A compound comprising five agonists that together tackle weight loss, glucose reduction, insulin sensitization, and blood fat normalization has shown promise in mouse models of obesity.

The compound under investigation is called a quintuple agonist because, together with GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, it contains lanifibranor, a molecule that activates three different peroxisome proliferator-activated receptors (PPARs) — the alpha, delta, and gamma variants — all of which are involved in energy regulation.

Notably, this is not a combination therapy — the five agonists are included in a single molecule.

Daniela Liskiewicz, PhD, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, and the German Center for Diabetes Research, both in Munich, Germany, discussed the development of the novel agonist at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting.

Mouse Results Encouraging

“PPARs are master regulators of metabolism expressed in key metabolic tissues,” explained Liskiewicz. PPAR-gamma drives adipose tissue differentiation and lipid storage, thereby improving systemic insulin sensitivity.

PPAR-alpha is highly expressed in the liver, heart, and muscle, where it promotes fatty acid oxidation and reduces circulating triglycerides. PPAR-delta is broadly expressed across tissues and enhances fatty acid utilization and energy expenditure.

The team chose to include lanifibranor, a pan-PPAR agonist that activates all three PPAR isoforms, in its therapeutic. Lanifibranor is currently in phase 3 clinical trials for metabolic dysfunction-associated steatotic liver disease and has demonstrated a favorable safety profile, Liskiewicz said.

In the new therapeutic, lanifibranor’s delivery is targeted — instead of being distributed throughout the body, it is delivered only to cells expressing receptors for GIP or GLP-1, as part of a precision treatment.

Currently, novel GLP-1/GIP/pan-PPAR quintuple agonist is being tested in genetic and diet-induced obesity mouse models, as well as in models with incretin receptor deletion or adipocyte-specific GIP receptor overexpression. Recent experiments showed that the quintuple agonist demonstrated superior efficacy than the GLP-1/GIP or semaglutide in reducing body weight, decreasing food intake, and improving hyperglycemia in mice with obesity and insulin resistance.

“These enhanced effects stem from the synergistic actions of incretin and PPAR pathways in the brain and adipose tissue,” Liskiewicz said.

The new compound also was shown to be significantly more effective in reducing body weight and enhancing energy metabolism and glucose control than either GLP-1/GIP or the pan-PPAR agonist alone, or as a combination treatment.

A date to launch trials in humans has not yet been set.

The work was funded by the European Union within the scope of the European Research Council ERC-CoG Trusted #101044445, awarded to the principal investigator T.D. Müller, also from the Institute for Diabetes and Obesity, Helmholtz Zentrum München. Liskiewicz declared no competing interests.

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.