Adipose‐tissue regulatory T cells: Critical players in adipose‐immune crosstalk

Abstract

Obesity and type-2 diabetes (T2D) are associated with metabolic defects and inflammatory processes in fat depots. FoxP3+ regulatory T cells (Tregs) control immune tolerance, and have an important role in controlling tissue-specific inflammation. In this mini-review we will discuss current insights into how cross-talk between T cells and adipose tissue shapes the inflammatory environment in obesity-associated metabolic diseases, focusing on the role of CD4 + T cells and Tregs. We will also highlight potential opportunities for how the immunoregulatory properties of Tregs could be harnessed to control inflammation in obesity and T2D and emphasize the critical need for more research on humans to establish mechanisms that are conserved in both mice and humans.Keywords: Adipose tissue function r FoxP3 r IL-33 r Immune-adipose crosstalk r Regulatory T cells (Tregs) r T cell tolerance r Type 2 diabetes IntroductionObesity in mice and humans is associated with chronic low-grade inflammation within adipose tissues (ATs) [1,2]. This inflammation is thought to play an important role in the development of pathological processes underlying obesity and metabolic comorbidities such as type-2 diabetes (T2D) [3], which affected 422 million people in 2014 with dramatically-rising incidence worldwide [4,5]. Notably, the observed inflammatory phenotypes within ATs are distinct from the classical definition of pathogeninduced inflammation, i.e. lacking features of color, dolor, rubor and tumor [6], and rather presenting as "sterile" inflammation with detrimental effects. In particular, the size, weight and inflammatory status of visceral AT (VAT) has a major impact on the development of metabolic aberrations and T2D [2,7], highlighting the importance of understanding the physiology of this tissue in health versus disease. Adipocytes, a major constituent of AT, exist in two forms: white and brown. White AT stores lipids as the main energy source, Correspondence: Dr. Carolin Daniel e-mail: carolin.daniel@helmholtz-muenchen.de and regulates lipid and glucose homeostasis. Brown AT (BAT) burns excessive calories via mitochondrial uncoupled respiration using uncoupling protein 1 (UCP1) to produce heat [8,9]. Recent concepts suggest that white adipocytes can undergo a process called "beiging/browning" upon external stimuli such as cold, β3-adrenergic stimulation or short term high-caloric feeding [8,10,11], thereby increasing energy expenditure.One critical feature of AT is the secretion of soluble factors, such as adipokines (e.g. leptin adipsin and adiponectin), as well as chemokines and cytokines (e.g. IL-6, IL-33, CCL2 and TNF-α). These factors are sensed by key circuits within the arcuate nucleus in the hypothalamus, that integrate neuronal and endocrine inputs to regulate systemic metabolism and feeding behaviour [12,13]. Recent evidence shows that these key hypothalamic circuits are critically affected by high-caloric feeding-and obesity-induced inflammation, thereby further promoting obesity exacerbation and progression to T2D [14]...

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“…Dysfunction of processes in adipose tissue compartments may trigger various metabolic disorders, including obesity, metabolic syndrome, lipodystrophy, and cachexia . Studies show that cross‐talk between T cells and adipose tissue shapes the inflammatory environment in obesity‐associated metabolic diseases . Likewise, obesity‐induced changes to macrophages and adipocytes may lead to chronic inflammation and insulin resistance .…”

“…65 Studies show that crosstalk between T cells and adipose tissue shapes the inflammatory environment in obesity-associated metabolic diseases. 66 Likewise, obesity-induced changes to macrophages and adipocytes may lead to chronic inflammation and insulin resistance. 67 Adipose tissue dysfunction has been associated with an increased number of M1 macrophages, B cells, regulatory B cells, T helper (Th) 1 cells, Th17 cells, eosinophils, neutrophils, and mast cells.…”

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“…WAT presents an energy-storing property and a secretory function [3][4][5]. WAT is anatomically divided into distinct depots: subcutaneous and visceral fat [2,9].…”

“…In an obese condition, the ingestion of excess nutrients and energy results in hypertrophy, consequent rupturing of adipocytes, and increased local inflammatory cell accumulation, including macrophages, T cells, and altered production of adipokines. These adipose tissue changes and their systemic consequences lead to the concept of obesity as a chronic inflammatory state, and they increase the risk for multiple chronic diseases, such as type 2 diabetes, cardiovascular disease, several types of cancer, and inflammatory bowel disease (IBD) [1,3,5,9].…”

“…These substances exhibit endocrine or paracrine functions, and they are important in maintaining energy homeostasis [1,[3][4][5][6].…”