Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, 
delivered superior glycemic control and weight loss compared with GLP-1R agonism 
in patients with type 2 diabetes. However, the mechanism by which tirzepatide 
improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully 
understood. Here, we show that tirzepatide is an effective insulin sensitizer, 
improving insulin sensitivity in obese mice to a greater extent than GLP-1R 
agonism. To determine whether GIPR agonism contributes, we compared the effect 
of tirzepatide in obese WT and Glp-1r-null mice. In the absence of 
GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by 
enhancing glucose disposal in white adipose tissue (WAT). In support of this, a 
long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by 
augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and 
LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino 
acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was 
associated with upregulation of genes associated with the catabolism of glucose, 
lipid, and BCAAs in brown adipose tissue. Together, our studies show that 
tirzepatide improved insulin sensitivity in a weight-dependent and -independent 
manner. These results highlight how GIPR agonism contributes to the therapeutic 
profile of dual-receptor agonism, offering mechanistic insights into the 
clinical efficacy of tirzepatide.