Obestatin and its fragment analog Nt8U influence levels of satiety peptides in diet-induced obese mice

Imbalance in energy intake and energy expenditure due to changes in lifestyle and genetic issues results in obesity, which is a serious health problem. Appetite-inducing signals and satiety peptides in the enteroendocrine system have a definite role in the management of obesity. To regulate food intake and digestive signals, gut-derived satiety peptides act in a coordinated network to regulate appetite and metabolic homeostasis. Among these peptides, obestatin has garnered interest for its role in modulating food intake and obesity-associated lipid parameters, as demonstrated in mouse models. This study investigates the interaction among major satiety peptides in the enteroendocrine system on administration of obestatin and its fragment analog, Nt8U, for 30 days. Obestatin and Nt8U, along with a positive control, Orlistat, were administered to high-fat fed mice. Circulating Cholecystokinin-8 (CCK-8) levels increased in obestatin-treated mice but decreased with Nt8U, while Oxyntomodulin (OXM) levels increased by 20% in the obestatin group. In contrast, glucagon-like peptide-1 (GLP-1) levels were reduced following obestatin and orlistat treatment. These alterations were accompanied by significant changes in intestinal mRNA expression of the corresponding peptide precursors, suggesting altered gene expression. Long-term indicators of energy stores, including leptin and adiponectin, were reduced across all treatment groups, while insulin levels were significantly decreased in obestatin-treated mice. These hormonal changes were associated with reductions in body weight, plasma total cholesterol, and triglycerides. Collectively, these findings indicate that obestatin and Nt8U administration altered circulating satiety peptide concentrations and the intestinal expression of genes encoding gut-derived satiety hormones. These coordinated changes suggest modulation of metabolic hormone networks associated with energy balance in diet-induced obesity.