Energy balance effects of central melanocortin, cocaine and amphetamine related transcript and leptin: Moving outside of the hypothalamic box

Due to increasing rates of obesity and its comorbidities, there is tremendous interest in the central nervous system (CNS) control of energy balance. This basic science interest is guided in part by the need to develop effective drugs for the overweight and the obese patient. Despite a large literature, our understanding of the circuits and neurochemical receptors that mediate energy balance is still limited. The studies described here address this limitation by defining neural circuits that mediate melanocortin's effects on energy balance. Disruption in CNS melanocortin receptor (MCR) signaling is the single largest monogenic cause of human obesity and also produces severe hyperphagia and reduced energy expenditure in rodents. Forebrain ventricular application of MCR agonists, triggers sympathetically mediated expenditure responses that have been attributed to signaling at hypothalamic structures. However, caudal flow of the injected ligands in CSF makes them available to extrahypothalamic sites. Given the widespread distribution of MCRs it is impossible to define which MCR-bearing neurons---among them several hypothalamic and hindbrain nuclei---contribute to the observed effects. Here we characterized the respective contributions of the hypothalamic and caudal hindbrain MCRs to energetic and intake control with ventricular (3rd and 4 th v) as well as selective parnechymal MCR agonist delivery. Results demonstrate that thermogenic, cardiovascular and anorexic responses of similar size and duration can be obtained by stimulation of several hypothalamic and hindbrain MCR populations. Using an antagonist treatment we evaluated the endogenous hindbrain MCR contributions to the intake and thermogenic responses driven by leptin (a hormone produced by the adipose tissue) and an exposure to palatable, high-energy diet. Results indicated that hindbrain MCRs are required for mediation of anorexic and thermogenic effects of hindbrain leptin and for limiting overeating induced by palatable high-energy diet. The data presented here confirm the hypothesis that the melanocortin system's contribution to food intake and energy expenditure is distributed across spatially distinct regions of the brain. Taken together results demonstrate the presence of an independent hindbrain MCR-driven energy balance circuitry that responds to peripheral inputs (e.g. leptin) and physiological challenges (e.g. high-energy diet) similarly to what has been earlier ascribed to the hypothalamic MCR populations.