biostudies-literatureJacobsen JMIntramural NIH HHSNovo Nordisk A/SNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of Health114501https://www.ebi.ac.uk/biostudies/studies/S-EPMC11380917biostudies-literatureUnknown43(8)Evaluation of weight loss drugs is usually performed in diet-induced obese mice housed at ∼22°C. This is a cold stress that increases energy expenditure by ∼35% compared to thermoneutrality (∼30°C), which may overestimate drug-induced weight loss. We investigated five anti-obesity mechanisms that have been in clinical development, comparing weight loss in mice housed at 22°C vs. 30°C. Glucagon-like peptide-1 (GLP-1), human fibroblast growth factor 21 (hFGF21), and melanocortin-4 receptor (MC4R) agonist induced similar weight losses. Peptide YY elicited greater vehicle-subtracted weight loss at 30°C (7.2% vs. 1.4%), whereas growth differentiation factor 15 (GDF15) was more effective at 22°C (13% vs. 6%). Independent of ambient temperature, GLP-1 and hFGF21 prevented the reduction in metabolCell reportsHousing mice near vs. below thermoneutrality affects drug-induced weight loss but does not improve prediction of efficacy in humans.PMC11380917ZIA DK075062ZIA DK075063Ostergaard SPedersen KPetersen NTorz LRaun KJacobsen JMGerstenberg MKWulff BSJohn LMChristoffersen BOKuhre REAndersen BReitman MLfalseHousing mice near vs. below thermoneutrality affects drug-induced weight loss but does not improve prediction of efficacy in humans.Evaluation of weight loss drugs is usually performed in diet-induced obese mice housed at ∼22°C. This is a cold stress that increases energy expenditure by ∼35% compared to thermoneutrality (∼30°C), which may overestimate drug-induced weight loss. We investigated five anti-obesity mechanisms that have been in clinical development, comparing weight loss in mice housed at 22°C vs. 30°C. Glucagon-like peptide-1 (GLP-1), human fibroblast growth factor 21 (hFGF21), and melanocortin-4 receptor (MC4R) agonist induced similar weight losses. Peptide YY elicited greater vehicle-subtracted weight loss at 30°C (7.2% vs. 1.4%), whereas growth differentiation factor 15 (GDF15) was more effective at 22°C (13% vs. 6%). Independent of ambient temperature, GLP-1 and hFGF21 prevented the reduction in metabol2024-01-01T00:00:00Z2024 Aug2026-05-29T09:31:28.517Z2025-04-04T00:29:11.01ZS-EPMC113809173906702410.1016/j.celrep.2024.114501