ABSTRACT
Despite the occurrence of dyslipidemia and its contribution to the development of insulin resistance in obese subjects, a growing number of studies have described abnormal lipid profiles among leaner persons. For example, individuals with an abnormal paucity or distribution of fat (lipodystrophy) develop severe insulin resistance, dyslipidemia, and hepatic steatosis. Deranged adipocyte metabolism and differentiation contribute to ectopic fat deposition and consequent development of insulin resistance. Growth hormone (GH) therapy has been shown to correct body composition abnormalities in some lipodystrophy patients. However, little is known about the effects of GH-releasing peptides in this regard. Hexarelin, a GH secretagogue, has recently been shown to have beneficial effects on fat metabolism via the CD36 receptor. In this study, the effects of twice daily intraperitoneal injections of hexarelin (200 µg/kg body weight) were examined in nonobese insulin-resistant MKR mice and corresponding wild-type FVB mice for 12 days. Hexarelin treatment significantly improved glucose and insulin intolerance and decreased plasma and liver triglycerides in MKR mice. These beneficial metabolic effects could be due to the improved lipid metabolism and enhanced adipocyte differentiation of white adipose tissue with hexarelin treatment. Interestingly, although food intake of hexarelin-treated MKR mice was significantly increased, this did not change total body weight. Moreover, hexarelin treatment corrected the abnormal body composition of MKR mice, as demonstrated by a decrease in fat mass and an increase in lean mass. Our results suggest a possible application of hexarelin in treatment of lipid disorders associated with the metabolic syndrome.
Subject(s)
Dyslipidemias/drug therapy , Growth Hormone/metabolism , Insulin Resistance , Oligopeptides/administration & dosage , Adipocytes/drug effects , Adipose Tissue/metabolism , Animals , Blood Glucose/analysis , Body Composition/drug effects , Dyslipidemias/complications , Glucose Intolerance/drug therapy , Growth Hormone/drug effects , Insulin/blood , Lipid Metabolism/drug effects , Lipids/blood , Liver/chemistry , Male , Metabolic Syndrome/complications , Mice , Mice, Mutant Strains , Muscle, Skeletal/metabolism , Mutation , Obesity , Receptor, IGF Type 1/genetics , Triglycerides/analysis , Triglycerides/bloodABSTRACT
Total flavonoids in Herba epimedii (HEP) have been demonstrated to protect against bone loss and bone deterioration associated with estrogen deficiency without exerting any uterotrophic effects. However, it is unclear how flavonoids in HEP exert their protective effects on bone and if different flavonoids exert estrogenic actions in bone cells via similar mechanism of actions. The present study aims to investigate the bone anabolic effects of four major flavonoids isolated from HEP, namely icariin, baohuoside-I, epimedin B and sagittatoside A as well as the mechanism involved in mediating their estrogenic actions in rat osteoblastic-like UMR-106 cells. All tested compounds significantly stimulated the cell proliferation rate, alkaline phosphate (ALP) activity and osteoprotegerin (OPG)/receptor activator of nuclear factor κ-B ligand (RANKL) mRNA expression in UMR-106 cells and their effects could be abolished by co-incubation with 10(-6)M ICI 182,780. None of the flavonoids exhibited binding affinities toward ERα and ERß. However, sagittatoside A selectively activated estrogen response element (ERE)-luciferase activity via ERα. In addition, icariin and sagittatoside A induced ERα phosphorylation at serine 118 residue. Taken together, our results indicated that all four flavonoids from HEP stimulated ER-dependent osteoblastic functions in UMR-106 cells, but only two of them appeared to exert their actions by ligand-independent activation of ERα. Our study provides evidence to support the hypothesis that the estrogen-like protective effects on bone by flavonoids are mediated via mechanisms that are distinct from the classical actions of estrogen.
