Inflammatory mechanisms linking obesity and metabolic disease

Abstract

We are in the midst of a worldwide obesity epidemic. Over 1.9 billion people are now obese or overweight, including more than 50 million children under age 5, and the worldwide prevalence of obesity has doubled since 1980 (1). The complications of obesity are taking a major public health toll, which will only worsen in future years. Among the most devastating of these complications is type 2 diabetes (T2D). Most patients with T2D are obese or overweight, and there are numerous longitudinal studies linking obesity with insulin resistance, a frequent forerunner of diabetes.Over the past two decades, the search for a mechanism linking the pathogenesis of obesity with insulin resistance and diabetes has revealed a close relationship between nutrient excess and activation of the innate immune system in most organs pertinent to energy homeostasis (2-4). Numerous studies indicate that inflammation occurs as a consequence of obesity, and recent insights suggest that it may play a causative role in generating insulin resistance, defective insulin secretion, and disruption of other aspects of energy homeostasis. The nature of obesityinduced inflammation differs from other inflammatory paradigms in that it involves tonic activation of the innate immune system that impacts metabolic homeostasis, in some cases over a lifetime. Inflammation also leads to maladaptive responses such as fibrosis and necrosis that can cause significant tissue damage. Moreover, obesity-induced inflammation is unique in that it involves multiple organs, including adipose, pancreas, liver, skeletal muscle, heart, and brain. These features of obesity-induced inflammation present a challenge to understanding the underlying mechanisms and the manner by which they impact metabolic systems. In this issue of the JCI, a group of experts have provided reviews that dive deeply into the mechanisms by which obesity-induced inflammation influences metabolic homeostasis, surveying the modes and mechanisms of inflammation in different tissues and how they might contribute to disease. These Reviews also discuss how inflammation can lead to other aspects of metabolic syndrome, including hyperphagia, reduced energy expenditure, β cell dysfunction, and liver disease, and summarize the status of therapeutic interventions that target inflammation in the context of metabolic syndrome. Activation of the innate immune system in obesityMuch of what has been learned about the immune response to obesity has come from studies in adipose tissue, although it is clear that inflammation occurs in other organs as well. Adipose depots normally contain multiple immune cells that together surveil and maintain the integrity and hormonal sensitivity of adipocytes. In lean animals, these immune cells operate in an overall Th2 or type 2 state that coordinately controls tissue integrity and metabolism by controlling the activity of subsets of T lymphocytes. These cells release a cascade of cytokines that coordinately regulate other immune cells, including eosinophils, mast cells, and othe...

Metabolic Instruction of Immunity

“…These are generally considered to be produced in response to local tissue damage or infection, which can regulate not only the metabolic activities of neighboring cells, but also act on distal sensors that control host metabolism (Febbraio, 2014). For example, circulating IL-6 levels are elevated in patients with chronic inflammation, which can modulate fatty acid metabolism and cell survival in many tissues including skeletal muscle, hepatocytes, the central nervous system (CNS), and neuroendocrine system (Saltiel and Olefsky, 2017). …”

Warming the mouse to model human diseases

“…However, it should be noted that while many initial studies linked obesity-induced inflammation to insulin resistance, recent studies in mice and humans demonstrate that insulin resistance often precedes the onset of inflammation in adipose tissue 57-59 . In light of this, it has been suggested that inflammation in metabolic tissues might participate in the maintenance rather than initiation of insulin resistance 60,61 . Despite this controversy, it is not known whether these results from murine studies are translatable to humans because nearly all of these studies have been performed in thermally stressed mice, whereas humans mostly live in their thermal comfort or neutral zone.…”

Muscle and adipose tissue insulin resistance: malady without mechanism?

“…We recommend several other reviews that have focused on other aspects of insulin resistance that will not be discussed in this review. Most notably, Czech provided an elegant distillation of the complex relationship between hyperinsulinemia and insulin resistance (9), while others have presented evidence in support of a range of other factors as causes of insulin resistance including diacylglycerols (10), ceramides (11) and inflammation (12).…”