C H A P T E R

13Obesity, Insulin Resistance, and Inflammaging

Bianca K. Itariu, Thomas M. StulnigChristian Doppler Laboratory for Cardio-Metabolic Immunotherapy, and Clinical Division of Endocrinology and

Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria

Inflammation, Advancing Age and Nutrition. http://dx.doi.org/10.1016/B978-0-12-397803-5.00013-7

157

AbbreviationsAT adipose tissueATMs adipose tissue macrophagesBMI body mass indexCRP C-reactive proteinERK extracellular signal-regulated kinaseFFA free fatty acidsGDF-15 growth differentiation factor 15GLP-1 glucagon-like peptide 1HIF1-α hypoxia inducible factor 1-αIFN-ɣ interferon gammaIKK inhibitor of nuclear factor kappa-B kinaseIL interleukinIR insulin resistanceIRS insulin receptor substrateJNK c-jun N-terminal kinaseLPS lipopolysaccharideMAPK mitogen-activated protein kinaseMCP-1 C-C motif chemokine 2/monocyte chemotactic protein 1MIP-1α C-C motif chemokine 3/macrophage inflammatory protein 1-αNF-κB nuclear factor-kappa-BOPN osteopontinPI-3K phosphatidylinositol 3-kinasePKC protein kinase CSAT subcutaneous adipose tissueSOCS suppressor of cytokine signalingTLR Toll-like receptorVAT visceral adipose tissue.

INTRODUCTION

Increased population aging in both industrialized and developing countries is associated with an increased susceptibility to chronic noncommunicable diseases, which limit the human life span [1]. The burden of aging-associated chronic conditions is considerable, as they accounted for 42% of the deaths in the European Union in 2007 [2]. Obesity, defined by a body mass index (BMI) ≥ 30 kg/m2, has spread alarmingly worldwide,

Copyright © 2014 Elsevier Inc. All rights reserved.

especially in elderly individuals, and is independently associated with a greater risk of atherosclerotic cardio-vascular disease, type 2 diabetes mellitus (T2DM), and death [3,4]. If the caloric intake of an adult person, with a normal BMI of 22 kg/m2, exceeds energy expenditure by only 50 kcal/day, weight will increase by 2 kg within a year and by 20 kg within 10 years, at which time point that person’s BMI will have reached 30 kg/m2. The prev-alence of both generalized obesity and central obesity increases with age [5].

The distribution of adipose tissue (AT) in obesity is important for determining health risks of patients. Visceral obesity due to an increased accumulation of visceral (intra-abdominal) adipose tissue (VAT) is a strong predictor for T2DM and metabolic syndrome [6,7]. Visceral obesity is a major determinant of insulin resistance (IR) [8,9], i.e. a decreased responsiveness to the metabolic actions of insu-lin in AT, muscle, liver, and endothelial and immune cells [10,11]. The degree of IR increases with age in rodents and humans, while compensatory hyperinsulinemia, found in insulin-resistant subjects, may accelerate the aging process [12,13]. IR observed in aging is directly linked to obesity [14]. Physiologically, excess energy is stored as fat, pre-dominantly in subcutaneous adipose tissue (SAT). Once the storage capacity of SAT is exceeded, lipids accumulate in VAT [15]. AT hypertrophy is associated with endoplas-mic reticulum stress, which provokes AT inflammation, particularly in visceral AT. Inflammation triggers an efflux of free fatty acids (FFA) into the circulation [16]. Lipotox-icity due to overload of metabolic intermediates, such as ceramides or diacylglycerol in metabolic tissues includ-ing liver, muscle, and pancreatic islets, further aggravates IR and can lead to diabetes by interfering with pancreatic beta-cell function and survival [17,18].

IR does not occur solely due to lipotoxicity. The expan-sion of the vascular network does not meet the increased

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oxygen demand of expanded obese AT, resulting in insuf-ficient capillary density, local hypoxia, and upregulation of transcription factors, such as hypoxia inducible factor-1α (HIF-1α) [19]. Under hypoxic conditions, AT secretes proinflammatory mediators that impair insulin signal-ing and potentiate IR [20]. Proinflammatory cytokines are also released from adipocytes and other cell popula-tions from the AT stroma vascular fraction, such as mac-rophages and lymphocytes, upon sensing the increased energy storage levels characteristic of obesity and over-nutrition, partly via pattern recognition receptors of the innate immune system such as Toll-like receptors (TLRs) 2 and 4 [21–23]. Moreover, aging per se increases this inflammatory response to overnutrition [24].

