Glucagon-like peptide-1 receptor in the human hypothalamus is associated with body mass index and colocalizes with the anorexigenic neuropeptide nucleobindin-2/nesfatin-1

Introduction Glucagon-like peptide-1 (GLP-1) anorexigenic and anti-obesogenic effects are centrally mediated. Data on animals emphasize the importance of neuronal GLP-1 receptor (GLP-1R) for feeding suppression, although it is unclear whether astrocytes participate in the transduction of anorectic GLP-1R-dependent signals. In humans, the brain circuitry underlying these effects remains insufficiently investigated. GLP-1R neuroanatomic localization in human hypothalamus, a brain region with a pivotal role in energy homeostasis regulation, is essential in order to improve our understanding of GLP-1 signaling pathways and central metabolic functions. The present study aimed to explore GLP-1R protein expression in human hypothalamus and its correlation with body mass index (BMI). Methods Sections of hypothalamus from 28 autopsy cases, 11 with normal weight (BMI < 25 Kg/m 2 ) and 17 with non-normal weight (BMI ≥ 25 Kg/m 2 ), were examined using immunohistochemistry and double immunofluorescence labeling. Results Prominent GLP-1R immunoexpression was detected in neurons of several hypothalamic nuclei, including paraventricular, supraoptic, and infundibular nuclei, lateral hypothalamic area (LH), and basal forebrain nuclei. Interestingly, in LH, GLP-1R protein expression was significantly decreased in individuals with BMI ≥ 25 Kg/m2, compared with normal weight counterparts (p=0.03). Furthermore, GLP-1R was moderately and negatively correlated (τb=-0.347, p=0.024) with BMI levels only in the LH. GLP-1R extensively colocalized with the anorexigenic and anti-obesogenic neuropeptide nucleobindin-2/nesfatin-1, but not with the astrocytic marker glial fibrillary acidic protein (GFAP). Conclusion These data suggest a potential role for GLP-1R in the regulation of energy balance in human hypothalamus, possibly through interactions with nesfatin-1. In LH, an appetite- and reward-related brain region, reduced GLP-1R immunoexpression may contribute to dysregulation of homeostatic and/or hedonic feeding behavior. GLP-1R colocalization with nesfatin-1 in the basal forebrain, a cognition-related brain area, might give impetus towards elucidating additional central actions of GLP-1R.