Skeletal muscle inflammation and insulin resistance in obesity

Abstract

Obesity is associated with chronic inflammation, which contributes to insulin resistance and type 2 diabetes mellitus. Under normal conditions, skeletal muscle is responsible for the majority of insulin-stimulated whole-body glucose disposal; thus, dysregulation of skeletal muscle metabolism can strongly influence whole-body glucose homeostasis and insulin sensitivity. Increasing evidence suggests that inflammation occurs in skeletal muscle in obesity and is mainly manifested by increased immune cell infiltration and proinflammatory activation in intermyocellular and perimuscular adipose tissue. By secreting proinflammatory molecules, immune cells may induce myocyte inflammation, adversely regulate myocyte metabolism, and contribute to insulin resistance via paracrine effects. Increased influx of fatty acids and inflammatory molecules from other tissues, particularly visceral adipose tissue, can also induce muscle inflammation and negatively regulate myocyte metabolism, leading to insulin resistance.

Figure 1. Inflammation in skeletal muscle in obesity.

(A) In lean conditions, few immune cells with resting or antiinflammatory phenotypes reside in skeletal muscle. (B) As obesity develops and progresses along with expansion of visceral and subcutaneous AT, adipose depots expand between muscle fibers or surrounding muscle, so-called IMAT/PMAT. In obesity, immune cells including macrophages and T cells infiltrate into IMAT/PMAT and polarize into proinflammatory phenotypes, leading to increased inflammation in skeletal muscle. At the same time, myocytes may become inflamed and express proinflammatory cytokines and chemokines. (C) Chemokines and cytokines secreted by myocytes, adipocytes, and immune cells, along with FFAs that are transferred into skeletal muscle and ANG II produced within skeletal muscle, may themselves further accelerate immune cell recruitment and activation and myocyte inflammation, forming a feed-forward loop of inflammation in skeletal muscle.

Figure 2. Inflammatory effects on myocytes in obesity.

In obesity, increased infiltration and activation of immune cells in skeletal muscle (mainly in IMAT/PMAT) and myocyte inflammation lead to increased secretion of proinflammatory cytokines, which negatively regulate myocyte metabolic functions through paracrine or autocrine effects. Inflammation in visceral AT, with increased secretion of inflammatory adipokines, may also adversely affect myocyte metabolic function through endocrine effects. In addition, inflammatory effects on adipocytes in visceral AT and IMAT/PMAT may accelerate FFA release and transfer into myocytes, resulting in myocyte inflammation and metabolic dysfunction. Furthermore, elevated levels of TGRLs, including diet/enterocyte-derived chylomicrons (CM) and liver-derived VLDL may undergo enhanced LPL-mediated triglyceride hydrolysis, increasing FA release and transfer into skeletal muscle (and AT) and contributing to myocyte inflammation and metabolic dysfunctions. Activation of the RAS in skeletal muscle with local production of ANG II and ANG 1–7 may also regulate myocyte inflammation and metabolic functions.

Figure 3. Inflammatory signaling mediates insulin resistance in myocytes.

Increased levels of cytokines such as TNF-α and IL-1β from M1-like macrophages, saturated FFAs derived from TGRL–triglyceride hydrolysis and adipocyte lipolysis, LTB4 derived from arachidonic acid metabolism, and ANG II derived from RAS activate the PKC, JNK, and IKK/NF-κB pathways in myocytes via interactions with their receptors on the cells. These inflammatory pathways can all impair insulin signaling by increasing serine or threonine phosphorylation and disrupting insulin-stimulated tyrosine phosphorylation of IR or IRS, or by downregulating molecules involved in insulin signaling. IFN-γ from Th1 cells and IL-6 activate JAK/STAT1/3 pathways, which may also impair insulin signaling in myocytes (possibly through SOCS proteins, particularly SOCS1 and SOCS3, which interrupt the interaction of IR with IRS-1 and IRS-2, inhibit IR tyrosine kinase activity, and interact with IRS-1 and IRS-2, leading to their ubiquitin-mediated degradation). PKCs, JNK, IKK/NF-κB, and STAT1/3 may also impair insulin signaling through other, undefined inflammatory pathways. SOCSs are involved in a negative feedback loop that leads to the termination of inflammatory effects of STAT through downregulation of JAK activity, which blocks further STAT phosphorylation.