Hepatokine Fetuin B Expression is Regulated by Leptin-STAT3 Signalling and Associated with Leptin in Obesity

Overview

Journal Sci Rep

Specialty Science

Date 2022 Jul 27

PMID 35896788

Authors

Dongmei Wang

Menghua Wu

Xiaofang Zhang

Long Li

Mingzhu Lin

Xiulin Shi

Yan Zhao

Caoxin Huang

Xuejun Li

Affiliations

Soon will be listed here.

Abstract

Obesity is an expanding global public health problem and a leading cause of metabolic disorders. The hepatokine Fetuin B participates in regulating insulin resistance, glucose metabolism and liver steatosis. However, the mechanism underlying Fetuin B activation remains unclear. Our previous population-based study demonstrated a significant association between serum Fetuin B and body fat mass in an obese population, which indicates its potential in mediating obesity-related metabolic disorders. In the present study, we further revealed a significant correlation between Fetuin B and leptin, the classic adipokine released by expanding adipose tissue, in this obese population. Consistently, elevated Fetuin B and leptin levels were confirmed in diet-induced obese mice. Furthermore, an in vitro study demonstrated that the leptin signalling pathway directly activated the transcription and expression of Fetuin B in primary hepatocytes and AML12 cells in a STAT3-dependent manner. STAT3 binds to the response elements on FetuB promoter to directly activate FetuB transcription. Finally, the mediating effect of Fetuin B in insulin resistance induced by leptin was confirmed according to mediation analysis in this obese population. Therefore, our study identifies leptin-STAT3 as an upstream signalling pathway that activates Fetuin B and provides new insights into the pathogenic mechanisms of obesity-related metabolic disorders.

Citing Articles

Metabolically Healthy Obesity Is Characterized by a Distinct Proteome Signature.

Mir F, Abdesselem H, Cyprian F, Iskandarani A, Doudin A, Shraim M Int J Mol Sci. 2025; 26(5).

PMID: 40076884 PMC: 11901089. DOI: 10.3390/ijms26052262.

The interplay between the muscle and liver in the regulation of glucolipid metabolism.

Chen C, Xie L, Zhang M, Shama , Cheng K, Jia W J Mol Cell Biol. 2023; 15(12).

PMID: 38095440 PMC: 11078061. DOI: 10.1093/jmcb/mjad073.

The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease-The Transition from an Adipocentric to Liver-Centric Approach.

Veskovic M, Sutulovic N, Hrncic D, Stanojlovic O, Macut D, Mladenovic D Curr Issues Mol Biol. 2023; 45(11):9084-9102.

PMID: 37998747 PMC: 10670061. DOI: 10.3390/cimb45110570.

Inter-organ crosstalk during development and progression of type 2 diabetes mellitus.

Xourafa G, Korbmacher M, Roden M Nat Rev Endocrinol. 2023; 20(1):27-49.

PMID: 37845351 DOI: 10.1038/s41574-023-00898-1.

Insulin resistance and cardiovascular disease.

Kosmas C, Bousvarou M, Kostara C, Papakonstantinou E, Salamou E, Guzman E J Int Med Res. 2023; 51(3):3000605231164548.

PMID: 36994866 PMC: 10069006. DOI: 10.1177/03000605231164548.

References

Adamska A, Polak A, Krentowska A, Lebkowska A, Hryniewicka J, Lesniewska M . Increased serum fetuin-B concentration is associated with HOMA-β and indices of liver steatosis in women with polycystic ovary syndrome: a pilot study. Endocr Connect. 2019; 8(8):1159-1167. PMC: 6686951. DOI: 10.1530/EC-19-0243. View

Huynh F, Neumann U, Wang Y, Rodrigues B, Kieffer T, Covey S . A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice. Hepatology. 2012; 57(2):543-54. DOI: 10.1002/hep.26043. View

Olivier E, Soury E, Ruminy P, Husson A, Parmentier F, DAVEAU M . Fetuin-B, a second member of the fetuin family in mammals. Biochem J. 2000; 350 Pt 2:589-97. PMC: 1221288. View

Kim M, Namkung J, Chang J, Kim S, Park K, Kong I . Leptin regulates the expression of angiopoietin-like 6. Biochem Biophys Res Commun. 2018; 502(3):397-402. DOI: 10.1016/j.bbrc.2018.05.180. View