Obesity, IR, and aging are hence associated with chronic systemic low-grade inflammation [25]. This type of inflammation represents a driving force for human aging [26]. Moreover, inflammaging (i.e. inflammation and aging) has been linked to negative health outcomes. Chronic obesity-associated inflammation is character-ized by (1) increased circulating levels of proinflam-matory markers; (2) increased proinflammatory gene expression in insulin target tissues; and (3) immune cell, mainly macrophage and T cell, activation and infiltration in AT [27–29]. Currently, the concept that AT is a highly active endocrine organ, secreting more than a hundred so-called adipokines, e.g. chemokines and cytokines, is well established [30]. In obesity, these molecules orches-trate the inflammatory response locally within AT as well as in the whole body and have predominantly proinflam-matory effects. A link between chronic inflammation and both obesity and IR was first shown for the proinflam-matory cytokine tumor necrosis factor (TNF-α), which directly causes IR; administration of an anti-TNF-α anti-body improves insulin sensitivity, as TNF-α secretion from AT is induced by obesity [31].

Immigrated AT macrophages, which are recruited from the circulation, are the primary sources of pro-inflammatory cytokines and, together with T cells, propagate the inflammatory reactions in AT. Local AT inflammation is thus a key regulator of the chronic sys-temic inflammatory phenotype observed in murine and human obesity [32]. Although the relationship between inflammaging, obesity, and IR is not yet completely understood, the molecular pathophysiology leading to novel therapeutic options is of particular importance for reducing negative health outcomes in aging populations.

INFLAMMATORY MEDIATORS, OBESITY, AND AGING

Acute inflammation is a self-regulated physiological adaptive defense mechanism triggered by infection or harmful stimuli (either self or nonself) that is meant to

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protect the host and restore homeostasis [33]. The chronic low-grade systemic inflammation commonly associated with aging and obesity differs from the inflammatory response to infection or autoimmune reactions [34,35]. Although the cardinal signs of inflammation (redness, swelling, heat, pain, and loss of function) are absent in this state, the hallmark of obesity-associated inflamma-tion is the increase in circulating inflammatory factors. Both obesity and aging are characterized by elevated cir-culating levels of:

(1) Acute-phase proteins such as C-reactive protein (CRP) [29] or serum amyloid A [36];

(2) Inflammatory cytokines such as TNF-α, interleukin-6 (IL-6), IL-8 [37], IL-1β [38], and growth differentiation factor 15 (GDF-15) [39];

(3) Chemokines such as monocyte chemotactic protein 1 (MCP-1; CCL2 gene) [37] and macrophage inflammatory protein 1 α (MIP-1α; CCL3 gene) [40];

(4) Soluble adhesion molecules (P-selectin, E-selectin) [41]; and

(5) Multifunctional proteins such as leptin [42] or osteopontin (OPN) [43].

In older persons, serum levels of inflammatory mark-ers are increased 2- to 4-fold [44]. In aging, chronic anti-genic stimulation is thought to be a major driver of the systemic proinflammatory state [45], while AT (mainly VAT) is the starting point of the obesity-associated inflammatory response and a considerable source of pro-inflammatory mediators. Mediators secreted from VAT are directly transported to the liver via portal circulation. Increased IL-6 concentration upregulates CRP secretion in the liver. Both increased IL-6 and CRP concentrations are independent risk factors for T2DM and cardiovas-cular disease [46,47], and positively correlate with BMI.

Serum levels and AT expression of molecules belong-ing to the CC chemokine family and their receptors are increased in obesity, correlate positively with BMI, and are associated with increased systemic inflammation and IR [29,48]. Furthermore, gene sets related to chemo-kine activity and receptor binding are highly upregu-lated in VAT and SAT from insulin-resistant, compared to insulin-sensitive, obese subjects [29,49]. The multi-functional cytokine and extracellular matrix protein OPN is a modulator of IR and inflammation, and may be a therapeutic target for the treatment of IR [50,51]. OPN was found to be massively upregulated in obesity and is critically involved in macrophage activation, cell adhe-sion and migration, inflammation, and fibrosis, as well as an important modulator of IR in AT, liver, and muscle [50,52–54]. OPN knockout mice exhibit improved insu-lin sensitivity and reduced macrophage infiltration into AT, while neutralization of OPN with an anti-OPN anti-body also reduces AT inflammation and IR [50,53]. The exact effects of the inflammatory mediators involved in

ADIPOSE TISSUE M

obesity-associated inflammation are yet not fully elu-cidated and their characterization represents a prolific field of research, especially when considering their clini-cal utility as predictive biomarkers.

