LEPTIN CONSTRAINS ACETYLCHOLINE-INDUCED INSULIN-SECRETION FROM PANCREATIC-ISLETS OF OB OB MICE/

Hypersecretion of insulin from the pancreas is among the earliest dete ctable metabolic alterations in some genetically obese animals includi ng the ob/ob mouse and in some obesity-prone humans, Since the primary cause of obesity in the ob/ob mouse is a lack of leptin due to a muta tion in the ob gene, we tested the hypothesis that leptin targets a re gulatory pathway in pancreatic islets to prevent hypersecretion of ins ulin, Insulin secretion is regulated by changes in blood glucose, as w ell as by peptides from the gastrointestinal tract and neurotransmitte rs that activate the pancreatic islet adenylyl cyclase (e.g., glucagon -like peptide-1) and phospholipase C (PLC) (e,g., acetylcholine) signa ling pathways to further potentiate glucose-induced insulin secretion, Effects of leptin on each of these regulatory pathways were thus exam ined. Leptin did not influence glucose or glucagon-like peptide-1-indu ced insulin secretion from islets of either ob/ob or lean mice, consis tent with earlier findings that these regulatory pathways do not contr ibute to the early-onset hypersecretion of insulin from islets of ob/o b mice. However, leptin did constrain the enhanced PLC-mediated insuli n secretion characteristic of islets from ob/ob mice, without influenc ing release from islets of lean mice, A specific enhancement in PLC-me diated insulin secretion is the earliest reported developmental altera tion in insulin secretion from islets of ob/ob mice, and thus a logica l target for leptin action. This action of leptin on PLC-mediated insu lin secretion was dose-dependent, rapid-onset (i,e., within 3 min), an d reversible, Leptin,was equally effective in constraining the enhance d insulin release from islets of ob/ob mice caused by protein kinase C (PKC) activation, a downstream mediator of the PLC signal pathway. On e function of leptin in control of body composition is thus to target a PKC-regulated component of the PLC-PKC signaling system within islet s to prevent hypersecretion of insulin.