Tirzepatide reverses hypothalamic inflammation, cellular stress, and neuropeptide imbalance in metabolic-menopausal dysfunction.

Obesity, diabetes, and menopause impair hypothalamic regulation of energy balance by inducing inflammation, cellular stress, and disruption of neuropeptide signaling. In a female mouse model combining these conditions, we investigated whether tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, restores hypothalamic homeostasis by integrating gene and protein expression analyses. Ovariectomized and sham-operated mice were fed either a control or high-fat, high-sucrose diet and then treated with tirzepatide for four weeks. Metabolic and hormonal stress induced robust activation of inflammatory pathways, elevated cytokine and chemokine expression, marked endoplasmic reticulum stress, and enhanced microglial reactivity, accompanied by a shift toward appetite-stimulating neuropeptides and reduced expression of appetite-suppressing neuropeptides. Tirzepatide produced broad hypothalamic benefits, markedly suppressing inflammatory and stress-related markers, reprogramming microglia toward an anti-inflammatory phenotype, and restoring neuropeptide balance by reducing agouti-related peptide and neuropeptide Y while increasing proopiomelanocortin and melanocortin 4 receptor expression. Treatment also lowered suppressor of cytokine signaling 3 and normalized doublecortin expression, indicating enhanced neuronal plasticity and recovery of hypothalamic circuitry. Multivariate analysis demonstrated that tirzepatide shifted the overall hypothalamic molecular profile of obese-diabetic and ovariectomized mice to that of control groups, highlighting coordinated improvement across inflammatory, glial, and neuropeptidergic pathways. In conclusion, these findings show that tirzepatide exerts potent and broad central nervous system actions capable of counteracting hypothalamic inflammation, cellular stress, microglial activation, and neuropeptide dysregulation under severe metabolic-hormonal challenge, supporting its therapeutic potential to restore hypothalamic integrity and metabolic control in obesity and diabetes during menopause.