The inflammation highway: metabolism accelerates inflammatory traffic in obesity

Abstract

Summary 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 (PPARs), Toll-like receptors (TLRs), and fatty acid-binding proteins (FABPs) 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 while 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.

Shaping Immune Responses by Dysregulated Adipokines in Obesity

“…The increasing prevalence of obesity poses a major threat to public health. Clinical and epidemiological data have established that obesity not only links to the development of diabetes, atherosclerosis and cardiovascular diseases, but also increases the risk of many types of cancer [1]. Although tremendous effort has been taken to investigate the pathogenesis of obesity and its associated diseases, the molecular mechanisms by which obesity negatively impacts on metabolic and immunologic homeostasisand increases the morbidity and mortality of many maladies remain largely unknown.…”

Bowman lecture on the role of inflammation in degenerative disease of the eye

“…Current concept of diabetes pathogenesis, and more broadly the Metabolic Syndrome, highlights the role of inflammation in pathogenesis of disease and particularly its complications (reviewed in Johnson et al 40 ). For a number of years now, the role of inflammation specifically in DR has been recognised, 41 particularly recent studies on the role of bone marrow-derived monocyte/macrophages.…”

“…Retinal ischaemia due to capillary occlusion is understood to be the trigger for the sightthreatening damage including the capillary leakage and neovascularisation, proposed many years ago by Michaelson et al 47 and promulgated by Ashton. 48 Previously, the capillary occlusion in DR was attributed to the hypercoagulability of diabetes (also a criteria of the Metabolic Syndrome 40 ) and low fibrinolytic activity of diabetic plasma. In 1990, Schroder et al 49 demonstrated that activated leucocytes were the major contributors to capillary occlusion in alloxan diabetic rats, and this has been confirmed in many models (see review in Zhang et al 41 ).…”

“…53 This macrophage behaviour 2. is also mirrored in dysregulated adipose tissue by infiltrating monocytes/macrophages in the Metabolic Syndrome, once more highlighting the common pathology of these conditions. 40 Age-related macular degeneration…”

Broad-Spectrum Antibiotic Abuse and its Connection to Obesity

“…Dysbiosis refers to an alteration of the endogenous flora in our gut, predisposing an individual to microbial overgrowth and a loss of normal gut function. This microbial imbalance in the gut is mechanistically linked to a disruption of metabolic and immune response pathways throughout the body [106,107]. To best understand the significance of this effect, it is useful to view the gastrointestinal tract as a rainforest, containing an abundance of microbial species, each inhabiting a unique niche, with community ecology playing a crucial role for overall function.…”