Oligosaccharides ameliorate insulin resistance and hepatic metabolism by promoting the leptin/POMC axis to accelerate short stature growth and development

Background: Leptin and pro-opiomelanocortin (POMC) signaling critically regulates metabolism and growth. The potential of oligosaccharides to modulate this axis and its physiological impacts remains unclear.

Methods: Male wild-type (WT) and leptin-deficient (ob/ob) mice received daily oral oligosaccharides for 8 weeks. Lentiviral POMC overexpression (LV-POMC) or control (LV-NC) was administered to ob/ob mice. Metabolic function was assessed via glucose/Insulin tolerance tests (GTT/ITT). Serum/tissue levels of Leptin, POMC, metabolic markers, growth Hormones, and bone regulators were quantified by enzyme-linked immunosorbent assay and Western blot. Femur length was recorded, and trabecular architecture was evaluated by hematoxylin-eosin staining.

Results: Oligosaccharides increased Leptin and POMC levels in WT but not ob/ob mice. Oligosaccharides improved Insulin sensitivity, hepatic metabolism (reduced triglycerides, aspartate aminotransferase, alanine aminotransferase, and free fatty acids), and bone growth (increased femur length, osteoprotegerin; decreased receptor activator of nuclear factor kappa-B ligand/Cathepsin K) in WT mice. These benefits were absent in ob/ob mice. Crucially, POMC overexpression in ob/ob mice rescued metabolic dysfunction (improved GTT/ITT and normalized hepatic markers), restored growth hormone balance (reduced adrenocorticotropic hormone/cortisol and increased insulin-like growth factor 1), and reversed bone defects.

Conclusion: Oligosaccharides exert insulin-sensitizing, hepatoprotective, and growth-promoting effects via leptin-dependent POMC activation. POMC restoration rescues deficits in Leptin deficiency, establishing the Leptin/POMC axis as the essential mechanistic pathway.

Insulin resistance; Leptin; Oligosaccharides; POMC; Short stature.