ORF45-04 - Effects of LEAP2-KO on Glucose Metabolism and Growth Hormone Secretion in High-Fat Diet Mice

Metabolic disorders such as obesity and type 2 diabetes represent significant public health challenges, with the ghrelin-GHSR system playing a pivotal role in energy balance and glucose metabolism. This study aimed to elucidate the physiological implications of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) deficiency in regulating body weight, glucose homeostasis, insulin sensitivity, and growth hormone (GH) secretion under high-fat diet (HFD) conditions. Utilizing a LEAP2 knockout (KO) mouse model, we conducted longitudinal assessments of body weight, food intake, glucose tolerance tests (OGTT), insulin tolerance tests (ITT), and analyzed GH pulsatile secretion profiles through high-frequency blood sampling. Our findings revealed that LEAP2-KO mice exhibited increased body weight gain, particularly in males, under both normal diet (ND) and HFD conditions, suggesting that LEAP2 deficiency predisposes to obesity due to unopposed GHSR activity. Furthermore, LEAP2-KO improved glucose tolerance in HFD-fed female mice while impairing insulin sensitivity in male mice across dietary contexts. Notably, LEAP2-KO restored GH pulsatility in HFD-fed females, indicating a regulatory role in the GH axis. Gene expression analysis demonstrated upregulation of gluconeogenic genes and downregulation of insulin receptor expression in the liver of LEAP2-KO mice, aligning with observed metabolic disturbances. These results highlight the multifaceted role of LEAP2 in metabolic regulation and suggest that targeting the LEAP2/GHSR axis may present therapeutic opportunities for metabolic disorders.