CROSSTALK BETWEEN INSULIN AND INFLAMMATORY SIGNALING

Insulin regulates glucose homeostasis, promotes the storage of lipids and lipogenesis, decreases lipolysis in AT, and promotes protein synthesis in muscle [55].The insulin signaling pathway is fundamental for ensuring nutrient and energy homeostasis, and is highly con-served. Under physiological conditions, insulin binds to the insulin receptor and promotes autophosphoryla-tion of a trio of regulatory loop tyrosine residues, thus disinhibiting tyrosine kinase activity toward the insu-lin receptor substrate (IRS) 1 and 2, which is essential for insulin-mediated metabolic control. The subsequent tyrosine phosphorylation of IRS activates two major pathways: the phosphatidylinositol 3-kinase (PI-3K)/AKT pathway and the mitogen-activated protein kinase (MAPK) pathway [56,57]. The former is involved in insu-lin-stimulated glucose uptake, inhibition of gluconeo-genesis, and regulation of lipid metabolism, whereas the latter primarily controls cell growth and differentiation.

Proinflammatory cytokines impair insulin signaling through activation of downstream inflammatory signal-ing pathways [58], which interfere with insulin signal-ing network transduction downstream of IRS through the induction of serine kinases such as c-jun amino ter-minal kinase (JNK), and activation of nuclear factor-κB (NF-κB) and suppressor of cytokine signaling (SOCS) pathways [58,59]. Obesity- and aging-associated chronic inflammation, but also hyperglycemia and lipotoxicity, drastically impair insulin signaling through activation of MAPK members JNK and extracellular signal-regulated kinase (ERK), inhibitor of nuclear factor kappa-B kinase (IKK), and protein kinase C (PKC) [60,61]. When serine kinases that respond to inflammatory stimuli, such as IKK or JNK, phosphorylate critical serine sites on IRS, downstream insulin signaling is impaired, which results in disinhibited lipolysis in AT and dysregulated glu-cose uptake in muscle [62,63]. The released FFAs further promote the local and systemic inflammatory response [64,65]. In pancreatic beta cells, long-term exposure to FFA inhibits insulin synthesis and secretion by activation of PKC [66]. Insulin itself can activate JNK and other ser-ine kinases as part of a negative feedback mechanism.

Targeting signaling molecules from the inflammatory pathway leads to improved insulin sensitivity: JNK1 knockout mice do not develop high-fat diet-induced obesity and glucose intolerance and are protected from IR [67]. Cytokine signaling (IL-6 and TNF-α) can induce

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in vitro serine phosphorylation via induction of IKK-β and SOCS 1 and 3 expression [68,69], which degrade IRS proteins. IL-1β downregulates IRS expression and IL-6 blocks insulin signaling via IRS and SOCS proteins [68–71].

NF-κB is another transcription factor with a pivotal role in chronic inflammatory disease [72]. NF-κB induces the expression of genes that promote IR. NF-κB signal-ing may be stimulated by (especially saturated) FFA and lipopolysaccharide (LPS) via binding to TLR4, which is expressed on adipocytes and macrophages and upregu-lated in obesity [73]. Lipotoxicity may be an important mediator of IR early in the development of obesity, whereas inflammation becomes more relevant once obe-sity is reached [74]. Elevated circulating FFA concentra-tions found in obesity and insulin-resistant states cause AT macrophages to release TNF-α directly through TLR4 and subsequent NF-κB activation [75]. NF-κB transloca-tion to the nucleus promotes further IL-6 and TNF-α synthesis [76]. Systemic IR continuously worsens with increasing AT inflammation [74]. Enhanced absorption of high-fat diets in the gut increases circulating LPS concentrations. LPS enters the circulation via chylo-microns, elicits low-grade endotoxemia, and potently stimulates TLR4, causing AT inflammation and com-pensatory hyperinsulinemia due to hepatic IR [25,77]. In the absence of functional TLR4 in mice, inflammatory signaling is blunted and the animals are protected from high-fat diet-induced IR [22]. IR is also improved when NF-κB activation is inhibited by salicylates [78]. Thus, FFA- and LPS-sensing in AT may initiate inflammatory and insulin-desensitizing processes. Interestingly, inhi-bition of NF-κB activation in myeloid cells provides the highest protection from systemic IR, highlighting the importance of this cell population in linking metabolic and inflammatory conditions [62,73].

