Abstract 16797: Inhibition of Bone Morphogenetic Protein Signaling Reduces Weight Gain and Hepatic Lipid Accumulation in a Murine Model of Obesity
Background: Obesity and hepatic steatosis are independent risk factors for coronary artery disease. Bone morphogenetic protein (BMP) signaling is known to regulate adipogenesis and promote atherosclerosis, and serum BMP4 levels correlate with metabolic syndrome in humans. We hypothesized that inhibition of BMP signaling would reduce weight gain and hepatic lipid accumulation in obese leptin receptor deficient (db) mice.
Methods: Male 4 wk old wild type (wt) and db mice received a daily IP injection of either a small molecule inhibitor of BMP signaling, LDN-193189 (LDN, 3.0 mg/kg), or vehicle (veh) for 4 wks with or without pair feeding. Plasma markers of liver injury, alanine aminotransferase (ALT) and alkaline phosphatase (ALP), were measured. Livers were harvested for histology, triglyceride levels (TGs) and mRNAs encoding markers of lipid synthesis: fatty acid synthase (FAS) and glycerol 3 phosphate acyltransferase 1 (GPAT1). In separate studies, db mice received LDN or veh (n=6 per group) for 3 days to measure plasma β hydroxybutyrate (βHB), a marker of hepatic fatty acid oxidation (FAO), or for 14 days to measure respiratory exchange ratio (RER) using metabolic cages.
Results: After 4 wks, db mice treated with LDN weighed 18% less than veh treated db mice (p=0.0002) despite equal food consumption. BMP inhibition in db mice reduced histologic hepatic steatosis, decreased hepatic TGs by 44% (p=0.0002), and reduced plasma ALT and ALP by 67% (p=0.001) and 56% (p<0.001), respectively. Treatment of db mice with LDN reduced hepatic mRNA levels of FAS by 70% and GPAT1 by 65% (p<0.002 for both). There was no difference in weight, hepatic TGs, or plasma ALT and ALP levels between LDN and veh treated wt mice. 24h RER was reduced in LDN vs veh treated db mice (0.70 ± 0.01 vs 0.75 ± 0.01, Mean ± SEM, p=0.02) despite similar activity levels. Furthermore, βHB levels were increased in LDN vs veh treated db mice (3.3 ± 0.3 vs 0.7 ± 0.2 mM, p=0.0002).
Conclusions: Inhibition of BMP signaling reduces weight gain and hepatic lipid accumulation in a murine model of obesity. This reduction is associated with increased FAO and improved hepatic mRNA levels of mediators of lipid synthesis. The BMP signaling pathway may be a novel therapeutic target for the treatment of obesity and hepatic steatosis.
- © 2013 by American Heart Association, Inc.