Animal onlyPreprint
This mouse study investigated the effects of semaglutide, a GLP-1 receptor agonist (GLP-1 RA), administered from preconception through lactation in dams fed either a high-fat diet (HFD) or a standard diet. Researchers assessed metabolic outcomes in both the treated mothers and their offspring, who were weaned onto a standard diet. The study found that semaglutide improved body composition and glucose metabolism in HFD-fed dams during pregnancy, and these benefits persisted approximately 10 weeks after weaning even after treatment was discontinued. Offspring born to HFD-fed, untreated dams showed impaired glucose homeostasis and hepatic steatosis (fatty liver) at 18 weeks of age. These metabolic disturbances were attenuated in offspring whose mothers received semaglutide. Notably, semaglutide treatment did not adversely affect conception rates or fetal viability. The authors conclude that GLP-1 RA therapy during the perinatal period may improve both maternal and offspring metabolic health in an obesity mouse model, and they call for further investigation into GLP-1–based therapies in this context. Key limitations include the exclusive use of a mouse model, limiting direct translation to human pregnancy, and the fact that this appears to be a preprint not yet formally peer-reviewed.
Unknown journal · Jun 2026DOI ↗ Animal only
This mouse study investigated the molecular mechanisms by which tirzepatide (TZP), a dual GIP/GLP-1 receptor agonist, affects the liver in metabolic dysfunction-associated steatotic liver disease (MASLD). Male C57BL/6J mice (n=32) were fed a high-fat, high-fructose (HFHFr) diet to induce MASLD and then randomized to receive no treatment, semaglutide (Sema), or TZP. Researchers combined RNA sequencing and liquid chromatography-mass spectrometry (LC-MS) to generate hepatic transcriptomic and proteomic profiles, with key targets validated by PCR and immunoblotting. The study found that HFHFr feeding produced hyperglycemia, insulin resistance, elevated liver enzymes, and hepatic steatosis and inflammation. Both TZP and Sema were associated with improvements in these parameters; TZP was associated with reductions in pro-inflammatory markers (MCP-1, IL-1β, TNF-α, GSDMD) and partial restoration of IL-10. Integrated omics analysis implicated the CCL2/CCR2 chemokine axis and PI3K-AKT signaling pathway as key molecular signatures associated with TZP's hepatic effects. Key limitations include the exclusive use of an animal model, a small sample size, and the mechanistic (non-causal) nature of omics associations.
BMC gastroenterology · Jun 2026DOI ↗ Animal only
This animal study compared the anti-atherosclerotic effects of tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a selective GLP-1 receptor agonist) in ApoE knockout mice. Mice were treated with streptozotocin to induce diabetes and divided into early diabetes, late diabetes, and non-diabetic groups, each receiving either agent or saline for 12 weeks. The study found that in the early diabetes group, both tirzepatide and semaglutide significantly reduced aortic plaque formation compared to controls, with modest improvements in blood glucose and lipid levels. No significant vascular effects were observed in the late diabetes or non-diabetic groups in terms of plaque reduction. Tirzepatide more broadly reduced inflammatory markers—including Mcp-1, Il-6, I-cam, and Cd68—compared to semaglutide. Anti-inflammatory effects were also detected in non-diabetic mice, suggesting possible vascular protective mechanisms independent of metabolic control. The authors conclude that dual incretin receptor agonism may offer cardiovascular benefits, though the specific contribution of GIP signaling requires further investigation. Key limitations include the use of an animal model, which may not translate directly to human cardiovascular disease.
Scientific reports · 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 study investigated whether milk-derived small extracellular vesicles (sEVs) could serve as oral delivery vehicles for two GLP-1 receptor agonists (GLP-1RAs): semaglutide and tirzepatide. Researchers loaded both peptides onto sEVs in vitro and administered them orally to diabetic db/db mice—a well-established mouse model of type 2 diabetes. The study found that both peptides were efficiently incorporated into the sEV carrier system and that oral administration of the loaded vesicles effectively reduced blood glucose levels in the diabetic mice. The authors compared this approach to the existing SNAC (sodium N-[8-(2-hydroxybenzoyl) amino] caprylate) technology used in the commercially approved oral semaglutide formulation (Rybelsus), arguing that sEVs offer broader applicability across multiple peptide drugs, not just semaglutide. Key limitations include the exclusive use of an animal model with no human pharmacokinetic or efficacy data, a relatively small and homogeneous study design, and the early-stage, preclinical nature of the platform. Translation to humans remains undemonstrated.
