Academic Journal
FGF21 synergizes with leptin to counteract obesity-related metabolic comorbidities by reversing hepatic leptin resistance.
| Τίτλος: | FGF21 synergizes with leptin to counteract obesity-related metabolic comorbidities by reversing hepatic leptin resistance. |
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| Συγγραφείς: | Shen Q; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong SAR, China., Zou H; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China; Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong SAR, China; National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China., Jin L; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong SAR, China., Liu J; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong SAR, China., Wang S; Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou 510005, Guangdong Province, China; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China., Li N; The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Centre for Stem Cell Translational Biology, The University of Hong Kong, Hong Kong SAR, China., Zhou R; AIDS Institute and Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China., Yue M; AIDS Institute and Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China., Wang B; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong SAR, China., Yang R; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong SAR, China., Song E; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China; Institute of Metabolic Science, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510005, Guangdong Province, China., Lin Y; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong SAR, China., Liao S; The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Centre for Stem Cell Translational Biology, The University of Hong Kong, Hong Kong SAR, China., Chen Z; AIDS Institute and Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China., Xiao Y; National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China; Furong Laboratory, Central South University, Changsha 410008, Hunan Province, China., Chan YS; Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou 510005, Guangdong Province, China; The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, Guangdong Province, China., Tse HF; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China; The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Centre for Stem Cell Translational Biology, The University of Hong Kong, Hong Kong SAR, China., Xu A; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China; Department of Medicine, The University of Hong Kong, Hong Kong SAR, China; Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong SAR, China. Electronic address: amxu@hku.hk. |
| Πηγή: | Cell metabolism [Cell Metab] 2026 Sep 01; Vol. 38 (9), pp. 1815-1834.e8. Date of Electronic Publication: 2026 Jul 16. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | 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 |
| Imprint Name(s): | Original Publication: Cambridge, Mass. : Cell Press, c2005- |
| Ιατρικοί όροι (MeSH): | Leptin*/metabolism , Leptin*/agonists , Fibroblast Growth Factors*/metabolism , Fibroblast Growth Factors*/pharmacology , Obesity*/metabolism , Obesity*/complications , Liver*/metabolism , Liver*/drug effects, Receptors, Leptin/metabolism ; Adiponectin/metabolism ; Hepatocytes/metabolism ; Hepatocytes/drug effects ; Fatty Liver/metabolism ; Animals ; Humans ; Mice ; Male ; Mice, Inbred C57BL ; Insulin Resistance |
| Περίληψη: | Leptin resistance hinders its therapeutic potential for obesity-related metabolic comorbidities. Here, we show that fibroblast growth factor 21 (FGF21) synergizes with leptin in metabolic regulation by reversing obesity-induced peripheral leptin resistance. FGF21 acts in adipocytes to promote the secretion of adiponectin, which in turn induces the expression of leptin receptors by phosphorylation and activation of the signal transducer and activator of transcription 1 (STAT1) in hepatocytes. Intraperitoneal injection of a long-acting FGF21/leptin dual agonist achieves much more robust pharmacological effects than FGF21 or leptin mono-agonists in protecting mice from diet-induced weight gain, insulin resistance, hyperglycemia, dyslipidemia, and metabolic dysfunction-associated steatotic liver disease without affecting food intake. In human primary hepatocytes and liver organoids, adiponectin but not FGF21 counteracts palmitate/oleate-induced downregulation of leptin receptor b, thereby restoring the effects of leptin in suppressing gluconeogenesis and hepatic steatosis. Thus, FGF21 and leptin dual agonism may represent a promising therapeutic approach for obesity-related multimorbidity through their synergistic and complementary actions in peripheral tissues. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests The authors declare no competing interests. |
| Contributed Indexing: | Keywords: MASLD; interorgan crosstalk; leptin resistance; metabolic multimorbidity; obesity; peptide hormones |
| Substance Nomenclature: | 0 (Leptin) 62031-54-3 (Fibroblast Growth Factors) 0 (fibroblast growth factor 21) 0 (Receptors, Leptin) 0 (Adiponectin) |
| Entry Date(s): | Date Created: 20260716 Date Completed: 20260901 Latest Revision: 20260901 |
| Update Code: | 20260902 |
| DOI: | 10.1016/j.cmet.2026.06.021 |
| PMID: | 42462724 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1932-7420 |
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| DOI: | 10.1016/j.cmet.2026.06.021 |