BMP7 improves insulin signal transduction in the liver via inhibition of mitogen-activated protein kinases

in Journal of Endocrinology
Correspondence should be addressed to Y Gu: desette@ntu.edu.cn

*(H Ma and J Yuan contributed equally to this work)

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Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-β (TGF-β) family, plays pivotal roles in energy expenditure. However, whether and how BMP7 regulates hepatic insulin sensitivity is still poorly understood. Here, we show that hepatic BMP7 expression is reduced in high-fat diet (HFD)-induced diabetic mice and palmitate (PA)-induced insulin-resistant HepG2 and AML12 cells. BMP7 improves insulin signaling pathway in insulin resistant hepatocytes. On the contrary, knockdown of BMP7 further impairs insulin signal transduction in PA-treated cells. Increased expression of BMP7 by adenovirus expressing BMP7 improves hyperglycemia, insulin sensitivity and insulin signal transduction. Furthermore, BMP7 inhibits mitogen-activated protein kinases (MAPKs) in both the liver of obese mice and PA-treated cells. In addition, inhibition of MAPKs recapitulates the effects of BMP7 on insulin signal transduction in cultured hepatocytes treated with PA. Activation of p38 MAPK abolishes the BMP7-mediated upregulation of insulin signal transduction both in vitro and in vivo. Together, our results show that hepatic BMP7 has a novel function in regulating insulin sensitivity through inhibition of MAPKs, thus providing new insights into treating insulin resistance-related disorders such as type 2 diabetes.

 

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    BMP7 expression is reduced in insulin-resistant liver and hepatocyte. (A) Body weight changes over 14 weeks. Male C57BL/6J mice were fed with NCD or HFD diet for 14 weeks. Body weight and blood glucose were monitored throughout the whole treatment. At the end of treatments, mice were killed and livers were sampled for further analyses. (B) Fasting blood glucose levels. For analyzing blood glucose, mice were fasted for 6 h (8:00–14:00) and blood samples were collected from the tail vein. Blood glucose was measured by a glucometer. (C) Glucose tolerance tests. (D) Triglyceride levels in the liver. (E) The protein levels of BMP7 and insulin signal transduction in the liver were analyzed by Western blot. GAPDH was used as a loading control. (F) Quantitative analysis of the blots as shown in (E). (G) BMP7 expression was reduced in the liver of obese mice. Total RNA was extracted for measuring mRNA levels of BMP7 by qRT-PCR. 18S was used as a house keeping gene. (H) Effects of palmitate on BMP7 expression and insulin signal pathway. HepG2 cells were incubated with or without 0.4 mM palmitate (PA) for 24 h. Insulin signal transduction was stimulated by 10 nM insulin for 5 min. Total cell lysates were prepared and subjected to Western blot. GAPDH was used as a loading control. (I) Quantitative analysis of the blots as shown in (H). (J) Palmitate reduces BMP7 expression induced by insulin in HepG2 cells. Cell treatments were described in (I). Total RNA was extracted for measuring mRNA levels of BMP7 by qRT-PCR. 18S was used as a house keeping gene. NCD, normal chow diet; HFD, high-fat diet; CON, control; INS, insulin; PA, palmitate. Data are expressed as mean ± s.e.m. from n = 3 independent experiments. *P < 0.05, ***P < 0.001 vs NCD in (A, B, C, D, F and G). *P < 0.05 vs CON, # P < 0.05 vs INS in (I and J).

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    Increased expression of BMP7 ameliorates palmitate-induced insulin resistance in HepG2 cells. HepG2 cells were transduced with adenovirus expressing GFP (Ad-GFP) or BMP7 (Ad-BMP7) for 24 h and then cells were incubated with or without 0.4 mM palmitate (PA) for 24 h. Insulin signal transduction was stimulated by 10 nM insulin for 5 min. (A) Effects of BMP7 on insulin signal transduction. The protein levels were detected by Western blot. GAPDH was used as a loading control. (B) Quantitative analysis of the blots as shown in (A). (C) BMP7 promotes glucose uptake in PA-treated HepG2 cells. (D) BMP7 stimulates GLUT4 translocation in plasma membrane of HepG2 cells. At the end of treatments, protein fraction in plasma membrane was isolated and subjected to Western blot analysis. Na/K-ATPase was used as a loading control. (E) Quantitative analysis of the blots as shown in (D). (F) BMP7 reduces G6Pase and PEPCK expression. Gene expression was analyzed by qRT-PCR. 18S was used as a house keeping gene. (G) Lipid accumulation was determined by Oil red O staining. CON, control; PA, palmitate; INS, insulin. Data are expressed as mean ± s.e.m. from n = 3 independent experiments. *P < 0.05 vs INS, # P < 0.05 vs INS + PA. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0693.

