Bone morphogenetic protein (BMP)‐9 has been reported to regulate energy balance in vivo. However, the mechanisms underlying BMP9‐mediated regulation of energy balance remain incompletely understood. Here, we investigated the role of BMP9 in energy metabolism. In the current study, we found that hepatic BMP9 expression was down‐regulated in insulin resistance (IR) mice and in patients who are diabetic. In mice fed a high‐fat diet (HFD), the overexpression of hepatic BMP9 improved glucose tolerance and IR. The expression of gluconeogenic genes was down‐regulated, whereas the level of insulin signaling molecule phosphorylation was increased in the livers of Adenovirus‐BMP9‐treated mice and glucosamine‐treated hepatocytes. Furthermore, BMP9 overexpression ameliorated triglyceride accumulation and inhibited the expression of lipogenic genes in both human hepatocellular carcinoma HepG2 cells treated with a fatty acid mixture as well as the livers of HFD‐fed mice. In hepatocytes isolated from sterol regulatory element‐binding protein (SREBP)‐1c knockout mice, the effects of BMP9 were ablated. Mechanistically, BMP9 inhibited SREBP‐1c expression through the inhibition of liver X receptor response element 1 activity in the SREBP‐1c promoter. Taken together, our results show that BMP9 is an important regulator of hepatic glucose and lipid metabolism.—Yang, M., Liang, Z., Yang, M., Jia, Y., Yang, G., He, Y., Li, X., Gu, H. F., Zheng, H., Zhu, Z., Li, L. Role of bone morphogenetic protein‐9 in the regulation of glucose and lipid metabolism. FASEB J. 33, 10077–10088 (2019). http://www.fasebj.org

Aims/hypothesis Besides serving as a traditional inflammatory marker, C-reactive protein (CRP) is closely associated with the development of obesity, diabetes and cardiovascular diseases as a metabolic and inflammatory marker. We hypothesise that CRP protein directly participates in the regulation of energy and glucose metabolism rather than just being a surrogate marker, and that genetic deficiency of CRP will lead to resistance to obesity and insulin resistance. Methods Crp gene deletion was achieved by transcription activator-like effector nuclease (TALEN) technology in rats. The Crp knockout animals were placed on either a standard chow diet or a high-fat diet. Phenotypic changes in body weight, glucose metabolism, insulin sensitivity, energy expenditure and inflammation condition were examined. The central impact of CRP deficiency on leptin and insulin hypothalamic signalling, as well as glucose homeostasis, were examined via intracerebral ventricular delivery of leptin and CRP plus glucose clamp studies in the wild-type and Crp knockout rats. Results CRP deficiency led to a significant reduction in weight gain and food intake, elevated energy expenditure and improved insulin sensitivity after exposure to high-fat diet. Glucose clamp studies revealed enhanced hepatic insulin signalling and actions. Deficiency of CRP enhanced and prolonged the weight-reducing effect of central injected leptin and promoted the central and peripheral roles of leptin. By contrast, reinstatement of CRP into the hypothalamus of the knockout rats attenuated the effects of central leptin signalling on insulin sensitivity and peripheral glucose metabolism.Conclusions/interpretation This study represents the first line of genetic evidence that CRP is not merely a surrogate blood marker for inflammation and metabolic syndromes but directly regulates energy balance, body weight, insulin sensitivity and glucose homeostasis through direct regulation of leptin's central effect and hypothalamic signalling.

Aims Irisin, Betatrophin and Zinc-α2-glycoprotein (ZAG) have been shown to be associated with insulin resistance (IR) and polycystic ovary syndrome (PCOS), respectively. The purpose of this study is to explore the potential accuracy of this combination of three cytokines in screening PCOS. Methods 186 individuals were recruited for this study. Circulating Irisin, Betatrophin and ZAG concentrations were measured by enzyme-linked immunosorbent assay. The association between these serum biomarkers and PCOS was assessed by logistic regression analysis. Receiver operating curve (ROC) analysis was performed to evaluate the diagnostic value of these biomarkers for PCOS women. Results In women with PCOS, serum Irisin and Betatrophin levels were markedly elevated compared to those in healthy controls (p<0.01), while ZAG levels were lower (p<0.01). PCOS women with IR (M-value<6.28) had lower circulating ZAG concentrations, and higher circulating Irisin and Betatrophin levels relative to PCOS women without IR (M-value ≥ 6.28). ROC curve analyses showed that the AUC for Irisin, ZAG and Betatrophin for predicting PCOS were 0.77, 0.83 and 0.85, respectively. In a joint ROC curves analysis of these serum markers and other parameters, the results showed that the AUC was 0.93, and the sensitivity and specificity were 82.1 % and 92.3 %, respectively. Conclusions When compared to using single cytokine, the analysis of Irisin, ZAG and Betatrophin elevates the accuracy in diagnosing PCOS.

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Background: Insulin resistance (IR) is a common characteristic of women with polycystic ovary syndrome (PCOS). It has been reported that circulating Fetuin-A levels were associated with IR and type 2 diabetes mellitus (T2DM). However, previous reports were inconsistent. Methods: Two hundred seven subjects were screened for PCOS according to the diagnostic guideline of the Rotterdam consensus criterion. Serum Fetuin-A levels were measured using an ELISA kit. An independent t-test or Nonparametric test was used to detect differences between PCOS and control groups. Spearman's correlation analysis was used to examine the association of the serum Fetuin-A with other parameters. Results: Our findings showed that circulating Fetuin-A concentration ranged from 196.6 to 418.2 μg/L for most women without PCOS (95%). Women with PCOS had higher circulating Fetuin-A levels than healthy women (437.9 ± 119.3 vs. 313.8 ± 60.5 μg/L; p < 0.01). Serum Fetuin-A was positively correlated with BMI, WHR, TG, TC, LDL-C, HOMA-IR, LH, T, and DHEA-S. Multivariate regression analysis showed that WHR, TG, HOMA-IR, and DHEA-S were independent predictors of the levels of circulating Fetuin-A. Binary logistic regression revealed that serum Fetuin-A was associated with the occurrence of PCOS. In addition, our ROC curve analysis found that the cutoff values for Fetuin-A to predict PCOS and IR were 366.3 and 412.6 μg/L. Conclusion: Blood Fetuin-A may be a useful biomarker for screening women for PCOS and IR.