دورية أكاديمية
Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor.
| العنوان: | Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor. |
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| المؤلفون: | Regmi A; Eli Lilly and Company, Indianapolis, IN 46285, USA., Aihara E; Eli Lilly and Company, Indianapolis, IN 46285, USA., Christe ME; Eli Lilly and Company, Indianapolis, IN 46285, USA., Varga G; Eli Lilly and Company, Indianapolis, IN 46285, USA., Beyer TP; Eli Lilly and Company, Indianapolis, IN 46285, USA., Ruan X; Eli Lilly and Company, Indianapolis, IN 46285, USA., Beebe E; Eli Lilly and Company, Indianapolis, IN 46285, USA., O'Farrell LS; Eli Lilly and Company, Indianapolis, IN 46285, USA., Bellinger MA; Eli Lilly and Company, Indianapolis, IN 46285, USA., Austin AK; Eli Lilly and Company, Indianapolis, IN 46285, USA., Lin Y; Eli Lilly and Company, Indianapolis, IN 46285, USA., Hu H; Eli Lilly and Company, Indianapolis, IN 46285, USA., Konkol DL; Eli Lilly and Company, Indianapolis, IN 46285, USA., Wojnicki S; Eli Lilly and Company, Indianapolis, IN 46285, USA., Holland AK; Eli Lilly and Company, Indianapolis, IN 46285, USA., Friedrich JL; Eli Lilly and Company, Indianapolis, IN 46285, USA., Brown RA; Eli Lilly and Company, Indianapolis, IN 46285, USA., Estelle AS; Eli Lilly and Company, Indianapolis, IN 46285, USA., Badger HS; Eli Lilly and Company, Indianapolis, IN 46285, USA., Gaidosh GS; Eli Lilly and Company, Indianapolis, IN 46285, USA., Kooijman S; Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands., Rensen PCN; Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands., Coskun T; Eli Lilly and Company, Indianapolis, IN 46285, USA., Thomas MK; Eli Lilly and Company, Indianapolis, IN 46285, USA., Roell W; Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: bill_roell@lilly.com. |
| المصدر: | Cell metabolism [Cell Metab] 2024 Jul 02; Vol. 36 (7), pp. 1534-1549.e7. Date of Electronic Publication: 2024 Jun 14. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101233170 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-7420 (Electronic) Linking ISSN: 15504131 NLM ISO Abbreviation: Cell Metab Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Cambridge, Mass. : Cell Press, c2005- |
| مواضيع طبية MeSH: | Adipocytes*/metabolism , Adipocytes*/drug effects , Gastric Inhibitory Polypeptide*/metabolism , Gastric Inhibitory Polypeptide*/pharmacology , Receptors, Gastrointestinal Hormone*/metabolism , Receptors, Gastrointestinal Hormone*/agonists, Animals ; Humans ; Male ; Mice ; Glucagon-Like Peptide-1 Receptor/metabolism ; Glucagon-Like Peptide-1 Receptor/agonists ; Glucagon-Like Peptide-2 Receptor ; Glucose/metabolism ; Insulin/metabolism ; Lipolysis/drug effects ; Mice, Inbred C57BL ; Nutrients/metabolism ; Obesity/metabolism ; Obesity/drug therapy ; Signal Transduction/drug effects ; Triglycerides/metabolism |
| مستخلص: | Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state. Competing Interests: Declaration of interests A.R., E.A., M.E.C., G.V., T.P.B., X.R., E.B., L.S.O., M.A.B., A.K.A., Y.L., H.H., D.L.K., S.W., A.K.H., J.L.F., R.A.B., A.S.E., H.S.B., G.S.G., T.C., M.K.T., and W.R. are employees and shareholders at Eli Lilly and Company. P.C.N.R. is supported by the Cardiovascular Research Netherlands for the GENIUS-2 project “Generating the best evidence-based pharmaceutical targets for atherosclerosis” (CVON 2017-20). (Copyright © 2024 Eli Lilly and Company. Published by Elsevier Inc. All rights reserved.) |
| التعليقات: | Erratum in: Cell Metab. 2024 Aug 6;36(8):1898-1899. doi: 10.1016/j.cmet.2024.06.012. (PMID: 38945123) |
| فهرسة مساهمة: | Keywords: GIP; GLP-1; adipocyte; adipose; carbohydrate metabolism; insulin; lipid metabolism; nutrient partitioning; tirzepatide |
| المشرفين على المادة: | 59392-49-3 (Gastric Inhibitory Polypeptide) D6H00MV7K8 (gastric inhibitory polypeptide receptor) 0 (Glucagon-Like Peptide-1 Receptor) 0 (Glucagon-Like Peptide-2 Receptor) IY9XDZ35W2 (Glucose) 0 (Insulin) 0 (Receptors, Gastrointestinal Hormone) OYN3CCI6QE (tirzepatide) 0 (Triglycerides) |
| تواريخ الأحداث: | Date Created: 20240615 Date Completed: 20240703 Latest Revision: 20240807 |
| رمز التحديث: | 20240808 |
| DOI: | 10.1016/j.cmet.2024.05.010 |
| PMID: | 38878772 |
| قاعدة البيانات: | MEDLINE |
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