Housing mice near vs. below thermoneutrality affects drug-induced weight loss but does not improve prediction of efficacy in humans
Julie M. Jacobsen,
Natalia Petersen,
Lola Torz,
Marina K. Gerstenberg,
Kent Pedersen,
Søren Østergaard,
Birgitte S. Wulff,
Birgitte Andersen,
Kirsten Raun,
Berit Ø. Christoffersen,
Linu M. John,
Marc L. Reitman,
Rune E. Kuhre
Affiliations
Julie M. Jacobsen
Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark
Natalia Petersen
Liver and Gut Biology, Obesity & NASH, Global Drug Discovery, Novo Nordisk A/S, Bagsværd, Denmark
Lola Torz
Liver and Gut Biology, Obesity & NASH, Global Drug Discovery, Novo Nordisk A/S, Bagsværd, Denmark
Marina K. Gerstenberg
Translational Medicine, Global Translation, Novo Nordisk A/S, Bagsværd, Denmark
Kent Pedersen
Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark
Søren Østergaard
Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark
Birgitte S. Wulff
Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark
Birgitte Andersen
Diabetes, Obesity and NASH, Global Drug Discovery, Novo Nordisk A/S, Bagsværd, Denmark
Kirsten Raun
Lead Portfolio Projects, Research and Early Development, Novo Nordisk A/S, Bagsværd, Denmark
Berit Ø. Christoffersen
Large Animal Pharmacology, Global Drug Discovery, Novo Nordisk A/S, Bagsværd, Denmark
Linu M. John
Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark
Marc L. Reitman
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA
Rune E. Kuhre
Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark; Department of Biomedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Corresponding author
Summary: 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.
