The outliers become a stampede as immunometabolism reaches a tipping point

Abstract

Obesity and Type 2 diabetes mellitus (T2D) are characterized by pro-inflammatory alterations in the immune system including shifts in leukocyte subset differentiation and in cytokine/chemokine balance. The chronic, low-grade inflammation resulting largely from changes in T-cell, B-cell, and myeloid compartments promotes and/or exacerbates insulin resistance (IR) that, together with pancreatic islet failure, defines T2D. Animal model studies show that interruption of immune cell-mediated inflammation by any one of several methods almost invariably results in the prevention or delay of obesity and/or IR. However, anti-inflammatory therapies have had a modest impact on established T2D in clinical trials. These seemingly contradictory results indicate that a more comprehensive understanding of human IR/T2D-associated immune cell function is needed to leverage animal studies into clinical treatments. Important outstanding analyses include identifying potential immunological checkpoints in disease etiology, detailing immune cell/adipose tissue cross-talk, and defining strengths/weaknesses of model organism studies to determine whether we can harness the promising new field of immunometabolism to curb the global obesity and T2D epidemics.

Fig. 1. Pattern of excess adipose tissue deposition associates with metabolic health

Overnutrition is perhaps the best understood cause of obesity and T2D; however, common obesogenic insults such as bisphenol A (BPA) ingestion are also present in human diets. Unlike mice, individual differences in AT deposition in humans are highly variable, but can be grouped based on dominance of central obesity (the ‘apple’ shape) or peripheral obesity (the ‘pear’ shape). Individuals with central obesity are generally metabolically less healthy, with exception of the metabolically healthy obese group, and are characterized by pro-inflammatory immune cell infiltration and crown-like structures (CLS) in the expanded visceral fat depots (omental, mesenteric, and epiploic). They often have fatty liver disease with or without liver inflammation and immune cell infiltration. Cardiovascular and microvascular disease are common in ‘apples’. Excess lower body fat, as seen in ‘pears’, generally associates with non-inflamed AT. We speculate this peripheral obesity might also associate with elevated AT-associated Tregs, as seen in AT from morbidly obese individuals (see also Fig. 2). People with peripheral AT excess are generally more insulin sensitive and lack the comorbidities common to those who are centrally obese.

Fig. 2. A working model for the role of immune system cells in obesity and T2D

(A) Immune cell/AT cross-talk in non-diabetic (ND) lean individuals. Monocytes (M) and T cells (T) interact through cell-cell contact mechanisms (black double headed arrow between monocytes and T cells) to induce low, non-pathogenic levels of T-cell-produced IL-17. B cells (B) can indirectly inhibit T cells by inducing Treg expansion, although the exact mechanism is still unknown (arrow from B cells to Tregs). B-cell-produced IL-10 can also inhibit T cells. The baseline balance of immune cell cytokines interacts negligibly with adipocytes. Adipocytes also produce inflammatory/immune cell mediators (black two-headed arrow below bracket) at significant levels even in lean ND individuals. The dominance of anti-inflammatory adipokines such as adiponectin in lean individuals does not support pro-inflammatory immune cells. Overall, there is a non-inflammatory homeostasis between AT and the immune system. (B) Immune cell/AT cross-talk in obese/T2D individuals. Increased free fatty acids or endotoxin (stars) due to increasing obesity are ligands that activate monocytes and B cells in mechanisms that may involve TLR4 (arrows from stars). Activated monocytes produce elevated levels of inflammatory cytokines. B cells produce increased IL-8 and very low levels of the anti-inflammatory cytokine IL-10. Monocytes and T cells interact to produce ND-equivalent levels of IL-17 (black double-headed arrows between monocytes and T cells). However, pro-inflammatory B cells induce T cells, through ill-defined mechanisms (black double-headed arrows between B cells and T cells), to produce elevated levels of IL-17 only in T2D samples. Mechanisms that drive IFN-γ elevation in T2D may also involve B cells. Additionally, we speculate that B cells lose their ability to induce Tregs (black X). Overall pathogenic pro-inflammatory cytokines produced by immune cells promote AT IR (red double-headed arrow). Increasing necrosis in the expanding AT can induce migration of T cells, B cells, and monocytes into AT (not indicated). Increasing obesity also affects AT by inducing adipocytes to produce a pro-inflammatory balance of adipokines (red double-headed arrow), which can affect immune cells and further support a feed-forward pro-inflammatory loop. Taken together, all of these factors promote IR and systemic inflammation in T2D. (C) Immune cell/AT cross-talk in morbidly obese individuals. Treg expansion in morbidly obese individuals may curb, at least in part, inflammation-mediated metabolic imbalance/IR. The immune system in either morbidly obese or metabolically healthy obese individuals remains to be thoroughly characterized. Although adipocyte size is generally increased in obesity, the subset of individuals highlighted in this panel maintain IS adipocytes.