Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity

Until the identification of leptin, the first adipokine discovered in 1994, adipose tissue was considered only as an energy storage tissue. However, it is now clear that adipose tissue is an endocrine/paracrine/autocrine organ, which plays a relevant role in physiopathology of several inflammatory diseases. Actually, it is mainly involved not only in the low-grade inflammatory status in obesity but also in other relevant inflammatory conditions and autoimmune disorders. In this review article, we discuss the main biological activities of leptin, adiponectin, lipocalin-2, resistin, and visfatin, as well as their contributions to certain inflammatory conditions.     

NF-kappaB: linking inflammation and immunity to cancer development and progression

There has been much effort recently to probe the long-recognized relationship between the pathological processes of infection, inflammation and cancer. For example, epidemiological studies have shown that approximately 15% of human deaths from cancer are associated with chronic viral or bacterial infections. This Review focuses on the molecular mechanisms that connect infection, inflammation and cancer, and it puts forward the hypothesis that activation of nuclear factor-kappaB (NF-kappaB) by the classical, IKK-beta (inhibitor-of-NF-kappaB kinase-beta)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.     

Activation-induced cytidine deaminase (AID) linking immunity, chronic inflammation, and cancer

Activation-induced cytidine deaminase (AID) is critically involved in class switch recombination and somatic hypermutation of Ig loci resulting in diversification of antibodies repertoire and production of high-affinity antibodies and as such represents a physiological tool to introduce DNA alterations. These processes take place within germinal centers of secondary lymphoid organs. Under physiological conditions, AID is expressed predominantly in activated B lymphocytes. Because of the mutagenic and recombinogenic potential of AID, its expression and activity is tightly regulated on different levels to minimize the risk of unwanted DNA damage. However, chronic inflammation and, probably, combination of other not-yet-identified factors are able to create a microenvironment sufficient for triggering an aberrant AID expression in B cells and, importantly, in non-B-cell background. Under these circumstances, AID may target also non-Ig genes, including cancer-related genes as oncogenes, tumor suppressor genes, and genomic stability genes, and modulate both genetic and epigenetic information. Despite ongoing progress, the complete understanding of fundamental aspects is still lacking as (1) what are the crucial factors triggering an aberrant AID expression/activity including the impact of Th2-driven inflammation and (2) to what extent may aberrant AID in human non-B cells lead to abnormal cell state associated with an increased rate of genomic alterations as point mutations, small insertions or deletions, and/or recurrent chromosomal translocations during solid tumor development and progression.     

Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer

Clinical and epidemiologic studies have suggested an association between infectious agents and chronic inflammatory disorders and cancer. Better understanding of microbial pattern-recognition receptors and innate immune signaling pathways of the host is helping to elucidate the connection between microbial infection and chronic disease. We propose that a key aspect of pathogenesis is an aberrant epithelial barrier that can be instigated by microbial toxins, environmental insults, or the genetic predisposition of the host. Loss of epithelial integrity results in activation of resident inflammatory cells by microbial invaders or endogenous ligands. When coupled with a failure of normal control mechanisms that limit leukocyte activation, a cascade is established that induces chronic inflammation and its consequences. Here, we outline this mechanistic framework and briefly review how alteration of innate immune response genes in murine models can provide insights into the potential microbial origins of diverse conditions including Crohn's disease, psoriasis, atherosclerosis, diabetes, and liver cancer.     

Hypothalamic inflammation and thermogenesis: the brown adipose tissue connection

Hypothalamic inflammation and dysfunction are common features of experimental obesity. An imbalance between caloric intake and energy expenditure is generated as a consequence of this inflammation, leading to the progressive increase of body adiposity. Thermogenesis, is one of the main functions affected by obesity-linked hypothalamic dysfunction and the complete characterization of the mechanisms involved in this process may offer new therapeutic perspectives for obesity. The brown adipose tissue is an important target for hypothalamic action in thermogenesis. This tissue has been thoroughly studied in rodents and hibernating mammals; however, until recently, its advocated role in human thermogenesis was neglected due to the lack of substantial evidence of its presence in adult humans. The recent demonstration of the presence of functional brown adipose tissue in adult humans has renovated the interest in this tissue. Here, we review some of the work that shows how inflammation and dysfunction of the hypothalamus can control brown adipose tissue activity and how this can impact on whole body thermogenesis and energy expenditure.     

