Research Papers: Gerotarget (Focus on Aging):

Circulating betatrophin is associated with insulin resistance in humans: cross-sectional and interventional studies in vivo and in vitro

Han Wang, Lin Du, Tong Wu, Gangyi Yang, Wenjing Hu, Hansheng Wang, Mengliu Yang, Dongfang Liu, Harvest F. Gu, Zhiming Zhu, Hongting Zheng and Ling Li _

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Oncotarget. 2017; 8:96604-96614. https://doi.org/10.18632/oncotarget.21852

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Han Wang1,*, Lin Du1,*, Tong Wu2, Gangyi Yang2, Wenjing Hu2, Hansheng Wang1, Mengliu Yang2, Dongfang Liu2, Harvest F. Gu3,4, Zhiming Zhu5, Hongting Zheng6 and Ling Li1

1 The Key Laboratory of Laboratory Medical Diagnostics in The Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China

2 Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China

3 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden

4 Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Solna, Stockholm, Sweden

5 Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China

6 Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China

* These authors have contributed equally to this project

Correspondence to:

Ling Li, email:

Keywords: betatrophin; insulin resistance; metabolic disorders; interventional study; cell cross-talk; Gerotarget

Received: August 15, 2017 Accepted: October 05, 2017 Published: October 16, 2017


Betatrophin has a closely relationship with metabolism. However, its effect on metabolism disorder remains unclear. This study was comprised of a series of cross-sectional and interventional studies in vivo and vitro. PCOS women with IR and healthy women were recruited from the general population and outpatients. Plasma betatrophin levels were measured with ELISA. Insulin sensitivity was assessed with EHC. Gene expressions at mRNA and protein levels were determined with RT-PCR and Western blotting. Influences of insulin, metformin, rosiglitazone and over- or knockdown-expression of betatrophin were analyzed ex vivo. Our results indicated that IR women had higher betatrophin levels compared with the controls. Circulating betatrophin was positively correlated with BMI, WHR, Fat%, triglyceride, total cholesterol, LDL-C, AUCglucose and AUCinsulin, luteinizing Hormone, FAI and HOMA-IR but negatively with M-value. Metformin treatment in PCOS women with IR led to a reduction of betatrophin levels. Insulin stimulation in hepatocytes increased betatrophin expression. Metformin or rosiglitazone led to a reduction of betatrophin expression in insulin-stimulated hepatocytes. In hepatocytes/macrophages co-culture systems, betatrophin expression was significantly increased, whereas this increase was eliminated by rosiglitazone. In hepatocytes, overexpression and knockdown of betatrophin decreased or increased insulin-stimulated insulin receptor, protein kinase B and insulin receptor substrate-1 phosphorylation respectively. Serum from metformin-treated women with IR decreased betatrophin expression and reinforced insulin signals. Thus, the present study provides the in vivo and in vitro evidence, suggesting that there is a cell cross-talking between hepatocytes with macrophages for the regulating betatrophin and it may be a useful marker for IR and metabolic disorders.

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