There is an unmet global medical need to develop novel therapeutic approaches for the treatment of obesity and obesity-associated insulin resistance and type 2-diabetes mellitus. During the last funding period of the CMMC we have identified a novel neuronal cell type, located in the arcuate nucleus of the hypothalamus (ARC), characterized by the expression of the neuropeptide Prepronociceptin (PNOC). These cells are readily activated upon consumption of a highly palatable, calory-dense food, their optogenetic activation promotes food intake in part via inhibition of food intake-suppressing, anorexigenic pro-opiomelanocortin (POMC)-expressing neurons, and their ablation protects from the development of high-fat diet (HFD)-induced obesity in mice. Collectively, PNOCARC neurons represent a novel neuronal subclass of critical importance for the development of obesity, which is potentially amendable for novel therapeutic interventions. Further analysis of these neurons via single nuclei sequencing of hypothalamic neurons as well as multiscope RNA in situ hybridization revealed a considerable degree of heterogeneity within this cell population. Therefore, the aim of the current proposal is to define the critical subset of PNOCARC neurons, which is responsible for obesity development.
PNOCARC neurons represent an attractive novel target for the treatment of obesity and obesity-associated co-morbidities such as type 2-diabetes mellitus, non-alcoholic steatohepatitis (NASH) as well as cardiovascular complications. Defining the specific subset of PNOCARC neurons responsible for obesity-induced weight gain carries a potential to identify novel druggable targets for specific inhibition of PNOCARC neurons in obesity.
Policlinic for Endocrinology, Diabetes and Preventive Medicine
CMMC - PI - C 03
Executive Board Member
Marie Holm Solheim
Tamara Sotelo Hitschfeld