Liu Y, Nakagawa Y, Wang Y, Li R, Li X, Ohzeki T . Leptin activation of corticosterone production in hepatocytes may contribute to the reversal of obesity and hyperglycemia in leptin-deficient ob/ob mice. Diabetes. 2003; 52(6):1409-16. DOI: 10.2337/diabetes.52.6.1409. View

Dsouza A, Neumann U, Glavas M, Kieffer T . The glucoregulatory actions of leptin. Mol Metab. 2017; 6(9):1052-1065. PMC: 5605734. DOI: 10.1016/j.molmet.2017.04.011. View

Polyzos S, Kountouras J, Mantzoros C . Leptin in nonalcoholic fatty liver disease: a narrative review. Metabolism. 2014; 64(1):60-78. DOI: 10.1016/j.metabol.2014.10.012. View

Watt M, Miotto P, De Nardo W, Montgomery M . The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance. Endocr Rev. 2019; 40(5):1367-1393. DOI: 10.1210/er.2019-00034. View

Nimptsch K, Konigorski S, Pischon T . Diagnosis of obesity and use of obesity biomarkers in science and clinical medicine. Metabolism. 2018; 92:61-70. DOI: 10.1016/j.metabol.2018.12.006. View

10.

Lu Y, Wang E, Chen Y, Zhou B, Zhao J, Xiang L . Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor. J Clin Invest. 2020; 130(7):3791-3804. PMC: 7324200. DOI: 10.1172/JCI134485. View

11.

Xue S, Han H, Rui S, Yang M, Huang Y, Zhan B . Serum Fetuin-B Levels Are Elevated in Women with Metabolic Syndrome and Associated with Increased Oxidative Stress. Oxid Med Cell Longev. 2021; 2021:6657658. PMC: 8505080. DOI: 10.1155/2021/6657658. View

12.

Yan B, Shi X, Zhang H, Pan L, Ma Z, Liu S . Association of serum irisin with metabolic syndrome in obese Chinese adults. PLoS One. 2014; 9(4):e94235. PMC: 3978033. DOI: 10.1371/journal.pone.0094235. View

13.

Becerril S, Rodriguez A, Catalan V, Ramirez B, Unamuno X, Gomez-Ambrosi J . Gene Ablation Prevents Liver Fibrosis in Leptin-Deficient Mice. Genes (Basel). 2019; 10(3). PMC: 6470935. DOI: 10.3390/genes10030184. View

14.

Zheng F, Cai Y . Concurrent exercise improves insulin resistance and nonalcoholic fatty liver disease by upregulating PPAR-γ and genes involved in the beta-oxidation of fatty acids in ApoE-KO mice fed a high-fat diet. Lipids Health Dis. 2019; 18(1):6. PMC: 6320624. DOI: 10.1186/s12944-018-0933-z. View

15.

Li Z, Lin M, Liu C, Wang D, Shi X, Chen Z . Fetuin-B links nonalcoholic fatty liver disease to type 2 diabetes via inducing insulin resistance: Association and path analyses. Cytokine. 2018; 108:145-150. DOI: 10.1016/j.cyto.2018.03.023. View

16.

Zampieri T, Ramos-Lobo A, Furigo I, Pedroso J, Buonfiglio D, Donato Jr J . SOCS3 deficiency in leptin receptor-expressing cells mitigates the development of pregnancy-induced metabolic changes. Mol Metab. 2015; 4(3):237-45. PMC: 4338315. DOI: 10.1016/j.molmet.2014.12.005. View

17.

Ikejima K, Lang T, Zhang Y, Yamashina S, Honda H, Yoshikawa M . Expression of leptin receptors in hepatic sinusoidal cells. Comp Hepatol. 2004; 3 Suppl 1:S12. PMC: 2410235. DOI: 10.1186/1476-5926-2-S1-S12. View

18.

Aiston S, Agius L . Leptin enhances glycogen storage in hepatocytes by inhibition of phosphorylase and exerts an additive effect with insulin. Diabetes. 1999; 48(1):15-20. DOI: 10.2337/diabetes.48.1.15. View

19.

Polyzos S, Kountouras J, Zavos C, Deretzi G . The potential adverse role of leptin resistance in nonalcoholic fatty liver disease: a hypothesis based on critical review of the literature. J Clin Gastroenterol. 2010; 45(1):50-4. DOI: 10.1097/MCG.0b013e3181ec5c66. View

20.

Denroche H, Huynh F, Kieffer T . The role of leptin in glucose homeostasis. J Diabetes Investig. 2014; 3(2):115-29. PMC: 4020728. DOI: 10.1111/j.2040-1124.2012.00203.x. View