Pancreatic mu opioid receptors regulate metabolism and ingestive behaviors

The mu opioid receptor system has long been recognized for its role in regulating ingestive behaviors and food palatability. However, beyond their robust expression in the brain, opioid receptors are also found throughout the body, including the stomach, intestines, and pancreas. Previous studies suggest that opioids may directly regulate glycemia through actions in the endocrine pancreas, but whether these metabolic effects are linked to their influence on ingestive behavior remains unclear. Here, we used metabolic, ingestive, and genetic approaches to determine how the mu opioid receptor (MOPR) regulates in vivo phenotypes via its actions in endocrine pancreas. Glucose and insulin tolerance tests in male Oprm1 KO mice had enhanced glucose tolerance and insulin sensitivity. Conditional deletion of MOPRs in alpha cells had no effect. To test if loss of MOPRs influence overt ingestive behaviors, we measured 24-hour ad libitum food consumption using Feeding Experimental Devices (FEDs) in wild type, Oprm1 knockout (MOPR-deficient) and GCG-Cre x Oprm1fl/fl mice (10-12 weeks old). We found that Oprm1 KO male, but not female, mice exhibited increased mass and food intake, and dysregulated ingestive microstructures relative to wild type controls. Conditional deletion of MOPRs in alpha cells only recapitulated some of the phenotypes related to ingestive microstructure. These findings suggest that MOPR regulation of ingestive behaviors extends beyond typical neural circuits of reward to include peripheral metabolic organ mechanisms. Highlights- Male Oprm1 knockout mice show increased body mass and food intake - Male, but not female, Oprm1 knockout mice have enhanced glucose tolerance and insulin sensitivity - MOPR deletion in pancreatic alpha cells did not alter glucose metabolism - MOPR deletion in alpha cells increased meal frequency but reduced meal size in males - MOPR deletion in alpha cells only reduced meal size in females