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Individuals with hepatic steatosis often display several metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis results in an altered hepatokine secretion profile, thereby inducing skeletal muscle insulin resistance via inter-organ crosstalk. In this study, we aimed to investigate whether the altered secretion profile in the state of hepatic steatosis also induces skeletal muscle atrophy via effects on muscle protein turnover. To investigate this, eight-week-old male C57BL/6J mice were fed a chow (4.5% fat) or a high-fat diet (HFD; 45% fat) for 12 weeks to induce hepatic steatosis, after which the livers were excised and cut into ~200-µm slices. Slices were cultured to collect secretion products (conditioned medium; CM). Differentiated L6-GLUT4myc myotubes were incubated with chow or HFD CM to measure glucose uptake. Differentiated C2C12 myotubes were incubated with chow or HFD CM to measure protein synthesis and breakdown, and gene expression via RNA sequencing. Furthermore, proteomics analysis was performed in chow and HFD CM. It was found that HFD CM caused insulin resistance in L6-GLUT4myc myotubes compared with chow CM, as indicated by a blunted insulin-stimulated increase in glucose uptake. Furthermore, protein breakdown was increased in C2C12 cells incubated with HFD CM, while there was no effect on protein synthesis. RNA profiling of C2C12 cells indicated that 197 genes were differentially expressed after incubation with HFD CM, compared with chow CM, and pathway analysis showed that pathways related to anatomical structure and function were enriched. Proteomics analysis of the CM showed that 32 proteins were differentially expressed in HFD CM compared with chow CM. Pathway enrichment analysis indicated that these proteins had important functions with respect to insulin-like growth factor transport and uptake, and affect post-translational processes, including protein folding, protein secretion and protein phosphorylation. In conclusion, the results of this study support the hypothesis that secretion products from the liver contribute to the development of muscle atrophy in individuals with hepatic steatosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pasmans, Adriaens, Olinga, Langen, Rensen, Schaap, Olde Damink, Caiment, van Loon, Blaak and Meex.)

Insulin resistance and muscle mass loss often coincide in individuals with type 2 diabetes. Most patients with type 2 diabetes are overweight, and it is well established that obesity and derangements in lipid metabolism play an important role in the development of insulin resistance in these individuals. Specifically, increased adipose tissue mass and dysfunctional adipose tissue lead to systemic lipid overflow and to low-grade inflammation via altered secretion of adipokines and cytokines. Furthermore, an increased flux of fatty acids from the adipose tissue may contribute to increased fat storage in the liver and in skeletal muscle, resulting in an altered secretion of hepatokines, mitochondrial dysfunction, and impaired insulin signalling in skeletal muscle. Recent studies suggest that obesity and lipid derangements in adipose tissue can also lead to the development of muscle atrophy, which would make insulin resistance and muscle atrophy two sides of the same coin. Unfortunately, the exact relationship between lipid accumulation, type 2 diabetes, and muscle atrophy remains largely unexplored. The aim of this review is to discuss the relationship between type 2 diabetes and muscle loss and to discuss some of the joint pathways through which lipid accumulation in organs may affect peripheral insulin sensitivity and muscle mass., (© 2019 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)