Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model

Abstract

A balanced diet is crucial for healthy development and prevention of musculoskeletal related diseases. Diets high in fat content are known to cause obesity, diabetes and a number of other disease states. Our group and others have previously reported that activity of the urea cycle enzyme arginase is involved in diabetes-induced dysregulation of vascular function due to decreases in nitric oxide formation. We hypothesized that diabetes may also elevate arginase activity in bone and bone marrow, which could lead to bone-related complications. To test this we determined the effects of diabetes on expression and activity of arginase, in bone and bone marrow stromal cells (BMSCs). We demonstrated that arginase 1 is abundantly present in the bone and BMSCs. We also demonstrated that arginase activity and expression in bone and bone marrow is up-regulated in models of diabetes induced by HFHS diet and streptozotocin (STZ). HFHS diet down-regulated expression of healthy bone metabolism markers (BMP2, COL-1, ALP, and RUNX2) and reduced bone mineral density, bone volume and trabecular thickness. However, treatment with an arginase inhibitor (ABH) prevented these bone-related complications of diabetes. In-vitro study of BMSCs showed that high glucose treatment increased arginase activity and decreased nitric oxide production. These effects were reversed by treatment with an arginase inhibitor (ABH). Our study provides evidence that deregulation of L-arginine metabolism plays a vital role in HFHS diet-induced diabetic complications and that these complications can be prevented by treatment with arginase inhibitors. The modulation of L-arginine metabolism in disease could offer a novel therapeutic approach for osteoporosis and other musculoskeletal related diseases.

Glucagon-Like Peptide-1 (GLP-1) Treatment Ameliorates Cognitive Impairment by Attenuating Arc Expression in Type 2 Diabetic Rats

“…Thus, we preferred to induce diabetic rats with a high-glucose, high-fat diet and STZ injection in our experiment. This experimental model of type 2 diabetes replicates the natural history and metabolic characteristics of the syndrome and is widely accepted in diabetes studies [ 25 , 30 ]. A high-sugar, high-fat diet represents the eating habits of many people who prone to obesity and diabetes.…”

Anti-diabetic Effects of Clostridium butyricum CGMCC0313.1 through Promoting the Growth of Gut Butyrate-producing Bacteria in Type 2 Diabetic Mice

“…All mice of groups (1), (2), and (3) were fed HFD for 8 weeks along with the corresponding intervention and then injected with a single low dose (80 mg/kg body weight) STZ (Sigma S0130, St. Louis, MO, USA) intraperitoneally 48 – 51 . All the mice were kept on corresponding chow and intervention until euthanasia (Fig.…”

Arginase-I enhances vascular endothelial inflammation and senescence through eNOS-uncoupling

“…Studies also report that Arg-I is the major isoform expressed in rat endothelial cells and contributes to impaired endothelial function in aging of this species [ 12 , 20 , 21 ]. Moreover, Arg-I is shown to be upregulated in the bone marrow stromal cells of diabetic mouse models, contributing to diabetes-associated osteoporosis [ 22 ]. A recent study also reports that Arg-I is upregulated in a mouse myocardial infarction model and in human aortic endothelial cells under ischemia through the transcription factor FoxO4, leading to decreased NO production and cardiac damage [ 23 ].…”