As part of the Symposium on “Central and Peripheral Messengers of Metabolism,” this presentation will focus on complementary actions of novel peptide hormones in two important sites of metabolic regulation, pancreas and hypothalamus. Recently discovered, endogenous peptides have been demonstrated to be produced in both sites and to exert significant and potentially physiologically relevant actions on glucose homeostasis in both tissues. Central to the discussion will be the interaction of autonomic, behavioral and endocrine actions of these peptides related to energy homeostasis. Two peptides in particular, nesfatin-1 and neuronostatin, will be described as examples. Both exert profound anorexigenic and antidipsogenic actions in brain, stimulate gluco-regulatory hormone secretion from the pituitary gland and, by unique CNS mechanisms, activate the sympathetic nervous system. The relationship of those central actions to their effects on pancreatic islet cell function, in particular beta cell response to glucose challenge, will described and those in vitro actions supplemented by a discussion of their effects on glucose tolerance in vivo. It will be suggested that both peptides provide the opportunity for not only the understanding of the physiologic mechanisms controlling energy balance but also the potential development of novel therapeutic approaches to the treatment of obesity and its attendant co-morbidities.