Abstract
Only recently has the complexity of adipose tissue become more apparent and appreciated. The two well-known forms of adipose tissue have been recognized: brown and white. This chapter focuses on white adipose tissue, and its derangement with the onset and progression of obesity and insulin resistance. It begins with a brief overview characterizing white adipose tissue and the adipocyte, and then proceeds to a discussion regarding the multifaceted dysfunction that accompanies obesity.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Adipocyte dysfunction
- Inflammation
- Insulin resistance
- Adipose tissue
- White adipose tissue
- Ectopic fat deposition
- Hypoxia
- Free fatty acid
Only recently has the complexity of adipose tissue become more apparent and appreciated. The two well-known forms of adipose tissue have been recognized: brown and white. Historically, these have been seen as two separate entities, with brown adipose tissue (BAT) primarily playing its role in thermogenesis through uncoupling protein 1, and white adipose tissue (WAT) with its role as fat storage [1–4]. Even this concept is riddled with controversy given the transdifferentiation and plasticity that exists between these two, as observed with alterations in temperature, pregnancy and lactation, and fasting and obesity [5, 6]. This chapter, however, focuses on white adipose tissue, and its derangement with the onset and progression of obesity and insulin resistance. It begins with a brief overview characterizing white adipose tissue and the adipocyte, and then proceeds to a discussion regarding the multifaceted dysfunction that accompanies obesity.
1 White Adipose Tissue
Less than 50 % of white adipose tissue is composed of preadipocytes and lipid-filled adipocytes [7, 8]. White adipose tissue is also composed not only of precursors, but also stromal cells, endothelial cells, fibroblasts, and a multitude of immune cells including macrophages, lymphocytes, natural killer cells, and mast cells [5, 9, 10]. M1 Macrophages, induced by pro-inflammatory cytokines, are found in equal amounts to M2 macrophages, induced by anti-inflammatory cytokines [11]. The mature adipocytes are responsible for synthesis, storage (in the form of the lipid droplet), and mobilization of triglycerides [12, 13]. Adipocytes are organized into lobules separated and surrounded by loose connective tissue organized in an extracellular matrix composed primarily of collagen [13].
In humans, the major fat depots are intra-abdominal including omental and mesenteric (visceral), lower body including gluteal, intramuscular, subcutaneous lower body, and subcutaneous upper body fat [14] The distribution of WAT within these sites varies significantly between sexes and individuals, with central obesity portending a higher risk of diabetes, dyslipidemia, and several other comorbidities, along with mortality [15]. The importance of this distribution is noteworthy even in normal weight individuals with centrally focused obesity [16]. Significant functional regional differences lie with regards to free fatty acid (FFA) release, hyperplasia and/or hypertrophy, preadipocyte characteristics, and adipocytokine secretion [14, 17–19].
Innervation to WAT is primarily mediated via the sympathetic nervous system (SNS). Youngstrom and Bartness supplied evidence when single neuron tract tracing was used to demonstrate postganglionic sympathetic innervation bidirectionally [20]. Along with insulin, SNS is a primary mediator of lipolysis in WAT [21]. Mansfield first observed this in 1913 after witnessing that patients with hemiplegia and cancer cachexia only mobilized lipid from their neurally intact leg [21, 22]. Further evidence in support of SNS function has been observed in a number of animal models in which surgical denervation of SNS to WAT blocks or attenuates lipolysis with food deprivation [23–26].
2 Brief Overview: Adipocyte Function
As noted above, the lipid droplets composing the adipocytes are specialized in energy storage and release. Glucose transport and lipogenesis are stimulated by insulin. Once activated by insulin, glucose transport activity is redistributed from intracellular to the plasma membrane [27, 28]. The transport is mediated via membrane transporters belonging to the Major Facilitator Superfamily, part of the Glut protein family [29]. Most studied is Glut4, whose role has been highlighted in scenarios in which mice without Glut4 in adipose tissue develop adipocyte and systemic insulin resistance, whereas mice with overexpression are protected [30, 31]. The uptaken glucose then serves as the substrate for pyruvate and glycerol-3-phosphate and then the production of triglycerides. The other manner of increasing lipid storage is via direct uptake, in which insulin remains the main regulator. Fatty acids delivered via diet are esterified and bound to a glycerol backbone, and then stored as triglycerides in the lipid droplet. Triglycerides can then be hydrolyzed back into fatty acids and 2-monoacylglycerol by lipoprotein lipase (LPL). Notably, the LPL gene promoter is activated by the transcription factors sterol regulatory element-binding protein (SREBP) 1 and 2, and peroxisome proliferator-activated receptor γ (PPARγ) [32, 33]. While PPARγ is expressed in many tissues, it is 30–40-fold higher in WAT [34]. Its importance in lipid homeostasis is no more highlighted in serving as the main target for the thiazolidinedione receptor class of insulin-sensitizing drugs, in serving its role in adipogenesis [35–37]. Thus, adipocytes have a crucial role in controlling circulating FFA levels (Fig. 5.1).
More recently, the endocrine role of adipocytes has been gaining attention given its relative complexity and underlying pathologic involvement in a number of disease states. Adipose tissue synthesizes and secretes a number of different proteins with systemic action, termed adipocytokines, or adipokines [38–40]. While more than 100 different adipokines have been identified, proteomic studies have indicated the possibility of several hundreds. Their roles vary, and include controlling appetite, insulin sensitivity, blood pressure, hemostasis, and inflammation [12, 41, 42]. They also affect several organs, including the liver, pancreas, and muscle, along with the central nervous system [43]. The adipocyte’s role in inflammation has been of particular interest given its ability to secrete a variety of the well-known cytokines and chemokines including TNF-α, IL-1β, IL-6, IL-10, and several others [44, 45]. Few others have garnered particular interest as well, notably leptin and adiponectin. Leptin, first identified by Friedman and colleagues in 1994, serves a primarily antidiabetic role modulating food intake and energy expenditure, regulating hepatic lipogenesis, and enhancing muscle fatty acid oxidation [43, 46–48]. It has been shown to protect mice from obesity as well [49]. Thus, leptin concentration increases as the proportion of stored fat increases [50]. Adiponectin has roles in insulin sensitizing, as an anti-inflammatory agent, and is anti-atherogenic in character [51–53].
