Activation State of the Supramammillary Nucleus Regulates Body Composition and Peripheral Fuel Metabolism

Whole body fuel metabolism and energy balance are controlled by an interactive brain neuronal circuitry involving multiple brain centers regulating cognition, circadian rhythms, reward, feeding and peripheral biochemical metabolism. The hypothalamic supramammillary nucleus (SuMN) comprises an integral node having connections with these metabolically relevant centers, and thus could be a key central coordination center for regulating peripheral energy balance. This study investigated the effect of chronically diminishing or increasing SuMN neuronal activity on body composition and peripheral fuel metabolism. The influence of neuronal activity level at the SuMN area on peripheral metabolism was investigated via chronic (2-4 week) direct SuMN treatment with agents that inhibit neuronal activity (GABAa receptor agonist [Muscimol] and AMPA plus NMDA glutamate receptor antagonists [CNQX plus dAP5, respectively]) in high fat fed animals refractory to the obesogenic effects of high fat diet. Such treatment reduced SuMN neuronal activity and induced metabolic syndrome, and likewise did so in animals fed low fat diet including inducement of glucose intolerance, insulin resistance, hyperinsulinemia, hyperleptinemia, and increased body weight gain and fat mass coupled with both increased food consumption and feed efficiency. Consistent with these results, circadian-timed activation of neuronal activity at the SuMN area with daily local infusion of glutamate receptor agonists, AMPA or NMDA at the natural daily peak of SuMN neuronal activity improved insulin resistance and obesity in high fat diet-induced insulin resistant animals. These studies are the first of their kind to identify the SuMN area as a novel brain locus that regulates peripheral fuel metabolism.