INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Weiting Hu,Wenyu Gong,Fan Yang,Rui Cheng,Gerong Zhang,Lu Gan,Yikun Zhu,Weiwei Qin,Ying Gao,Xing Li,Jing Liu
Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors and is a promising therapeutic option for type 2 diabetes mellitus (T2DM). Nevertheless, its effect and underlying mechanism on hepatic steatosis remain ambiguous. Herein, we explored the impact of tirzepatide on improving hepatic steatosis in diabetic mice, with a particular focus on the gut microbiota and bile acids (BAs) using animal models. The tirzepatide effectively reduced body weight, improved insulin resistance, decreased serum and hepatic lipid levels, and mitigated liver injury. Compared to semaglutide, tirzepatide exhibited superior efficacy in reducing hepatic lipid accumulation. 16S rRNA gene sequencing and targeted metabolomics of BAs revealed that tirzepatide ameliorated gut microbiota dysbiosis and BAs metabolism in diabetic mice. Notably, tirzepatide observably increased the abundance of beneficial genera such as Akkermansia , elevated the ratio of farnesoid X receptor (FXR) antagonists (glycoursodeoxycholic acid: GUDCA, β-muricholic acid: β-MCA, hyodeoxycholic acid: HDCA, ursodeoxycholic acid: UDCA) to natural agonists (cholic acid: CA, lithocholic acid: LCA, chenodeoxycholic acid: CDCA, glycocholic acid: GCA, taurodeoxycholic acid: TDCA), and reduced FXR expression in intestinal tissues. In conclusion, tirzepatide attenuated hepatic steatosis in diabetic mice and regulated the gut microbiota and BAs metabolism, which may help to provide a novel therapeutic approach and therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD).
研究领域:
药理学
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代谢组学
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微生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
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2025
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IF 13
Lin Mi,Tan Li,Xiaoxin Xiang,Yimin Zhou,Na Xiong,Yanyu Chen,Jiaoting Chen,Sijia Shang,Shumeng Chen,Wai W. Cheung,Zecong Xiao,Yanming Chen,Jiahai Wang,Jun Peng,Xintao Shuai,Guojun Shi
Introduction 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. Objectives 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. Methods 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. Results 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. Conclusion 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.
研究领域:
内分泌学
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代谢学
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药物递送
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肥胖研究
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分子信号传导
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
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2024
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IF 3.3
Yuanzhen Dong,Jinhua Zhang,Hongjiang Xu,Hengqiao Shen,Qin Lu,Jun Feng,Zhengyan Cai
Tirzepatide , the first approved dual GLP-1/GIP receptor agonist (RA), has achieved better clinical outcomes than other GLP-1RAs. However, it is an imbalanced dual GIP/GLP-1 RA, and it remains unclear whether the degree of imbalance is optimal. Here, we present a novel long-acting dual GLP-1/GIP RA that exhibits better activity than tirzepatide toward GLP-1R. A candidate conjugate, D314, identified via peptide design, synthesis, conjugation, and experimentation, was evaluated using chronic studies in db/db and diet induced obese (DIO) mice. D314 achieved favorable blood glucose and body weight-lowering effects, equal to those of tirzepatide. Its half-life in dogs (T 1/2 : 78.3 ± 14.01 h) reveals its suitability for once-weekly administration in humans . This preclinical study suggests the potential role of D314 as an effective agent for treating T2DM and obesity.
研究领域:
药理学
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内分泌学
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糖尿病研究
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药物开发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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