Oxyntomodulin

Dual GLP-1/glucagon receptor agonist. GLP-1 component suppresses appetite; glucagon component increases energy expenditure and fatty acid oxidation. Net effect is reduced caloric intake and elevated metabolic rate.

Oxyntomodulin is an endogenous 37-amino-acid proglucagon-derived peptide co-secreted with GLP-1 and PYY by intestinal L-cells in response to nutrient ingestion, distinguished from GLP-1 by a C-terminal octapeptide extension that enables dual agonism at both the GLP-1 receptor and the glucagon receptor, producing combined effects on appetite suppression, energy expenditure, and glucose homeostasis. GLP-1 receptor activation by oxyntomodulin reduces food intake through central satiety signaling, while concurrent glucagon receptor activation stimulates hepatic glucose production, thermogenesis in brown adipose tissue, and elevated energy expenditure — a combination that theoretically produces greater weight loss than GLP-1 receptor activation alone while the glucogenic and GLP-1 effects approximately offset each other's glycemic impact. A double-blind randomized controlled trial of subcutaneous oxyntomodulin in overweight and obese human subjects demonstrated significant body weight reduction versus placebo over a 4-week treatment period, establishing proof-of-concept for dual GLP-1/glucagon receptor co-agonism as a human anti-obesity mechanism and validating the pharmacological rationale for long-acting dual agonist drug development programs. Native oxyntomodulin has no FDA approval; its short plasma half-life from DPP-IV degradation precludes clinical development in its native form, and commercial research interest has shifted to stabilized long-acting dual agonist analogs such as cotadutide and retatrutide, which use this dual mechanism in engineered molecules with drug-like pharmacokinetics.