Tirzepatide is an anti-obesity drug based on dual agonism of the incretin receptors GLP-1R and GIPR. Its anti-obesity effect is largely based on its action of reducing food intake. However, there are indications that tirzepatide exerts effects on adipose tissues beyond those resulting from fat loss due to reduced food intake. To investigate this, we treated mice, previously been made obese through high-fat diet, with tirzepatide. We also established an experimental group of mice pair-fed with those treated with tirzepatide, key to distinguish the specific effect of tirzepatide from food intake reduction-mediated effects. Both groups experienced similar reduction in body weight, with a trend toward greater loss in visceral and subcutaneous white fat in mice under tirzepatide treatment. Glucose tolerance improved in tirzepatide-treated obese mice, independently of reduced food intake. Tirzepatide treatment also lowered the inflammatory status of obese mice, which in this case, was attributable to decreased food consumption. Tirzepatide exerted distinct effects on brown adipose tissue relative to white adipose tissues, significantly boosting thermogenic activity and modifying its gene expression pattern, including the upregulation of genes linked to thermogenesis and substrate oxidation. White adipose tissues responded differently, being primarily affected in their lipid metabolism. These effects were specific to tirzepatide treatment and not attributable to reduced food intake. Our results indicate that tirzepatide affects the function and metabolism of adipose tissues and especially induces activation of brown adipose tissue in mice, which may be relevant for future human studies to ascertain the mechanisms of tirzepatide metabolic benefits.
