Beneficial effects of high BMP-9 levels under diabetic and high fat conditions

Bone morphogenetic protein (BMP)-9, a member of the TGFbeta family of cytokines is constantly produced in the liver and circulates in the body in an active conformation. The potential functions of BMP-9 are diverse and include regulation of liver homeostasis as well as fibrogenesis, inflammation or angiogenesis. The published findings that the serum levels of BMP-9 are reduced in newly diagnosed diabetic patients and that BMP-9 overexpression ameliorated steatosis in high fat diet induced obese mice, prompted us to further investigate the role of BMP-9 in conditions of steatosis and/or diabetes. We followed the hypothesis that BMP-9 might act similar as insulin itself in diabetic conditions and that via gut-liver-cross-talk BMP-9 might be protective against high-fat diet induced steatosis. BMP-9 KO mice (on a C57/Bl6 background) appeared rather over-weight with partially massive visceral fat deposition whereas the livers appeared quite normal and were rather small. This resulted in a significantly decreased liver to body weight ratio in these mice. To reproduce published data obtained with human serum from diabetic patients, we analyzed the blood of STZ rats (animal model for diabetes type I) and could confirm that BMP-9 levels are reduced. However, when looking at the RNA levels of the livers from these rats by real-time PCR we did not find any reduced BMP-9 expression in the diabetic animals. This implies that the basal amounts of BMP-9 in the serum have already been used up but without a subsequent, compensatory upregulation of hepatic expression. Using human gut organoids we additionally found that BMP-9 upregulates expression of Fgf19, a factor that was described to protect the liver from steatosis. This correlated well with enhanced expression of the FGF19 receptor beta-Klotho in BMP-9 stimulated human hepatocytes.In summary these data support the conclusion that under high sugar and/or high fat conditions increased levels of BMP-9 would most likely be beneficial but with insulin resistance or lack of insulin such upregulation may not occur any more, making supplementation of BMP-9 also an interesting approach for future therapies.