Adipose inflammation, insulin resistance, and cardiovascular disease

Abstract

Adiposity-associated inflammation and insulin resistance are strongly implicated in the development of type 2 diabetes and atherosclerotic cardiovascular disease. This article reviews the mechanisms of adipose inflammation, because these may represent therapeutic targets for insulin resistance and for prevention of metabolic and cardiovascular consequences of obesity. The initial insult in adipose inflammation and insulin resistance, mediated by macrophage recruitment and endogenous ligand activation of Toll-like receptors, is perpetuated through chemokine secretion, adipose retention of macrophages, and elaboration of pro-inflammatory adipocytokines. Activation of various kinases modulates adipocyte transcription factors, including peroxisome proliferator-activated receptor-gamma and NFkappaB, attenuating insulin signaling and increasing adipocytokine and free fatty acid secretion. Inflammation retards adipocyte differentiation and further exacerbates adipose dysfunction and inflammation. Paracrine and endocrine adipose inflammatory events induce a local and systemic inflammatory, insulin-resistant state promoting meta-bolic dyslipidemia, type 2 diabetes, and cardiovascular disease. Developing therapeutic strategies that target both adipose inflammation and insulin resistance may help to prevent type 2 diabetes and cardiovascular disease in the emerging epidemic of obesity.

Figure 1

Macrophage–adipocyte interplay in adipose tissue. Adipocytes secrete chemokines, which attract macrophages to adipose tissue. Binding of fatty acids (FAs) and innate antigens to Toll-like receptors (TLRs) on macrophages and adipocytes activates NFκB, modulating cytokine and adipokine biosynthesis and secretion. Adipocytokines can then bind to receptors on adipocytes and, via kinases, activate NFκB to stimulate suppression of cytokine signaling (SOCS) protein transcription. Kinases, via direct phosphorylation, and SOCS proteins, via insulin receptor substrate (IRS) binding and degradation, interfere with insulin signaling and prevent GLUT-4 translocation, leading to insulin resistance. Adipose inflammation also retards adipocyte differentiation, promoting a pro-inflammatory, insulin-resistant preadipocyte phenotype. Inflammatory modulation of adipocytokine and FA production and secretion results in hepatic, skeletal muscle, and vascular insulin resistance; metabolic dyslipidemia; and a systemic pro-inflammatory, atherogenic state. Adipokines (ie, leptin, resistin, lipocalin-2, etc); cytokines (ie, tumor necrosis factor [TNF]-α, interleukin-6 [IL-6], interleukin-18 [IL-18], plasminogen activator inhibitor-1 [PAI-1], etc); chemokines (ie, monocyte chemotactic protein-1 [MCP-1]; regulated on activation, normal T cell expressed and secreted [RANTES]; fractalkine) and chemokine receptors (CCRs); kinases (ie, c-Jun N-terminal kinase [JNK], extracellular signal-regulated kinase [ERK], protein kinase C-θ [PKC-θ], p38 mitogen activated protein kinase [MAPK], phosphoinositide 3-kinase [PI3K], v-akt murine thymoma viral oncogene homolog 1 [AKT]). InsR, insulin receptors.