An Integrated View of Immunometabolism

Abstract

The worldwide obesity epidemic has emerged as a major cause of insulin resistance and Type 2 diabetes. Chronic tissue inflammation is a well-recognized feature of obesity, and the field of immunometabolism has witnessed many advances in recent years. Here, we review the major features of our current understanding with respect to chronic obesity-related inflammation in metabolic tissues and focus on how these inflammatory changes affect insulin sensitivity, insulin secretion, food intake, and glucose homeostasis. There is a growing appreciation of the varied and sometimes integrated crosstalk between cells within a tissue (intraorgan) and tissues within an organism (interorgan) that supports inflammation in the context of metabolic dysregulation. Understanding these pathways and modes of communication has implications for translational studies. We also briefly summarize the state of this field with respect to potential current and developing therapeutics.

Figure 1.. Obesity Is the Major Cause of Insulin Resistance in Humans and Is a Driver of the Global Type 2 Diabetes Mellitus Epidemic

Obesity-induced chronic tissue inflammation is a key mechanism of the dys-metabolism that occurs in this condition. Chronic tissue inflammation induces a range of effects on adipose tissue, muscle, liver, pancreatic islets, the gut, and the CNS. These inflammatory changes contribute to insulin resistance (adipocytes, muscle, liver), decreased insulin secretion (islets), dysbiosis and intestinal permeability (gut), and increased food intake (CNS).

Figure 2.. Mechanisms of Intraorgan Cross-talk

Obesity leads to various triggering events, such as ER stress, hypoxia, and lipotoxicity, which can initiate activation of proinflammatory pathways within tissue parenchymal cells (Step 1). As part of the activation mechanism in these parenchymal cells, they secrete a variety of chemokines (Step 2), which lead to chemotaxis and migration of macrophages, as well as other immune cell types, into the underlying tissue (Step 3). Overall, these immune cells take on a proinflammatory phenotype and secrete a number of factors (cytokines, galectin-3, miRNA-containing exosomes, etc.), which exert local paracrine effects to cause insulin resistance in adipocytes, hepatocytes, and myocytes, or decreased GSIS in β cells (Step 4).

Figure 3.. Inflammation-Mediated Interorgan Crosstalk

Obesity leads to chronic inflammation in metabolic tissues (liver, adipose tissue, and muscle). It also causes dysbiosis in the GI tract and gliosis in the CNS. Once these events are established, these tissues then elaborate a large number of secretory factors which not only act locally (paracrine effects), but can also enter the circulation to cause distal effects on insulin sensitivity, GSIS, and food intake. These factors, exemplified by cytokines, miRNA-containing exosomes, galectin-3, FFAs, fetuin A, and LPS do not act in isolation but can work in an additive or coordinated fashion on tissue sites of action. Each factor has the potential to influence production and secretion of some of the other factors, adding to the complexity of the integrated network comprising metabolic interorgan crosstalk.