Adipose tissue inflammation and metabolic dysfunction in obesity

Abstract

Several lines of preclinical and clinical research have confirmed that chronic low-grade inflammation of adipose tissue is mechanistically linked to metabolic disease and organ tissue complications in the overweight and obese organism. Despite this widely confirmed paradigm, numerous open questions and knowledge gaps remain to be investigated. This is mainly due to the intricately intertwined cross-talk of various pro- and anti-inflammatory signaling cascades involved in the immune response of expanding adipose depots, particularly the visceral adipose tissue. Adipose tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines and by infiltration of bone marrow-derived immune cells that signal via production of cytokines and chemokines. Despite its low-grade nature, adipose tissue inflammation negatively impacts remote organ function, a phenomenon that is considered causative of the complications of obesity. The aim of this review is to broadly present an overview of adipose tissue inflammation by highlighting the most recent reports in the scientific literature and summarizing our overall understanding of the field. We also discuss key endogenous anti-inflammatory mediators and analyze their mechanistic role(s) in the pathogenesis and treatment of adipose tissue inflammation. In doing so, we hope to stimulate studies to uncover novel physiological, cellular, and molecular targets for the treatment of obesity.

Keywords: adipocytes; immunity; inflammation; insulin resistance; obesity.

Figure 1.

The inflammatory phenotype of expanding adipose tissue. Hypertrophic adipocytes and tissue resident immune cells experience phenotype changes that halt secretion of anti-inflammatory, protective cytokines to begin secretion of inflammatory adipokines and cytokines that act both locally and systemically to induce peripheral insulin resistance. The inflammatory reaction is sustained by adipocyte-derived chemoattractants such as C-C chemokine receptor type 2 (CCR2), monocyte chemoattractant protein (MCP), and semaphorin 3A (SEMA3A).

Figure 2.

With increased energy storage and free fatty acid (FFA) cargo, white adipocytes undergo abnormal expansion, which results in hypoxia and remodeling-induced senescence. Hypoxia and senescence initiate and sustain chronic low-grade inflammation. Under these conditions, adipocytes experience endoplasmic reticulum (ER) stress and increased reactive oxygen species (ROS) production. Dysfunctional adipocytes also secrete inflammatory cytokines at the expense of production of protective adipokines, such as adiponectin. Noteworthy, inflamed adipose depots also express anti-inflammatory mediators, such as IL-10 and IL-19, whose role in the overall regulation of the immunometabolic response of adipose tissue remains largely unexplored.