energy intake and expenditure.
Experiments are proposed to:
With these studies, molecular and cellular details of novel signaling pathways influencing energy intake and expenditure will emerge, as will a clearer picture of how dysfunction in such pathways can translate into unhealthy weight gain.
ZEB1 and the Development of Obesity
Oxyntomodulin and the Regulation of Non-Exercise Activity Thermogenesis
Hypothalamic Acyl-CoA Metabolism and Food Intake Regulation
Parents as the Agent of Change for Childhood Obesity
Identifying Novel Roles of Lipocalin 2 in Insulin Action and Glucose Metabolism
GIRK$: A New Obesity Gene?
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