3 Obesity and Changes to the Adipocyte and WAT
Globally, it has long been observed that the prevalence of obesity has been on the rise. This is not only true in the adult population, but also alarmingly so in the pediatric population, with potentially significant impact on the future of health care [54]. Long-known associated risks of obesity include type 2 diabetes mellitus (T2DM), cardiovascular disease, arthritis, and increased mortality, among others [55–58]. These pathologic outcomes are the product of significant changes resulting primarily from an energy imbalance, and start at the level of cellular mechanisms involving the adipocyte, its relation its neighboring cells, and beyond with its interplay with the body as a whole.
With persistent consumption of calories in excess of expenditure naturally comes the demand for increasing storage capacity. During states of excess, lipogenic enzymes, localized in the cytoplasm and endoplasmic reticulum (ER), synthesize triglyceride, which is then incorporated into the fat droplet. Adipocytes have a significant capacity to synthesize and store triglycerides. Early on, adipocytes compensate for the increase FFA load by increased expression of enzymes associated with triglyceride synthesis [59]. With progression, accommodation occurs via hypertrophy and hyperplasia [60]. Regional tissue variability associated with adipogenesis has been observed. Intraperitoneal (visceral) fat general enlarges via hypertrophy, whereas regions of subcutaneous fat tend to expand via hyperplasia [61]. It has been suggested in animal models that hyperplasia occurs first in increasing the number of preadipocytes, and then proceeding to mature adipocytes [62]. While much remains to be delineated, larger cells release more FFA, which may underlie the significance of fat distribution and elevated free fatty acid levels in obesity. This was portrayed in a mouse model in which overdevelopment of subcutaneous adipose tissue resulted improved glucose and lipid homeostasis [63]. Thus, and not surprisingly, visceral adipose tissue is significantly linked to increased risk of cardiovascular disease and a strong predictor for developing T2DM, and may act as a surrogate marker for ectopic fat distribution, namely the liver and muscle [64, 65]. Another regional difference is the significantly greater FFA release in upper body in addition to the aforementioned visceral fat, when compared to the nonobese or lower body-obese state. Hence, lower body stores, mainly the gluteo-femoral region, may be viewed as a protective metabolic region [66]. Aging and sedentary lifestyles also serve as factors in increasing the ratio of visceral to subcutaneous fat [67].
Histologically, beyond the changes to the adipocytes themselves, macrophage infiltration increases in WAT. Macrophages typically organize in a ring around the adipocyte; such organization is specific to adipose tissue, and more prevalent in visceral WAT than subcutaneous WAT, and intimates their role in the phagocytosis of necrotic adipocytes [68]. In contrast to the relative balance of M1 and M2 macrophages, these macrophages are M1, and thus pro-inflammatory in nature. T-cell infiltration is also present in WAT without an increase in systemic circulation, presumably due to dysfunctional adipokine release, discussed below [69]. Not surprisingly, accompanying the pro-inflammatory state is fibrosis of the extracellular matrix, organized in clusters and fibrotic bundles, and surrounding adipocytes [70]. Interestingly, M2 macrophages expressing higher levels of tumor growth factor β (TGFβ), which stimulates collage VI production, were found in greater number. They also express increased IL-1, suggesting more of a pro-inflammatory role contrasting M2 macrophages in the non-obese state [71]. It has been shown that patients with a higher degree of adipose tissue fibrosis were found to lose less fat mass after gastric bypass, and that fibrosis may serve a protective role in omental WAT in limiting hypertrophy and its associated deleterious effects [70].
4 Excessive FFA, Ectopic Fat Deposition, and Insulin Resistance
Naturally, with progression of obesity comes an increased release of FFAs into the blood stream [72]. Circulating levels of FFAs are a significant mediator connecting obesity with insulin resistance. Elevated levels have been shown to cause insulin resistance in both animals and humans, with an acute decrease in levels resulting in enhanced insulin activity and peripheral glucose uptake [73, 74]. With the accumulation of fatty acids and its metabolites, activation via phosphorylation of serine kinases such as JNK and IKK results in blocking and inactivating insulin receptors. Said mechanism is present in a multitude of cells including adipocytes, myocytes, and hepatocytes [75–77]. Knockout mouse models of JNK and IKK show resistance to the effects of high fat diet on insulin receptor signaling [78, 79]. JNK is required for FFA-mediated macrophage release of inflammatory cytokines such as TNFα, IL-6, and MCP-1 [80]. Additionally, FFAs may induce insulin resistance via their activation of Toll-like receptors (TLR) on adipocytes and macrophages, as mutation of TLR4 prevents obesity and insulin resistance in mice on a high fat diet [60, 81, 82]. Mice with myeloid-specific TLR4 deletion became obese on a high fat diet but were protected from insulin resistance [83]. Cells from TLR4 knock out mice were unresponsive to the inflammatory effects of FFAs [82, 84]. One of the end results is decreased membrane mediated glucose transport via disruption of Glut4. As such, hyperinsulinemia ensues as compensation [84] (Fig. 5.2).
At a cellular level, obesity decreases the rate of lipid turnover, and is related to decreased catecholamine stimulated lipolysis given the sympathetic innervation of WAT [85–87]. The primary mediators of lipolysis are adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL) [88]. HSL is responsible for converting triacylglycerol to diacylglycerol and monoacylglycerol, while ATGL participates in fat mobilization and MGL in the final hydrolysis of the 2-monoacylglycerols produced by HSL [89]. ATGL is important for basal lipolysis, whereas HSL is important during catecholamine-stimulated lipolysis, via the SNS, as previously noted [90]. Obesity results in significantly decreased HSL and ATGL in obese patients. Regionally, ATGL is not significantly different between omental and subcutaneous storage depots, but HSL does differ and is much higher in omental stores correlating with adipocyte size and fasting plasma insulin concentrations [91]. The activity of HSL is further affected by a blunted catecholamine response seen in obesity, correlating with the notion that catecholamines exert their strongest influence over visceral fat [92]. Hypertrophy, observed more so in visceral obesity, correlates with a decrease in lipolytic activity governed by a higher density of α-2 adrenergic receptors, and a lower density of lipolytic β-1/2 adrenergic receptors presumably in an effort to limit contributing to the already elevated circulating FFA levels [92, 93].
