ABSTRACT
AIMS: The purpose of this study was to determine the effect of insulin on ceramide metabolism in skeletal muscle. METHODS: Skeletal muscle cells were treated with insulin with or without palmitate for various time periods. Lipids (ceramides and TAG) were isolated and gene expression of multiple biosynthetic enzymes were quantified. Additionally, adult male mice received daily insulin injections for 14 days, followed by muscle ceramide analysis. RESULTS: In muscle cells, insulin elicited an increase in ceramides comparable to palmitate alone. This is likely partly due to an insulin-induced increase in expression of multiple enzymes, particularly SPT2, which, when knocked down, prevented the increase in ceramides. In mice, 14 days of insulin injection resulted in increased soleus ceramides, but not TAG. However, insulin injections did significantly increase hepatic TAG compared with vehicle-injected animals. CONCLUSIONS: This study suggests that insulin elicits an anabolic effect on sphingolipid metabolism in skeletal muscle, resulting in increased ceramide accumulation. These findings reveal a potential mechanism of the deleterious consequences of the hyperinsulinemia that accompanies insulin resistance and suggest a possible novel therapeutic target to mitigate its effects.
Subject(s)
Ceramides/biosynthesis , Insulin/pharmacology , Muscle, Skeletal/metabolism , Animals , Cell Line , Histone Chaperones/metabolism , Insulin/administration & dosage , Insulin Resistance , Lipids/blood , Lipids/chemistry , Male , Mice , Mice, Inbred C57BL , Myoblasts/cytology , Palmitates/chemistry , Polymerase Chain Reaction , Sphingolipids/chemistryABSTRACT
Rats bred for a high-capacity to run (HCR) do not develop insulin resistance on a high-fat diet (HFD) vs. those bred for a low-capacity for running (LCR). Recently, a link between obesity and insulin resistance has been established via IKKbeta action and IRS-1 Ser (312/307) phosphorylation. This study measured IkappaBalpha and IRS-1 pSer (307) in mixed gastrocnemius muscle in HCR and LCR rats challenged with a 12-wk HFD. HFD treatment resulted in significantly higher glucose and insulin levels in LCR vs. HCR rats. IkappaBalpha levels, an inverse indicator of IKKbeta activity, were lower in LCR vs. HCR rats maintained on chow diet and were reduced further following HFD in LCR rats only. IRS-1 pSer (307) in the LCR rats increased on the HFD vs. chow. We conclude that differences in glucose tolerance between LCR and HCR rats are at least partly explained by differences in IKKbeta activity and pSer (307) levels.
