Cytokines and inflammation in adipogenesis: an updated review

Abstract

The biological relevance of cytokines is known for more than 20 years. Evidence suggests that adipogenesis is one of the biological events involved in the regulation of cytokines, and pro-inflammatory cytokines (e.g., TNFα and IL-1β) inhibit adipogenesis through various pathways. This inhibitory effect can constrain the hyperplastic expandability of adipose tissues. Meanwhile, chronic low-grade inflammation is commonly observed in obese populations. In some individuals, the impaired ability of adipose tissues to recruit new adipocytes to adipose depots during overnutrition results in adipocyte hypertrophy, ectopic lipid accumulation, and insulin resistance. Intervention studies showed that pro-inflammatory cytokine antagonists improve metabolism in patients with metabolic syndrome. This review focuses on the cytokines currently known to regulate adipogenesis under physiological and pathophysiological circumstances. Recent studies on how inhibited adipogenesis leads to metabolic disorders were summarized. Although the interplay of cytokines and lipid metabolism is yet incompletely understood, cytokines represent a class of potential therapeutic targets in the treatment of metabolic disorders.

Keywords

cytokines / inflammation / adipogenesis / type 2 diabetes mellitus / metabolic disorder

Introduction

The adipose tissue has been recognized as a dynamic component of the endocrine system and plays an important role in the maintenance of energy balance and nutritional homeostasis [¹]. Mature adipocytes are the most distinctive cell type of the adipose tissue and occupy more than 90% of its volume [²]. Meanwhile, leukocytes, macrophages, fibroblasts, endothelial cells, and preadipocytes are called stromal-vascular cells. Each gram of adipose tissue contains four to six million stromal–vascular cells, more than half of which are immune cells [³]. Thus, adipose tissues are known as a large source of macrophages and other immune cells [⁴].

Precursor cells become lipid-laden mature adipocytes via a two-step developmental process called adipogenesis. A mesenchymal cell differentiates into preadipocyte, which then undergoes terminal differentiation to become a lipid-filled adipocyte. The fate of adipogenesis is determined by cell–cell and cell–extracellular matrix (ECM) interactions within the adipose tissue. These interactions rely on numerous factors including peroxisome proliferator-activated receptor g (PPARg), CCAAT/enhancer-binding proteins (C/EBPs), Wingless and INT-1 proteins (Wnts), and cytokines. PPARg and C/EBPs are considered essential factors in adipogenesis [¹,⁵]. During the early stages of adipogenesis, multiple inducers activate PPARg expression. PPARg then activates C/EBPa expression, and these two factors act in cooperation to maintain adipogenesis [¹].

Both adipocytes and immune cells participate in the secretion of cytokines, which play a pivotal role in adipogenesis. The secreted cytokines then affect appetite regulation, energy metabolism, and immunological interactions [³]. Table 1 summarizes the cytokines that regulate adipogenesis. This review focuses on how cytokines regulate adipogenesis and how dysregulated adipogenesis leads to complications associated with inflammation-mediated metabolic diseases, such as type 2 diabetes mellitus (T2DM), cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD).

Tumor necrosis factor-a

Tumor necrosis factor-a (TNFa) is primarily a pro-inflammatory cytokine that plays a key role in the regulation of inflammatory response, cell differentiation, cell proliferation, and apoptosis [³⁸,³⁹]. TNFa binds to two distinct receptors, namely, TNFa receptors (TNFR) type 1 or 2 (Fig.1) [⁴⁰]. Upon binding to either receptor, TNFa activates NF-kB and MAPK (JNK, ERK, and p38) signaling [⁴¹]. In adipose tissues, the majority of TNFa is produced by stromal–vascular cells and adipose tissue macrophages (ATMs) [⁴,⁴²]. Furthermore, TNFa contributes to insulin resistance in obesity [⁴³–⁴⁶], and its circulating levels are elevated in individuals with obesity or T2DM [⁴⁷,⁴⁸]. TNFa treatment in 3T3-L1 cells and rats also induces insulin resistance [⁴⁹,⁵⁰]. Moreover, blockage of TNFa using null mutation of TNFa gene and its two receptors genes improves insulin sensitivity in ob/ob rodent model [⁵¹].

TNFa is a potent inhibitor of adipogenesis and blocks adipocyte differentiation mainly by activating TNFR1 [⁸], which stimulates the NF-kB, ERK1/2 and JNK signaling pathways [⁸,⁹,⁵²]. The differentiation of 3T3-L1 cells is restored once NF-kB and JNK signaling are blocked by specific inhibitors [⁹]. TNFa inhibits adipogenesis through multiple mechanisms, including the activation of Wnt/b-catenin/TCF dependent pathway and inhibition of transcription factors, such as PPARg and C/EBPs [⁵³–⁵⁵].

In 3T3-L1 cells and mouse models, the inhibition of PPARg by TNFa involves thiazolidinediones, a class of PPARg agonists that restore adipogenesis [⁵³,⁵⁴]. The TNFa-induced blockage of adipogenesis through PPARg inhibition may act at the transcriptional [⁵⁶,⁵⁷] and post-translational levels. In 3T3-L1 adipocytes, treatment with TNFa enhances the activities of JNK1/2 and p38 SAP kinase. Activated JNK1/2 and p38 SAP kinase promotes the c-Jun and ATF2 activity, thereby increasing Map4k4 expression, which negatively regulates PPARg expression and adipogenesis in 3T3-L1 cells [⁷,⁵⁸]. TNFa may induce cleavage of PPARg by activating the caspase cascade, which disrupts the nuclear localization of PPARg [⁵⁹].

TNFa also inhibits adipogenesis by stimulating other negative physiological regulators, such as Wnt/b-catenin signaling. Wnt/b-catenin pathway downregulates PPARg and C/EBPa expression and inhibits adipocyte differentiation [⁵⁵]. In animal models, TNFa activates Wnt/b-catenin/T-cell factor 4 pathways by stimulating TNFR1-mediated death domain signals [⁶]. Meanwhile, TNFa deficiency downregulates Wnt10b and b-catenin, upregulates adipocyte-specific genes in epididymal white adipose tissues, and promotes significant body weight gain in chow diet mice [⁶⁰].

Numerous microRNAs regulate biological processes in adipose tissues, especially adipogenesis [⁶¹] (Table 2). Recent studies have shown that microRNAs regulate adipogenesis in different stages and may act as downstream factors of TNFa. Price et al. found that the levels of microRNAs are altered in adipose tissues during the development of obesity and insulin resistance [⁶²]. Certain microRNAs, including miR-221, miR-155, miR-103, miR-143, miR-335, miR-27, has-miR-26b and miR-378, in adipose tissues are regulated by TNFa [³⁵–³⁷,⁶³–⁶⁷]. In cultured human preadipocytes, miR-221 expression is suppressed by TNFa [³⁵]. By contrast, human adipocytes transfected with miR-221 express increased level of proteins involved in lipid metabolism, including PPARg [³⁵]. Despite these facts, how TNFa, adipogenesis, and related microRNAs interact with one another remains unknown, although several mechanisms have been proposed in vitro. In 3T3-L1 cells, Liu et al. demonstrated that TNFa upregulates miR-155 and miR-27 by activating the NF-kB pathway [³⁶]. miR-155 and miR-27 expression both inhibit early adipogenic transcription factors, such as C/EBPb and cAMP-response element binding protein (CREB), by directly targeting their 3' untranslated regions (UTRs) [³⁶,⁶⁴]. TNFa downregulates miR-103 and miR-143, which accelerate adipogenesis [³⁷]. These findings show that miRNAs act as mediators in the regulation of adipogenesis and insulin sensitivity via TNFa and give rise to the idea of using microRNA targeting as a novel therapeutic strategy for obesity and T2DM treatment.

In general, current studies show that TNFa inhibits adipogenesis through multiple mechanisms, but the importance of each mechanism is not fully understood. Integration of these mechanisms should be considered when investigating the regulation of adipogenesis by TNFa.

IL-1 family

The IL-1 family contains 11 members playing important roles in the regulation of immunity and inflammatory responses. Among these members, some are pro-inflammatory cytokines, such as IL-1b, IL-18, IL-1F6 (IL-36a), whereas others are anti-inflammatory cytokines, such as IL1Ra and IL-37 [⁶⁸]. IL-1b is a well-known inhibitor of adipogenesis [⁶⁹]. It is mainly produced by THP-1 macrophages in adipose tissues and, to a lesser extent, in adipocytes [⁷⁰]. IL-1b binds to type 1 IL-1 receptor to activate intracellular signaling including NF-kB pathway, which inhibits adipogenesis (Fig.2) [⁷¹,⁷²]. In obese mice models, IL-1b is upregulated in adipose tissue [⁷⁰] and is found to inhibit adipocyte differentiation and fat accumulation [¹⁰] at the physiological concentration of 500 pg/mL [¹⁰]. Additionally, immunodepleting IL-1b does not affect the anti-adipogenic potential of macrophages [¹⁰], indicating that this cells synthesize other factors that also possess anti-adipogenic activity. Interestingly, previous studies showed that the knockout of IL-1Ra, the natural inhibitor of IL-1b, results in increased food intake, reduced body weight, and reduced adipogenesis in mice [¹⁴]. Additionally, IL-1Ra^−/− mice showed decreased levels of leptin, IL-1b, IL-6, and TNFa. These results suggest that IL-1Ra and IL-1b, along with other unknown factors, form a network that regulates energy expenditure and adipogenesis.

