2.1. Adipose tissue inflammation crucially contributes to the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus (DM)

According to the World Health Organization, the worldwide prevalence of obesity and its metabolic complications have increased substantially in recent decades. More than 1.9 billion adults were overweight and over 600 million of these were obese in 2014 [1]. Excess adiposity and adipocyte dysfunction in the state of obesity result in dysregulation of a wide range of adipose tissue-derived secretory factors, which may contribute to the development of various metabolic diseases via altered glucose and lipid homeostasis as well as inflammatory responses. Two important publications in 2003 [2,3] have demonstrated the crucial role of adipose tissue macrophage infiltration in obesity-associated adipose tissue inflammation and associated insulin resistance [4]. Progression of morbid obesity is closely linked to a phenotype switch of the macrophage activation state in adipose tissue. In the obese insulin-resistant state, anti-inflammatory M2 macrophages initially resided in adipose tissue would be progressively replaced by pro-inflammatory M1 macrophages [5]. On the other hand, in the previous issue of Nature Medicine, three different groups published the related aspects of an important link between adaptive immunity (T-cell mediated) in obesity-induced adipose tissue inflammation and insulin resistance in mice. Their results implicate that the alteration in the infiltrated adipose tissue T cells occurs early in obesity and shows the causal relationship between immunity and metabolism. For instance, Nishimura et al. [6] analyzed the dynamics of the inflammatory infiltrate in the visceral fat of C57Bl/6 mice with diet-induced obesity. They used mice with immunological and genetic depletion of CD8<sup>+</sup> T cells (lose and gain of function) to and demonstrated that these T cells are critical mediators of systemic metabolic dysfunction. In addition, obesity alters the balance between Th1 and Th2 stimulation in fat, perhaps through the depletion of Th2 and Treg T cells, and subsequently inducing the increase in CD8<sup>+</sup> and Th1 T cells [6–8]. Thereby, these findings suggest that phenotype switch and immune cell infiltration in adipose tissue are crucial for the development of obesity-related adipose tissue inflammation and metabolic dysfunction [3,9,10].

Adipocytes in an obesity setting, especially in morbid obesity, are characterized by hypertrophy and hypoxia, and they are the important sources to initialize adipose tissue inflammation. This inflammation is mediated by producing a large number of cytokines and chemokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and regulated upon activation, normal T-cell expressed and secreted (RANTES). These cytokines and chemokines produced by adipocytes during hypertrophy and hypoxia significantly contribute to the development of obesity-associated adipose tissue inflammation. The capacity of constitutive and regulated release of immune mediators from adipocytes demonstrates a causal link between the biology of adipocytes and immune cells, such as macrophages and T cells. Moreover, the interplay of hypertrophic, hypoxia adipocytes and adipose tissue immune cells has been speculated to play the key regulatory role in the devel-

This review provides update evidence to emphasize the important role of adipocyte hypertrophy and hypoxia in the development of obesity-associated adipose tissue (AT) inflammation

According to the World Health Organization, the worldwide prevalence of obesity and its metabolic complications have increased substantially in recent decades. More than 1.9 billion adults were overweight and over 600 million of these were obese in 2014 [1]. Excess adiposity and adipocyte dysfunction in the state of obesity result in dysregulation of a wide range of adipose tissue-derived secretory factors, which may contribute to the development of various metabolic diseases via altered glucose and lipid homeostasis as well as inflammatory responses. Two important publications in 2003 [2,3] have demonstrated the crucial role of adipose tissue macrophage infiltration in obesity-associated adipose tissue inflammation and associated insulin resistance [4]. Progression of morbid obesity is closely linked to a phenotype switch of the macrophage activation state in adipose tissue. In the obese insulin-resistant state, anti-inflammatory M2 macrophages initially resided in adipose tissue would be progressively replaced by pro-inflammatory M1 macrophages [5]. On the other hand, in the previous issue of Nature Medicine, three different groups published the related aspects of an important link between adaptive immunity (T-cell mediated) in obesity-induced adipose tissue inflammation and insulin resistance in mice. Their results implicate that the alteration in the infiltrated adipose tissue T cells occurs early in obesity and shows the causal relationship between immunity and metabolism. For instance, Nishimura et al. [6] analyzed the dynamics of the inflammatory infiltrate in the visceral fat of C57Bl/6 mice with diet-induced obesity. They used mice with immunological and genetic depletion of CD8<sup>+</sup> T cells (lose and gain of function) to and demonstrated that these T cells are critical mediators of systemic metabolic dysfunction. In addition, obesity alters the balance between Th1 and Th2 stimulation in fat, perhaps through the depletion of Th2 and Treg T cells, and subsequently inducing the increase in

and insulin resistance and also discusses possible underlying mechanism.

2.1. Adipose tissue inflammation crucially contributes to the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus (DM)

opment of obesity-induced insulin resistance.

128 Adiposity - Omics and Molecular Understanding

2. Main subjects

On the other hand, the excess fat accumulation promotes the release of free fatty acids from adipose tissue into the circulation and affects many other tissues, including the liver, skeletal muscle, and heart. [11]. The detrimental effects of fatty acids and their metabolites, such as acylcoenzyme A, ceramides, and diacyglycerol, on insulin signaling through activating protein kinases such as protein kinase C, mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK), and the inhibitor of nuclear factor-κβ kinase B have been reported [12]. Moreover, free fatty acids serve as ligands for the Toll-like receptor 4 (TLR4) complex [13] and stimulate cytokine production of macrophages [14], thereby modulating inflammation of adipose tissue which also significantly contributes to obesity-associated metabolic complications.
