The “Big Bang” in obese fat: Events initiating obesity‐induced adipose tissue inflammation

Abstract

Obesity is associated with the accumulation of pro-inflammatory cells in visceral adipose tissue (VAT), which is an important underlying cause of insulin resistance and progression to diabetes mellitus type 2 (DM2). Although the role of pro-inflammatory cytokines in disease development is established, the initiating events leading to immune cell activation remain elusive. Lean adipose tissue is predominantly populated with regulatory cells, such as eosinophils and type 2 innate lymphocytes. These cells maintain tissue homeostasis through the excretion of type 2 cytokines, such as IL-4, IL-5, and IL-13, which keep adipose tissue macrophages (ATMs) in an anti-inflammatory, M2-like state.Diet-induced obesity is associated with the loss of tissue homeostasis and development of type 1 inflammatory responses in VAT, characterized by IFN-γ. A key event is a shift of ATMs toward an M1 phenotype. Recent studies show that obesity-induced adipocyte hypertrophy results in upregulated surface expression of stress markers. Adipose stress is detected by local sentinels, such as NK cells and CD8 + T cells, which produce IFN-γ, driving M1 ATM polarization. A rapid accumulation of pro-inflammatory cells in VAT follows, leading to inflammation. In this review, we provide an overview of events leading to adipose tissue inflammation, with a special focus on adipose homeostasis and the obesity-induced loss of homeostasis which marks the initiation of VAT inflammation.Keywords: Adiponectin r Adipose tissue r Diabetes mellitus type 2 r IFN-γ r Inflammation r Insulin resistance r Macrophages r NK cells r Obesity r TNF IntroductionOver the past few decades, we have seen a dramatic worldwide increase in the incidence of obesity and its associated pathologies, such as insulin resistance, which contributes to the development of metabolic syndrome and diabetes mellitus type 2 (DM2) [1]. Metabolic syndrome is a cluster of conditions such as elevated blood glucose, elevated blood pressure, excess body fat, and Correspondence: Dr. Bojan Polić e-mail: bojan.polic@medri.uniri.hr abnormal lipid (cholesterol) levels, which together increase the risk of diabetes mellitus and cardiovascular disease. DM2 is characterized by high blood glucose levels, which is a direct result of reduced systemic sensitivity to the anabolic hormone insulin. An important underlying cause of obesity-induced insulin resistance is chronic low-grade systemic inflammation (reviewed in [2]). The long-term presence of pro-inflammatory cytokines in the blood blunts the signal transduction capacity of the insulin receptor in * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2446-2456 HIGHLIGHTS 2447insulin-sensitive tissues [3]. Obesity-induced systemic inflammation is thought to originate predominantly in adipose tissue. The human body contains various types of fat depots, generally divided in white and brown fat. The role of brown adipose tissue is to produce body heat and in humans is mostly found in newborns, even though adults do ...

Efficacy of dietary and physical activity intervention in non-alcoholic fatty liver disease: a systematic review

“…It is possible that it is the fat loss which is important as systemic fat loss is associated with a reduction in IHTG,33 or increased metabolic activity of new muscle mass confers benefits including increased resting metabolic rate 49. An alternative hypothesis is that NAFLD and obesity are inflammatory metabolic states and it is the anti-inflammatory effects of the exercise that lead to the improvements seen 9 50…”

The Effects of Endurance Exercise and Diet on Atherosclerosis in Young and Aged ApoE^–/– and Wild-Type Mice

“…Even though we do not know the specificity of the increased T REGs in the lymph nodes, they are clearly only increased in most exercising mice, and hence it seems plausible that exercise leads to an increase in the levels of anti-inflammatory TGF-β, which in turn could be strongly associated with increased frequency and function of T REGs [37]. Both aging and obesity, as a result of a high-fat diet and/or physical inactivity, are associated with low-grade inflammation [8,39]. Even though we did observe a decrease in atherosclerosis in aged WT running mice on a WD, they, like the aged ApoE -/-mice on WD, did not have an increase in T REGs .…”

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Macrophage functions in lean and obese adipose tissue

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