Housing mice near vs. below thermoneutrality affects drug-induced weight loss but does not improve prediction of efficacy in humans
Julie Jacobsen, Natalia Petersen, Lola Torz, Marina Kjærgaard Gerstenberg, Kent Pedersen, Søren Østergaard, Birgitte S. Wulff, Birgitte Andersen, Kirsten Raun, Berit Østergaard Christoffersen, Linu M. John, Marc L. Reitman, Rune E. Kuhre
Abstract
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.