Asprosin attenuates insulin signaling pathway through PKCdelta-activated ER stress and inflammation in skeletal muscle

Asprosin siRNA (100 μg/mouse), given twice at 48 hr intervals using in vivo‐jetPEI , was injected into the HFD‐fed asprosin knockdown group via the tail vein for siRNA delivery for 8 weeks (Jung, Kang, et al., 2018).

It has been reported that asprosin is a novel adipokine which is augmented in mice and humans with type 2 diabetes (T2DM). Asprosin stimulates hepatic gluconeogenesis under fasting conditions. However, the roles of asprosin in inflammation, endoplasmic reticulum (ER) stress, and insulin resistance in skeletal muscle has not been studied. In the currents study, elevated levels of asprosin expression were observed in adipocytes under hyperlipidemic conditions. Treatment of C2C12 myocytes with asprosin-induced ER stress markers (phosphorylated inositol-requiring enzyme 1 and eukaryotic initiation factor 2, and CHOP expression) as well as inflammation markers (interleukin-6 expression, phosphorylated IkappaB, and nuclear translocated nuclear factor-kappabeta). Finally, asprosin treatment promoted exacerbation of insulin sensitivity as determined by levels of insulin receptor substrate 1 and Akt phosphorylation as well as glucose uptake. Moreover, treatment of asprosin augmented protein kinase C-delta (PKCdelta) phosphorylation and nuclear translocation, but suppressed messenger RNA expression of sarcoplasmic reticulum Ca(2+) ATPase 2b in both C2C12 myocytes and in mouse soleus skeletal muscle. These asprosin-induced effects were markedly decreased in small interfering (si) RNA-mediated PKCdelta-knockdown in C2C12 myocytes. These results suggest that asprosin results in impairment of insulin sensitivity in skeletal muscle through PKCdelta-associated ER stress/inflammation pathways and may be a valuable strategy for management of insulin resistance and T2DM.