Once FFA storage capacity has been met coupled with the decreased lipid mobilization, a spillover effect is observed, at which point organs are exposed to the deleterious effects of unoxidized FFA. Increased hepatic FFA uptake results in hepatic steatosis, then worsening insulin resistance and hyperglycemia in addition to leading to nonalcoholic steatotic hepatitis (NASH) [94]. Evidence suggests that hepatic fat is strongly associated with insulin resistance [95, 96]. As visceral fat increases, so does hepatic delivery via the splanchnic bed, more selectively so than increases in subcutaneous fat do [94]. This in turn stimulates hepatic VLDL-triglyceride production [97]. FFA deposition and intracellular accumulation may also be observed in muscle, pancreatic β-cells, and the heart, which exacerbate insulin resistance perpetuating a vicious cycle [98]. Elevated circulating FFA is also associated with inhibition of carbohydrate oxidation and glycogen synthesis in muscle [99]. The direct lipotoxicity to pancreatic β-cells is significant as it can lead to their dysfunction and apoptosis hindering their capacity to accommodate the metabolic derangement at a time of increased insulin requirements [100, 101]. In rodents, lipid accumulation in cardiac myocytes results in cellular damage and ventricular dysfunction [98]. The effects of ectopic distribution of adipose tissue are observed as well in lipodystrophic patients with defects in triglyceride storage in adipose tissue, and in mice without WAT, as both populations exhibit severe insulin resistance. Upon surgical transplantation of functional adipose tissue in mice, there is a dramatic reversal of hyperglycemia, hyperinsulinemia, and insulin resistance [102, 103].
As noted earlier, the effective nature of thiazolidinediones is due to their action on PPARγ receptors which stimulate FFA uptake by subcutaneous adipocytes resulting in decreased ectopic fat distribution and the increased insulin sensitivity [104]. PPARγ is also present in macrophages where they negatively regulate a multitude of inflammatory genes [105]. In PPARγ knockout mice, insulin resistance is impaired, and worsens following high-fat feeding [106, 107]. An important aspect of adipocyte dysfunction arises from downregulation of PPARγ by inflammatory cytokines, and in particular TNFα, both from macrophages and adipocytes. TNFα has been shown to negatively impact PPARγ in many ways, including transcription, posttranscription, and translation [108]. When treated with TNFα, PPARγ mRNA is more rapidly turned over in adipocytes [109]. Another factor negatively affecting PPARγ expression in preadipocytes and adipocytes is hypoxia. This may also be the underlying reason for the inhibited adipocyte differentiation in a hypoxic state [110].
5 Hypoxia and Inflammation
As indicated by the histologic changes accompanying obesity, inflammatory changes are a significant driver of pathogenicity as well. With the advent of hyperplasia and more so hypertrophy comes macrophage infiltration and aggregation around necrotic adipocytes. Adipocytes enlarge to accommodate for the increased FFA load. However, their growth will then reach a limit given restraints from oxygen tension, which could explain the ensuing cell death and initiation of macrophage infiltration [68, 111]. The degree of infiltration correlates with obesity and insulin resistance regardless of BMI. Thus, of two similarly obese patients, the patient with increased macrophage infiltration will exhibit worse insulin resistance [112]. The concept of hypoxia-induced inflammation is supported given that adipocytes can increase in size to up to 200 μM in the obese state which is similar to or greater than that of normal oxygen diffusion distance, and although lean patients have the ability to increase postprandial blood flow to WAT, no such increase in blood flow is observed in obese patients [113, 114]. Both qualitative and quantitative studies via the hypoxyprobe system and needle-type fiber-optic O2 sensor, respectively, have also demonstrated hypoxia present in adipose tissue in the obese mouse model [8, 115, 116]. Macrophage tissue infiltration is evident in hypoxic tissue areas as well, thus providing a link between hypoxia, adipocyte stress and apoptosis, and inflammation [114]. In humans, the PO2 of oxygen has been observed to be decreased in the adipose tissue of obese patients, when compared to lean counterparts, with PO2 levels inversely correlating with percent body fat [117].
One of the main aspects lending support to hypoxia as a factor in inflammation is the up-regulation of hypoxic induced factors, mainly hypoxia-inducible factor 1α (HIF-1α) , a key regulator of oxygen homeostasis [118]. Using a transgenic mouse model of HIF-1α overexpression, adipose tissue fibrosis and increased local inflammation are observed [119]. With selective pharmacologic and genetic inhibition of HIF-1α activity, high-fat diet-fed obese mice demonstrated significant metabolic improvements and reduced inflammation in WAT [120]. A key role in the increased inflammation may be the role HIF-1α has in downregulating the expression of PPARγ [110].
6 Inflammation, Endoplasmic Reticulum, and Mitochondria
As the demand for increased lipid storage expands, so does the capacity and activity of the adipocyte endoplasmic reticulum, which is responsible for synthesizing proteins, forming lipid droplets, and regulating cholesterol [101]. Thus, with obesity and increasing FFA load, ER “stress” develops. This state is characterized by its functional disturbance in which case proper folding and modification of proteins and lipid droplet creation are disturbed [101]. The ER is able to identify the imbalance in supply and production via the Unfolded Protein Response (UPR), which is subsequently activated through its three arms: PKR-like eukaryotic initiation factor 2α kinase (PERK), inositol-requiring enzyme-1 (IRE-1), and activating transcription factor-6 (ATF-6) [121, 122]. PERK activation leads to decreased protein translation and increased expression of a multitude of genes, including those related to apoptosis [123]. Another UPR response is to induce transcription of chaperones to assist with the increasing volume of unfolded proteins. IRE-1 contributes to the increase in chaperone proteins produced to assist with the unfolded protein load, while ATF-6 is responsible for increasing the expression of ER degradation-enhancing α-mannosidase like protein (EDEM) facilitating the clearance of chaperone proteins [124, 125]. The increased chaperone load is likely responsible for the increased oxidative stress via increased reactive oxidative species (ROS) from mediating oxidation-reduction reactions [121, 126]. IRE-1 also upregulates JNK and IKK resulting in increased expression of inflammatory genes responsible for increased cytokine production [127, 128]. While the goal of such changes brought about by UPR are for preserving cell function and stressor accommodation, the end result of inadequate adaptation may yet be apoptosis [121].
