Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis

Abstract

Metabolism and immunity are inextricably linked both to each other and to organism-wide function, allowing mammals to adapt to changes in their internal and external environments. In the modern context of obesogenic diets and lifestyles, however, these adaptive responses can have deleterious consequences. In this Review, we discuss the pleiotropic actions of inflammation and insulin resistance in metabolic homeostasis and disease. An appreciation of the adaptive context in which these responses arose is useful for understanding their pathogenic actions in disease.

Figure 1. Inflammatory signaling pathways link nutrient excess to insulin resistance

Insulin’s presence at the cell surface is transduced to cytoplasmic and nuclear responses by tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and -2. Serine phosphorylation of these same proteins by Jun N-terminal kinases (JNK) and inhibitor of nuclear factor κB (NF-κB) kinases (IKK), however, potently inhibits insulin signaling. Many diverse cell-intrinsic and -extrinsic sequelae of chronic nutrient excess activate these signaling pathways, directly linking overfeeding to insulin resistance. Furthermore, JNK and IKK activation triggers inflammatory cytokine production, further activating JNK/IKK in an autocrine and paracrine manner and reinforcing insulin resistance. Abbreviations: ER, endoplasmic reticulum; AP-1, activator protein-1.

Figure 2. Inflammation and insulin resistance are central to obesity-induced metabolic disease

Under conditions of acute intake-expenditure imbalance, metabolic tissues store excess nutrients for future use. With chronic imbalance, physiologic storage capacity is exceeded, activating cellular stress signaling pathways that attempt to stem further nutrient influx by inhibiting insulin signaling and promoting inflammation. In adaptive obesity, such as is seen in hibernators, nutrient excess is time-limited with eventual resumption of physiologic normality before tissue damage can occur. In obesity-induced metabolic disease, however, continued nutrient imbalance drives this process forward, leading to chronic inflammation and insulin resistance and, ultimately, to diabetes, cardiovascular disease, and other overtly pathologic consequences.

Figure 3. Lean and obese adipose tissues are associated with distinct macrophage phenotypes

In lean adipose tissue (a), eosinophil-derived interleukin (IL)-4 supports alternatively activated M2 macrophages characterized by production of tolerogenic cytokines such as IL-10 and minimal production of inflammatory mediators. This phenotype establishes a tolerogenic immune environment and directly promotes adipocyte insulin sensitivity. In turn, lean adipocytes produce adiponectin, which collaborates with IL-4 signaling to enhance alternative M2 macrophage activation. In obese adipose tissue (b), inflammatory M1 macrophages, activated by the stigmata of chronic nutrient excess, produce pro-inflammatory cytokines and chemokines that exacerbate adipocyte insulin resistance, enhance cellular stress, and recruit additional leukocytes. Adipocytes, in turn, also secrete inflammatory cytokines and saturated fatty acids that, along with signals from necrotic cells, reinforce the inflammatory environment. Abbreviations: STAT, signal transducer and activator of transcription; PPAR, peroxisome proliferator-activated receptor; KLF, Kruppel-like factor; TLRs, Toll-like receptors; DRRs, Danger Recognition Receptors; MR, mineralocorticoid receptor; IRF, interferon regulatory factor; TNF, tumor necrosis factor; Ccl, CC chemokine ligand.