Asprosin attenuates insulin signaling pathway through PKCδ‐activated ER stress and inflammation in skeletal muscle

• Published in: Journal of cellular physiology 2019-11, Vol.234 (11), p.20888-20899
• Main Authors: Jung, Tae Woo, Kim, Hyoung‐Chun, Kim, Ho Ung, Park, Taekwang, Park, Jinwoo, Kim, Uiseok, Kim, Min Kyoon, Jeong, Ji Hoon
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Adipocytes; AKT protein; asprosin; Ca2+-transporting ATPase; Calcium (reticular); Calcium ions; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Endoplasmic reticulum; ER stress; Gene expression; Gluconeogenesis; Glucose; Inflammation; Inositol; Insulin; Insulin receptor substrate 1; Insulin resistance; Interleukins; Kinases; Markers; Muscles; Musculoskeletal system; myocyte; Myocytes; Nuclear transport; Phosphorylation; Protein kinase C; Sarcoplasmic reticulum; Sensitivity; Signal transduction; siRNA; Skeletal muscle; Substrates; Translocation
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.28694

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 IκB, and nuclear translocated nuclear factor‐κβ). 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‐δ (PKCδ) phosphorylation and nuclear translocation, but suppressed messenger RNA expression of sarcoplasmic reticulum Ca2+ 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 PKCδ‐knockdown in C2C12 myocytes. These results suggest that asprosin results in impairment of insulin sensitivity in skeletal muscle through PKCδ‐associated ER stress/inflammation pathways and may be a valuable strategy for management of insulin resistance and T2DM. 1. Palmitate and high‐fat diet induce asprosin expression in mouse adipocytes 2. Recombinant asprosin induces inflammation and ER stress in skeletal muscle cells 3. Recombinant asprosin induces impairment of insulin signaling in skeletal muscle cells 4. Recombinant asprosin causes insulin resistance through PKCδ/ER stress or PKCδ/inflammation