Tirzepatide Synergizes with Leptin on Weight Loss and Restoring Metabolic Homeostasis in Diet-induced Obesity Model
Leptin resistance limits anti-obesity efficacy. We identified a leptin-sensitizing mechanism through tirzepatide (TZP), a glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) dual-agonist. Our tirzepatide clinical trial revealed that circulating leptin levels at baseline correlated with weight loss efficacy in patients with obesity, suggesting leptin and tirzepatide could interact to achieve stronger effects on weight loss. Next, we utilized the diet-induced obesity (DIO) mice and demonstrated the synergistic effects of tirzepatide and leptin combination (TZP+Lep) on weight loss. TZP+Lep treatment further improved hepatic insulin sensitivity and upregulated thermogenetic gene expression in brown adipose tissue. Metabolic profiling under thermoneutrality revealed TZP+Lep treatment further reduced food intake and increased energy expenditure. Tirzepatide sensitized leptin signaling in hypothalamic pro-opiomelanocortin (POMC) and GLP-1R expressing neurons. TZP+Lep synergistically increased POMC neuronal firing by decreasing the inhibitory postsynaptic input. Together, our work showed combining tirzepatide and leptin as a potential way for better maintenance of metabolic homeostasis in obesity management. HighlightsO_LITirzepatide and leptin synergistically promote weight loss through reduced food intake and increased energy expenditure. C_LIO_LITirzepatide and leptin synergistically improve insulin sensitivity and metabolic homeostasis with altered hepatic and adipose gene expression. C_LIO_LITirzepatide sensitizes leptin signaling in hypothalamic GLP-1R and POMC neurons. C_LIO_LITirzepatide and leptin synergistically increase POMC neuronal firing by decreasing inhibitory postsynaptic input. C_LI