Abstract
This study investigated whether oxidative and glycolytic rat skeletal muscles respond differently to a high-fat (HF) sucrose-enriched diet with respect to diacylglycerol (DAG) and ceramides accumulation, protein kinase C (PKC) activation, glucose metabolism, and the expression of inflammatory genes. HF diet (8 weeks) suppressed insulin-stimulated glycogen synthesis and glucose oxidation in soleus (Sol), extensor digitorum longus (EDL) and epitrochlearis (Epit) muscles. However, DAG and ceramides levels increased in Sol and EDL, but not in Epit muscles of HF-fed rats. Additionally, membrane-bound PKC-delta and PKC-theta increased in Sol and EDL, whereas in Epit muscles both PKC isoforms were reduced by HF diet. In Epit muscles, HF diet also increased the expression of tumor necrosis factor-α (TNF-α) receptors (CD40 and FAS), toll-like receptor 4 (TLR4), and nuclear factor kappa light polypeptide gene enhancer in B cells (NF-kB), whereas in Sol and EDL muscles the expression of these inflammatory genes remained unchanged upon HF feeding. In conclusion, HF diet caused DAG and ceramides accumulation, PKC activation, and the induction of inflammatory pathways in a fiber type-specific manner. These findings help explain why oxidative and glycolytic muscles similarly develop insulin resistance, despite major differences in their metabolic characteristics and responsiveness to dietary lipid abundance.
Highlights
This study investigated whether oxidative and glycolytic rat skeletal muscles respond differently to a high-fat (HF) sucrose-enriched diet with respect to diacylglycerol (DAG) and ceramides accumulation, protein kinase C (PKC) activation, glucose metabolism, and the expression of inflammatory genes
We provide evidence of a muscle fiber type-specific adaptation with regards to the accumulation of DAG and ceramides, PKC activation, and the expression of receptors involved in inflammatory cytokines and glucocorticoid signalling in response to chronic exposure to a HF-sucrose enriched diet
Insulin is well known for its ability to potently stimulate glucose uptake and glycogen synthesis in skeletal muscles, and conditions that limit glycogen synthesis in this tissue are associated with hyperglycemia and other metabolic disorders typically found in type 2 diabetes (T2D) patients[2]
Summary
This study investigated whether oxidative and glycolytic rat skeletal muscles respond differently to a high-fat (HF) sucrose-enriched diet with respect to diacylglycerol (DAG) and ceramides accumulation, protein kinase C (PKC) activation, glucose metabolism, and the expression of inflammatory genes. It has been reported that H2O2 emission rates in red Sol were much lower than in the mixed EDL and the white Epit m uscles[15] In this context, it is plausible that the mechanisms governing diet-induced insulin resistance vary depending on the fiber type composition of various skeletal muscles. These observations provide support to the idea that circulating factors (e.g., inflammatory cytokines and hormones) and altered intramuscular lipid metabolism, either independently or in combination, determine the pathophysiology of obesity-induced skeletal muscle insulin resistance To test this hypothesis, we measured insulin-stimulated glycogen synthesis and glucose oxidation, DAG and ceramides content, membrane-associated PKCδ and PKCθ levels, and the expression of inflammatory genes in slow- and fasttwitch skeletal muscles extracted from rats exposed for 8 weeks to a HF diet. The findings support that HF feeding causes impairment of glucose metabolism in predominately slow- or fast-twitch rat muscles through distinct mechanisms
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