PLIN2 inhibits insulin-induced glucose uptake in myoblasts through the activation of the NLRP3 inflammasome

Abstract

Abstract. Impaired lipid metabolism and inflammatory pathways have individually been implicated in the development of insulin resistance in skeletal muscle; however, little evidence is available to date linking the two in this context. In this study, we explored a potential molecular mechanism underlying insulin resistance in myoblasts mediated by the crosstalk between lipid accumulation and inflammatory pathways. We examined the influence of perilipin 2 (PLIN2), one of the most highly expressed lipid droplet-associated proteins in skeletal muscle, on glucose uptake and on the nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) inflammasome in vitro. PLIN2 overexpression in C2C12 cells led to an increased expression of NLRP3, caspase-1 and interleukin (IL)-1β, along with an impaired insulin-induced glucose uptake. This defect was remedied by the RNAi-mediated knockdown of NLRP3 expression. We also found that insulin receptor substrate-1 (IRS-1), a component of insulin signaling, was negatively regulated by NLRP3 and IL-1β, and that IL-1β inhibited insulin-induced glucose uptake in myoblasts. These results suggest that PLIN2 inhibits insulin-induced glucose uptake by activating NLRP3, caspase-1 and IL-1β, leading to a decreased IRS-1 expression. This study provides in vitro evidence supporting an association between lipid metabolism and inflammatory pathways in the pathogenesis of insulin resistance in skeletal muscle, and suggests potential therapeutic targets that warrant further investigation.

Conditioned media from human palatine tonsil mesenchymal stem cells regulates the interaction between myotubes and fibroblasts by IL‐1Ra activity

“…We previously reported that excessive lipid accumulation within skeletal muscle cells as a result of overexpressing lipid droplets induces IL‐1β production via activation of the NLRP3 inflammasome pathway 15. Thus, we speculated that exogenous treatment with PA might also stimulate IL‐1β secretion by C2C12 myotubes.…”

“…Thus, we speculated that skeletal muscle cells could produce pro‐inflammatory mediators in response to PA. Previously, we found that C2C12 myoblasts produce IL‐1β following the accumulation of intracellular lipids by increasing lipid droplets within the cells 15. Therefore, we hypothesized that C2C12 myotubes were capable of producing IL‐1β following exposure to PA because FFAs cause intracellular lipid accumulation.…”

Deletion of Nlrp3 protects from inflammation-induced skeletal muscle atrophy

“…SAA1 induces IL-1β expression [46] and secretion [47] and activates the Nlrp3 inflammasome in immune cells [46]. The Nlrp3 inflammasome is contained and active in C2C12 myocytes [48] . IL-1β induces atrogene expression in myocytes [23].…”

Lipotoxicity plays a key role in the development of both insulin resistance and muscle atrophy in patients with type 2 diabetes

“…In addition, also, resistin has been shown to promote IMCL storage in primary human myotubes . Importantly, increased IMCL storage results in the accumulation and dysregulation of detrimental lipid intermediates such as diacylglycerols (DAGs) and ceramides, and those intermediates lead to insulin resistance through activation of protein kinase C (PKC) . High levels of DAG and ceramides have also been suggested to play a role in the development of muscle loss .…”

“…71 Importantly, increased IMCL storage results in the accumulation and dysregulation of detrimental lipid intermediates such as diacylglycerols (DAGs) and ceramides, and those intermediates lead to insulin resistance through activation of protein kinase C (PKC). [90][91][92][93][94][95][96][97][98][99][100] High levels of DAG and ceramides have also been suggested to play a role in the development of muscle loss. 16, [101][102][103] In C2C12 and L6 myotubes, treatment with the fatty acid palmitate induced ceramide accumulation, and this was associated with increased expression of pro-atrophic genes such as atrogin-1/MAFbx, increased levels of FoxO3, upregulated eIF2α phosphorylation, and decreased protein synthesis.…”