Osteocalcin Protects Against Nonalcoholic Steatohepatitis in a Mouse Model of Metabolic Syndrome

Abstract

Nonalcoholic fatty liver disease, particularly its more aggressive form, nonalcoholic steatohepatitis (NASH), is associated with hepatic insulin resistance. Osteocalcin, a protein secreted by osteoblast cells in bone, has recently emerged as an important metabolic regulator with insulin-sensitizing properties. In humans, osteocalcin levels are inversely associated with liver disease. We thus hypothesized that osteocalcin may attenuate NASH and examined the effects of osteocalcin treatment in middle-aged (12-mo-old) male Ldlr Ϫ/Ϫ mice, which were fed a Western-style high-fat, high-cholesterol diet for 12 weeks to induce metabolic syndrome and NASH. Mice were treated with osteocalcin (4.5 ng/h) or vehicle for the diet duration. Osteocalcin treatment not only protected against Western-style high-fat, high-cholesterol diet-induced insulin resistance but substantially reduced multiple NASH components, including steatosis, ballooning degeneration, and fibrosis, with an overall reduction in nonalcoholic fatty liver disease activity scores. Further, osteocalcin robustly reduced expression of proinflammatory and profibrotic genes (Cd68, Mcp1, Spp1, and Col1a2) in liver and suppressed inflammatory gene expression in white adipose tissue. In conclusion, these results suggest osteocalcin inhibits NASH development by targeting inflammatory and fibrotic processes. (Endocrinology 155: 4697-4705, 2014)

Serum undercarboxylated osteocalcin correlates with hemoglobin A1c in children with recently diagnosed pediatric diabetes

“…In recent years, the theory that bone metabolism and its hormones contribute to the regulation of glycemic and lipid homeostasis has gained acceptance. Osteocalcin (OC), the osteoblast‐specific secreted molecule, was found in its activated, undercarboxylated form (uOC) to induce β‐cell proliferation and have positive effects on peripheral insulin sensitivity, hepatic metabolism and on visceral fat and energy expenditure in animal models . Since the publication of these data, several studies examined, albeit indirectly, the relationship between serum OC levels and glucose, lipids, and atherosclerosis in humans.…”

“…Osteocalcin (OC), the osteoblast-specific secreted molecule, was found in its activated, undercarboxylated form (uOC) to induce β-cell proliferation and have positive effects on peripheral insulin sensitivity, hepatic metabolism and on visceral fat and energy expenditure in animal models. 3,4 Since the publication of these data, several studies examined, albeit indirectly, the relationship between serum OC levels and glucose, lipids, and atherosclerosis in humans. Pittas et al showed in a crosssectional analysis of clinical trials of adults aged 65 years and older that serum OC was inversely associated with fasting glucose, insulin, homeostasis model assessment (HOMA) for insulin resistance, C-reactive protein, interleukin (IL)-6, body mass index (BMI), and body fat.…”

Serum osteocalcin levels are inversely associated with the presence of nonalcoholic fatty liver disease in patients with coronary artery disease

“…All statistical analyses were performed with SPSS ver. 19.0 (SPSS, Chicago, USA). The one-sample Kolmogorov-Smirnov test was used to explore the normality of data distribution.…”

“…In women, serum osteocalcin levels were independently and inversely associated with the presence of NAFLD in both pre-and post-menopausal women without osteopenia or osteoporosis [16]. Animal studies showed that subcutaneous infusion or intermittent intraperitoneal injection of osteocalcin into wild-type mice fed high-fat diets improved hepatic steatosis, degeneration caused by ballooning, and fibrosis [17][18][19]. Osteocalcin attenuated endoplasmic reticulum stress via the NF-κB signaling pathway, and robustly reduced the liver expression levels of pro-inflammatory and pro-fibrotic genes, alleviating NAFLD [18,19].…”

Searching for additional endocrine functions of the skeleton: genetic approaches and implications for therapeutics

“…Gupte et al . demonstrated that osteocalcin treatment substantially reduced nonalcoholic steatohepatitis in mice fed a HFD or high-cholesterol diet [130]. Interestingly, osteocalcin can also be administered through oral route to improve glucose tolerance in mice by triggering GLP-1-mediated stimulation of insulin secretion, which also suggested another potential mechanism of action of osteocalcin in regulating glucose homeostasis [131, 132].…”