An important cause of obesity-induced insulin resistance is chronic systemic inflammation originating in visceral adipose tissue (VAT). VAT inflammation is associated with the accumulation of proinflammatory macrophages in adipose tissue, but the immunological signals that trigger their accumulation remain unknown. We found that a phenotypically distinct population of tissue-resident natural killer (NK) cells represented a crucial link between obesity-induced adipose stress and VAT inflammation. Obesity drove the upregulation of ligands of the NK cell-activating receptor NCR1 on adipocytes; this stimulated NK cell proliferation and interferon-γ (IFN-γ) production, which in turn triggered the differentiation of proinflammatory macrophages and promoted insulin resistance. Deficiency of NK cells, NCR1 or IFN-γ prevented the accumulation of proinflammatory macrophages in VAT and greatly ameliorated insulin sensitivity. Thus NK cells are key regulators of macrophage polarization and insulin resistance in response to obesity-induced adipocyte stress.

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 ...

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