ADIPOSE TISSUE MACROPHAGES

In obesity, AT macrophages (ATMs) play a central role in the crosstalk between inflammation and IR, and may also be key players in inflammaging-related pathological alterations [79–81]. Bone marrow-derived macrophages are recruited from the circulation into obese AT. In order to scavenge cell debris and lipid droplets, they localize mainly as “crown-like structures” around hypertrophic “stressed” adipocytes, which have undergone necrotic-like death [82]. Hence, AT growth by adipocyte hyper-trophy is limited and ongoing stimulated fat deposition leads to a chronic inflammatory response to induce IR.

In obesity, ATM recruitment from the circulation depends on various factors, including endocrine, paracrine, and mechanical ones. ATMs are a main source of inflammatory mediators (such as C-C chemokines, IL-6, and TNF-α), which

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contribute to the recruitment of other macrophages, result-ing in a chronic inflammatory response [83,84]. The MCP-1/C-C motif chemokine receptor 2 (CCR2) axis is involved in macrophage recruitment to sites of inflammation [85,86]. MCP-1 (CCL2 gene) is secreted by AT and its production is stimulated by insulin and increased in obesity [87]. MCP-1 or CCR2 deficiency partially prevents macro-phage infiltration in obese AT and ameliorates IR [88,89]. In animal models, knocking out components of the mac-rophage inflammatory pathway can protect against obe-sity-induced IR [90,91].

Obesity causes a phenotypic switch in macrophage activation and polarization [92]. All ATMs express the overall macrophage marker CD68 [93]. Based on the surface expression of other antigens, ATM can be classi-fied into proinflammatory, classically activated M1 macro-phages [stimulated by interferon gamma (IFN-ɣ) and TLR ligands] and alternatively activated, anti-inflammatory M2 macrophages (stimulated by IL-4) [94]. M1 macrophages express a wide range of proinflammatory cytokines and inflammatory factors involved in IR [92,95] such as: F4/80, CD11c, CCR2 [92,96], and CD40 [92,95,97]. They are the predominant ATM population in obesity, whereas M2 macrophages express mannose and galactose recep-tors (MR/CD206 and MGL-1/CD301), IL-10 and chitinase-3-like protein 3 (Ym1) [98] have immunoregulatory and tissue-remodeling functions and are mainly found in lean subjects and animals. The M1/M2 paradigm is how-ever an oversimplification because in vivo macrophages exhibit great plasticity along the entire continuum from classical to alternative activation, and are characterized by various chemokine receptor expression patterns [99,100]. Mature adipocytes cultured in conditioned medium from activated macrophages exhibit IR and increased NF-κB activation, indicating the functional capability of mac-rophage secretion products to interfere with adipocyte function [101]. Impaired macrophage polarization in the elderly may dysregulate the development of the host response, making them more susceptible to infectious dis-eases; thus, the aging microenvironment may also be a key modulator of these macrophage-elicited responses [102].

ROLE OF OTHER IMMUNE CELL TYPES IN OBESITY-ASSOCIATED

INFLAMMAGING

Macrophages are far from being the only infiltrating immune cells described in AT. Lymphocytes and mast cells have been shown to play a part in obesity-induced inflammation and IR [103,104]. These cells act in an integrated, manner to influence ATM polarization and recruitment. Various T cell subtypes are recruited to AT and modulate inflammation: CD4+ proinflammatory T helper (Th) 1 and CD8+ cytotoxic T cells promote the

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attraction and differentiation of ATMs. On the other hand, CD4+ Th2 cells and regulatory T (Treg) cells coun-teract inflammation by inhibiting macrophage migra-tion and inducing alternative ATM activation [105,106]. The number of Th1 cells increases with obesity, while the number of Th2 and Treg cells decreases in mice. A detrimental ratio of Th1 : Th2 cells may also contrib-ute to the inflammatory response associated with obe-sity in humans; however, the obesity-associated loss of Treg cells found in murine AT could not be detected in humans [107]. The function and proportion of T cell sub-sets, and their proliferation and cytokine production is also affected by aging. Thus, aging itself can enhance the inflammatory response associated with obesity [108].

Accumulation of mast cells in AT has been described in murine models of diet-induced obesity and in human obesity, and mast cell-deficient mice have been shown to exhibit enhanced insulin sensitivity [109]. Moreover, mast cells seem to link obesity and T2DM, as the number of mast cells found in the AT of human obese diabetic subjects is increased compared to lean healthy controls. Mast cell numbers in AT correlate with macrophage activation, the degree of inflammation and fibrosis, and most notably with parameters of glucose homeostasis such as fasting glycemia and HbA1c [104].