Overproduction of angiotensinogen from adipose tissue induces adipose inflammation, glucose intolerance, and insulin resistance

Although obesity is associated with overactivation of the white adipose tissue (WAT) renin-angiotensin system (RAS), a causal link between the latter and systemic insulin resistance is not established. We tested the hypothesis that overexpression of angiotensinogen (Agt) from WAT causes systemic insulin resistance via modulation of adipose inflammation. Glucose tolerance, systemic insulin sensitivity, and WAT inflammatory markers were analyzed in mice overexpressing Agt in the WAT (aP2-Agt mice). Proteomic studies and in vitro studies using 3T3-L1 adipocytes were performed to build a mechanistic framework. Male aP2-Agt mice exhibited glucose intolerance, insulin resistance, and lower insulin-stimulated glucose uptake by the skeletal muscle. The difference in glucose tolerance between genotypes was normalized by high-fat (HF) feeding, and was significantly improved by treatment with angiotensin-converting enzyme (ACE) inhibitor captopril. aP2-Agt mice also had higher monocyte chemotactic protein-1 (MCP-1) and lower interleukin-10 (IL-10) in the WAT, indicating adipose inflammation. Proteomic studies in WAT showed that they also had higher monoglyceride lipase (MGL) and glycerol-3-phosphate dehydrogenase levels. Treatment with angiotensin II (Ang II) increased MCP-1 and resistin secretion from adipocytes, which was prevented by cotreating with inhibitors of the nuclear factor-κB (NF-κB) pathway or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, we show for the first time that adipose RAS overactivation causes glucose intolerance and systemic insulin resistance. The mechanisms appear to be via reduced skeletal muscle glucose uptake, at least in part due to Ang II-induced, NADPH oxidase and NFκB-dependent increases in WAT inflammation.     

Selective suppression of adipose tissue apoE expression impacts systemic metabolic phenotype and adipose tissue inflammation

apoE is a multi-functional protein expressed in several cell types and in several organs. It is highly expressed in adipose tissue, where it is important for modulating adipocyte lipid flux and gene expression in isolated adipocytes. In order to investigate a potential systemic role for apoE that is produced in adipose tissue, mice were generated with selective suppression of adipose tissue apoE expression and normal circulating apoE levels. These mice had less adipose tissue with smaller adipocytes containing fewer lipids, but no change in adipocyte number compared with control mice. Adipocyte TG synthesis in the presence of apoE-containing VLDL was markedly impaired. Adipocyte caveolin and leptin gene expression were reduced, but adiponectin, PGC-1, and CPT-1 gene expression were increased. Mice with selective suppression of adipose tissue apoE had lower fasting lipid, insulin, and glucose levels, and glucose and insulin tolerance tests were consistent with increased insulin sensitivity. Lipid storage in muscle, heart, and liver was significantly reduced. Adipose tissue macrophage inflammatory activation was markedly diminished with suppression of adipose tissue apoE expression. Our results establish a novel effect of adipose tissue apoE expression, distinct from circulating apoE, on systemic substrate metabolism and adipose tissue inflammatory state.     

Aging up-regulates expression of inflammatory mediators in mouse adipose tissue

Obesity is a leading risk factor for type 2 diabetes (T2D). Aging is associated with an increase in T2D incidence, which is not totally explained by the much lower prevalence of obesity in the elderly. Low-grade inflammation in adipose tissue (AT) contributes to insulin resistance and T2D. Thus, we determined whether inflammatory responses are up-regulated with age in AT. The results showed that visceral AT from old C57BL mice had significantly higher mRNA expression of the proinflammatory cytokines IL-1beta, IL-6, TNF-alpha, and COX-2 and lower expression of anti-inflammatory PPAR-gamma than those of young mice. We further showed that adipocytes (AD) and not stromal vascular cells including macrophages (Mphi) were the cells responsible for this higher inflammatory state of the aged AT, suggesting that the age-associated increase in AT inflammation is distinguished from that seen in obesity, in which Mphi are the main contributors. However, peritoneal Mphi of either age (young or old) produced more TNF-alpha and IL-6 after incubation in old AD-conditioned medium compared with young AD-conditioned medium. This suggests that in addition to producing more inflammatory cytokines, AD from old mice induce a higher inflammatory response in other cells. Sphingolipid ceramide was higher in old compared with young AD. Reducing ceramide levels or inhibiting NF-kappaB activation decreased cytokine production, whereas the addition of ceramide increased cytokine production in young AD to a level comparable to that seen in old AD, suggesting that ceramide-induced activation of NF-kappaB plays a key role in AT inflammation.     

Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism

Dysregulation of lipid metabolism in individual tissues leads to systemic disruption of insulin action and glucose metabolism. Utilizing quantitative lipidomic analyses and mice deficient in adipose tissue lipid chaperones aP2 and mal1, we explored how metabolic alterations in adipose tissue are linked to whole-body metabolism through lipid signals. A robust increase in de novo lipogenesis rendered the adipose tissue of these mice resistant to the deleterious effects of dietary lipid exposure. Systemic lipid profiling also led to identification of C16:1n7-palmitoleate as an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses hepatosteatosis. Our data reveal a lipid-mediated endocrine network and demonstrate that adipose tissue uses lipokines such as C16:1n7-palmitoleate to communicate with distant organs and regulate systemic metabolic homeostasis.     

The role of GM-CSF in adipose tissue inflammation

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine that has a central action to reduce food intake and body weight. Consistent with this, GM-CSF knockout mice are more obese and hyperphagic than wild-type mice. However, in lung, GM-CSF is an important determinant of macrophage infiltration. Consequently, we sought to determine if GM-CSF might contribute to adipose tissue macrophage accumulation, insulin resistance, and low-grade inflammation that occurs when animals gain weight on a high-fat diet (HFD). We therefore determined how targeted genetic disruption of GM-CSF can affect adipose tissue macrophage and cytokine gene expression as well as glucose homeostasis by performing hyperinsulinemic-euglycemic clamps. The number of macrophages and CCR2 gene expression in adipose tissue of GM-CSF knockout mice was decreased relative to those in wild-type mice, and the adipocyte size of mesenteric fat was increased in GM-CSF knockout mice on a HFD compared with wild-type mice. The level of mRNA of the proinflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha, and macrophage inflammatory protein-1alpha was significantly lower in mesenteric fat of GM-CSF knockout mice on the HFD than in wild-type mice. Using the hyperinsulinemic-euglycemic clamp technique, GM-CSF knockout mice had greater overall insulin sensitivity. This increase was due to enhanced peripheral uptake and utilization of glucose rather than to increased hepatic insulin sensitivity. Collectively, the data suggest that the GM-CSF knockout mutation ameliorates peripheral insulin resistance in spite of increased adiposity by reducing inflammation in adipose tissue in response to a HFD.     

Bone morphogenetic proteins in inflammation,glucose homeostasis and adipose tissue energy metabolism

Bore morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-β superfamily, a group of secreted proteins that regulate embryonic development. This review summarizes the effects of BMPs on physiological processes not exclusively linked to the musculoskeletal system. Specifically, we focus on the involvement of BMPs in inflammatory disorders, e.g. fibrosis, inflammatory bowel disease, anchylosing spondylitis, rheumatoid arthritis. Moreover, we discuss the role of BMPs in the context of vascular disorders, and explore the role of these signalling proteins in iron homeostasis (anaemia, hemochromatosis) and oxidative damage. The second and third parts of this review focus on BMPs in the development of metabolic pathologies such as type-2 diabetes mellitus and obesity. The pancreatic beta cells are the sole source of the hormone insulin and BMPs have recently been implicated in pancreas development as well as control of adult glucose homeostasis. Lastly, we review the recently recognized role of BMPs in brown adipose tissue formation and their consequences for energy expenditure and adiposity. In summary, BMPs play a pivotal role in metabolism beyond their role in skeletal homeostasis. However, increased understanding of these pleiotropic functions also highlights the necessity of tissue-specific strategies when harnessing BMP action as a therapeutic target.     

SOCS2 modulates adipose tissue inflammation and expansion in mice

IntroductionObesity is usually triggered by a nutrient overload that favors adipocyte hypertrophy and increases the number of pro-inflammatory cells and mediators into adipose tissue. These mediators may be regulated by suppressors of cytokine signaling (SOCS), such as SOCS2, which is involved in the regulation of the inflammatory response of many diseases, but its role in obesity is not yet known. We aimed to investigate the role of SOCS2 in metabolic and inflammatory dysfunction induced by a high-refined carbohydrate-containing diet (HC).Material and methodsMale C57BL/6 wild type (WT) and SOCS2 deficient (SOCS2^−/−) mice were fed chow or an HC diet for 8 weeks.ResultsIn general, SOCS2 deficient mice, independent of the diet, showed higher adipose tissue mass compared with their WT counterparts that were associated with decreased lipogenesis rate in adipose tissue, lipolysis in adipocyte culture and energy expenditure. An anti-inflammatory profile was observed in adipose tissue of SOCS2^−/− by reduced secretion of cytokines, such as TNF and IL-6, and increased M2-like macrophages and regulatory T cells compared with WT mice. Also, SOCS2 deficiency reduced the differentiation/expansion of pro-inflammatory cells in the spleen but increased Th2 and Treg cells compared with their WT counterparts.ConclusionThe SOCS2 protein is an important modulator of obesity that regulates the metabolic pathways related to adipocyte size. Additionally, SOCS2 is an inflammatory regulator that appears to be essential for controlling the release of cytokines and the differentiation/recruitment of cells into adipose tissue during the development of obesity.     

Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis

Although aging enhances atherosclerosis, we do not know if this occurs via alterations in circulating immune cells, lipid metabolism, vasculature, or adipose tissue. Here, we examined whether aging exerts a direct pro-atherogenic effect on adipose tissue in mice. After demonstrating that aging augmented the inflammatory profile of visceral but not subcutaneous adipose tissue, we transplanted visceral fat from young or aged mice onto the right carotid artery of Ldlr^−/− recipients. Aged fat transplants not only increased atherosclerotic plaque size with increased macrophage numbers in the adjacent carotid artery, but also in distal vascular territories, indicating that aging of the adipose tissue enhances atherosclerosis via secreted factors. By depleting macrophages from the visceral fat, we identified that adipose tissue macrophages are major contributors of the secreted factors. To identify these inflammatory factors, we found that aged fat transplants secreted increased levels of the inflammatory mediators TNFα, CXCL2, and CCL2, which synergized to promote monocyte chemotaxis. Importantly, the combined blockade of these inflammatory mediators impeded the ability of aged fat transplants to enhance atherosclerosis. In conclusion, our study reveals that aging enhances atherosclerosis via increased inflammation of visceral fat. Our study suggests that future therapies targeting the visceral fat may reduce atherosclerosis disease burden in the expanding older population.     

Exercise training decreases adipose tissue inflammation in cachectic rats

Bearing in mind that cancer cachexia is associated with chronic systemic inflammation and that endurance training has been adopted as a nonpharmacological anti-inflammatory strategy, we examined the effect of 8 weeks of moderate intensity exercise upon the balance of anti- and pro-inflammatory cytokines in 2 different depots of white adipose tissue in cachectic tumour-bearing (Walker-256 carcinosarcoma) rats. Animals were assigned to a sedentary control (SC), sedentary tumour-bearing (ST), sedentary pair-fed (SPF) or exercise control (EC), exercise tumour-bearing (ET), and exercise pair-fed (EPF) group. Trained rats ran on a treadmill (60% VO(2)max) 60?min/day, 5 days/week, for 8 weeks. The retroperitoneal (RPAT) and mesenteric (MEAT) adipose pads were excised and the mRNA (RT-PCR) and protein (ELISA) expression of IL-1β, IL-6, TNF-α, and IL-10 were evaluated. The number of infiltrating monocytes in the adipose tissue was increased in cachectic rats. TNF-α mRNA in MEAT was increased in the cachectic animals (p<0.05) in relation to SC. RPAT protein expression of all studied cytokines was increased in cachectic animals in relation to SC and SPF (p<0.05). In this pad, IL-10/TNF-α ratio was reduced in the cachectic animals in comparison with SC (p<0.05) indicating inflammation. Exercise training improved IL-10/TNF-α ratio and induced a reduction of the infiltrating monocytes both in MEAT and RPAT (p<0.05), when compared with ST. We conclude that cachexia is associated with inflammation of white adipose tissue and that exercise training prevents this effect in the MEAT, and partially in RPAT.     

Modulation of adipose tissue inflammation by bioactive food compounds

Adipose tissue has an important endocrine function in the regulation of whole-body metabolism. Obesity leads to a chronic low-grade inflammation of the adipose tissue, which disrupts this endocrine function and results in metabolic derangements, such as type-2 diabetes. Dietary bioactive compounds, such as polyphenols and certain fatty acids, are known to suppress both systemic and adipose tissue inflammation and have the potential to improve these obesity-associated metabolic disorders. Mechanistically, polyphenolic compounds including non-flavonoids, such as curcumin and resveratrol, and flavonoids, such as catechins (tea-polyphenols), quercetin and isoflavones, suppress nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinases (MAPK) pathways while activating the 5′ adenosine monophosphate-activated protein kinase (AMPK) pathway in adipose tissue. Dietary polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), conjugated linoleic acid (CLA) and monounsaturated fatty acids (MUFA), such as oleic acid, also impart anti-inflammatory effects through several mechanisms. These include activation of AMPK and peroxisome proliferator-activated receptor gamma (PPAR-γ), as well as suppression of toll-like receptors (TLRs) and NF-κB pathway. This review discusses the major molecular mechanisms of dietary polyphenols and fatty acids, alone or in combination, which are responsible for adipose tissue-associated anti-inflammatory effects.