Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action

Abstract

Obesity is characterized by adipose tissue expansion as well as macrophage infiltration of adipose tissue. This results in an increase in circulating inflammatory cytokines and nonesterified fatty acids, factors that cause skeletal muscle insulin resistance. Whether obesity also results in skeletal muscle inflammation is not known. In this study, we quantified macrophages immunohistochemically in vastus lateralis biopsies from eight obese and eight lean subjects. Our study demonstrates that macrophages infiltrate skeletal muscle in obesity, and we developed an in vitro system to study this mechanistically. Myoblasts were isolated from vastus lateralis biopsies and differentiated in culture. Coculture of differentiated human myotubes with macrophages in the presence of palmitic acid, to mimic an obese environment, revealed that macrophages in the presence of palmitic acid synergistically augment cytokine and chemokine expression in myotubes, decrease IkappaB-alpha protein expression, increase phosphorylated JNK, decrease phosphorylated Akt, and increase markers of muscle atrophy. These results suggest that macrophages alter the inflammatory state of muscle cells in an obese milieu, inhibiting insulin signaling. Thus in obesity both adipose tissue and skeletal muscle inflammation may contribute to insulin resistance.

Muscle inflammatory signaling in response to 9 days of physical inactivity in young men with low compared with normal birth weight

“…The link between obesity and increased macrophage content in adipose tissue is well established (36,44,47). In accordance with Varma et al (38), our study indicates that obesity is associated with elevated macrophage infiltration (CD68 mRNA expression) in muscle. Furthermore, our data suggest that a high physical fitness level might be linked to decreased macrophage infiltration.…”

“…MCP1 is not only involved in the recruitment of macrophages (32) but may also induce insulin resistance in myocytes directly (33,34). Infiltration of inflammatory cells, including macrophages, directly into the inflamed muscle tissue or in the adipose tissue surrounding the muscle fibers has been demonstrated previously (35,36,37,38). These cells are thought to maintain the inflammatory state and may also represent a source of cytokines acting in a paracrine and/or endocrine manner (35).…”

Dietary intervention-induced weight loss decreases macrophage content in adipose tissue of obese women

“…It has indeed been shown that macrophages resident in these tissues (such as Kupffer cells in the liver) could be activated and induce worsening of insulin sensitivity in obese patients. 39,40 It is known that the nature of macrophages is heterogeneous and their phenotype can be modified in various conditions. 26,41,42 It is therefore important to determine not only the total number of macrophages but also their phenotype in AT.…”

Expression of anti-inflammatory macrophage genes within skeletal muscle correlates with insulin sensitivity in human obesity and type 2 diabetes

“…Muscle-infiltrating macrophages in obesity might affect muscle glucose metabolism via secreted factors that impair glucose homeostasis. Although the rise in human muscle inflammatory genes in obesity and type 2 diabetes correlates with insulin resistance [5], evidence for elevated immune cells in human muscle in obesity and type 2 diabetes is scant and controversial [6,7]. Moreover, the phenotypic polarisation of muscle macrophages in obesity and type 2 diabetes is unknown, as is any possible correlation to metabolic status.…”