NPFFR2 Deletion Improves Hypothalamic Insulin Sensitivity and Metabolic Outcomes in Mice with Diet-Induced Obesity

Abstract

Neuropeptide FF receptor 2 (NPFFR2) is a key regulator of energy homeostasis, influencing feeding behavior, insulin sensitivity, and lipid metabolism. This study investigates the metabolic consequences of Npffr2 deletion in a mouse model of diet-induced obesity. Wild-type and Npffr2 knockout mice were fed a high-fat high-sucrose diet to induce obesity, followed by comprehensive metabolic assessments. Npffr2 knockout mice exhibited reduced food intake, accompanied by significant downregulation of hypothalamic orexigenic neuropeptides agouti-related peptide and neuropeptide Y. Enhanced energy expenditure was observed in knockout mice, as evidenced by increased thermogenic capacity, elevated uncoupling protein 1 expression in brown adipose tissue, and improved core temperature maintenance under cold exposure. Lipid metabolism was also improved, with reduced hepatic and adipose lipid accumulation and lower circulating triglyceride and non-esterified fatty acid levels. Molecular analyses revealed increased AKT phosphorylation in the hypothalamus and skeletal muscle, along with downregulation of protein tyrosine phosphatase 1B in the mediobasal hypothalamus, indicating improved central and peripheral insulin signaling. Here, we demonstrated that NPFFR2 plays a critical role in obesity-associated energy regulation, lipid accumulation, and insulin resistance. These findings highlight NPFFR2 as a potential therapeutic target for obesity and related metabolic disorders.

Keywords: Adipocyte hypertrophy; Energy metabolism; Insulin signaling; NPFFR2; Obesity.