THERAPEUTIC OPTIONS

The central role of inflammation in obesity should facilitate the identification of drug targets to improve prognosis by interfering with crucial molecular mecha-nisms underlying this inflammatory response. Moreover, a pragmatic approach for assessing the interrelationship between IR and inflammation in humans is analyz-ing the consequences of anti-inflammatory therapies on insulin sensitivity and of antidiabetic therapies on inflammatory status. Dietary factors are either induc-ers or mitigators of obesity-associated inflammation [47,110]. Notably, long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) are known for their cardioprotective and anti-inflammatory effects, and we have recently shown in a randomized clinical trial that n-3 PUFA suc-ceeded in lessening adipose and systemic inflammation in severely obese nondiabetic subjects after 8 weeks of treatment [111–113]. Adherence to the treatment regi-men of 3.36 g/day of highly purified n-3 PUFA (eicosa-pentaenoic acid and docosahexaenoic acid) was high in this trial and the dose was well tolerated. Long-chain n-3 PUFA decreased AT gene expression of CCL2, CCL3, HIF1A, and TGFB, as well as circulating IL-6 concentra-tions, indicating reduced AT and systemic inflammation. Although improvements in insulin sensitivity were not detected in this setting, n-3 PUFAs have been shown to ameliorate IR and risk profiles in subjects with metabolic

COnClU

syndrome, indicating that beneficial metabolic effects probably occur with long-term treatment [114].

Antidiabetic and anti-inflammatory medications seem to go hand in hand when it comes to blocking lipolysis. Both metformin and salicylate inhibit TNF-α-induced lipolysis in primary adipocyte cultures in rats [115,116]. Salicylate together with pioglitazone protects pancreatic beta cells against IL-1β-induced damage [117]. Acetyl-salicylic acid inhibits prostaglandin and thromboxane biosynthesis but also favorably affects the formation of new classes of eicosanoids generated from long-chain n-3 PUFA. These so-called resolvins and protectins are anti-inflammatory and can actively resolve inflamma-tory responses even at very low doses [118]. Notably, we detected resolvins E1 and D1, as well as protectin D1, in AT of n-3 PUFA-treated patients. Thus, by increasing substrate availability for the synthesis of anti-inflamma-tory lipid mediators, n-3 PUFAs actively dampen obe-sity-associated inflammation [112].

Salicylates are weak inhibitors if IKKβ and serine phos-phorylation of IRS1, which might explain their favorable effect on glucose tolerance when given in very high doses [119]. High (4.5 g/day) and standard (3 g/day) doses of the anti-inflammatory drug salsalate improved glucose and lipid homeostasis via targeting NF-κB activity, and increased insulin secretion in healthy obese subjects [120,121]. Inter-estingly, methotrexate is an immunosuppressant drug that has in vivo insulin-sensitizing and antilipolytic effects [122]. Patients on methotrexate therapy have a reduced propensity for developing metabolic syndrome [123], and studies are ongoing to assess whether patients at risk of car-diovascular disease can benefit from its anti-inflammatory effects in terms of risk reduction. The anti-inflammatory actions of incretin-based therapies seem to contribute indi-rectly to their insulin-sensitizing effects. Glucagon-like pep-tide 1 (GLP-1) affects immune functions both directly and indirectly, improves insulin secretion [124], and may offer protection against degenerative age-related disorders [125]. Current pharmaceutical investigations are focusing on cytokine and chemokine receptor antagonism, particularly CCR2, as novel options for patients at high cardiometabolic risk [126]. Interference with IL-1 action through admin-istration of an IL-1 receptor (IL-1R) antagonist or specific antibodies against IL-1R lowers blood glucose levels, pre-dominantly improves beta-cell function, and reduces sys-temic inflammation [127,128]. However, investigations into tailored anti-inflammatory strategies for the prevention and treatment of obesity-related complications such as T2DM are still in their initial stages.

CONCLUSION

In the last 20 years, research focus has shifted from the metabolic pathophysiology of IR to the underlying

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chronic low-grade inflammation; this has improved our understanding of aging- and obesity-related complica-tions such as T2DM and cardiovascular disease. Whether increased inflammatory activity causes age-associated pathologies or reflects the sum of ongoing pathologi-cal processes remains uncertain. With respect to obesity, inflamed AT produces proinflammatory adipokines, cytokines, and chemokines, which promote local and sys-temic inflammatory reactions and IR by interfering with insulin signaling. Serum concentrations of adipokines are sensitive markers of subclinical inflammation in the elderly. Anti-inflammatory therapeutic strategies may prove beneficial for preventing obesity- and age-related diseases; however, further studies are necessary for a better understanding of the complex crosstalk between inflammation and metabolism in human disease.

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