Review
Regulatory T cells in obesity: the leptin connection

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Studies to understand the pathogenesis of obesity have revealed mediators that are responsible for the control of food intake and metabolism at the hypothalamic level. However, molecular insight explaining the link between obesity and low-degree chronic inflammation remains elusive. The adipocyte-derived hormone leptin, and thereby the nutritional status, could control immune self-tolerance by affecting regulatory T (Treg) cell responsiveness and function. Furthermore, resident Treg cells, which are capable of modulating metabolism and glucose homeostasis, are abundant in adipose tissue. Here, we provide an update on recent findings relating Treg cells to obesity and discuss how the intricate network of interactions among leptin, Treg cells and adipose tissue might provide new strategies for therapeutic interventions.

Introduction

Obesity is a worldwide epidemic of enormous proportion, particularly in the west, and is caused by interactions among predisposing genetic factors, abundant caloric intake and/or low levels of physical activity. Because genetics contributes significantly to obesity, fundamental insights into the molecular mechanisms of obesity have come from the discovery of genes controlling basal metabolism and food intake 1, 2. In the clinic, however, obesity associates with severe conditions such as an increased risk of cardiovascular disease and atherosclerosis, diabetes, fatty liver disease, inflammation and cancer. All of these pathological conditions seem to be promoted in obesity through long-term low-degree chronic inflammation 3, 4.

Obesity is now of particular interest to immunologists because immune response, nutrition and metabolism are closely interconnected [5]. Following the cloning of the genes that encode leptin (Lep), leptin receptor, pro-opiomelanocortin (POMC), pro-protein convertase 1 (PCSK1) and melanocortin-4 receptor, it became evident that certain genetic alterations (i.e. mutation or loss of function) cause obesity and significantly affect immune responses 6, 7, 8, 9, 10, 11, 12, 13, 14, 15. Linking obesity to immune function is a new avenue of investigation that will lead to a better understanding of obesity and possibly lead to therapies that modulate the inflammatory conditions associated with obesity 16, 17. Here, we review the most recent findings relating Treg cell biology with obesity and discuss how the modulation of leptin secretion, Treg cell function and adipose tissue activity might provide new strategies for therapeutic interventions in obesity and its metabolic consequences.

Section snippets

Treg cells: a renaissance

Treg cells are a small subset of T cells, usually constituting only 5–15% of the peripheral CD4+ T cell compartment in mice and humans 18, 19, 20. Treg cells are important in the control of the inappropriate immune responses that characterize autoimmunity and allergy. In general, Treg cells control effector T cell responses and also influence the activities of cells of the innate immune system 18, 19, 20. Treg cells display several surface markers, none of which are unique, and express the

The pathogenesis of obesity and the neural control of food intake

Obesity is a state in which the total amount of triglycerides stored in adipose tissue is increased abnormally. Typically, obesity results from a chronic, positive imbalance between energy intake and energy expenditure and associates with a wide variety of adverse outcomes including type 2 diabetes (T2DM), insulin resistance, inflammation, cardiovascular disease and tumors 1, 4.

Adiposity, which is the result of an excessive number and/or size of white adipose cells caused by genetic and

Low-degree chronic inflammation in obesity

Obesity, insulin resistance and T2DM closely associate with chronic inflammation as characterized by abnormal cytokine production, increased acute phase reactants and other mediators, and the activation of a network of inflammatory signaling pathways 41, 42. Unequivocal experimental, epidemiological and clinical evidence from the past decade have causally linked inflammation (or molecules and networks in inflammatory responses) to the development of metabolic diseases and/or related

Treg cells and obesity: leptin as the missing link?

A link between leptin and immune tolerance has recently been defined (Box 1). Leptin affects the generation and proliferative capacity of Treg cells, which are central players in the control of peripheral immune tolerance [74]. In mice, chronic leptin and leptin receptor deficiencies are characterized by increased percentages, absolute numbers and activities of Treg cells together with a resistance to autoimmune diseases [75]; leptin replacement returns Treg cell levels to those found in

Obesity as an autoimmune disorder

The presence of abundant immune cell infiltrates in the adipose tissue of obese individuals is a classical pathologic lesion in obesity (Figure 2). Although the significance of these infiltrates is currently unknown, they result directly or indirectly from the attraction of immune cells towards adipocytes, particularly those immune cells belonging to the natural immune system (macrophages, neutrophils, natural killer [NK] cells and DCs) 50, 51, 86, 87, 88. The attraction of immune cells by

Concluding remarks and future perspectives

Although a strong relationship between obesity and chronic inflammation is clear, the precise temporal/sequential details that define this relationship are not. Obesity-related alterations including immune dysregulation and autoimmunity in adipose tissue represent new avenues of investigation for the common form of obesity and T2DM, which are not directly linked to single-gene mutations. One open question is how adipose tissue infiltration by immune cells favors changes in food intake and basal

Acknowledgements

G.M. is supported by grants from the EU Ideas Programme, ERC-Starting Independent Grant “LeptinMS” n. 202579 and Telethon-JDRF Grant n. GJT08004. A.L.C. is supported in part by the NIH grant n. AR53239 and the Arthritis Foundation Southern California Chapter. The authors thank Salvatore De Simone and Francesco D’Agnello for critically reading the manuscript and the conception of the artwork. This work is dedicated to the memory of Eugenia Papa and Serafino Zappacosta.

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