In mice, putting tirzepatide into a special gel that sticks to fat tissue makes the drug stay longer in that spot, leading to bigger weight loss and better blood fats, but it only works if the animal’s leptin system is working. The glucose‑lowering effect stays the same. This shows tirzepatide may act directly on fat via leptin signals, but the method isn’t ready for people yet.

Tirzepatide (TZP), a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, has been showing superior benefits in weight loss and glucose lowering in patients with obesity, while the tissue-specific mechanisms of TZP as well as its side effects remain to be investigated. We aimed to explore whether localized injection of TZP into inguinal white adipose tissue (iWAT) would be as effective as subcutaneous injection for weight loss, in order to understand the local effects and signaling pathways of TZP for precision medicine. Mesoporous polydopamine was synthesized and mixed with TZP for encapsulation (MPDA@TZP), followed by characterization of its retention in iWAT after local injection. Both diet-induced obesity (DIO) mice and db/db mice received local injection of TZP, and transcriptomic analysis of iWATs was performed. iWATs were also dissected for ex vivo assays. MPDA@TZP successfully increased the retention time of TZP in the iWAT of mice and had a more dramatic effect on weight loss and improvement in plasma lipid profiles compared to TZP alone in DIO mice, while showing comparable glucose-lowering efficacy. Transcriptomic analysis indicated that iWAT injection of MPDA@TZP improved leptin resistance, beiging, lipid metabolism, mitochondrial activity and branched-chain amino acid (BCAA) catabolism in iWAT. Leptin receptor deficiency in db/db mice abolished the weight reduction effect of MPDA@TZP via iWAT local injection compared to that in DIO mice, while the glucose-lowering effects were comparable in both db/db and DIO mice. These findings indicate that the retention of TZP in iWAT via MPDA encapsulation amplified its effect on weight loss in mice through leptin receptor signaling compared with TZP alone, which provides new insights into the tissue-specific mechanism and alternative delivery strategies of TZP for targeting specific WAT tissues.