Housing 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 metabolic rate caused by weight loss. There was no simple rule for a better prediction of human drug efficacy based on ambient temperature, but since humans live at thermoneutrality, drug testing using mice should include experiments near thermoneutrality. [Display omitted] •Housing mice at 22°C is a thermal stress, which greatly increases energy expenditure•The amount of weight loss produced by some drugs is affected by housing temperature•Blood glucose and plasma lipids are not affected by housing at 22°C vs. 30°C•There is no simple rule predicting human drug efficacy based on ambient temperature Jacobsen et al. investigated the effect of housing temperature on pharmacotherapy-induced weight loss in mice. Housing temperature (22°C vs. 30°C) affected the weight loss due to some drugs and not others. They found no simple rule to predict human drug efficacy based on the ambient temperature used in mouse studies.