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    BMP7 improves insulin signal transduction in AML12 cells treated with palmitate. (A) BMP7 potentiates insulin signal transduction in insulin-resistant AML12 cells induced by palmitate (PA). AML12 cells were transduced with adenovirus expressing GFP (Ad-GFP) or BMP7 (Ad-BMP7). 24 h post-viral transduction, cells were treated with 0.4 mM PA for additional 24 h. At the end of treatments, cells were incubated with insulin (10 nM) for 5 min to stimulate insulin signal pathway. Total cell lysates were prepared and subjected to Western blot analysis. GAPDH was used as a loading control. (B) Quantitative analysis of the blots as shown in (A). *P < 0.05 vs INS; # P < 0.05 vs INS + PA + Ad-GFP. (C) Effects of BMP7 siRNAs on mRNA levels of BMP7. AML12 cells were transfected with three pairs of siRNAs targeting Bmp7. 72 h post-transfection, total RNA was extracted for measuring mRNA levels of BMP7 by qRT-PCR. 18S was used as a house-keeping gene. ***P < 0.001 vs NS. (D) Effects of BMP7 siRNAs on protein levels of BMP7. AML12 cells were treated as mentioned in (C). At the end of treatment, total cell lysates were prepared and subjected to Western blot analysis. GAPDH was used as a loading control. *P < 0.05 and ***P < 0.001 vs NC. (E) Knockdown of BMP7 further impedes insulin signal transduction in PA-treated AML12 cells. Cells were transfected with BMP7 siRNA-2 for 48 h and then cells were treated with 0.4 mM PA for additional 24 h. To stimulate insulin signal pathway, cells were incubated with insulin (10 nM) for 5 min. Total cell lysates were prepared and subjected to Western blot analysis. GAPDH was used as a loading control. (F) Quantitative analysis of the blots as shown in (E). *P < 0.05 vs INS; # P < 0.05 vs INS + PA + NC. INS, insulin; PA, palmitate; NC, negative control. Data are represented as mean ± s.e.m. from n = 3 independent experiments.

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    Increased expression of BMP7 ameliorates insulin resistance in obese mice. Male C57BL/6J mice were fed with NCD or HFD diet for 14 weeks and then injected with Ad-BMP7 or Ad-GFP via the tail vein. Blood glucose, insulin, GTT and ITT were assayed at different time points as indicated. (A) Hepatic BMP7 expression and insulin signaling pathway at 14 days post-adenovirus transduction. (B) Quantitative analysis of the blots as shown in (A). (C) BMP7 decreases fasting and fed blood glucose levels in obese mice. For fasting, mice deprived of food for 6 h (8:00 h–14:00 h). Blood samples were collected from the tail vein at 7 days post-adenovirus injection. (D) BMP7 reduces fasting and fed serum insulin levels in obese mice. For fasting, mice deprived of food for 6 h (8:00 h–14:00 h). Blood samples were collected from the tail vein at 7 days post-adenovirus injection. (E) Homeostasis model assessment-insulin resistance (HOMA-IR) index. (F) BMP7 increases GLUT4 expression in plasma membrane of hepatic cells. Protein fraction in plasma membrane was isolated from the liver and subjected to Western blot analysis. Na/K-ATPase was used as a loading control. (G) BMP7 improves glucose tolerance in obese mice. GTT was performed at 9 days post-adenovirus injection. (H) BMP7 improves insulin tolerance in obese mice. ITT was performed at 11 days post-adenovirus injection. (I–J) Expression of BMP7 in skeletal muscle (I) and white adipose tissues (J) in obese mice transduced with adenovirus expressing BMP7. Total cell lysates were prepared from gastrocnemius muscle and epididymal fat tissues. Protein levels were analyzed by Western blot and GAPDH was used as a loading control. NCD, normal chow diet; HFD, high-fat diet; Ad-GFP, adenovirus expressing GFP; Ad-BMP7, adenovirus expressing BMP7. Data are expressed as mean ± s.e.m. (n = 7). The experiments were performed two times independently. *P < 0.05, ***P < 0.001 vs NCD; # P < 0.05, ## P < 0.01 vs HFD + Ad-GFP.

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    Increased expression of BMP7 ameliorates lipid deposition in the liver of obese mice. Male C57BL/6J mice were fed with NCD or HFD diet for 14 weeks and then injected with Ad-BMP7 or Ad-GFP via the tail vein. At 14 days post-adenovirus injection, mice were killed and liver samples were collected for histological analyses and biochemical assays. (A) Immunochemical analysis of BMP7 expression in the liver. (B) H&E staining (upper panel) and Oil Red O staining of the liver (lower panel). (C) Liver triglyceride concentrations. (D) Liver free cholesterol levels. NCD, normal chow diet; HFD, high-fat diet; Ad-GFP, adenovirus expressing GFP; Ad-BMP7, adenovirus expressing BMP7. Data are presented as means ± s.e.m. (n = 7). The experiments were performed two times independently. *P < 0.05, ***P < 0.001 vs NCD; # P < 0.05, ### P < 0.001 vs HFD + Ad-GFP. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0693.

