Abstract
Osteocalcin is a bone-derived hormone that plays an important role in the crosstalk between bone and energy metabolism. Previous studies have found that treatment with uncarboxylated osteocalcin can protect mice from high-fat diet-induced nonalcoholic fatty liver disease (NAFLD). However, the potential mechanisms remain unclear. Although the G protein-coupled receptor family C group 6 subtype A (GPRC6A) is the putative receptor of osteocalcin, there is no direct evidence showing that GPRC6A mediates the effects of uncarboxylated osteocalcin in alleviating NAFLD in mice. We aimed to figure out this using liver-specific GPRC6A knockout (GPRC6ALKO) mice. Consistent with previous studies, uncarboxylated osteocalcin significantly protected high-fat diet-fed wild-type mice from obesity and NAFLD, while it did not protect high-fat diet-fed GPRC6ALKO mice from NAFLD. Differential mRNA expression of lipogenesis and lipolysis between GPRC6ALKO mice and control mice revealed that GPRC6A mediated the effects of osteocalcin in alleviating NAFLD through inhibiting lipid synthesis and promoting lipolysis. In conclusion, this study found that uncarboxylated osteocalcin alleviates NAFLD in mice through the GPRC6A signaling pathway. Our study suggests that liver GPRC6A may be a potential target for treating NAFLD.
Highlights
We examined how hepatocyte GPRC6A inactivation modulates the progression of high-fat diet (HFD)-induced hepatic steatosis. e analysis of hepatic gene expression indicated that the mRNA levels of key genes involved in lipogenesis (SCD1, sterol regulatory element-binding transcription factor 1 (SREBP1), diacylglycerol O-acyltransferase 1 (DGAT1), and CIDEA) were significantly decreased and that the mRNA levels of genes involved in lipolysis (ACOX1, peroxisome proliferator-activated receptor alpha (PPARA), acyl-coenzyme A dehydrogenase medium chain (ACADM), and PPARGC1A) were significantly increased in the WT : HFD + OCN group compared with the WT : HFD + NS group
A liver-specific conditional GPRC6A knockout mouse model was used to explore the potential mechanisms underlying the ability of uncarboxylated osteocalcin to alleviate nonalcoholic fatty liver disease (NAFLD)
Our results found that uncarboxylated osteocalcin alleviates NAFLD in mice through the GPRC6A signaling pathway
Summary
Osteocalcin is a bone-derived hormone that plays an important role in the crosstalk between bone and energy metabolism. Previous studies have found that treatment with uncarboxylated osteocalcin can protect mice from high-fat diet-induced nonalcoholic fatty liver disease (NAFLD). This study found that uncarboxylated osteocalcin alleviates NAFLD in mice through the GPRC6A signaling pathway. Epidemiological studies have found that serum total osteocalcin levels are inversely correlated with NAFLD [7], abdominal obesity [8], subclinical atherosclerosis [9], and metabolic syndrome [10]. Treatment with uncarboxylated osteocalcin protects mice from diet-induced hepatic triglyceride accumulation [12, 13]. The mechanisms underlying the role of uncarboxylated osteocalcin in NAFLD remain unclear and need to be investigated.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
