Animal only
This preclinical study investigated whether obesity could be reversed without activating the GLP-1 receptor (GLP-1R), which is commonly associated with adverse gastrointestinal side effects in current therapies. Using diet-induced obese (DIO) mice and rats, as well as GLP-1R knock-out (KO) mice, researchers tested selective, dual, and triple agonists targeting the GIP receptor (GIPR), glucagon receptor (GCGR), and GLP-1R in various combinations. Three independent experimental approaches — (1) administering the triagonist retatrutide to GLP-1R KO mice, (2) physically combining separate selective GIPR and GCGR agonists, and (3) testing a novel unimolecular GIPR:GCGR co-agonist called BWB3054 — all demonstrated meaningful reductions in body weight and improvements in blood glucose without meaningful GLP-1R engagement. BWB3054 showed potency at the mouse GIPR comparable to retatrutide, 4-fold reduced potency at the mouse GCGR, and more than 100-fold reduced potency at the mouse GLP-1R. Indirect calorimetry and pair-feeding studies were used to characterize mechanisms of weight loss. A key limitation is that all experiments were conducted in rodents, leaving the translatability of these findings to humans uncertain. The study raises the possibility that GLP-1R-independent obesity treatment strategies could avoid the GI tolerability issues seen with current agents.
Molecular metabolism · Apr 2026DOI ↗ Animal only
This animal study investigated the anti-obesity effects of three GLP-1 receptor agonist peptides — semaglutide, tirzepatide, and retatrutide — in melanocortin 4 receptor knockout (MC4R KO) mice, a model of genetically driven obesity caused by disruption of the POMC-MC4R signaling pathway. All three compounds were administered for 21 days, after which body weight, body composition, metabolic markers, liver health, and gene expression were assessed. The study found that all three GLP-1 analogs produced statistically significant reductions in body weight, with tirzepatide showing the greatest effect (approximately 31.6%), followed by retatrutide (approximately 24.1%) and semaglutide (approximately 19.7%). All three agents reduced both fat and lean mass, improved plasma insulin levels and insulin resistance (HOMA-IR), lowered cholesterol, and reduced markers of liver damage (AST and ALT) as well as liver hypertrophy. Gene expression analysis showed suppression of fatty acid synthesis genes, but no significant effect on inflammatory gene expression. Energy expenditure was reduced by all agents; only tirzepatide significantly decreased the respiratory quotient. A key limitation is that this is a mouse model study, and findings may not directly translate to humans. The authors suggest MC4R KO mice are a valid model for studying obesity-related drug efficacy.
International journal of obesity (2005) · Feb 2026DOI ↗ Animal only
This preclinical study investigated whether three GLP-1-based receptor agonists — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP receptor agonist), and retatrutide (triple GIP/GLP-1/glucagon receptor agonist) — could alter the interoceptive (subjective-like) effects of alcohol in rats. Using an operant drug discrimination paradigm in both male and female rats, researchers trained animals to distinguish alcohol from vehicle, then tested whether these compounds disrupted that learned discrimination. The study found that acute administration of all three agents attenuated alcohol's discriminative stimulus effects, suggesting modulation of how alcohol "feels" internally. Repeated semaglutide treatment maintained this effect over a 15-day period, and the effect reversed within three days of cessation. The authors suggest these findings may help explain clinically observed reductions in alcohol craving and drinking in humans receiving GLP-1 receptor agonists. Limitations include the exclusive use of animal models, meaning direct translation to human subjective alcohol experience remains uncertain, and the study does not assess long-term outcomes or dependence-related endpoints.
Psychopharmacology · Jul 2025DOI ↗ Animal onlyPreprint
This preclinical study examined whether three incretin-based receptor agonists — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP receptor agonist), and retatrutide (triple GIP/GLP-1/glucagon receptor agonist) — could alter the interoceptive (subjective) effects of alcohol in rats using an operant drug discrimination paradigm. Male and female rats were trained to discriminate alcohol from saline, then tested after acute or repeated drug administration. The study found that acute administration of all three compounds reduced alcohol's discriminative stimulus effects, suggesting each compound modulated how the animals internally perceived alcohol. Repeated semaglutide treatment sustained this effect across a 15-day period, though discrimination returned to baseline levels within three days of stopping treatment. The authors interpret these findings as potentially relevant to understanding why GLP-1 receptor agonists reduce drinking behavior in humans, hypothesizing that blunting alcohol's subjective effects may be a contributing mechanism. Key limitations include the exclusive use of an animal model, meaning translation to human subjective experience remains uncertain, and the study does not establish clinical efficacy or safety in people with alcohol use disorder.
Unknown journal · Apr 2025DOI ↗ Animal only
This pre-clinical study investigated whether retatrutide (RETA, LY3437943) — a triple incretin agonist targeting GIP, GLP-1, and glucagon receptors — could reduce obesity-associated cancer progression beyond its known weight-loss effects. Using mouse models, researchers found that RETA-induced weight loss was associated with reduced pancreatic cancer engraftment, delayed tumor onset, and a 14-fold reduction in tumor volume compared to controls, outperforming single-agonist semaglutide (which achieved a 4-fold reduction). In a lung cancer model, RETA was associated with 50% reduced tumor engraftment and a 17-fold reduction in tumor volume. Notably, anti-tumor benefits persisted even after RETA withdrawal and subsequent weight regain, suggesting potential durable immune effects. Proposed mechanisms included systemic immune reprogramming: elevated circulating IL-6, increased antigen-presenting cells, reduced immunosuppressive cells, and activation of pro-inflammatory pathways within the tumor microenvironment. Key limitations include the exclusive use of pre-clinical (mouse) models, meaning findings may not translate directly to humans, and the mechanistic basis of durable immunity requires further investigation. The authors suggest these results warrant clinical exploration of RETA's potential to reduce cancer risk and improve outcomes in patients with obesity.
npj metabolic health and disease · Mar 2025DOI ↗