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    BMP7 regulates insulin signal transduction via inhibition of MAPKs. (A) Mitogen-activated protein kinases (MAPKs) signaling pathway in the liver of obese mice was analyzed by Western blot. GAPDH was used as a loading control. Male C57BL/6J mice were fed with NCD or HFD diet for 14 weeks and then injected with Ad-BMP7 or Ad-GFP via the tail vein. At 14 days post-adenovirus injection, mice were killed and liver samples were collected. Total cell lysates were prepared and subjected to Western blot analysis. (B) Quantitative analysis of the blots as shown in (A). (C) BMP7 counteracts palmitate-stimulated MAPKs signaling pathway in HepG2 cells. HepG2 cells were transduced with Ad-GFP or Ad-BMP7 as indicated. 12 h post transduction, cells were incubated with or without 0.4 mM palmitate (PA) for 24 h. Insulin signal transduction was stimulated by 10 nM insulin for 5 min. Total cell lysates were prepared and subjected to Western blot analysis. GAPDH was used as a loading control. (D) Quantitative analysis of the blots as shown in (C). (E) BMP7 blocks MAPKs signaling pathway in palmitate-treated AML12 cells. Cell treatments were similar to the procedures described in (C). Protein levels were examined by Western blot and GAPDH was used as a loading control. (F) Quantitative analysis of the blots as shown in (E). NCD, normal chow diet; HFD, high-fat diet; Ad-GFP, adenovirus expressing GFP; Ad-BMP7, adenovirus expressing BMP7; INS, insulin; PA, palmitate. Data are presented as means ± s.e.m. from two (in vivo; n = 7) or three (in vitro; n = 3) independent experiments. *P < 0.05 vs NCD; # P < 0.05 vs HFD + Ad-GFP in (B); *P < 0.05 vs INS; # P < 0.05 vs INS + PA + Ad-GFP in (D).

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    Inhibition of the MAPKs pathway is responsible for BMP7-mediated upregulation in insulin signal transduction in HepG2 cells. The HepG2 cells were pre-treated with ERK inhibitor (U0126, 10 μM), or p38 inhibitor (SB203580, 10 μM) or JNK inhibitor SP600125 (10 μM) for 30 min and then 0.4 mM PA was added for additional 24 h. Insulin signal transduction was stimulated by 10 nM insulin for 5 min. (A) Effects of ERK inhibition on insulin signal transduction. The protein levels were analyzed by Western blot. GAPDH was used as a loading control. (B) Effects of p-P38 MAPK inhibition on insulin signal transduction. Protein levels were analyzed by Western blot. GAPDH was used as a loading control. (C) Effects of JNK inhibition on insulin signal transduction. Protein levels were analyzed by Western blot. GAPDH was used as a loading control. (D) p-P38 MAPK activation abolishes the stimulating effect of BMP7 on insulin signal transduction. HepG2 cells were transduced with Ad-BMP7 or Ad-GFP for 24 h, and then the cells were transfected with MKK6Glu. Palmitate (PA; 0.4 mM) was added for 24 h to induce insulin resistance. Insulin signal transduction was stimulated by 10 nM insulin for 5 min. Total cell lysates were prepared and subjected to Western blot analysis. GAPDH was used a loading control. INS, insulin; PA, palmitate; Ad-GFP, adenovirus expressing GFP; Ad-BMP7, adenovirus expressing BMP7. Data are expressed as mean ± s.e.m. from three independent experiments (n = 3). *P < 0.05 vs INS, # P < 0.05 vs INS + PA in (A, B and C). *P < 0.05 vs INS, # P < 0.05 vs INS + PA, $ P < 0.05 vs INS + PA + BMP7 in (D).

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    Activation of p-P38 MAPK counteracts the effects of BMP7 on insulin resistance in obese mice. (A) Activation of p-P38 MAPK by MKK6Glu mitigates the beneficial role of BMP7 on glucose tolerance in obese mice. HFD-induced obese mice were injected with adenovirus expressing GFP (Ad-GFP), BMP7 (Ad-BMP7) or MKK6Glu (Ad-MKK6Glu) as indicated. GTT was performed at 14 days post-viral injection. (B) Activation of p-P38 MAPK by MKK6Glu eliminates BMP7-induced insulin signal transduction in the liver of obese mice. At 21 days post-viral injection, mice were killed and livers were collected for preparing total cell lysates. Protein levels were analyzed by Western blot and GAPDH was used as a loading control. (C) Quantitative analysis of the blots as shown in (B). HFD, high-fat diet; Ad-GFP, adenovirus expressing GFP; Ad-BMP7, adenovirus expressing BMP7; Ad-MKK6Glu, adenovirus expressing MKK6Glu. Data are presented as means ± s.e.m. from two (n = 8) independent experiments. *P < 0.05, **P < 0.01 vs HFD; # P < 0.05 vs HFD + BMP7.

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