Glucagon-like peptide-1 amide (GLP-1) and gastric inhibitory polypeptide (GIP) are incretin hormones regulating energy metabolism. GLP-1 and GIP combination is suggested as a promising therapeutic strategy for treatment of obesity and diabetes. However, the neuronal mechanisms are not yet investigated. In the present study, we investigated the role of central GLP-1 and GIP in regulation of body weight homeostasis. The effect of GLP-1 with GIP on food intake, body weight, locomotor activity were determined following intracerebroventricular (ICV) administration of GLP-1 and/or GIP in mice. ICV administration of low dose GLP-1 (0.3 nmol) and GIP (1 and 3 nmol) did not change food intake. However, ICV administration of higher doses GLP-1 (1 and 3 nmol) and GIP (6 nmol) significantly decreased food intake and body weight. To investigate the synergic effect of ICV GLP-1 and GIP, sub effective dose GLP-1 (0.3 nmol) and subeffective dose GIP (1 nmol) were chosen for further co-administration study. ICV co-administration of GLP-1 and GIP significantly decreased food intake, body weight and drinking. ICV co-administration of GLP-1 and GIP significantly increased neuronal activation and pro-opiomelanocortin (POMC) expression in hypothalamic arcuate nucleus. The neuronal activation and POMC expression were observed in two distinct neuronal populations. These results provide neuronal mechanisms supporting the development of GLP-1 and GIP combination therapeutics for treatment of obesity and diabetes. (C) 2017 The Authors. Published by Elsevier Inc.