Mitochondria also exhibit signs of distress, not only in adipocytes, but in multiple organs as well. Increases in FFA causes increased release of ROS in obese patients [129]. Lipid infusion in lean human subjects results in decreased mRNAs for many mitochondrial genes [130]. Mitochondrial dysfunction is evident in the pancreas, liver, and muscle as well [125, 131, 132]. In the pancreas, insulin production is negatively affected by ROS. In muscle, there is decreased fat oxidation and ectopic fat accumulation contributing to insulin resistance [133]. Increased intramyocellular lipid content has been observed with down-regulation of genes encoding mitochondrial respiratory complexes I–IV, and genes responsible for cytochrome c oxidase complexes I and III which are subunits of the electron transport chain [134, 135]. PPARγ is responsible for controlling mitochondrial gene subsets, and with its reduced activity may contribute to the decreased mitochondrial function [136]. Also contributing to the decreased mitochondrial function is the increased amount of inflammatory cytokines [137]. Notably, with the mitochondrial dysfunction comes decreased fatty acid oxidation and metabolites that inhibit glucose transport [138].
The presence of ROS associated with obesity is thought to play a central role in the decreased mitochondrial activity [139]. Once again, with the elevated FFA levels in obesity comes increased ROS [140]. In diabetic patients, endothelial cells portray elevated ROS via NADPH oxidase activation [141]. Mice overexpressing superoxide dismutase 2 have decreased levels of ROS, improved hepatic insulin sensitivity, and normalization of glucose and insulin levels [142]. In rats, soleus muscle exposure to nitric oxide donors caused decreased insulin sensitivity, and were associated with decreased insulin-stimulated phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), critical in the insulin intracellular signaling pathway [143]. Other kinases are also activated, including JNK and NFκB, further inhibiting IRS-1 progressing insulin resistance [144–146].
Uncoupling proteins (UCP) are mitochondrial inner membrane proteins that mediate the coupling of electrons through the electron transport chain, primarily allowing for a proton leak through the inner membrane [147]. UCP2 is expressed in several tissues, and because of its distribution in multiple tissues, it has been hypothesized to have a significant role in decreasing ROS, thus protecting against oxidative stress [148, 149]. At the same time, several studies have shown that increased UCP2 production leads to decreased insulin secretion from pancreatic β cells, predisposing to diabetes mellitus [150–152]. In UCP2 knockout mice, pancreatic islets have increased insulin secretion in response to glucose when compared to wild-type mice [153]. Furthermore, double-mutant leptin/UCP2 knockouts also have improved beta cell function independent of obesity [153]. FFAs seem to be a key mediator of UCP2 as in preadipocytes, UCP2 mRNA expression increases significantly when exposed to FFAs [154].
7 Inflammation and Adipocytokines
The complex role of the adipocyte as an endocrine organ has gained significant attention given its ability to secrete several different types of factors. With the infiltration of macrophages into adipose tissue, cytokine secretion accompanies and influences the adipose tissue environment. FFAs have been shown to strongly stimulate TNF-α production in macrophages via TLR4 receptor activating NFκB [155]. Further activation from ER stress and UPR along with secretion from adipocytes also increases local TNF-α concentration [121]. Conversely, TNF-α secretion inhibits lipoprotein lipase activity, thus increasing FFA release from adipocytes [156]. Thus, a vicious paracrine loop develops that perpetuates the macrophage-adipocyte inflammatory state [157]. TNF-α leads to activation of JNK1 via phosphorylation of IRS-1 and its inhibition, as mentioned above, linking TNF-α with insulin resistance [158]. The cycle is worsened as adipocyte hypertrophy develops given their capacity for increased FFA release [63]. TNF-α also decreases adiponectin secretion, whose actions result in increased insulin sensitivity by decreasing hepatic glucose production and increasing fatty acid oxidation in both liver and muscle [159]. Multiple studies have implicated low adiponectin levels as a strong indicator for the development of insulin resistance and T2DM [160, 161]. Adiponectin-deficient mice develop insulin resistance in the setting of elevated TNF-α and reduced responsiveness to PPARγ [161]. Adiponectin acts via its two receptors, AdipoR1 and AdipoR2. AdipoR1 is universally expressed whereas AdipoR2 is primarily localized to the liver. Mouse knockouts of these two receptors have increased lipid accumulation, and inflammation, and exhibit increased insulin resistance [43, 160, 162].
Whereas adiponectin production is decreased in hypertrophic and inflamed tissue, leptin production is significantly increased [50]. In leptin-deficient mice models and humans, leptin administration leads to decreased hyperphagia and reduced body mass [163]. However, it has also been seen to increase IL-6 and TNF-α production by macrophages [164]. Leptin acts via a number of different pathways including the JAK-STAT pathway which regulates the expression of anorexic neuropeptides, and the phosphatylinositol-3-kinase pathway which stimulates insulin sensitivity in peripheral tissues [43, 165]. The interesting concept of leptin resistance, similar to insulin resistance, has also been proposed, and been shown in states of inflammation whereby subsequent metabolic stress negatively regulates leptin signaling [166]. Similar resistance has been proposed to be evident in the hypothalamus as well [167]. Overall, energy expenditure and appetite remains poorly controlled even as leptin levels increase in obese patients [43, 163].
Other chemokines play important roles in attracting macrophages and perpetuating the inflammatory response, including IL-6 and monocyte chemotactic protein I (MCP-I). Other factors are also released from adipocytes, which increase macrophage diapedesis, including PECAM-I and ICAM-I [168–170].
8 Conclusion
The complexity that characterizes insulin resistance is underscored by the remarkable evolution of our understanding of the adipocyte and its role in metabolic homeostasis. The mechanisms underlying the progression from an insulin sensitive state to that of adipocyte dysfunction, inflammation, and local and systemic insulin resistance are complex, and include a series of vicious cycles that perpetuate the inflammatory state. As we continue to delineate the mechanisms that accompany the changes in the adipocyte correlating with obesity, potential therapeutic targets will continue to emerge. For now, surgery will continue to serve as one of the mainstays in the treatment of obesity, and will remain a source for potential answers in reversing some of the deleterious effects of obesity and insulin resistance.
References
Cannon B, Hedin A, Nedergaard J. Exclusive occurrence of thermogenin antigen in brown adipose tissue. FEBS Lett. 1982;150:129–32.
Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277–359.