IL-18 is member of the IL-1 family and is a pro-inflammatory cytokine. In human adipose tissues, stromal–vascular cells are the main sources of IL-18 [⁷³], with higher levels of IL-18 in visceral adipose tissue compared with subcutaneous adipose tissue [⁷⁵]. The circulating levels of IL-18 are elevated in obese subjects [⁷³], although these levels are restored to normal after bariatric surgery [⁷⁴]. Paradoxically, IL-18 knockout mice show increased body weight and insulin resistance, whereas administration of recombinant IL-18 reduces food intake and body weight gain in wild type mice [⁷⁶,⁷⁷]. IL-18 also increases insulin sensitivity in mice and 3T3 cells [⁷⁶,⁷⁸] (reviewed in [⁷⁹]). Nlrp1 knockout mice, which are IL-18 deficient, shows increased adipose tissue mass, adipocyte size, and lipid deposition in their livers [⁸⁰]. IL-18 signals through STAT3 and activates AMPK in muscles [⁸¹], which elicit positive metabolic effects by enhancing fatty acid oxidation and reducing obesity [⁸¹]. The effect of IL-18 on adipogenesis and lipid metabolism must be further investigated.

Meanwhile, IL-33 provides protection against obesity-induced inflammation and insulin resistance in mouse models and humans [⁷⁰,⁸²]. IL-33 is abundant in human adipose tissues, including adipocytes, endothelial cells, and fibroblast-like reticular cells [⁸³–⁸⁵]. It potently induces type 2 immunity and inflammation, which are mediated by IL-4, IL-5, IL-9, and IL-13. Hence, IL-33 inhibits the infiltration of pro-inflammatory immune cells into the adipose tissue by maintaining the number and functions of ST2⁺ cells and M2 macrophages [¹²,⁸⁶]. ST2 is the receptor for IL-33 and is highly expressed in group 2 innate lymphoid cells (ILC2s) and T helper 2 (Th2) cells [¹¹]. In rodent models, IL-33 or ST2 deficiency causes aggravated obesity and insulin resistance and decreased ILC2s, eosinophils, Tregs, and M2 polarized macrophages in white adipose tissue [⁸⁷]. In contrast, administration of recombinant IL-33 into diabetic (ob/ob) mice ameliorates obesity and diabetes mellitus [¹²]. Moreover, IL-33 may influence adipogenesis by targeting adipocyte precursors. An in vitro study shows that IL-33 treatment reduces expression of adipogenic genes and inhibits aldosterone-induced adipose differentiation and inflammation [¹¹]. Further studies are needed to elucidate the pathway by which IL-33 influences differentiation of adipocyte precursors.

IL-37 acts as an anti-inflammatory cytokine. In humans, elevated IL-37 mRNA levels in adipose tissues are positively correlated with increased insulin sensitivity and decreased inflammatory levels [¹⁵]. Moreover, IL-37 directly activates AMPK signaling that reduces adipocyte differentiation in SGBS cells [¹⁵]. These results indicate that IL-37 affects adipogenesis and insulin sensitivity by regulating the inflammatory response and by directly targeting preadipocytes.

Gp130 cytokines

The IL-6 family or gp130 cytokines, contains multiple members, including IL-6, IL-11, IL-27, ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), leukemia inhibitory factor (LIF), oncostatin M (OSM), and neuropoietin (NP) [⁸⁸]. All members of gp130 cytokines form homodimers or heterodimers with gp130 receptors to facilitate signaling transduction. Most gp130 cytokines bind to their specific a-receptors (IL-6Ra); this induces dimerization of b-receptors before intracellular signaling [⁸⁸].

Binding of IL-6 to IL-6Rα leads to the generation of a receptor complex and signal transmission into cells. The intracellular signaling process is initiated by the recruitment and activation of Janus-activated kinase/signal transducer and activator of transcription factor (JAK/STAT) molecules, which then activate the transcription factors of various genes [⁸⁹]. Meanwhile, soluble IL-6Rα (sIL-6Rα) exists apart from membrane-bound IL-6Rα [⁹⁰]. IL-6 can bind to sIL-6Rα to form a ligand/receptor complex [⁹⁰]. The complex transduces signals in cells with membrane-bound gp130Rβ without the need of a transmembrane IL-6Rα [⁹⁰]. This process is known as “trans-signaling.” IL-6 is pro-inflammatory when it trans-signals but has beneficial effects on energy metabolism when it signals via the transmembrane IL-6Rα [⁹⁰]. IL-6 is recognized as an important cytokine in the chronic inflammatory state of obesity. During obesity, IL-6 production in adipose tissues is consistently elevated, especially in insulin resistance populations [¹⁶,⁹¹]. This condition is associated with reduced subcutaneous adipogenesis capacity, decreased PPARg and C/EBPα expression, and increased GATA3 transcription [¹⁶]. Accordingly, treatment with 20 ng/mL IL-6 causes diminished rate of adipogenesis in preadipocytes from insulin-sensitive and insulin-resistant subjects [¹⁶]. Drugs, such as chito-oligosaccharide and D-dopachrome tautomerase inhibit adipogenesis by inducing IL-6 expression in preadipocytes [¹⁸,⁹²].

The effect of IL-6 on insulin sensitivity is still debatable. In 3T3-F442A and 3T3-L1 cells, long-term (8 days) treatment with IL-6 reduces insulin-induced lipogenesis and glucose transportation [¹⁷]. Moreover, Carey et al. reported that IL-6 reduces obesity-induced insulin resistance in muscle cells by activating AMPK [⁹³]. In insulin resistant, obese IL-6^–/– mice [⁹⁴,⁹⁵], intracerebroventricular, but not intraperitoneal IL-6 treatment increases energy expenditure [⁹⁴]. These results suggest that IL-6 has different effects on energy metabolism in different body compartments, with centrally acting IL-6 exerting anti-obesity effects in rodents [⁹⁴]. Different IL-6 dosage, cell types or animal models may have contributed to the inconsistent results [⁹⁰].

The effects of other Gp130 cytokines on adipogenesis and insulin resistance are not fully elucidated. In earlier studies, IL-11 was found to inhibit preadipocyte differentiation and lipid accumulation in human long-term bone marrow cultures [¹⁹]. Though CNTF shows positive effects on adipocyte metabolism [⁹⁶], there is no direct evidence for the influence of CNTF on adipogenesis. NP and CNTF have nearly similar structures and functions [⁹⁷]. In cultured 3T3-L1 pre-adipocytes, NP inhibits adipogenesis by reducing the expression of PPARg and adiponectin [²²]. Moreover, NP increases insulin resistance by inhibiting insulin signaling proteins such as IRS-1 and Akt [²²]. In general, the effects of IL-11, CNTF, and NP on adipogenesis only draw minimal attention. Future studies will be needed to assess the effects of gp130 cytokines on adipogenesis and metabolic disorders.

IL-15, IL-4, and IL-10

IL-15 is a member of a widely expressed immunoregulatory cytokine family [⁹⁸] and mainly acts as a pro-inflammatory cytokine [⁹⁸]. IL-15 can activate multiple immune cells, including NK cells, and promote the release of pro-inflammatory cytokines [⁹⁸]. IL-15 KO mice show decreased expression of pro-inflammatory mediators, such as TNFa, IL-6, and Ccl-5 in their adipose tissues [⁹⁹]. The administration of IL-15 in animal models reduces body weight and amount of white adipose tissues [¹⁰⁰–¹⁰²]. These reductions are partially due to decreased lipogenesis and VLDL triacylglycerol uptake [¹⁰⁰]. In 3T3-L1 cells, IL-15 inhibits adipogenesis by upregulating a-calcineurin expression, a calcium-dependent serine/threonine phosphatase, and mediates the calcium-dependent inhibition of adipocyte differentiation [²⁴,¹⁰³]. IL-15 KO mice show decreased accumulation of fat in the white adipose tissues and increased lipid utilization via adaptive thermogenesis [⁹⁹]. In humans, subcutaneous adipose tissue of obese individuals contains more IL-15 than that of lean individuals. There is also a significant positive correlation between IL-15 and resting lipolysis in subcutaneous adipose tissue [¹⁰⁴]. This result indicates that IL-15 partially enhances lipolysis of subcutaneous fat. More studies are needed to fully illustrate the effect of IL-15 on adipose tissue metabolism.

IL-4 can be secreted by lymphocytes, basophils, and mast cells [¹⁰⁵]. As a Th2 cytokine, IL-4 plays an important role in the pathogenesis of asthma [¹⁰⁶]. However, in mice and human psoriasis, IL-4 attenuates TH17 cell-mediated inflammation by selectively suppressing IL-23 production in antigen-presenting cells [¹⁰⁷]. It also acts as an anti-inflammatory cytokine in systemic sclerosis [¹⁰⁸]. Therefore IL-4 can act as either a pro-inflammatory or an anti-inflammatory cytokine in various diseases. IL-4 inhibits adipogenesis by downregulating PPARg and C/EBPα expression in 3T3-L1 cells [²³]. It also inhibits adipogenesis at the early phase of 3T3-L1 cell differentiation. This effect is not observed in STAT6 knockouts, indicating that the anti-adipogenesis effect of IL-4 is achieved through the STAT6 pathway [²³].

IL-10 is secreted by multiple cell types including T-helper cells (THs), monocytes/macrophages, dendritic cells, and B cells. IL-10 suppresses inflammation through various mechanisms. The effect of IL-10 on lipid and glucose metabolism is not well studied. In adipose tissue environments, stable overexpression of IL-10 in the macrophage cell line promotes a macrophage phenotypic switch from M1 to M2 phenotype [¹⁰⁹]. This result indicates that IL-10 may improve insulin resistance and metabolic syndrome by suppressing inflammation.