Journal of extracellular biology · Nov 2025DOI ↗ Animal only
This study describes the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method for measuring tirzepatide — a dual GIP/GLP-1 receptor agonist — in rat plasma. Researchers used protein precipitation with methanol for sample preparation, a peptide C18 column for chromatographic separation, and positive electrospray ionization with multiple reaction monitoring for detection, using semaglutide as an internal standard. The method demonstrated good linearity (1–1000 ng/mL), with intra- and inter-day accuracy and precision meeting regulatory criteria. Stability under various storage and handling conditions was also confirmed. The validated method was then applied to a pharmacokinetic study in rats administered tirzepatide intravenously and subcutaneously at 0.3 mg/kg. The study reports terminal half-lives of approximately 10 hours via both routes and estimates subcutaneous bioavailability at roughly 62%. Key limitations include the exclusive use of a rat model, a single dose level, and a small number of animals typical of preclinical PK studies, meaning findings may not translate directly to humans. The authors suggest the method could be adapted for quantifying other structurally similar peptide therapeutics.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences · Oct 2025DOI ↗ Animal only
This study developed a biodegradable buccal suction patch designed to improve the systemic delivery of peptide therapeutics by bypassing gastrointestinal degradation. Researchers replaced previously used non-degradable silicone materials with thermally crosslinked, synthesized copolyesters, fabricated via a scalable mold-casting process. Mechanical testing across multiple polymer formulations and patch shapes identified the best-performing biodegradable candidate, and degradation was confirmed in both aqueous media and simulated waste environments. An ex vivo model using porcine buccal tissue demonstrated that the biodegradable patch, when combined with a chemical permeation enhancer, improved permeation of a poorly permeable dye compared to controls. In an in vivo study conducted in beagle dogs, the patch substantially improved the bioavailability of semaglutide (4.11 kDa) relative to a commercially available oral tablet over a 10-minute application window. Additionally, the patch achieved a relative bioavailability of approximately 26% for bremelanotide (1.03 kDa) compared to subcutaneous injection. Limitations include the use of an animal model (beagle dogs) rather than human subjects, a small experimental scale, and the need for further clinical translation studies. The work highlights a potential sustainable alternative to silicone-based buccal delivery devices.
Journal of Controlled Release · Aug 2025
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 only
This study investigated the mechanisms underlying weight loss produced by CagriSema — a combination of cagrilintide (an amylin analogue) and semaglutide (a GLP-1 analogue) — in a rat model. Researchers quantified the contributions of reduced energy intake versus preserved energy expenditure to overall weight loss. Rats treated with CagriSema achieved approximately 12% body weight loss alongside a 39% reduction in food intake. To isolate the role of energy intake, the authors used two comparison conditions: pair-feeding (matching food intake to CagriSema-treated animals) and weight matching (determining how much food restriction alone would be needed to achieve equivalent weight loss, which required a 51% reduction in intake). The gap between these conditions suggested that roughly one-third of CagriSema's weight loss effect was attributable to blunting of metabolic adaptation — the phenomenon where the body typically reduces energy expenditure in response to caloric restriction. Limitations include that findings are from an animal model and may not directly translate to humans, and the study does not address long-term outcomes. The authors conclude that CagriSema's dual action on both energy intake and expenditure may contribute to its potential effectiveness as an obesity treatment.
Nature metabolism · Jul 2025DOI ↗ Animal only
This study introduces a biodegradable buccal suction patch designed to improve the systemic delivery of therapeutic peptides by bypassing gastrointestinal degradation. The researchers replaced previously used non-degradable silicone materials with biodegradable copolyesters, which were thermally crosslinked via a scalable mold-casting process. Mechanical testing identified the best-performing polymer formulation, and degradation was confirmed in both aqueous media and simulated waste environments. An ex vivo model using porcine buccal tissue demonstrated enhanced permeation of a poorly permeable dye when a chemical permeation enhancer was co-applied. In a beagle dog in vivo model, the biodegradable patch substantially improved the bioavailability of semaglutide (4.11 kDa) compared to a commercially available oral tablet within a 10-minute application window. The patch also achieved a relative bioavailability of approximately 26% for bremelanotide (1.03 kDa) versus subcutaneous injection. Key limitations include the use of an animal model rather than human subjects, a relatively small study scope, and the need for further safety and efficacy validation before clinical translation. The work highlights a promising, more sustainable alternative to silicone-based buccal delivery devices for peptide therapeutics.
Journal of controlled release : official journal of the Controlled Release Society · Jun 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 ↗