Cinti S, Zancanaro C, Sbarbati A, Cicolini M, Vogel P, Ricquier D, Fakan S. Immunoelectron microscopical identification of the uncoupling protein in brown adipose tissue mitochondria. Biol Cell. 1989;67:359–62.
Frontini A, Rousset S, Cassard-Doulcier AM, Zingaretti C, Ricquier D, Cinti S. Thymus uncoupling protein 1 is exclusive to typical brown adipocytes and is not found in thymocytes. J Histochem Cytochem. 2007;55:183–9.
Cinti S. The adipose organ: morphological perspectives of adipose tissues. Proc Nutr Soc. 2001;60:319–28.
Cinti S. Transdifferentiation properties of adipocytes in the adipose organ. Am J Physiol Endocrinol Metab. 2009;297(5):E977–86. doi:10.1152/ajpendo.00183.2009.
Hausman GJ. Anatomical and enzyme histochemical differentiation of adipose tissue. Int J Obes. 1985;9 Suppl 1:1–6.
Trayhurn P. Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity. Annu Rev Nutr. 2014;34:207–36. doi:10.1146/annurev-nutr-071812-161156.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821–30.
Aron-Wisnewsky J, Tordjman J, Poitou C, Darakhshan F, Hugol D, Basdevant A, Aissat A, Guerre-Millo M, Clément K. Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. J Clin Endocrinol Metab. 2009;94(11):4619–23. doi:10.1210/jc.2009-0925.
Trayhurn P. Hypoxia and adipose tissue dysfunction in obesity. Physiol Rev. 2013;93(1):1–21. doi:10.1152/physrev.00017.2012.
Bastard J, Feve B. Physiology and physiopathology of adipose tissue. Paris: Springer; 2013.
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):644–56. doi:10.1016/j.cmet.2013.03.008.
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. doi:10.1259/bjr/38447238.
Kahn SE, Prigeon RL, Schwartz RS, Fujimoto WY, Knopp RH, Brunzell JD, Porte Jr D. Obesity, body fat distribution, insulin sensitivity and Islet beta-cell function as explanations for metabolic diversity. J Nutr. 2001;131(2):354S–60.
Peinado JR, Jimenez-Gomez Y, Pulido MR, Ortega-Bellido M, Diaz-Lopez C, Padillo FJ, Lopez-Miranda J, Vazquez-Martínez R, Malagón MM. Cellular and molecular basis of functional differences among fat depots. Proteomics. 2010;10(18):3356–66. doi:10.1002/pmic.201000350.
Tchoukalova YD, Votruba SB, Tchkonia T, Giorgadze N, Kirkland JL, Jensen MD. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc Natl Acad Sci U S A. 2010;107(42):18226–31. doi:10.1073/pnas.1005259107.
Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL. Fat tissue, aging, and cellular senescence. Aging Cell. 2010;9(5):667–84. doi:10.1111/j.1474-9726.2010.00608.x.
Youngstrom TG, Bartness TJ. Catecholaminergic innervation of white adipose tissue in the Siberian hamster. Am J Physiol. 1995;268(3 Pt 2):R744–51.
Bartness TJ, Liu Y, Shrestha YB, Ryu V. Neural innervation of white adipose tissue and the control of lipolysis. Front Neuroendocrinol. 2014;35:473. doi:10.1016/j.yfrne.2014.04.001. pii: S0091-3022(14)00043-0.
Mansfeld G, Muller F. Der Einfluss der Nervensystem auf die Mobilisierung von Fett. Arch Physiol. 1913;152:61–7.
Hales CN, Luzio JP, Siddle K. Hormonal control of adipose tissue lipolysis. Biochem Soc Symp. 1978;43:97–135.
Bray GA, Nishizawa Y. Ventromedial hypothalamus modulates fat mobilisation during fasting. Nature. 1978;274(5674):900–2.
Bamshad M, Aoki VT, Adkison MG, Warren WS, Bartness TJ. Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue. Am J Physiol. 1998;275(1 Pt 2):R291–9.
Bartness TJ, Shrestha YB, Vaughan CH, Schwartz GJ, Song CK. Sensory and sympathetic nervous system control of white adipose tissue lipolysis. Mol Cell Endocrinol. 2010;318(1-2):34–43. doi:10.1016/j.mce.2009.08.031.
Suzuki K, Kono T. Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. Proc Natl Acad Sci U S A. 1980;77(5):2542–5.
Cushman SW, Wardzala LJ. Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane. J Biol Chem. 1980;255(10):4758–62.
Thorens B, Mueckler M. Glucose transporters in the 21st century. Am J Physiol Endocrinol Metab. 2010;298(2):E141–5. doi:10.1152/ajpendo.00712.2009.
Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, Minnemann T, Shulman GI, Kahn BB. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature. 2001;409(6821):729–33.
Carvalho E, Kotani K, Peroni OD, Kahn BB. Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle. Am J Physiol Endocrinol Metab. 2005;289(4):E551–61.
Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, Heyman RA, Briggs M, Deeb S, Staels B, Auwerx J. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 1996;15(19):5336–48.
Schoonjans K, Gelman L, Haby C, Briggs M, Auwerx J. Induction of LPL gene expression by sterols is mediated by a sterol regulatory element and is independent of the presence of multiple E boxes. J Mol Biol. 2000;304(3):323–34.
Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994;8:1224–34. doi:10.1101/gad.8.10.1224.
Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxi-some proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270:12953–6. doi:10.1074/jbc.270.22.12953.
Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47:507–14. doi:10.2337/diabetes.47.4.507.
Tang QQ, Lane MD. Adipogenesis: from stem cell to adipocyte. Annu Rev Biochem. 2012;81:715–36. doi:10.1146/annurev-biochem-052110-115718.
Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B. Recent advances in the relationship between obesity, inflammation and insulin resistance. Eur Cytokine Netw. 2006;17(1):4–12.
Antuna-Puente B, Fève B, Fellahi S, Bastard JP. Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab. 2008;34(1):2–11.
Frühbeck G, Gómez-Ambrosi J, Muruzabal FJ, Burrell MA. The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab. 2001;280(6):E827–47.
Dahlman I, Elsen M, Tennagels N, Korn M, Brockmann B, Sell H, Eckel J, Arner P. Functional annotation of the human fat cell secretome. Arch Physiol Biochem. 2012;118(3):84–91. doi:10.3109/13813455.2012.685745.