IL-7, IL-17, and IL-34t

IL-17 is a pro-inflammatory cytokine that plays a key role in anti-microbial host defense response and autoimmune diseases [¹¹⁰]. IL-17 signals through a multimeric receptor complex composed of IL-17RA and IL-17RC [²⁶]. In adipose tissue, IL-17 is predominantly produced by gd T cells [²⁸]. Obesity induces the proliferation of IL-17 that produces adipogenesis-inhibiting Th17 cells [²⁶]. IL-17 and IL-17RA-deficient mice exhibit increased body weight, and young IL-17 knockout mice show enhanced glucose tolerance and insulin sensitivity [²⁸]. 3T3-L1 preadipocytes show inhibited adipogenesis after IL-17A or IL-17F treatment [¹¹¹]. A mechanistic study revealed that IL-17 alters adipogenesis by regulating the expression of Krüppel-like family (KLF) members, such as KLF15, KLF2, and KLF3, and blocking PPARg and C/EBPα [²⁷]. Furthermore, IL-17A induces COX-2 production, which then activates prostaglandin E2 (PGE2) expression in mesenchymal stem cells derived from human bone marrow (hBM-MSCs) [¹¹²]. This process inhibits adipocyte differentiation [¹¹²].

IL-7 is a pro-inflammatory cytokine associated with the survival, proliferation, and maturation of B lymphocytes and T lymphocytes [¹¹³]. Elevated IL-7 expression is observed in obese populations [¹¹⁴]. IL-7-receptor-deficient (IL-7r KO) mice exhibit decreased body weight, reduced visceral fat, and decreased levels of PPARg2 and C/EBPa [²⁵], and IL-7r KO mice show reduced pro-inflammatory cytokine production and macrophage infiltration in white adipose tissue and has improved glucose tolerance and insulin sensitivity [²⁵].

IL-34 acts as an alternative ligand for colony-stimulating factor-1 (CSF-1) receptor [¹¹⁵]. IL-34 and CSF-1 are important regulatory factors of monocyte differentiation, proliferation, and survival [¹¹⁵–¹¹⁷]. IL-34 levels in adipose tissues are significantly elevated in obese people with expression levels being markedly elevated during adipogenesis [²⁹]. Recombinant human (rh) IL-34 promotes lipid accumulation and improves insulin sensitivity at 100 ng/mg in human isolated adipocytes [²⁹].

Interferons

Interferons (IFNs) represent a family of multifunctional immunoregulatory cytokines which is widely used in the treatment of cancer and virus infection [¹¹⁸,¹¹⁹]. Its mode of action usually involves binding receptors and activating STAT signaling complexes [¹²⁰]. IFNs influence insulin sensitivity, glucose tolerance, and lipid metabolism [¹²¹].

IFN-g knockout mice exhibit systemic inflammation, decreased size of VAT adipocytes, and enhanced insulin sensitivity, despite the fact that IFN-g is a pro-inflammatory cytokine [¹²²]. Previous studies on MSCs and 3T3-L1 cells demonstrated that IFN-g treatment considerably reduces the rates of adipocyte differentiation and lipid deposition [³¹,¹²³]. The adipogenic marker, PPARg, is downregulated in MSCs subjected to IFN-g treatment [³¹]. JAK/STAT signaling pathways mediate the inhibitory effect of interferons [³⁰,¹²⁴]. In another study, it was found that IFN-g reduces adipogenesis in 3T3-L1 cells by directly inhibiting the activation of hedgehog signaling [³²]. In adipocytes, IFN-a inhibits PPARg, C/EBPb, and C/EBPa [³⁰] and induces apoptosis in adipose tissue cells [¹²⁵]. Nevertheless, the importance of JAK/STAT signaling and hedgehog signaling pathways that mediate IFN must be further studied.

Monocyte chemotactic protein-1

Monocyte chemotactic protein-1 (MCP-1) is a member of the CC chemokine family and a potent chemotactic factor for monocytes. It is expressed by various cell types, including adipocytes, macrophages, and endothelial cells [¹²⁶]. CC chemokine receptors 2 (CCR2) is the receptor for MCP-1. In severely obese subjects, MCP-1 protein levels are higher in abdominal fat than in subcutaneous fat and the rate of macrophage infiltration into abdominal adipose tissue increases [¹²⁷]. In human primary adipocytes, chronic treatment of hypoxic adipocytes with TNFα resulted in a higher secretion of the chemokines, MCP-1 and IL-8, while attenuated TNFα-induced signaling caused by reduced expression of TNFR1 or Tacrolimus (FK506, an immunosuppressor) results in reduced MCP1 secretion [¹²⁸,¹²⁹].

MCP-1 has multiple effects on adipose tissue inflammation, energy metabolism, and obesity. In mice modela, treatment with MCP-1 results in insulin resistance [¹³⁰]. In mice fed with a high-fat diet, Ccr2 deficiency or treatment with CCR2 antagonist reduces macrophage accumulation and inflammation in adipose tissues and improves insulin sensitivity [¹³¹]. In 3T3-L1 cells, the administration of MCP-1 promotes the expression of the C/EBP family and PPARg. The adipogenic potential of MCP-1 is not associated with PPARg expression [³³]. MCP-1 treatment also increases adipose tissue mass in vivo in a murine tissue engineering model [³⁴]. The effect of MCP-1 occur via the induction of MCP-1 induced protein (MCPIP), which promotes adipogenesis via oxidative stress, endoplasmic reticulum (ER) stress, and autophagy [¹³²].

Different adipogenesis processes in humans and mice

Owing to the limitations of human clinical trials, mouse models are frequently used in the investigation of adipogenesis. Previous studies have shown that PPARg and C/EBPα are key transcriptional regulators of both human and mouse adipogenesis [¹³³]. Genome wide study of the binding sites of these two regulators shows that the overall regulatory regime of PPARg and C/EBPα between human and mouse adipocytes is highly conserved, including their potential direct cooperativity by binding to adjacent sites [¹³³]. Although the functional targets of the transcription factors important in adipogenesis are conserved, most binding sites and regulators are species-specific [¹³³–¹³⁵]. LIM domain only 3 (LMO3) is a human visceral-fat-specific and glucocorticoids-dependent positive regulator of adipogenesis [¹³⁵]. These findings may partially explain the difference between the results from mouse models and human trials. The mechanisms by which cytokines influence the species-specific regulators of adipogenesis remain unknown and whether this influence occur requires further investigation.

Crosstalk between cytokines and other pathways important for metabolism

Cytokines are associated with other essential molecules for metabolism, particularly leptin, resistin, and adiponectin. On the one hand, cytokines influence the secretion of these molecules, thereby influencing metabolism. On the other hand, these molecules can either promote or inhibit the secretion of other cytokines, therefore regulating the inflammatory states of the human body.

Leptin is the product of the obese (ob) gene. Several leptin receptor (LEPR) isoforms are present in humans [¹³⁶]. Leptin binds to the long form of LEPR and activates the JAK/STAT signaling pathway [¹³⁶]. Ob/ob mice that lack leptin exhibit hyperphagia, obesity, and insulin resistance [¹³⁷]. In patients with lipodystrophy, leptin improves glycemic control and decreases triglyceride levels [¹³⁸]. Previous studies regarding the expression of leptin within the inflammatory models of human-cultured adipocytes produced different results. In 3T3-L1 cells, human bone marrow adipocytes, adipocytes from subcutaneous white adipose tissue, and omental adipocytes from morbidly obese people, TNFa significantly decreases leptin expression [¹³⁹–¹⁴³]. However, a study shows that TNFa stimulates leptin expression in adipocytes from human omental adipose tissue. An in vivo study showed that TNFa also induces leptin expression in Syrian hamsters and C57BL/6 mice [¹⁴⁴,¹⁴⁵]. These different results may be explained by the use of different cell models, locality of adipose tissue, and duration and dose of exposure to the cytokines [¹³⁹]. The different results from in vitro and in vivo studies also indicate that pro-inflammatory cytokines may regulate leptin secretion through other means apart from directly binding to the receptors of target cells.

In discrete mouse colon cells, leptin upregulates pro-inflammatory cytokines, such as IL-6 and IL-1b [¹⁴⁶] and promotes the activation and proliferation of circulating monocytes, thereby inducing IL-1, TNFa, and IL-6 production [¹³⁶]. Furthermore, leptin enhances IL-18 secretion in cultured human THP-1 monocytes through caspase-1 activation [¹⁴⁷]. It also polarizes T helper cell subsets towards the TH1 phenotype that secretes IFN-g [¹³⁶].

Adiponectin is an adipocyte-specific secretory protein [¹⁴⁸]. Adiponectin signals through adiponectin receptors (AdipoRs). Adiponectin stimulates adipogenesis, attenuates inflammation, and regulates rates of lipolysis and fatty acid oxidation [¹⁴⁸]. There are opposing effects of adiponectin with TNFa on lipid metabolism and inflammation (reviewed in [¹⁴⁹,¹⁵⁰]). Adiponectin is negatively regulated by TNFa and IL-6 [¹⁴⁹]. In turn, TNFa production is negatively regulated by adiponectin [¹⁵¹]. Adiponectin also induces the production of anti-inflammatory cytokines like IL-10 and IL-Ra [¹⁴⁹].

