Increased energy expenditure through intermittent cold exposure does not enhance tirzepatide-induced weight loss in obese mice

Obesity results from an imbalance between energy intake and energy expenditure. Although pharmacological approaches such as tirzepatide, a dual gastric inhibitory protein/glucagon-like protein-1 receptor agonist, reduce food intake and body weight, enhancing energy expenditure via intermittent cold exposure (ICE)-induced activation of thermogenesis may provide complementary benefits. Intermittent cold exposure increases energy expenditure and improves glucose homeostasis independent of weight loss. The objective of this study was to investigate the individual and combined effects of tirzepatide and intermittent cold exposure (ICE) on weight loss and glucose homeostasis. We hypothesized that combining ICE with tirzepatide would lead to greater weight loss and improvements in glucose homeostasis than tirzepatide alone. Male and female C57BL/6J mice were fed a high-fat diet for 8 wk and then treated with tirzepatide (10 nmol/kg) or vehicle and exposed, or not, to ICE (4°C, 1 h/day, 5 days/wk) for 3 wk. Body weight/composition, energy expenditure, food intake, and glucose homeostasis were assessed. Tirzepatide reduced body weight, food intake, and adiposity in both sexes, whereas ICE acutely increased energy expenditure and improved glucose homeostasis independent of changes in body weight. There were no additive effects of combining tirzepatide and ICE. Our findings highlight that combining tirzepatide-mediated reduction in energy intake with ICE-induced activation of thermogenesis yields complementary, but not necessarily additive improvements in metabolic health.NEW & NOTEWORTHY The combined effects on metabolic health of reduced energy intake with tirzepatide and increased energy expenditure via intermittent cold exposure have not been examined. Despite increasing energy expenditure and improving glucose homeostasis, intermittent cold exposure did not augment tirzepatide-induced weight loss or improvements in glucose metabolism. These findings indicate that, in this model, pharmacological reduction of energy intake is more effective than transient, cold-induced increases in thermogenesis for weight loss and adiposity.