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Review
. 2012 Sep;249(1):218-38.
doi: 10.1111/j.1600-065X.2012.01151.x.

The inflammation highway: metabolism accelerates inflammatory traffic in obesity

Amy R Johnson  1 , J Justin Milner, Liza Makowski
Affiliations
Review

The inflammation highway: metabolism accelerates inflammatory traffic in obesity

Amy R Johnson et al. Immunol Rev. 2012 Sep.

Abstract

As humans evolved, perhaps the two strongest selection determinants of survival were a robust immune response able to clear bacterial, viral, and parasitic infection and an ability to efficiently store nutrients to survive times when food sources were scarce. These traits are not mutually exclusive. It is now apparent that critical proteins necessary for regulating energy metabolism, such as peroxisome proliferator-activated receptors, Toll-like receptors, and fatty acid-binding proteins, also act as links between nutrient metabolism and inflammatory pathway activation in immune cells. Obesity in humans is a symptom of energy imbalance: the scale has been tipped such that energy intake exceeds energy output and may be a result, in part, of evolutionary selection toward a phenotype characterized by efficient energy storage. As discussed in this review, obesity is a state of low-grade, chronic inflammation that promotes the development of insulin resistance and diabetes. Ironically, the formation of systemic and/or local, tissue-specific insulin resistance upon inflammatory cell activation may actually be a protective mechanism that co-evolved to repartition energy sources within the body during times of stress during infection. However, the point has been reached where a once beneficial adaptive trait has become detrimental to the health of the individual and an immense public health and economic burden. This article reviews the complex relationship between obesity, insulin resistance/diabetes, and inflammation, and although the liver, brain, pancreas, muscle, and other tissues are relevant, we focus specifically on how the obese adipose microenvironment can promote immune cell influx and sustain damaging inflammation that can lead to the onset of insulin resistance and diabetes. Finally, we address how substrate metabolism may regulate the immune response and discuss how fuel uptake and metabolism may be a targetable approach to limit or abrogate obesity-induced inflammation.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1. Mechanisms of inflammation-induced insulin resistance
(A). Insulin signaling is initiated via binding of insulin to the insulin receptor (IR) inducing autophosphorylation of tyrosine residues on intracellular domains, as shown on an insulin-responsive adipocyte. The activated IR subsequently phosphorylates tyrosine residues on a variety of substrates including the insulin receptor substrate (IRS) family of proteins and Shc isoforms. IRS interacts with various effector molecules such as phosphatidylinositol 3-kinase (PI3K). Simplified, PI3K phosphorylation of membrane phospholipids ultimately leads to recruitment and activation of several kinases such as protein kinase B/Akt and atypical protein kinase C (aPKC). Akt and aPCK are serine/threonine kinases that stimulate membrane translocation of GLUT4 from intracellular vesicles. GLUT4 accumulation at the plasma membrane allows insulin responsive uptake of glucose and reduces circulating glucose levels in the fed state. (B). As the adipose depot expands in size, a variety of cell populations begin to exhibit an inflamed or stressed state through various mechanisms including hypoxia, release of pro-inflammatory non-esterified fatty acids, elevated reactive oxygen species (ROS) production, and cytokines, among others. Increased adipose mass and adipocyte diameter can lead to increases (red arrow) in hypoxia. In addition, elevated levels of circulating saturated fatty acids (FAs) in the obese states can activate Toll-like receptor signaling (TLR) or become hydrolyzed into inflammatory bioactive lipid mediators such as diacylglyceride (DAG), which ultimately lead to activation of cellular stress signaling pathways. Additionally, inflammatory cytokines, such as TNF-α, are secreted into the microenvironment of the obese adipose, further propagating the immune response. Accelerated energy metabolism in the face of enhanced nutrient availability (glucose and FAs) can increase the production of ROS. The culmination of stress in an inflamed adipose cell induced by hypoxia, fatty acids, glucose, ROS, and inflammatory cytokines results in the transcription of inflammatory cytokines and enzymes via activation of transcription factors, such as interferon regulatory factor 3 (IRF-3), NFκB, hypoxia-inducible factor 1 (HIF-1), and AP-1. Furthermore, the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is activated by hypoxia and is glucose-dependent. NLRP3 regulates secretion of the inflammatory cytokine, IL-1β following cleavage of pro-IL-1β via caspase1. Taken together, through direct effects on adipocytes or through paracrine release of mediators, such as saturated fatty acids and cytokines, stress kinases are activated to blunt the insulin signaling cascade. Activated IKK and JNK prevent PI3K activation by phosphorylating IRS on inhibitory serine residues. Further, inflammatory cytokines increase SOCS3 expression, which can interfere with IR activity. Ultimately, insulin resistance leads to impaired insulin-dependent GLUT4 trafficking, and thus elevated levels of circulating glucose, compensatory secretion of insulin by pancreatic beta cells and ultimately type 2 diabetes.
Fig. 2
Fig. 2. Immune cell trafficking in obesity
(A). In lean adipose tissue, adipocytes store triglycerides in a large unilocular droplet. Insulin-mediated repression of lipolysis is present along with little hypoxia, absence of inflammation, and physiologic levels of NEFA, glucose, and ROS. In lean adipose, alternatively activated ‘M2’ macrophages are resident and their phenotype is maintained by the presence of T-regulatory (Treg) cells, Th2 cells, and eosinophils. Lean adipose secretes adipokines such as adiponectin, IL-4, and IL-10, which act to maintain insulin sensitivity. (B). As obesity progresses and adipose tissue expands, hypertrophy and hyperplasia ensues: adipocytes accumulate triglycerides and grow large, while pre-adipocytes are differentiated to mature adipocytes. Alterations in adipokines are prognostic: leptin rises and adiponectin falls with increasing obesity. Chemokines are released, such as MCP1, which recruit monocytes that polarize to pro-inflammatory M1 macrophages. M1 macrophages surround dying adipocytes in classic ‘crown-like structures’ and release many pro-inflammatory mediators. The loss of eosinophils, Tregs, and Th2 T cells as obesity progresses is paired with the infiltration of CD4+ Th1 cells, CD8+ T cells, NK cells, and other granulocytes such as neutrophils, mast cells, and basophils. Elevated cytokines, such as TNFα and IL-1β, levels of NEFA, acylcarnitines, and ROS release contribute to the pro-inflammatory microenvironment.
Fig. 3
Fig. 3. Metabolism drives macrophage polarization
Macrophages subtypes exist and can be broadly categorized as pro-inflammatory M1 or alternatively activated M2, although in vivo studies reveal that macrophage plasticity results in a spectrum of macrophage phenotypes. M1 macrophages are polarized from precursor M0 macrophages via the classical pathway, wherein components of bacteria such as lipopolysaccharide (LPS) and type 1 T-helper (Th1) inflammatory cytokines interferon γ (IFNγ) and TNFα drive expression of pro-inflammatory cytokines such as TNFα. In contrast, M2 macrophages are activated by type 2 (Th2) cytokines IL-4 and IL-13. M2 macrophages are resident in lean adipose and are thought to be involved in remodeling, tissue repair, and maintenance of insulin sensitivity through the production and expression of IL-10, IL-1 receptor antagonist, and arginase-1. Plasticity along the polarization spectrum is an intensely investigated topic. M1 macrophages tend to utilize the glycolytic pathway for energy and metabolite generation, while M2 macrophages are reliant upon β-oxidation of fatty acids. Regulating macrophage substrate metabolism is one potential means for manipulation of the inflammatory response.
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