Resistin is also an adipokine and has been associated with inflammatory response. Resistin gets its name from its resistance to insulin function. In adipose tissues, resistin is predominantly expressed in the macrophages [¹⁵²]. In rat pancreatic acinar AR42J cells, it stimulates TNFa and IL-6 production through NF-kB activation [¹⁵²].

Adipogenesis, inflammation, and metabolic disorder

Adipose tissue expansion can be accomplished by increasing the volume of each adipocyte (hypertrophy) or recruiting new adipocytes from precursors (hyperplasia) [²]. In adults, adipose tissue expands mainly by hypertrophy in spite of only ~10% adipocyte turnover annually [¹⁵³]. Although obesity is closely related to T2DM, approximately 30% of the obese population do not show insulin resistance and are considered as metabolic healthy obese [¹⁵⁴]. The metabolic consequences of obesity are influenced by the depots of fat and mode of adipose tissue expansion (reviewed in [²]). The storage of excess energy through lipid accumulation in subcutaneous adipose tissues is beneficial to metabolic health [¹⁵⁵]. Preadipocytes from subcutaneous adipose depots exhibit greater potential for proliferation and adipogenesis than those from visceral depots [¹⁵⁶–¹⁵⁸]. Moreover, TNFa and IL-6 levels in subcutaneous fat are much lower than those in visceral fat [¹⁵⁵].

Low grade chronic inflammatory state commonly exists in obese populations. Compared with normal adipocytes, hypertrophic adipocytes secrete more free fatty acids (FFAs) and adipokines (for example, MCP-1, TNFa, IL-1b, and IL-6), and recruit more pro-inflammatory M1-like macrophages and other immune cells [¹⁵⁷,¹⁵⁹]. This effect is caused by multiple factors, including hypoxia, ER stress in adipocytes, activation of Toll-like receptors (TLRs) by FFAs, and cell apoptosis [¹⁶⁰–¹⁶³].

Although acute inflammatory response promotes ECM-remodeling and angiogenesis, which benefits adipogenesis [¹⁶⁴], the chronic inflammation of adipose tissue has been considered closely associated with insulin resistance and inhibition of adipogenesis [¹⁶⁵]. During the development of obesity, the adipogenesis of subcutaneous adipose tissues can be inhibited by pro-inflammatory cytokines, such as TNFα, IL-1β, and IL-6. These pro-inflammatory cytokines are produced by stromal vascular cells, including adipose tissue macrophages and adipocytes [⁴,⁷⁰]. As a result, adipocyte turnover and adipose tissue expansion are blocked by these pro-inflammatory cytokines [¹⁶⁵]. The abdominal subcutaneous tissue of obese individuals is characterized by decreased number of pre-adipocytes, enlarged mature adipocytes, and elevated MAP4K4 levels [⁷,¹⁶⁶]. MAP4K4, which inhibits adipogenesis, can be induced by TNFα [⁷,¹⁶⁶]. When the hyperplastic expandability of subcutaneous adipose tissues is constrained by chronic inflammation, excess energy is stored by the hypertrophy of adipocytes and accumulation of triglyceride, which occur in the liver, muscles, myocardium, and perivisceral depots and will induce insulin resistance and cardiovascular diseases [¹⁵⁸,¹⁶⁷]. Excess visceral/intra-abdominal fat is considered as an important marker of ectopic storage of fat [¹⁶⁸,¹⁶⁹]. Moreover, increased abdominal fat is positively associated with increased risk of T2DM and cardiovascular disease [¹⁷⁰]. Inflammation, constrain of subcutaneous fat hyperplastic expandability, hypertrophy of adipocytes, accumulation of visceral fat, and ectopic fat storage are closely associated, and their combined effects exacerbate the comorbidities of obesity [¹⁷¹,¹⁷²].

Convergent evidence supports that pro-inflammatory cytokine antagonists improve glucose and lipid metabolism in T2DM patients. The inhibitory effect of TNFα on lipid accumulation in adipocytes is blocked by the inhibitors of NF-kB and IkBα [¹⁷³]. In clinical studies focused on rheumatoid arthritis (RA) and psoriasis patients, treatment with TNFα antagonists, such as etanercept, infliximab, and adalimumab, improves response to insulin [¹⁷⁴–¹⁷⁶]. A retrospective cohort study published in 2011 showed that TNF inhibitor or hydroxychloroquine treatment significantly reduces the risk of DM in patients with RA and psoriasis compared with using other non-biological disease modifying antirheumatic drugs (DMARDs) [¹⁷⁷]. In Crohn’s disease (CD) patients, infliximab maintenance therapy has no adverse effect on lipid metabolism and is accompanied by a decrease in blood glucose and HbA1c concentrations [¹⁷⁸]. Nevertheless, the effects of anti-TNFα therapy on patients with inflammatory diseases and patients with metabolic syndrome but without overt inflammatory disease must be determined. A mechanism study reveals that processing of IL-1β requires cleavage of pro IL-1β by caspase-1, which is regulated by nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing (NLRP3) inflammasome [¹⁷⁹]. Caspase-1 deficiency results in increased insulin sensitivity in mice and increases the production of metabolically active adipocytes; furthermore, treatment with caspase-1 inhibitors significantly improves the insulin sensitivity of obese mice [¹⁸⁰]. According to a review by Donath, several IL-1β inhibitors, such as IL-1 receptor antagonists (anakinra) and IL-1β-specific antibodies (canakinumab), improve T2DM status with good tolerance and no severe adverse effect [¹⁸¹]. Canakinumab, an IL-1β-specific monoclonal antibody, is the first and only drug that selectively targets inflammation and significantly reduces cardiovascular risk in patients with CVA history. Canakinumab, in combination with standard of care therapy, reduces cardiovascular risk in people with CVA history and inflammatory atherosclerosis (hsCRP level≥2 mg/L) during the 3.8 years of median follow-up time (Phase III Canakinumab Anti-inflammatory Thrombosis Outcomes Study-NCT01327846. https://www.novartis.com/news/media-releases/Novartis-phase-iii-study-shows-acz885-canakinumab-reduces-cardiovascular-risk). Although lipid and lipid-associated cardiovascular risk markers improve after treatment with TNFα antagonists (adalimumab) and IL-6 antagonists (tocilizumab), the clinical significance is still unclear and needs further study [¹⁸²].

For T2DM patients, hyperlipidemia is the highest risk factor for atherosclerosis [¹⁸³,¹⁸⁴]. Moreover, given that more than 60% of T2DM patients die of cardiovascular complications [¹⁸⁵] and 70% suffer from NAFLD [¹⁸⁶,¹⁸⁷], the management of lipid metabolism can be a prior consideration. As complications of T2DM such as atherosclerosis and NASH progress with time, reducing blood glucose per se may not reverse these diseases, and drugs targeting lipid metabolism may be more effective in managing T2DM complications. T2DM patients can benefit from statins, which can significantly reduce the risk of ASCVD [¹⁸⁸]. However, statins increases insulin resistance and diabetes risks by inhibiting the secretion of insulin and interfering with the insulin signaling pathway (reviewed in [¹⁸⁸]). Therefore, risk–benefit assessment and patient preference should be considered prior to the administration of statin for ASCVD therapy [¹⁸⁹].

Conclusions

We summarized the cytokines that influence adipogenesis. Low grade chronic inflammation commonly exists in obese populations. In T2DM, obesity and insulin resistance result in the persistent production of pro-inflammatory cytokines, such as TNFa, IL-1b, and IL-6, which typically inhibit adipogenesis. During overnutrition, the restricted recruitment of new adipocytes may result in adipocyte hypertrophy, ectopic fat accumulation, and insulin resistance, which in turn may lead to atherosclerosis and NAFLD. Moreover, pro-inflammatory cytokine antagonists, such as infliximab and etanercept, improve glucose and lipid metabolism in T2DM patients [¹⁷⁴–¹⁷⁶]. Future investigations on the relationship between cytokines and adipogenesis are expected to lead to the improvement of management strategies for T2DM and other comorbidities of obesity.

References

[1] Lefterova MI, Lazar MA. New developments in adipogenesis. Trends Endocrinol Metab 2009; 20(3): 107–114

[2] Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell 2014; 156(1-2): 20–44

[3] Kanneganti TD, Dixit VD. Immunological complications of obesity. Nat Immunol 2012; 13(8): 707–712

[4] Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112(12): 1796–1808

[5] Cristancho AG, Lazar MA. Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol 2011; 12(11): 722–734

[6] Cawthorn WP, Heyd F, Hegyi K, Sethi JK. Tumour necrosis factor-α inhibits adipogenesis via a β-catenin/TCF4(TCF7L2)-dependent pathway. Cell Death Differ 2007; 14(7): 1361–1373

[7] Isakson P, Hammarstedt A, Gustafson B, Smith U. Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-α and inflammation. Diabetes 2009; 58(7): 1550–1557

[8] Xu H, Sethi JK, Hotamisligil GS. Transmembrane tumor necrosis factor (TNF)-α inhibits adipocyte differentiation by selectively activating TNF receptor 1. J Biol Chem 1999; 274(37): 26287–26295

[9] Chae GN, Kwak SJ. NF-κB is involved in the TNF-α induced inhibition of the differentiation of 3T3-L1 cells by reducing PPARgamma expression. Exp Mol Med 2003; 35(5): 431–437

[10] Gagnon A, Foster C, Landry A, Sorisky A. The role of interleukin 1β in the anti-adipogenic action of macrophages on human preadipocytes. J Endocrinol 2013; 217(2): 197–206

