Housing Temperature Can Profoundly Influence Pharmacologically Induced Weight Loss Efficacy and Mode of Action in Diet-Induced Mice-A Cautionary Consideration for Human Translation

Objectives: Pre-clinical evaluation of drug efficacy on weight loss is usually done in diet-induced obese (DIO) mice housed at room temperature (∼22°C) , where the mice display adaptive thermogenic responses through brown adipose tissue (BAT) activation to increase energy expenditure (EE) and maintain core-temperature. These adaptive responses may influence drug-induced weight loss and ultimately likelihood for translatability to humans, who does not have thermogenic responses at room-temperature. We tested whether the efficacy of diverse weight-reducing pharmaco-therapies with distinct mode of action is impacted by housing temperature. Methods: Male DIO mice were studied with indirect calorimetry (Sable Systems International) at 22°C or 30°C (thermoneutrality) . Mice were treated daily for 10-21 days with analogues of weight-modulating compounds that have been in clinical development: glucagon-like peptide-1 (GLP-1) , melanocortin-4-receptor (MC4R) agonist, growth differentiation factor 15 (GDF15) , peptide YY (PYY) , and fibroblast growth factor 21 (FGF21) aiming for a weight loss (WL) of 10-25%. Results: Energy expenditure was ∼30% higher 22°C compared to 30°C. Housing temperature did not affect GLP-1 (∼20%) and MC4R (∼10%) mediated WL. However, FGF21 and PYY-mediated WL was higher at 30°C (∼20% vs. ∼17% for FGF21 and ∼9% vs. ∼1% for PYY) . In contrast, GDF15-mediated WL was higher at 22°C (∼14% vs. ∼8%) . The relative contribution of inhibition of food intake vs. increase in EE differed for FGF21 but not for the other compounds. In this case, increased EE, by BAT, drove more of the weight loss in the 22°C group. Conclusion: Ambient temperature may affect both efficacy and mode of action of weight-reducing pharmaco-therapies in DIO mice. This may affect human translatability, and we, therefore, suggest that studies at thermoneutrality should be included at an early stage in drug-development programs. Disclosure N. Petersen: Employee; Novo Nordisk A/S. B. Ø. Christoffersen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. L. M. John: None. R. E. Kuhre: Employee; Novo Nordisk. L. Torz: Other Relationship; Novo Nordisk A/S. M. K. Gerstenberg: Employee; Novo Nordisk. K. Pedersen: Employee; Novo Nordisk A/S. S. H. Madsen: None. S. Østergaard: Employee; Novo Nordisk A/S. B. S. Wulff: Employee; Novo Nordisk A/S. S. B. Jørgensen: Employee; Novo Nordisk A/S. B. S. Andersen: Employee; Novo Nordisk A/S. Funding Novo Nordisk A/S