Inflammatory links between obesity and metabolic disease

Abstract

The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity. This has led to a convergence of the fields of immunology and nutrient physiology and the understanding that they are inextricably linked. The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases. In this Review, we highlight the cellular and molecular mechanisms at play in the generation of obesity-induced inflammation. We also emphasize how defining the immune regulation in metabolic tissues has broadened the understanding of the diversity of inflammatory responses.

Figure 1. Cellular mediators of inflammation and immunity in obesity.

The multisystem effects of obesity are linked to an imbalance in homeostatic and proinflammatory immune responses. Obesity triggers inflammatory pathways in the brain and adipose tissue that dysregulate physiological responses that maintain insulin and leptin sensitivity. Over time, ectopic lipid accumulation in muscle, liver, and blood vessels activates tissue leukocytes, contributes to organ-specific disease, and exacerbates systemic insulin resistance. Cellular- and cytokine-mediated inflammation in pancreatic islets accelerates the progression toward diabetes. FFA, free FA; INS, insulin; KC, Kupffer cell; Tconv, conventional CD4⁺ T cells.

Figure 2. Molecular pathways at the interface between obesity and inflammation.

Multiple signaling pathways participate in translating obesity-derived nutrient and inflammatory signals into a cellular response relevant in disease. These include proinflammatory (red) and antiinflammatory (blue) signals from the cell surface that integrate through many common intracellular pathways to generate the coordinated increase in inflammatory genes while repressing genes important in maintaining proper nutrient metabolism. PKR, RNA-dependent protein kinase.