[11] Martinez-Martinez E, Cachofeiro V, Rousseau E, Alvarez V, Calvier L, Fernandez-Celis A, Leroy C, Miana M, Jurado-Lopez R, Briones AM, Jaisser F, Zannad F, Rossignol P, Lopez-Andres N. Interleukin-33/ST2 system attenuates aldosterone-induced adipogenesis and inflammation. Mol Cell Endocrinol 2015; 411:20–27

[12] Miller AM, Asquith DL, Hueber AJ, Anderson LA, Holmes WM, McKenzie AN, Xu D, Sattar N, McInnes IB, Liew FY. Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in mice. Circ Res 2010; 107(5): 650–658

[13] van Asseldonk EJ, Stienstra R, Koenen TB, van Tits LJ, Joosten LA, Tack CJ, Netea MG. The effect of the interleukin-1 cytokine family members IL-1F6 and IL-1F8 on adipocyte differentiation. Obesity (Silver Spring) 2010; 18(11): 2234–2236

[14] Somm E, Henrichot E, Pernin A, Juge-Aubry CE, Muzzin P, Dayer JM, Nicklin MJH, Meier CA. Decreased fat mass in interleukin-1 receptor antagonist-deficient mice — impact on adipogenesis, food intake, and energy expenditure. Diabetes 2005; 54(12): 3503–3509

[15] Ballak DB, van Diepen JA, Moschen AR, Jansen HJ, Hijmans A, Groenhof GJ, Leenders F, Bufler P, Boekschoten MV, Muller M, Kersten S, Li S, Kim S, Eini H, Lewis EC, Joosten LA, Tilg H, Netea MG, Tack CJ, Dinarello CA, Stienstra R. IL-37 protects against obesity-induced inflammation and insulin resistance. Nat Commun 2014; 5:4711 PMID: 25182023

[16] Almuraikhy S, Kafienah W, Bashah M, Diboun I, Jaganjac M, Al-Khelaifi F, Abdesselem H, Mazloum NA, Alsayrafi M, Mohamed-Ali V, Elrayess MA. Interleukin-6 induces impairment in human subcutaneous adipogenesis in obesity-associated insulin resistance. Diabetologia 2016; 59(11): 2406–2416

[17] Lagathu C, Bastard JP, Auclair M, Maachi M, Capeau J, Caron M. Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. Biochem Biophys Res Commun 2003; 311(2): 372–379

[18] Bahar B, O’Doherty JV, Sweeney T. A potential role of IL-6 in the chito-oligosaccharide-mediated inhibition of adipogenesis. Br J Nutr 2011; 106(8): 1142–1153

[19] Keller DC, Du XX, Srour EF, Hoffman R, Williams DA. Interleukin-11 inhibits adipogenesis and stimulates myelopoiesis in human long-term marrow cultures. Blood 1993; 82(5): 1428–1435

[20] Kawashima I, Ohsumi J, Mita-Honjo K, Shimoda-Takano K, Ishikawa H, Sakakibara S, Miyadai K, Takiguchi Y. Molecular cloning of cDNA encoding adipogenesis inhibitory factor and identity with interleukin-11. FEBS Lett 1991; 283(2): 199–202

[21] Miyaoka Y, Tanaka M, Naiki T, Miyajima A. Oncostatin M inhibits adipogenesis through the RAS/ERK and STAT5 signaling pathways. J Biol Chem 2006; 281(49): 37913–37920

[22] White UA, Stewart WC, Mynatt RL, Stephens JM. Neuropoietin attenuates adipogenesis and induces insulin resistance in adipocytes. J Biol Chem 2008; 283(33): 22505–22512

[23] Tsao CH, Shiau MY, Chuang PH, Chang YH, Hwang J. Interleukin-4 regulates lipid metabolism by inhibiting adipogenesis and promoting lipolysis. J Lipid Res 2014; 55(3): 385–397

[24] López S. Interleukin-15 increases calcineurin expression in 3T3-L1 cells: possible involvement on in vivo adipocyte differentiation. Int J Mol Med 2009; 24(04):453–458

[25] Lee M, Song SJ, Choi MS, Yu RN, Park T. IL-7 receptor deletion ameliorates diet-induced obesity and insulin resistance in mice. Diabetologia 2015; 58(10): 2361–2370

[26] Ahmed M, Gaffen SL. IL-17 in obesity and adipogenesis. Cytokine Growth Factor Rev 2010; 21(6): 449–453

[27] Ahmed M, Gaffen SL. IL-17 inhibits adipogenesis in part via C/EBPα PPARγ and Kruppel-like factors. Cytokine 2013; 61(3): 898–905

[28] Zuniga LA, Shen WJ, Joyce-Shaikh B, Pyatnova EA, Richards AG, Thom C, Andrade SM, Cua DJ, Kraemer FB, Butcher EC. IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 2010; 185(11): 6947–6959

[29] Chang EJ, Lee SK, Song YS, Jang YJ, Park HS, Hong JP, Ko AR, Kim DY, Kim JH, Lee YJ, Heo YS. IL-34 is associated with obesity, chronic inflammation, and insulin resistance. J Clin Endocrinol Metab 2014; 99(7): E1263–E1271

[30] Lee K, Um SH, Rhee DK, Pyo S. Interferon-α inhibits adipogenesis via regulation of JAK/STAT1 signaling. Biochim Biophys Acta 2016; 1860(11 11 Pt A): 2416–2427

[31] Vidal C, Bermeo S, Li W, Huang D, Kremer R, Duque G. Interferon γ inhibits adipogenesis in vitro and prevents marrow fat infiltration in oophorectomized mice. Stem Cells 2012; 30(5): 1042–1048

[32] Todoric J, Strobl B, Jais A, Boucheron N, Bayer M, Amann S, Lindroos J, Teperino R, Prager G, Bilban M, Ellmeier W, Krempler F, Muller M, Wagner O, Patsch W, Pospisilik JA, Esterbauer H. Cross-talk between interferon-γ and hedgehog signaling regulates adipogenesis. Diabetes 2011; 60(6): 1668–1676

[33] Younce CW, Azfer A, Kolattukudy PE. MCP-1 (monocyte chemotactic protein-1)-induced protein, a recently identified zinc finger protein, induces adipogenesis in 3T3-L1 pre-adipocytes without peroxisome proliferator-activated receptor γ. J Biol Chem 2009; 284(40): 27620–27628

[34] Hemmrich K, Thomas GP, Abberton KM, Thompson EW, Rophael JA, Penington AJ, Morrison WA. Monocyte chemoattractant protein-1 and nitric oxide promote adipogenesis in a model that mimics obesity. Obesity (Silver Spring) 2007; 15(12): 2951–2957

[35] Meerson A, Traurig M, Ossowski V, Fleming JM, Mullins M, Baier LJ. Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNF-α. Diabetologia 2013; 56(9): 1971–1979

[36] Liu S, Yang Y, Wu J. TNFα-induced up-regulation of miR-155 inhibits adipogenesis by down-regulating early adipogenic transcription factors. Biochem Biophys Res Commun 2011; 414(3): 618–624

[37] Xie H, Lim B, Lodish HF. MicroRNAs induced during adipogenesis that accelerate fat cell development are downregulated in obesity. Diabetes 2009; 58(5): 1050–1057

[38] Gaur U, Aggarwal BB. Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. Biochem Pharmacol 2003; 66(8): 1403–1408

[39] Aggarwal BB. Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-κB. Ann Rheum Dis 2000; 59 (Suppl 1): i6–i16

[40] Kaufman DR, Choi Y. Signaling by tumor necrosis factor receptors: pathways, paradigms and targets for therapeutic modulation. Int Rev Immunol 1999; 18(4): 405–427

[41] Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 2001; 11(9): 372–377

[42] Fain JN, Bahouth SW, Madan AK. TNFα release by the nonfat cells of human adipose tissue. Int J Obes Relat Metab Disord 2004; 28(4): 616–622

[43] Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 1993; 259(5091): 87–91

[44] Borst SE. The role of TNF-α in insulin resistance. Endocrine 2004; 23(2-3): 177–182

[45] Moller DE. Potential role of TNF-α in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 2000; 11(6): 212–217

[46] Stephens JM, Lee J, Pilch PF. Tumor necrosis factor-α-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J Biol Chem 1997; 272(2): 971–976

[47] Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J Clin Invest 1995; 95(5): 2409–2415

[48] Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier JC, Huston-Presley L, Friedman JE, Kalhan SC, Catalano PM. TNF-α is a predictor of insulin resistance in human pregnancy. Diabetes 2002; 51(7): 2207–2213

[49] Lang CH, Dobrescu C, Bagby GJ. Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 1992; 130(1): 43–52

[50] Palacios-Ortega S, Varela-Guruceaga M, Algarabel M, Ignacio Milagro F, Alfredo Martinez J, de Miguel C. Effect of TNF-α on caveolin-1 expression and insulin signaling during adipocyte differentiation and in mature adipocytes. Cell Physiol Biochem 2015; 36(4): 1499–1516

[51] Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 1997; 389(6651): 610–614

[52] Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARγ. Science 1996; 274(5295): 2100–2103

[53] Ohsumi J, Sakakibara S, Yamaguchi J, Miyadai K, Yoshioka S, Fujiwara T, Horikoshi H, Serizawa N. Troglitazone prevents the inhibitory effects of inflammatory cytokines on insulin-induced adipocyte differentiation in 3T3-L1 cells. Endocrinology 1994; 135(5): 2279–2282

