An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation

Abstract

The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow-derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type-specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.

Keywords: cardiovascular disease; diabetes mellitus; immunity, innate; insulin resistance; obesity.

Figure 1.. Obesity and Multi-Organ Metabolism: Roles of Innate Immunity in Lean, Homeostatic State, Obesity and Weight Loss.

This Review considers the driving roles for innate immune cells in the adipose tissue in the lean state (A), obesity (B) and upon weight loss (C) with respect to the mediators produced by these cells, their cross-talk with the adaptive immune system as well as the influence of intercellular communications with the brain, skeletal muscle, the gut, particularly the small intestine, and the liver. As these inflammatory mediators are most likely produced/released by multiple different types of innate immune cells, as well as cells of the adaptive immune system, this Figure does not attribute roles for one cell type to expression of specific mediators in the overall environment of metabolic perturbation triggered by obesity.

Figure 1.. Obesity and Multi-Organ Metabolism: Roles of Innate Immunity in Lean, Homeostatic State, Obesity and Weight Loss.

This Review considers the driving roles for innate immune cells in the adipose tissue in the lean state (A), obesity (B) and upon weight loss (C) with respect to the mediators produced by these cells, their cross-talk with the adaptive immune system as well as the influence of intercellular communications with the brain, skeletal muscle, the gut, particularly the small intestine, and the liver. As these inflammatory mediators are most likely produced/released by multiple different types of innate immune cells, as well as cells of the adaptive immune system, this Figure does not attribute roles for one cell type to expression of specific mediators in the overall environment of metabolic perturbation triggered by obesity.

Figure 1.. Obesity and Multi-Organ Metabolism: Roles of Innate Immunity in Lean, Homeostatic State, Obesity and Weight Loss.

This Review considers the driving roles for innate immune cells in the adipose tissue in the lean state (A), obesity (B) and upon weight loss (C) with respect to the mediators produced by these cells, their cross-talk with the adaptive immune system as well as the influence of intercellular communications with the brain, skeletal muscle, the gut, particularly the small intestine, and the liver. As these inflammatory mediators are most likely produced/released by multiple different types of innate immune cells, as well as cells of the adaptive immune system, this Figure does not attribute roles for one cell type to expression of specific mediators in the overall environment of metabolic perturbation triggered by obesity.