MOLECULAR MECHANISMS OF APPETITE AND ENERGY BALANCE

Abstract

Hypothalamic synaptic transmission has been largely understated in the regulation of appetitive behaviours. Environmental or epigenetic changes on synapse-specific activity may predispose individuals to obesogenic behaviours. We sought to address this by deleting active zone protein, ELKS1 and ELKS2, through Nkx2.1-cre-loxP recombination. Nkx2.1 is a developmental progenitor of hypothalamic nuclei; while the loss of ELKS proteins has been shown to reduce neurotransmitter release at both inhibitory and excitatory synapses. The conditional deletion of ELKS caused significant obesity, driven by sustained day-and-night hyperphagia. Deletion of ELKS in the dorsomedial hypothalamus, but not in other key feeding nuclei, also caused obesity and hyperphagia. Nkx2.1 neurons in the DMH are glutamatergic, co-express orexin-A, and project to brain reward centers. Synaptic transmission dynamics is crucial to the maintenance of energy balance and hypothalamic centers have different susceptibilities to changes in synaptic capacity, making them potential targets to external stressors during the progression to obesity.