[54] Bogacka I, Xie H, Bray GA, Smith SR. The effect of pioglitazone on peroxisome proliferator-activated receptor-γ target genes related to lipid storage in vivo. Diabetes Care 2004; 27(7): 1660–1667

[55] Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A. Adipogenesis and WNT signalling. Trends Endocrinol Metab 2009; 20(1): 16–24

[56] Zhang B, Berger J, Hu E, Szalkowski D, White-Carrington S, Spiegelman BM, Moller DE. Negative regulation of peroxisome proliferator-activated receptor-γ gene expression contributes to the antiadipogenic effects of tumor necrosis factor-α. Mol Endocrinol 1996; 10(11): 1457–1466

[57] Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF. Tumor necrosis factor-α suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-κB activation by TNF-α is obligatory. Diabetes 2002; 51(5): 1319–1336

[58] Tang X, Guilherme A, Chakladar A, Powelka AM, Konda S, Virbasius JV, Nicoloro SM, Straubhaar J, Czech MP. An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARγ adipogenesis, and insulin-responsive hexose transport. Proc Natl Acad Sci USA 2006; 103(7): 2087–2092

[59] Guilherme A, Tesz GJ, Guntur KVP, Czech MP. Tumor necrosis factor-α induces caspase-mediated cleavage of peroxisome proliferator-activated receptor in adipocytes. J Biol Chem 2009; 284(25): 17082–17091

[60] Gong ML, Liu CG, Zhang L, Zhang HB, Pan J. Loss of the TNFα function inhibits Wnt/β-catenin signaling, exacerbates obesity development in adolescent spontaneous obese mice. Mol Cell Biochem 2014; 391(1-2): 59–66

[61] Arner P, Kulyte A. MicroRNA regulatory networks in human adipose tissue and obesity. Nat Rev Endocrinol 2015; 11(5): 276–288

[62] Price NL, Fernandez-Hernando C. miRNA regulation of white and brown adipose tissue differentiation and function. Biochim Biophys Acta 2016; 1861(12): 2104–2110

[63] Zhu L, Chen L, Shi CM, Xu GF, Xu LL, Zhu LL, Guo XR, Ni YH, Cui Y, Ji CB. miR-335, an adipogenesis-related microRNA, is involved in adipose tissue inflammation. Cell Biochem Biophys 2014; 68(2): 283–290

[64] Zhu Y, Zhang X, Ding X, Wang H, Chen X, Zhao H, Jia Y, Liu S, Liu Y. miR-27 inhibits adipocyte differentiation via suppressing CREB expression. Acta Biochim Biophys Sin (Shanghai) 2014; 46(7): 590–596

[65] Xu G, Ji C, Shi C, Fu H, Zhu L, Zhu L, Xu L, Chen L, Feng Y, Zhao Y, Guo X. Modulation of hsa-miR-26b levels following adipokine stimulation. Mol Biol Rep 2013; 40(5): 3577–3582

[66] Song G, Xu G, Ji C, Shi C, Shen Y, Chen L, Zhu L, Yang L, Zhao Y, Guo X. The role of microRNA-26b in human adipocyte differentiation and proliferation. Gene 2014; 533(2): 481–487

[67] Xu LL, Shi CM, Xu GF, Chen L, Zhu LL, Zhu L, Guo XR, Xu MY, Ji CB. TNF-α IL-6, and leptin increase the expression of miR-378, an adipogenesis-related microRNA in human adipocytes. Cell Biochem Biophys 2014; 70(2): 771–776

[68] Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity 2013; 39(6): 1003–1018

[69] Simons PJ, van den Pangaart PS, van Roomen CP, Aerts JM, Boon L. Cytokine-mediated modulation of leptin and adiponectin secretion during in vitro adipogenesis: evidence that tumor necrosis factor-α- and interleukin-1β-treated human preadipocytes are potent leptin producers. Cytokine 2005; 32(2): 94–103

[70] Tack CJ, Stienstra R, Joosten LAB, Netea MG. Inflammation links excess fat to insulin resistance: the role of the interleukin-1 family. Immunol Rev 2012; 249(1):239–252

[71] Solt LA, Madge LA, Orange JS, May MJ. Interleukin-1-induced NF-κB activation is NEMO-dependent but does not require IKKβ. J Biol Chem 2007; 282(12): 8724–8733

[72] Tanti JF, Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol 2009; 9(6): 753–762

[73] Wood IS, Wang B, Jenkins JR, Trayhurn P. The pro-inflammatory cytokine IL-18 is expressed in human adipose tissue and strongly upregulated by TNFα in human adipocytes. Biochem Biophys Res Commun 2005; 337(2): 422–429

[74] Schernthaner GH, Kopp HP, Kriwanek S, Krzyzanowska K, Satler M, Koppensteiner R, Schernthaner G. Effect of massive weight loss induced by bariatric surgery on serum levels of interleukin-18 and monocyte-chemoattractant-protein-1 in morbid obesity. Obes Surg 2006; 16(6): 709–715

[75] Moschen AR, Molnar C, Enrich B, Geiger S, Ebenbichler CF, Tilg H. Adipose and liver expression of interleukin (IL)-1 family members in morbid obesity and effects of weight loss. Mol Med 2011; 17(7-8): 840–845

[76] Netea MG, Joosten LA, Lewis E, Jensen DR, Voshol PJ, Kullberg BJ, Tack CJ, van Krieken H, Kim SH, Stalenhoef AF, van de Loo FA, Verschueren I, Pulawa L, Akira S, Eckel RH, Dinarello CA, van den Berg W, van der Meer JW. Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat Med 2006; 12(6): 650–656

[77] Zorrilla EP, Sanchez-Alavez M, Sugama S, Brennan M, Fernandez R, Bartfai T, Conti B. Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency. Proc Natl Acad Sci USA 2007; 104(26): 11097–11102

[78] Yang YS, Li XY, Hong J, Gu WQ, Zhang YF, Yang J, Song HD, Chen JL, Ning G. Interleukin-18 enhances glucose uptake in 3T3-L1 adipocytes. Endocrine 2007; 32(3): 297–302

[79] Ballak DB, Stienstra R, Tack CJ, Dinarello CA, van Diepen JA. IL-1 family members in the pathogenesis and treatment of metabolic disease: focus on adipose tissue inflammation and insulin resistance. Cytokine 2015; 75(2): 280–290

[80] Murphy AJ, Kraakman MJ, Kammoun HL, Dragoljevic D, Lee MK, Lawlor KE, Wentworth JM, Vasanthakumar A, Gerlic M, Whitehead LW, DiRago L, Cengia L, Lane RM, Metcalf D, Vince JE, Harrison LC, Kallies A, Kile BT, Croker BA, Febbraio MA, Masters SL. IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome. Cell Metab 2016; 23(1): 155–164

[81] Lindegaard B, Matthews VB, Brandt C, Hojman P, Allen TL, Estevez E, Watt MJ, Bruce CR, Mortensen OH, Syberg S, Rudnicka C, Abildgaard J, Pilegaard H, Hidalgo J, Ditlevsen S, Alsted TJ, Madsen AN, Pedersen BK, Febbraio MA. Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice. Diabetes 2013; 62(9): 3064–3074

[82] Han JM, Wu D, Denroche HC, Yao Y, Verchere CB, Levings MK. IL-33 reverses an obesity-induced deficit in visceral adipose tissue ST2⁺ T regulatory cells and ameliorates adipose tissue inflammation and insulin resistance. J Immunol 2015; 194(10): 4777–4783

[83] Wood IS, Wang B, Trayhurn P. IL-33, a recently identified interleukin-1 gene family member, is expressed in human adipocytes. Biochem Biophys Res Commun 2009; 384(1): 105–109

[84] Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra A, Chawla A, Locksley RM. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 2013; 210(3): 535–549

[85] Zeyda M, Wernly B, Demyanets S, Kaun C, Hammerle M, Hantusch B, Schranz M, Neuhofer A, Itariu BK, Keck M, Prager G, Wojta J, Stulnig TM. Severe obesity increases adipose tissue expression of interleukin-33 and its receptor ST2, both predominantly detectable in endothelial cells of human adipose tissue. Int J Obes 2013; 37(5): 658–665

[86] Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 2015; 42(6): 1005–1019

[87] Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, Artis D. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 2015; 519(7542): 242–246

[88] White UA, Stephens JM. The gp130 receptor cytokine family: regulators of adipocyte development and function. Curr Pharm Des 2011; 17(4): 340–346

[89] Pal M, Febbraio MA, Whitham M. From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol 2014; 92(4): 331–339

[90] Kraakman MJ, Allen TL, Whitham M, Iliades P, Kammoun HL, Estevez E, Lancaster GI, Febbraio MA. Targeting gp130 to prevent inflammation and promote insulin action. Diabetes Obes Metab 2013; 15(Suppl 3):170–175

[91] Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-α overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 2003; 278(46): 45777–45784

[92] Ishimoto K, Iwata T, Taniguchi H, Mizusawa N, Tanaka E, Yoshimoto K. D-dopachrome tautomerase promotes IL-6 expression and inhibits adipogenesis in preadipocytes. Cytokine 2012; 60(3): 772–777

[93] Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, Kemp BE, Pedersen BK, Febbraio MA. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 2006; 55(10): 2688–2697

[94] Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 2002; 8(1): 75–79

[95] Fritsche L, Hoene M, Lehmann R, Ellingsgaard H, Hennige AM, Pohl AK, Haring HU, Schleicher ED, Weigert C. IL-6 deficiency in mice neither impairs induction of metabolic genes in the liver nor affects blood glucose levels during fasting and moderately intense exercise. Diabetologia 2010; 53(8): 1732–1742

