The myokine meteorin‐like (metrnl) improves glucose tolerance in both skeletal muscle cells and mice by targeting AMPKα2

Abstract

Meteorin-like (metrnl) is a recently identified adipomyokine that beneficially affects glucose metabolism; however, its underlying mechanism of action is not completely understood. We here show that the level of metrnl increases in vitro under electrical pulse stimulation and in vivo in exercised mice, suggesting that metrnl is secreted during muscle contractions. In addition, metrnl increases glucose uptake via the calcium-dependent AMPKa2 pathway in skeletal muscle cells and increases the phosphorylation of HDAC5, a transcriptional repressor of GLUT4, in an AMPKa2dependent manner. Phosphorylated HDAC5 interacts with 14-3-3 proteins and sequesters them in the cytoplasm, resulting in the activation of GLUT4 transcription. An intraperitoneal injection of recombinant metrnl improved glucose tolerance in mice with high-fat-diet-induced obesity or type 2 diabetes, but not in AMPK b1b2 muscle-specific null mice. Metrnl improves glucose metabolism via AMPKa2 and is a promising therapeutic candidate for glucose-related diseases such as type 2 diabetes.Abbreviations ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; BAPTA-AM, 1,2-Bis (2-aminophenoxy) ethane-N,N,N 0 ,N 0 -tetraacetic acid tetrakis (acetoxymethyl ester; EPS, electrical pulse stimulation; GLUT4, glucose transporter type 4; GST, glutathione S-transferase; GTT, glucose tolerance test; HDAC5, histone deacetylase 5; HFD, high-fat diet; ICC, immunocytochemistry; MAPK, mitogen-activated protein kinase; TBC1D1, TBC1 domain family member 1.

Adipokines and Inflammation: Focus on Cardiovascular Diseases

“…Meteorin-like (Metrnl) is a novel small (~27kDa) secreted adipocytokine that has a beneficial effect on glucose homeostasis and that also functions as a novel immunoregulatory cytokine associated with anti-inflammatory effects [ 307 , 308 , 309 ]. Metrnl has been proposed to connect adaptive responses to the regulation of energy homeostasis and tissue inflammation and to have therapeutic potential for metabolic and inflammatory diseases [ 310 ].…”

Meteorin-Like Ameliorates β Cell Function by Inhibiting β Cell Apoptosis of and Promoting β Cell Proliferation via Activating the WNT/β-Catenin Pathway

“…Metrnl-treated obese mice showed improved glucose tolerance during intraperitoneal glucose tolerance test (IPGTT) ( Rao et al, 2014 ). Lee reported that Metrnl increased glucose uptake in the skeletal muscle cells and increased the phosphorylation of transcriptional repressor of glucose transporter 4 ( Lee et al, 2020 ). In addition, Metrnl injection alleviated glucose tolerance status in mice with high-fat-diet-induced obesity or T2D ( Lee et al, 2020 ).…”

“…Lee reported that Metrnl increased glucose uptake in the skeletal muscle cells and increased the phosphorylation of transcriptional repressor of glucose transporter 4 ( Lee et al, 2020 ). In addition, Metrnl injection alleviated glucose tolerance status in mice with high-fat-diet-induced obesity or T2D ( Lee et al, 2020 ). Sun Y reported that intravenous administration of metrnl reduced blood glucose levels and the area under the curve of IPGTT in NOD mice ( Yao et al, 2020 ).…”

Effects of electrical stimulation‐induced resistance exercise training on white and brown adipose tissues and plasma meteorin‐like concentration in rats

“…On the other hand, although scWAT is highly responsive to exercise, its role is not necessary for the endurance training-induced improvement of whole-body glucose metabolism in mice (Peppler, Townsend, Knuth, Foster, & Wright, 2018). More recent work has demonstrated that Metrnl directly improves glucose tolerance in skeletal muscle cells (Lee et al, 2020). Future studies will need to elucidate whether the RT-induced alteration of brown and white adipocytes ameliorates metabolic dysfunction in obesity and metabolic diseases.…”