This study investigated the therapeutic potential of tirzepatide, a dual GIP/GLP-1 receptor agonist, in a mouse model combining obesity, type 2 diabetes, and estrogen deficiency. Four groups were initially established and maintained for 12 weeks under ovariectomy and/or a high-fat-high-sucrose diet: control sham (C), control ovariectomy (CO), obese-diabetic (Od), and obese-diabetic ovariectomy (OdO). Mice were then treated with tirzepatide (10 nmol/kg/day) for 4 weeks, generating CT, COT, OdT, and OdOT groups. Od and OdO mice exhibited a 1.3-fold increase in body weight (BW) compared with controls. Tirzepatide normalized BW and reduced relative BAT mass by 25 %. It also corrected the 3.6-fold elevation in leptin and the 1.8-fold increase in insulin observed in Od mice, and reduced Monocyte Chemotactic Protein-2 and resistin levels by approximately 60 % and 42 %, respectively. Histological and molecular analyses showed that tirzepatide reversed BAT whitening, restored multilocular adipocyte morphology, and increased the expression of key thermogenic markers, including uncoupling protein-1 and the β3-adrenergic receptor. Three-way ANOVA revealed tirzepatide as the most potent regulator of the BAT gene landscape. Treatment reversed the suppression of thermogenic and mitochondrial fusion genes in Od and OdO mice and normalized markers of endoplasmic reticulum stress and autophagy dysfunction. Principal component analysis further demonstrated this global rescue, with OdT and OdOT transcriptomic profiles clustering closely with those of healthy controls. In conclusion, tirzepatide acts as a multifaceted therapy that improves obesity, systemic inflammation, and impaired BAT thermogenic function in a model of postmenopausal metabolic dysfunction.