[96] Crowe S, Turpin SM, Ke F, Kemp BE, Watt MJ. Metabolic remodeling in adipocytes promotes ciliary neurotrophic factor-mediated fat loss in obesity. Endocrinology 2008; 149(5): 2546–2556

[97] Derouet D, Rousseau F, Alfonsi F, Froger J, Hermann J, Barbier F, Perret D, Diveu C, Guillet C, Preisser L, Dumont A, Barbado M, Morel A, deLapeyriere O, Gascan H, Chevalier S. Neuropoietin, a new IL-6-related cytokine signaling through the ciliary neurotrophic factor receptor. Proc Natl Acad Sci USA 2004; 101(14): 4827–4832

[98] Patidar M, Yadav N, Dalai SK. Interleukin 15: a key cytokine for immunotherapy. Cytokine Growth Factor Rev 2016; 31:49–59

[99] Lacraz G, Rakotoarivelo V, Labbe SM, Vernier M, Noll C, Mayhue M, Stankova J, Schwertani A, Grenier G, Carpentier A, Richard D, Ferbeyre G, Fradette J, Rola-Pleszczynski M, Menendez A, Langlois MF, Ilangumaran S, Ramanathan S. Deficiency of interleukin-15 confers resistance to obesity by diminishing inflammation and enhancing the thermogenic function of adipose tissues. PLoS One 2016; 11(9): e0162995

[100] Carbó N, Lopez-Soriano J, Costelli P, Alvarez B, Busquets S, Baccino FM, Quinn LS, Lopez-Soriano FJ, Argiles JM. Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control. Biochim Biophys Acta 2001; 1526(1): 17–24

[101] Barra NG, Reid S, MacKenzie R, Werstuck G, Trigatti BL, Richards C, Holloway AC, Ashkar AA. Interleukin-15 contributes to the regulation of murine adipose tissue and human adipocytes. Obesity (Silver Spring) 2010; 18(8): 1601–1607

[102] Barra NG, Chew MV, Reid S, Ashkar AA. Interleukin-15 treatment induces weight loss independent of lymphocytes. PLoS One 2012; 7(6): e39553

[103] Neal JW, Clipstone NA. Calcineurin mediates the calcium-dependent inhibition of adipocyte differentiation in 3T3-L1 cells. J Biol Chem 2002; 277(51): 49776–49781

[104] Pierce JR, Maples JM, Hickner RC. IL-15 concentrations in skeletal muscle and subcutaneous adipose tissue in lean and obese humans: local effects of IL-15 on adipose tissue lipolysis. Am J Physiol Endocrinol Metab 2015; 308(12): E1131–E1139

[105] Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE. The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 1999; 17:701–738

[106] Walsh GM. Biologics targeting IL-5, IL-4 or IL-13 for the treatment of asthma —an update. Expert Rev Clin Immunol 2017; 13(2): 143–149

[107] Guenova E, Skabytska Y, Hoetzenecker W, Weindl G, Sauer K, Tham M, Kim KW, Park JH, Seo JH, Ignatova D, Cozzio A, Levesque MP, Volz T, Koberle M, Kaesler S, Thomas P, Mailhammer R, Ghoreschi K, Schakel K, Amarov B, Eichner M, Schaller M, Clark RA, Rocken M, Biedermann T. IL-4 abrogates T(H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells. Proc Natl Acad Sci USA 2015; 112(7): 2163–2168

[108] Huang XL, Wang YJ, Yan JW, Wan YN, Chen B, Li BZ, Yang GJ, Wang J. Role of anti-inflammatory cytokines IL-4 and IL-13 in systemic sclerosis. Inflamm Res 2015; 64(3-4): 151–159

[109] Johannsen DL, Tchoukalova Y, Tam CS, Covington JD, Xie W, Schwarz JM, Bajpeyi S, Ravussin E. Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the “adipose tissue expandability” hypothesis. Diabetes Care 2014; 37(10): 2789–2797

[110] Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol 2009; 27:485–517

[111] Goswami J, Hernandez-Santos N, Zuniga LA, Gaffen SL. A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss. Eur J Immunol 2009; 39(10): 2831–2839

[112] Shin JH, Shin DW, Noh M. Interleukin-17A inhibits adipocyte differentiation in human mesenchymal stem cells and regulates pro-inflammatory responses in adipocytes. Biochem Pharmacol 2009; 77(12): 1835–1844

[113] Capitini CM, Chisti AA, Mackall CL. Modulating T-cell homeostasis with IL-7: preclinical and clinical studies. J Intern Med 2009; 266(2): 141–153

[114] Maury E, Ehala-Aleksejev K, Guiot Y, Detry R, Vandenhooft A, Brichard SM. Adipokines oversecreted by omental adipose tissue in human obesity. Am J Physiol Endocrinol Metab 2007; 293(3): E656–E665

[115] Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, Halenbeck R, Wu G, Zhou A, Behrens D, Hollenbaugh D, Linnemann T, Qin M, Wong J, Chu K, Doberstein SK, Williams LT. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 2008; 320(5877): 807–811

[116] Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 2008; 8(7): 533–544

[117] Nakamichi Y, Udagawa N, Takahashi N. IL-34 and CSF-1: similarities and differences. J Bone Miner Metab 2013; 31(5): 486–495

[118] Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer 2016; 16(3): 131–144

[119] Hoffmann HH, Schneider WM, Rice CM. Interferons and viruses: an evolutionary arms race of molecular interactions. Trends Immunol 2015; 36(3): 124–138

[120] He B. Viruses, endoplasmic reticulum stress, and interferon responses. Cell Death Differ 2006; 13(3): 393–403

[121] Koivisto VA, Pelkonen R, Cantell K. Effect of interferon on glucose tolerance and insulin sensitivity. Diabetes 1989; 38(5): 641–647

[122] O’Rourke RW, White AE, Metcalf MD, Winters BR, Diggs BS, Zhu X, Marks DL. Systemic inflammation and insulin sensitivity in obese IFN-γ knockout mice. Metabolism 2012; 61(8): 1152–1161

[123] Keay S, Grossberg SE. Interferon inhibits the conversion of 3T3-L1 mouse fibroblasts into adipocytes. Proc Natl Acad Sci USA 1980; 77(7): 4099–4103

[124] McGillicuddy FC, Chiquoine EH, Hinkle CC, Kim RJ, Shah R, Roche HM, Smyth EM, Reilly MP. Interferon γ attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. J Biol Chem 2009; 284(46): 31936–31944 doi:10.1074/jbc.M109.061655

[125] Birk RZ, Rubinstein M. IFN-α induces apoptosis of adipose tissue cells. Biochem Biophys Res Commun 2006; 345(2): 669–674

[126] Panee J. Monocyte chemoattractant protein 1 (MCP-1) in obesity and diabetes. Cytokine 2012; 60(1): 1–12

[127] Harman-Boehm I, Bluher M, Redel H, Sion-Vardy N, Ovadia S, Avinoach E, Shai I, Kloting N, Stumvoll M, Bashan N, Rudich A. Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity. J Clin Endocrinol Metab 2007; 92(6): 2240–2247

[128] Famulla S, Horrighs A, Cramer A, Sell H, Eckel J. Hypoxia reduces the response of human adipocytes towards TNFα resulting in reduced NF-κB signaling and MCP-1 secretion. Int J Obes 2012; 36(7): 986–992

[129] Aomatsu T, Imaeda H, Takahashi K, Fujimoto T, Kasumi E, Yoden A, Tamai H, Fujiyama Y, Andoh A. Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts. Int J Mol Med 2012; 30(5): 1152–1158

[130] Tateya S, Tamori Y, Kawaguchi T, Kanda H, Kasuga M. An increase in the circulating concentration of monocyte chemoattractant protein-1 elicits systemic insulin resistance irrespective of adipose tissue inflammation in mice. Endocrinology 2010; 151(3): 971–979

[131] Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL, Ferrante AW Jr. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006; 116(1): 115–124

[132] Younce C, Kolattukudy P. MCP-1 induced protein promotes adipogenesis via oxidative stress, endoplasmic reticulum stress and autophagy. Cell Physiol Biochem 2012; 30(2): 307–320

[133] Schmidt SF, Jorgensen M, Chen Y, Nielsen R, Sandelin A, Mandrup S. Cross species comparison of C/EBPα and PPARγ profiles in mouse and human adipocytes reveals interdependent retention of binding sites. BMC Genomics 2011; 12:152

[134] Mikkelsen TS, Xu Z, Zhang X, Wang L, Gimble JM, Lander ES, Rosen ED. Comparative epigenomic analysis of murine and human adipogenesis. Cell 2010; 143(1): 156–169

[135] Lindroos J, Husa J, Mitterer G, Haschemi A, Rauscher S, Haas R, Groger M, Loewe R, Kohrgruber N, Schrogendorfer KF, Prager G, Beck H, Pospisilik JA, Zeyda M, Stulnig TM, Patsch W, Wagner O, Esterbauer H, Bilban M. Human but not mouse adipogenesis is critically dependent on LMO3. Cell Metab 2013; 18(1): 62–74

[136] Abella V, Scotece M, Conde J, Pino J, Gonzalez-Gay MA, Gomez-Reino JJ, Mera A, Lago F, Gomez R, Gualillo O. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 2017; 13(2): 100–109

[137] Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395(6704): 763–770

[138] Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002; 346(8): 570–578

[139] Behnes M, Brueckmann M, Lang S, Putensen C, Saur J, Borggrefe M, Hoffmann U. Alterations of leptin in the course of inflammation and severe sepsis. BMC Infect Dis 2012; 12:217

