SAT-LB102 Obesity Is Associated With Reduced Expression of the Anorexigenic Neuropeptide Nucleobindin-2/Nesfatin-1 in the Human Nucleus of the Solitary Tract

Introduction: Feeding is a complex behavior coordinated by interrelated forebrain, hypothalamic, and brainstem neuronal networks. Brainstem neurons constitute an important input for the neural circuitry integrating nutrient signals to control ingestive behavior. Orexigenic and anorexigenic neuropeptides act in concert to regulate energy balance. Data from animal models suggest that altered neuropeptidergic expression contributes to obesity. Nucleobindin-2/nesfatin-1, an appetite-suppressing neuropeptide and negative regulator of body weight, is reduced in the hypothalamus of mouse obesity models. In obese and overweight humans, we have recently reported decreased nucleobindin-2/nesfatin-1 immunoexpression in the lateral hypothalamic area, which is critically involved in appetite and metabolic regulation and has extensive connections with brainstem feeding circuits. Objective: The present study explored nucleobindin-2/nesfatin-1 localization pattern as well as the association between nucleobindin-2/nesfatin-1 protein expression and body weight in human brainstem nuclei. Methods: Sections of 20 human brainstems (13 males, 7 females; 8 normal weight, 6 overweight, 6 obese) were examined by means of immunohistochemistry and double immunofluorescence labeling. Results: Nucleobindin-2/nesfatin-1 widespread distribution was observed in various brainstem areas, including nuclei with well-defined roles in energy homeostasis and in autonomic and behavioral processes, such as the nucleus of the solitary tract, dorsal motor nucleus of vagus, area postrema, inferior olive, raphe nuclei, reticular formation, locus coeruleus, parabrachial nuclei, and pontine nuclei, and in Purkinje cells of the cerebellum. Interestingly, nucleobindin-2/nesfatin-1 immunofluorescence signal extensively localized in neuronal subpopulations expressing neuropeptide Y and cocaine- and amphetamine-regulated transcript (peptides known to exert potent actions on food intake and energy balance) in nucleus of the solitary tract, inferior olive, locus coeruleus, and dorsal raphe nucleus. Of note, nucleobindin-2/nesfatin-1 immunoexpression was significantly lower in obese than normal weight subjects in the nucleus of the solitary tract (p<0.05). Conclusions: These data provide for the first time neuroanatomical support for the potential role of nucleobindin-2/nesfatin-1 in human brainstem circuits controlling energy homeostasis. In nucleus of the solitary tract, a key integrator of nutrient state signals and a neural substrate of food reward-related processes, altered neurochemistry such as nucleobindin-2/nesfatin-1 deficiency may contribute to dysregulation of homeostatic and/or hedonic feeding behavior and ultimately to obesity.