Glucose induces de novo lipogenesis in rat muscle satellite cells through a sterol-regulatory-element-binding-protein-1c-dependent pathway

Abstract

We previously reported that sterol-regulatory-element-binding-protein-1c (SREBP-1c) mediates insulin upregulation of genes encoding glycolytic and lipogenic enzymes in rat skeletal muscle. Here, we assessed whether glucose could regulate gene expression in contracting myotubes deriving from cultured muscle satellite cells. Glucose uptake increased twofold after a 30 minute treatment with a high glucose concentration, suggesting an acute glucose-stimulated glucose uptake. Time-course experiments showed that, within 3 hours, glucose stimulated the expression of hexokinase II, fatty acid synthase and acetyl-CoA-carboxylase-2 proteins, leading to an increased lipogenic flux and intracellular lipid accumulation in contracting myotubes. Furthermore, kinetic experiments indicated that glucose upregulated SREBP-1c precursor and nuclear proteins within 30 minutes, SREBP-1c nuclear translocation being confirmed using immunocytochemistry. In addition, the knockdown of SREBP-1 mRNA using a RNA-interference technique totally abrogated the glucose-induced upregulation of lipogenic enzymes, indicating that SREBP-1c mediates the action of glucose on these genes in rat skeletal muscle. Finally, we found that glucose rapidly stimulated SREBP-1c maturation through a Jak/STAT dependent pathway. We propose that increased intramuscular lipid accumulation associated with muscle insulin resistance in obesity or type-2 diabetes could arise partly from de novo fatty acid synthesis in skeletal muscle.

Weight gain related to treatment with atypical antipsychotics is due to activation of PKC-β

“…33 As in hyperglycemia, highglucose concentrations upregulate sterol regulatory element binding protein 1c, resulting in de novo lipogenesis and intracellular lipid accumulation in contracting myotubes. 34 In this study we show that when MDSCs are exposed to external stimuli of an adipogenic lineage, such as the presence of a high-glucose environment, the APD exposure induces a remarkable increase in adipogenic transformation. Interestingly, APD treatment affected only transdifferentional events of MDSCs and not cell number.…”

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

“…Glucose plays a central role in this cycle as a source of acetyl-CoA, Krebs cycle intermediates and NADPH molecules, which are required for the synthesis of FAs. It might also function as a stimulator of de novo lipogenesis, based upon the above-mentioned recent demonstrations in muscle satellite cells 47,48 that glucose, even in the absence of insulin, stimulates the gene expression of SREBP-1c as well as key genes encoding glycolytic and lipogenic enzymes, leading to an increased lipogenic flux.…”

High glucose induces adipogenic differentiation of muscle-derived stem cells

“…Activators of PPAR-␥ cause, in muscle, the induction of genes involved in fatty acid uptake, storage, and metabolism (7), and the myogenic cell line C2C12 can be converted to adipocytes by overexpression of PPAR-␥ and C/EBP (8). As in hyperglycemia, high-glucose concentrations up-regulating sterol regulatory element binding protein 1c (SREBP-1c) induce de novo lipogenesis and intracellular lipid accumulation in contracting myotubes (9).…”