[140] Fawcett RL, Waechter AS, Williams LB, Zhang P, Louie R, Jones R, Inman M, Huse J, Considine RV. Tumor necrosis factor-α inhibits leptin production in subcutaneous and omental adipocytes from morbidly obese humans. J Clin Endocrinol Metab 2000; 85(2): 530–535

[141] Granowitz EV. Transforming growth factor-β enhances and pro-inflammatory cytokines inhibit ob gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 1997; 240(2): 382–385

[142] Laharrague P, Truel N, Fontanilles AM, Corberand JX, Penicaud L, Casteilla L. Regulation by cytokines of leptin expression in human bone marrow adipocytes. Horm Metab Res 2000; 32(10): 381–385

[143] Gottschling-Zeller H, Birgel M, Scriba D, Blum WF, Hauner H. Depot-specific release of leptin from subcutaneous and omental adipocytes in suspension culture: effect of tumor necrosis factor-α and transforming growth factor-β1. Eur J Endocrinol 1999; 141(4): 436–442 doi:10.1530/eje.0.1410436

[144] Grunfeld C, Zhao C, Fuller J, Pollack A, Moser A, Friedman J, Feingold KR. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest 1996; 97(9): 2152–2157

[145] Sarraf P, Frederich RC, Turner EM, Ma G, Jaskowiak NT, Rivet DJ 3rd, Flier JS, Lowell BB, Fraker DL, Alexander HR. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med 1997; 185(1): 171–175

[146] Padidar S, Farquharson AJ, Williams LM, Kelaiditi E, Hoggard N, Arthur JR, Drew JE. Leptin up-regulates pro-inflammatory cytokines in discrete cells within mouse colon. J Cell Physiol 2011; 226(8): 2123–2130

[147] Jitprasertwong P, Jaedicke KM, Nile CJ, Preshaw PM, Taylor JJ. Leptin enhances the secretion of interleukin (IL)-18, but not IL-1β from human monocytes via activation of caspase-1. Cytokine 2014; 65(2): 222–230

[148] Tao C, Sifuentes A, Holland WL. Regulation of glucose and lipid homeostasis by adiponectin: effects on hepatocytes, pancreatic beta cells and adipocytes. Best Pract Res Clin Endocrinol Metab 2014; 28(1): 43–58

[149] Tilg H, Wolf AM. Adiponectin: a key fat-derived molecule regulating inflammation. Expert Opin Ther Targets 2005; 9(2): 245–251

[150] Robinson K, Prins J, Venkatesh B. Clinical review: adiponectin biology and its role in inflammation and critical illness. Crit Care 2011; 15(2): 221

[151] Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002; 8(7): 731–737

[152] Jiang CY, Wang W, Tang JX, Yuan ZR. The adipocytokine resistin stimulates the production of proinflammatory cytokines TNF-α and IL-6 in pancreatic acinar cells via NF-κB activation. J Endocrinol Invest 2013; 36(11): 986–992

[153] Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Naslund E, Britton T, Concha H, Hassan M, Ryden M, Frisen J, Arner P. Dynamics of fat cell turnover in humans. Nature 2008; 453(7196): 783–787

[154] Samocha-Bonet D, Chisholm DJ, Tonks K, Campbell LV, Greenfield JR. Insulin-sensitive obesity in humans — a ‘favorable fat’ phenotype? Trends Endocrinol Metab 2012; 23(3): 116–124

[155] Tchkonia T, Thomou T, Zhu Y, Karagiannides I, Pothoulakis C, Jensen MD, Kirkland JL. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab 2013; 17(5): 644–656

[156] Joe AW, Yi L, Even Y, Vogl AW, Rossi FM. Depot-specific differences in adipogenic progenitor abundance and proliferative response to high-fat diet. Stem Cells 2009; 27(10): 2563–2570

[157] van Beek L, van Klinken JB, Pronk AC, van Dam AD, Dirven E, Rensen PC, Koning F, Willems van Dijk K, van Harmelen V. The limited storage capacity of gonadal adipose tissue directs the development of metabolic disorders in male C57Bl/6J mice. Diabetologia 2015; 58(7): 1601–1609

[158] Gustafson B, Hedjazifar S, Gogg S, Hammarstedt A, Smith U. Insulin resistance and impaired adipogenesis. Trends Endocrinol Metab 2015; 26(4): 193–200

[159] Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW 2nd, DeFuria J, Jick Z, Greenberg AS, Obin MS. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 2007; 56(12): 2910–2918

[160] Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, Wang ZV, Landskroner-Eiger S, Dineen S, Magalang UJ, Brekken RA, Scherer PE. Hypoxia-inducible factor 1α induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 2009; 29(16): 4467–4483

[161] Kim S, Joe Y, Jeong SO, Zheng M, Back SH, Park SW, Ryter SW, Chung HT. Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways. Innate Immun 2014; 20(8): 799–815

[162] Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011; 17(2): 179–188

[163] Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 2011; 12(5): 408–415

[164] Wernstedt Asterholm I, Tao C, Morley TS, Wang QA, Delgado-Lopez F, Wang ZV, Scherer PE. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 2014; 20(1): 103–118

[165] Dali-Youcef N, Mecili M, Ricci R, Andres E. Metabolic inflammation: connecting obesity and insulin resistance. Ann Med 2013; 45(3): 242–253

[166] Tchoukalova Y, Koutsari C, Jensen M. Committed subcutaneous preadipocytes are reduced in human obesity. Diabetologia 2007; 50(1): 151–157

[167] Adiels M, Westerbacka J, Soro-Paavonen A, Hakkinen AM, Vehkavaara S, Caslake MJ, Packard C, Olofsson SO, Yki-Jarvinen H, Taskinen MR, Boren J. Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance. Diabetologia 2007; 50(11): 2356–2365

[168] Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444(7121): 881–887

[169] Neeland IJ, Turer AT, Ayers CR, Powell-Wiley TM, Vega GL, Farzaneh-Far R, Grundy SM, Khera A, McGuire DK, de Lemos JA. Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. JAMA 2012; 308(11): 1150–1159

[170] Shuster A, Patlas M, Pinthus JH, Mourtzakis M. The clinical importance of visceral adiposity: a critical review of methods for visceral adipose tissue analysis. Br J Radiol 2012; 85(1009): 1–10

[171] Smith U. Abdominal obesity: a marker of ectopic fat accumulation. J Clin Invest 2015; 125(5): 1790–1792

[172] Pellegrinelli V, Carobbio S, Vidal-Puig A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia 2016; 59(6): 1075–1088

[173] Wang Y, Wang H, Hegde V, Dubuisson O, Gao Z, Dhurandhar NV, Ye J. Interplay of pro- and anti-inflammatory cytokines to determine lipid accretion in adipocytes. Int J Obes 2013; 37(11): 1490–1498

[174] Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 2005; 64(5): 765–766

[175] Huvers FC, Popa C, Netea MG, van den Hoogen FH, Tack CJ. Improved insulin sensitivity by anti-TNFα antibody treatment in patients with rheumatic diseases. Ann Rheum Dis 2007; 66(4): 558–559

[176] Marra M, Campanati A, Testa R, Sirolla C, Bonfigli AR, Franceschi C, Marchegiani F, Offidani A. Effect of etanercept on insulin sensitivity in nine patients with psoriasis. Int J Immunopathol Pharmacol 2007; 20(4): 731–736

[177] Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA 2011; 305(24): 2525–2531

[178] Parmentier-Decrucq E, Duhamel A, Ernst O, Fermont C, Louvet A, Vernier-Massouille G, Cortot A, Colombel JF, Desreumaux P, Peyrin-Biroulet L. Effects of infliximab therapy on abdominal fat and metabolic profile in patients with Crohn’s disease. Inflamm Bowel Dis 2009; 15(10): 1476–1484

[179] O'Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev 2008; 226:10–18

[180] Stienstra R, Joosten LA, Koenen T, van Tits B, van Diepen JA, van den Berg SA, Rensen PC, Voshol PJ, Fantuzzi G, Hijmans A, Kersten S, Muller M, van den Berg WB, van Rooijen N, Wabitsch M, Kullberg BJ, van der Meer JW, Kanneganti T, Tack CJ, Netea MG. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 2010; 12(6): 593–605

[181] Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov 2014; 13(6): 465–476

[182] Gabay C, McInnes IB, Kavanaugh A, Tuckwell K, Klearman M, Pulley J, Sattar N. Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. Ann Rheum Dis 2016; 75(10): 1806–1812

[183] Laakso M, Kuusisto J. Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat Rev Endocrinol 2014; 10(5): 293–302

[184] Wang M, Gao M, Liao J, Qi Y, Du X, Wang Y, Li L, Liu G, Yang H. Adipose tissue deficiency results in severe hyperlipidemia and atherosclerosis in the low-density lipoprotein receptor knockout mice. Biochim Biophys Acta 2016; 1861(5): 410–418

[185] Fox CS, Coady S, Sorlie PD, D’Agostino RB Sr, Pencina MJ, Vasan RS, Meigs JB, Levy D, Savage PJ. Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation 2007; 115(12): 1544–1550

[186] Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, Bass NM. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012; 56(3): 943–951

[187] Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140(1): 124–131

[188] Betteridge DJ, Carmena R. The diabetogenic action of statins — mechanisms and clinical implications. Nat Rev Endocrinol 2016; 12(2): 99–110

[189] Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129(25 Suppl 2): S1–S45

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