Cell MetabWeight LossDecember 1, 2025

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

Feetham CH, Groom S, John LM, Christoffersen BO, Collabolletta V, Lyons D, Adamson A, Lundh S, Gerstenberg MK, Tang-Christensen M, Conde-Frieboes KW, Secher A, Kruse Hansen AM, Luckman SM

View on PubMed DOI: pii: S1550-4131(25)00481-4. 10.1016/j.cmet.2025.10.021

Key Finding

A new peptide called NN501 produces weight loss similar to GLP-1 drugs but works primarily by ramping up fat burning rather than reducing appetite, and mice kept the weight off better when treatment stopped.

What This Study Found

Think of your body's weight control system like a car with two main controls: the gas pedal (appetite) and the engine efficiency (metabolism). Most current weight loss drugs, including GLP-1 medications like Ozempic, work primarily by easing off the gas pedal - they make you feel full faster and eat less. But this new experimental drug NN501 works more like turbocharging your engine to burn fuel more efficiently. The researchers found that NN501 achieved weight loss comparable to GLP-1 drugs but with only modest effects on food intake. Instead, it cranked up energy expenditure and specifically enhanced fatty acid oxidation - essentially teaching your body to become a more efficient fat-burning machine. What's particularly intriguing is what happened when treatment stopped. Imagine two people who lost weight - one through strict dieting (like GLP-1 drugs) and another through ramping up their metabolism (like NN501). When the dieter stops their strict regimen, they often experience rebound hunger and rapid weight regain. But the person whose metabolism was enhanced showed more gradual weight regain and no compensatory overeating, suggesting their body had developed a more sustainable relationship with weight management.

Statistics Decoded

The abstract doesn't provide specific numerical values for weight loss percentages or statistical significance measures. However, it states that weight reduction was 'similar to that of GLP-1 receptor agonists' - which typically achieve 10-15% body weight reduction in clinical trials. The key finding is qualitative: NN501 had 'only a modest effect on food intake' compared to the substantial appetite suppression seen with GLP-1 drugs, yet achieved comparable weight loss through increased energy expenditure and sustained fatty acid oxidation.

Why This Matters

This could represent a game-changing approach to obesity treatment by targeting metabolism rather than appetite, potentially offering patients a weight loss option that's easier to maintain long-term without the rebound weight gain that often occurs when GLP-1 treatments are discontinued.

Original Abstract

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.