TY - JOUR
T1 - PLIN2 inhibits insulin-induced glucose uptake in myoblasts through the activation of the NLRP3 inflammasome
AU - Cho, Kyung Ah
AU - Kang, Peter B.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - Insulin resistance
KW - NLRP3 inflammasome
KW - PLIN2
KW - Skeletal muscle
UR - http://www.scopus.com/inward/record.url?scp=84938076057&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84938076057&partnerID=8YFLogxK
U2 - 10.3892/ijmm.2015.2276
DO - 10.3892/ijmm.2015.2276
M3 - Article
C2 - 26166692
AN - SCOPUS:84938076057
SN - 1107-3756
VL - 36
SP - 839
EP - 844
JO - International journal of molecular medicine
JF - International journal of molecular medicine
IS - 3
ER -