Analog of prolactin-releasing peptide reduces body weight primarily through sustained fatty acid oxidation rather than hypophagia

Prolactin-releasing peptide and its cognate receptor, G protein-coupled receptor (GPR)10, are important in the physiological regulation of body weight in both rodents and humans. Here, we describe a modified peptide, NN501, with agonist properties at both GPR10 and neuropeptide FF receptor 2 (NPFFR2), which reduces body weight when administered systemically without causing obvious aversive responses. Weight reduction is similar to that of glucagon-like peptide 1 (GLP-1) receptor agonists, but with only a modest effect on food intake, suggesting a different weight-lowering mechanism. Moreover, when treatment is discontinued, mice receiving NN501 display a more gradual weight regain and no compensatory hyperphagic response (as is observed with caloric restriction and GLP-1 receptor agonism). Instead, NN501 increases energy expenditure on treatment and has a sustained effect on fatty-acid oxidation. These results indicate that GPR10/NPFFR2 agonism produces weight loss by alternative mechanisms to GLP-1 receptor agonism, suggesting it could be a viable alternative or complementary therapy for obesity. • RF-amide receptors offer an alternative target for the treatment of obesity • A modified PrRP peptide with affinity to PRLHR and NPFFR2 receptors causes weight loss • There is a modest reduction in food intake and no rebound after withdrawal • The primary effect is for sustained fatty acid oxidation Although incretin (GLP-1)-based drugs are highly successful for weight loss, there are some limitations to their use. A modified prolactin-releasing peptide, NN501, causes significant weight loss without apparent side effects and with slower weight gain after cessation, potentially proving suitable as an alternative therapy for the treatment of obesity.