Rajala MW, Scherer PE. The adipocyte: at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology. 2003;144(9):3765–73.
Cao H. Adipocytokines in obesity and metabolic disease. J Endocrinol. 2014;220(2):T47–59. doi:10.1530/JOE-13-0339.
Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc. 2001;60(3):349–56.
Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006;444:847–53.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–32.
Cohen P, Miyazaki M, Socci ND, Hagge-Greenberg A, Liedtke W, Soukas AA, Sharma R, Hudgins LC, Ntambi JM, Friedman JM. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science. 2002;297:240–3.
Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature. 1997;389:374–7.
Wang MY, Orci L, Ravazzola M, Unger RH. Fat storage in adipocytes requires inactivation of leptin’s paracrine activity: implications for treatment of human obesity. Proc Natl Acad Sci U S A. 2005;102(50):18011–6.
Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, et al. Serum immunoreactive-leptin concentrations in normal- weight and obese humans. N Engl J Med. 1996;334(5):292–5.
Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, Funahashi T, Cao Y. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A. 2004;101(8):2476–81.
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941–6.
Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood. 2000;96(5):1723–32.
World Health Organization. World health statistics. Geneva: World Health Organization; 2014.
Picot J, Jones J, Colquitt JL, Gospodarevskaya E, Loveman E, Baxter L, Clegg AJ. The clinical-effectiveness and cost- effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation. Health Technol Assess. 2009;13(41):1–190. doi:10.3310/hta13410. 215-357, iii-iv.
Colquitt JL, Picot J, Loveman E, Clegg AJ. Cochrane Database Syst Rev. 2009;(2):CD003641. doi: 10.1002/14651858.CD003641.pub3.
Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. JAMA. 1999;282(16):1523–9.
Adams KF, Schatzkin A, Harris TB, Kipnis V, Mouw T, Ballard-Barbash R, Hollenbeck A, Leitzmann MF. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med. 2006;355(8):763–78.
Frayn KN, Shadid S, Hamlani R, Humphreys SM, Clark ML, Fielding BA, Boland O, Coppack SW. Regulation of fatty acid movement in human adipose tissue in the postabsorptive- to-postprandial transition. Am J Physiol. 1994;266:E308–17.
Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9(5):367–77. doi:10.1038/nrm2391.
Tchkonia T, Giorgadze N, Pirtskhalava T, Tchoukalova Y, Karagiannides I, Forse RA, DePonte M, Stevenson M, Guo W, Han J, Waloga G, Lash TL, Jensen MD, Kirkland JL. Fat depot origin affects adipogenesis in primary cultured and cloned human pre- adipocytes. Am J Physiol Regul Integr Comp Physiol. 2002;282(5):R1286–96.
Avram MM, Avram AS, James WD. Subcutaneous fat in normal and diseased states 3. Adipogenesis: from stem cell to fat cell. J Am Acad Dermatol. 2007;56:472–92.
Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, Schraw T, Durand JL, Li H, Li G, Jelicks LA, Mehler MF, Hui DY, Deshaies Y, Shulman GI, Schwartz GJ, Scherer PE. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007;117(9):2621–37.
Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444(7121):881–7. Review.
Thomas EL, Parkinson JR, Frost GS, Goldstone AP, Doré CJ, McCarthy JP, Collins AL, Fitzpatrick JA, Durighel G, Taylor-Robinson SD, Bell JD. The missing risk: MRI and MRS phenotyping of abdominal adiposity and ectopic fat. Obesity (Silver Spring). 2012;20(1):76–87. doi:10.1038/oby.2011.142.
Guo Z, Hensrud DD, Johnson CM, Jensen MD. Regional postprandial fatty acid metabolism in different obesity phenotypes. Diabetes. 1999;48(8):1586–92.
Gavi S, Feiner JJ, Melendez MM, Mynarcik DC, Gelato MC, McNurlan MA. Limb fat to trunk fat ratio in elderly persons is a strong determinant of insulin resistance and adiponectin levels. J Gerontol A Biol Sci Med Sci. 2007;62(9):997–1001.
Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005;46(11):2347–55.
Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15(8):914–20. doi:10.1038/nm.1964.
Divoux A, Tordjman J, Lacasa D, Veyrie N, Hugol D, Aissat A, Basdevant A, Guerre-Millo M, Poitou C, Zucker JD, Bedossa P, Clément K. Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes. 2010;59(11):2817–25. doi:10.2337/db10-0585.
Henegar C, Tordjman J, Achard V, Lacasa D, Cremer I, Guerre-Millo M, Poitou C, Basdevant A, Stich V, Viguerie N, Langin D, Bedossa P, Zucker JD, Clement K. Adipose tissue transcriptomic signature high- lights the pathological relevance of extracellular matrix in human obesity. Genome Biol. 2008;9:R14.
Campbell PJ, Carlson MG, Nurjhan N. Fat metabolism in human obesity. Am J Physiol. 1994;266:E600–5.
Kelley DE, Mokan M, Simoneau JA, Mandarino LJ. Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest. 1993;92:91–8.
Santomauro AT, Boden G, Silva ME, Rocha DM, Santos RF, Ursich MJ, Strassmann PG, Wajchenberg BL. Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes. 1999;48:1836–41.
Capurso C, Capurso A. From excess adiposity to insulin resistance: the role of free fatty acids. Vascul Pharmacol. 2012;57(2-4):91–7. doi:10.1016/j.vph.2012.05.003.
Greene MW, Sakaue H, Wang L, Alessi DR, Roth RA. Modulation of insulin- stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. J Biol Chem. 2003;278(10):8199–211.
Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3–L1 adipocytes. Mol Endocrinol. 2004;18(8):2024–34.
Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature. 2002;420(6913):333–6.
Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science. 2001;293:1673–7.
Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, Grivennikov S, Wynshaw-Boris A, Scadeng M, Olefsky JM, Karin M. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab. 2007;6:386–97.
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116:3015–25.
Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, Araújo EP, Vassallo J, Curi R, Velloso LA, Saad MJ. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes. 2007;56:1986–98.
Saberi M, Woods NB, de Luca C, Schenk S, Lu JC, Bandyopadhyay G, Verma IM, Olefsky JM. Hematopoeitic cell specific deletion of Toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high fat-fed mice. Cell Metab. 2009;10(5):419–29. doi:10.1016/j.cmet.2009.09.006.
Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46. doi:10.1146/annurev-physiol-021909-135846.
Arner P, Bernard S, Salehpour M, Possnert G, Liebl J, Steier P, Buchholz BA, Eriksson M, Arner E, Hauner H, Skurk T, Rydén M, Frayn KN, Spalding KL. Dynamics of human adipose lipid turnover in health and metabolic disease. Nature. 2011;478(7367):110–3. doi:10.1038/nature10426.
Arner P, Andersson DP, Thörne A, Wirén M, Hoffstedt J, Näslund E, Thorell A, Rydén M. Variations in the size of the major omentum are primarily determined by fat cell number. J Clin Endocrinol Metab. 2013;98:E897–901.
Sam S, Mazzone T. Adipose tissue changes in obesity and the impact on metabolic function. Transl Res. 2014;164:284. doi:10.1016/j.trsl.2014.05.008. pii: S1931-5244(14)00176-5.
Fredrikson G, Tornqvist H, Belfrage P. Hormone-sensitive lipase and monoacylglycerol lipase are both required for complete degradation of adipocyte triacylglycerol. Biochim Biophys Acta. 1986;876:288–93.
Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004;306:1383–6.
Rydén M, Jocken J, van Harmelen V, Dicker A, Hoffstedt J, Wirén M, Blomqvist L, Mairal A, Langin D, Blaak E, Arner P. Comparative studies of the role of hormone-sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis. Am J Physiol Endocrinol Metab. 2007;292:E1847–55.
Berndt J, Kralisch S, Klöting N, Ruschke K, Kern M, Fasshauer M, Schön MR, Stumvoll M, Blüher M. Adipose triglyceride lipase gene expression in human visceral obesity. Exp Clin Endocrinol Diabetes. 2008;116:203–10.
Lafontan M, Langin D. Lipolysis and lipid mobilization in human adipose tissue. Prog Lipid Res. 2009;48(5):275–97. doi:10.1016/j.plipres.2009.05.001.
Lafontan M, Berlan M. Fat cell alpha 2-adrenoceptors: the regulation of fat cell function and lipolysis. Endocr Rev. 1995;16:716–38.
Lewis GF, Carpentier A, Adeli K, Giacca A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev. 2002;23(2):201–29.
Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A. 2009;106(36):15430–5. doi:10.1073/pnas.0904944106.
Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest. 1995;96:1261–8.
Kissebah AH, Adams PW, Wynn V. Plasma free fatty acid and triglyceride transport kinetics in man. Clin Sci Mol Med. 1974;47:259–78.
Schaffer JE. Lipotoxicity: when tissues overeat. Curr Opin Lipidol. 2003;14:281–7.
Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996;97:2859–65.
Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, et al. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes. 2002;51:1437–42.
de Ferranti S, Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem. 2008;54(6):945–55. doi:10.1373/clinchem. 2007.100156.
Gavrilova O, Marcus-Samuels B, Graham D, Kim JK, Shulman GI, Castle AL, Vinson C, Eckhaus M, Reitman ML. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest. 2000;105(3):271–8.
Langin D. In and out: adipose tissue lipid turnover in obesity and dyslipidemia. Cell Metab. 2011;14:569–70.
Wang YX. PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell Res. 2010;20:124–37.
Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature. 1998;391(6662):79–82.
Hevener AL, Olefsky JM, Reichart D, Nguyen MT, Bandyopadyhay G, Leung HY, Watt MJ, Benner C, Febbraio MA, Nguyen AK, Folian B, Subramaniam S, Gonzalez FJ, Glass CK, Ricote M. Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest. 2007;117(6):1658–69.
Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature. 2007;447(7148):1116–20.
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;10:1457–66.
Christianson JL, Nicoloro S, Straubhaar J, Czech MP. Stearoyl CoA desaturase 2 is required for PPARγ expression and adipogenesis in cultured 3T3-L1 cells. J Biol Chem. 2007;283:2906–16.
Yun Z, Maecker HL, Johnson RS, Giaccia AJ. Inhibition of PPARγ2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell. 2002;2(3):331–41.
Trayhurn P, Wang B, Wood IS. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr. 2008;100(2):227–35. doi:10.1017/S0007114508971282.
Strissel KJ, Stancheva Z, Miyoshi H, Perfield 2nd JW, DeFuria J, Jick Z, Greenberg AS, Obin MS. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes. 2007;56:2910–8.
Goossens GH, Bizzarri A, Venteclef N, Essers Y, Cleutjens JP, Konings E, Jocken JW, Cajlakovic M, Ribitsch V, Clément K, Blaak EE. Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. Circulation. 2011;124(1):67–76. doi:10.1161/CIRCULATIONAHA.111.027813.
Karpe F, Fielding BA, Ilic V, Macdonald IA, Summers LK, Frayn KN. Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity. Diabetes. 2002;51(8):2467–73.
Rausch ME, Weisberg SP, Vardhana P, Tortoriello DV. Obesity in C57BL/6J mice is characterised by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond). 2008;32(3):451–63.
Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007;293(4):E1118–28.
Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, Rood JC, Burk DH, Smith SR. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes. 2009;58(3):718–25. doi:10.2337/db08-1098.
Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumié A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clément K. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes. 2005;54(8):2277–86.
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 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009;29(16):4467–83. doi:10.1128/MCB.00192-09.
Sun K, Halberg N, Khan M, Magalang UJ, Scherer PE. Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue dysfunction. Mol Cell Biol. 2013;33(5):904–17. doi:10.1128/MCB.00951-12.
Gregor MF, Hotamisligil GS. Thematic review series: adipocyte biology. adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res. 2007;48(9):1905–14.
Mori K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell. 2000;101(5):451–4.
Su Q, Wang S, Gao HQ, Kazemi S, Harding HP, Ron D, Koromilas AE. Modulation of the eukaryotic initiation factor 2 alpha-subunit kinase PERK by tyrosine phosphorylation. J Biol Chem. 2008;283:469–75.
Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313(5790):1137–40.
Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2008;29(1):42–61.
Haynes CM, Titus EA, Cooper AA. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell. 2004;15(5):767–76.
Wu J, Kaufman RJ. From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ. 2006;13:374–84.
Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Harding HP, Ron D. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol. 2004;24(23):10161–8.
Wojtczak L, Schonfeld P. Effect of fatty acids on energy coupling processes in mitochondria. Biochim Biophys Acta. 1993;1183:41–57.
Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, DeFronzo RA, Jenkinson CP, Mandarino LJ. Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. J Biol Chem. 2005;280(11):10290–7.
Qatanani M, Lazar MA. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev. 2007;21:1443–55.
Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003;300(5622):1140–2.
Coletta DK, Mandarino LJ. Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria. Am J Physiol Endocrinol Metab. 2011;301:749–55.
Chanseaume E, Malpuech-Brugère C, Patrac V, Bielicki G, Rousset P, Couturier K, Salles J, Renou JP, Boirie Y, Morio B. Diets high in sugar, fat, and energy induce muscle type specific adaptations in mitochondrial functions in rats. J Nutr. 2006;136(8):2194–200.
Heilbronn LK, Gan SK, Turner N, Campbell LV, Chisholm DJ. Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects. J Clin Endocrinol Metab. 2007;92:1467–73.
Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med. 2004;10:355–61.
Yasuhara R, Miyamoto Y, Akaike T, Akuta T, Nakamura M, Takami M, Morimura N, Yasu K, Kamijo R. Interleukin-1beta induces death in chondrocyte-like ATDC5 cells through mitochondrial dysfunction and energy depletion in a reactive nitrogen and oxygen species-dependent manner. Biochem J. 2005;389:315–23.
Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384–7.
Bloch-Damti A, Bashan N. Proposed mechanisms for the induction of insulin resistance by oxidative stress. Antioxid Redox Signal. 2005;7:1553–67.
Lambertucci RH, Hirabara SM, Silveira Ldos R, Levada-Pires AC, Curi R, Pithon-Curi TC. Palmitate increases superoxide production through mitochondrial electron transport chain and NADPH oxidase activity in skeletal muscle cells. J Cell Physiol. 2008;216:796–804.
Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NADPH oxidase in cultured vascular cells. Diabetes. 2000;49:1939–45.
Zhai L, Ballinger SW, Messina JL. Role of reactive oxygen species in injury-induced insulin resistance. Mol Endocrinol. 2011;25:492–502.
Carvalho-Filho MA, Ueno M, Hirabara SM, Seabra AB, Carvalheira JB, de Oliveira MG, Velloso LA, Curi R, Saad MJ. S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance. Diabetes. 2005;54:959–67.
Krebs M, Roden M. Molecular mechanisms of lipid-induced insulin resistance in muscle, liver and vasculature. Diabetes Obes Metab. 2005;7:621–32.
Talukdar I, Szeszel-Fedorowicz W, Salati LM. Arachidonic acid inhibits the insulin induction of glucose-6-phosphate dehydrogenase via p38 MAP kinase. J Biol Chem. 2005;280:40660–7.
Martins AR, Nachbar RT, Gorjao R, Vinolo MA, Festuccia WT, Lambertucci RH, Cury-Boaventura MF, Silveira LR, Curi R, Hirabara SM. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function. Lipids Health Dis. 2012;11:30.
Diano S, Horvath TL. Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends Mol Med. 2012;18(1):52–8. doi:10.1016/j.molmed.2011.08.003.
Diao J, Allister EM, Koshkin V, Lee SC, Bhattacharjee A, Tang C, Giacca A, Chan CB, Wheeler MB. UCP2 is highly expressed in pancreatic alpha-cells and influences secretion and survival. Proc Natl Acad Sci U S A. 2008;105(33):12057–62. doi:10.1073/pnas.0710434105.
Emre Y, Hurtaud C, Karaca M, Nubel T, Zavala F, Ricquier D. Role of uncoupling protein UCP2 in cell-mediated immunity: how macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes. Proc Natl Acad Sci U S A. 2007;104(48):19085–90.
Souza BM, Assmann TS, Kliemann LM, Gross JL, Canani LH, Crispim D. The role of uncoupling protein 2 (UCP2) on the development of type 2 diabetes mellitus and its chronic complications. Arq Bras Endocrinol Metabol. 2011;55(4):239–48.
Affourtit C, Brand M. On the role of uncoupling protein 2 in pancreatic beta cells. Biochim Biophys Acta. 2008;1777(7-8):973–9.
Brand M, Affourtit C, Esteves T, Green K, Lambert A, Miwa S, et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med. 2004;37(6):755–67.
Zhang C, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell. 2001;105(6):745–55.
Thompson M, Kim D. Links between fatty acids and expression of UCP2 and UCP3 mRNAs. FEBS Lett. 2004;568(1-3):4–9.
Nguyen MT, Satoh H, Favelyukis S, Babendure JL, Imamura T, Sbodio JI, Zalevsky J, Dahiyat BI, Chi NW, Olefsky JM. JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem. 2005;280:35361–71.
Wang S, Soni KG, Semache M, Casavant S, Fortier M, Pan L, Mitchell GA. Lipolysis and the integrated physiology of lipid energy metabolism. Mol Genet Metab. 2008;95:117–26.
Hajer GR, van Haeften TW, Visseren FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J. 2008;29(24):2959–71. doi:10.1093/eurheartj/ehn387.
Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem. 2000;275:9047–54.
Goldstein BJ, Scalia R. Adiponectin. A novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab. 2004;89:2563–8.
Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, Okada-Iwabu M, Kawamoto S, Kubota N, Kubota T, Ito Y, Kamon J, Tsuchida A, Kumagai K, Kozono H, Hada Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Awazawa M, Takamoto I, Froguel P, Hara K, Tobe K, Nagai R, Ueki K, Kadowaki T. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13:332–9.
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;8:731–7.
Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003;423:762–9.
Munzberg H, Myers Jr MG. Molecular and anatomical determinants of central leptin resistance. Nat Neurosci. 2005;8:566–70.
Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006;6:772–83.
St-Pierre J, Tremblay ML. Modulation of leptin resistance by protein tyrosine phosphatases. Cell Metab. 2012;15:292–7.
Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008;135:61–73.
Baskin DG, Figlewicz LD, Seeley RJ, Woods SC, Porte Jr D, Schwartz MW. Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight. Brain Res. 1999;848:114–23.
Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116(6):1494–505.
Nomiyama T, Perez-Tilve D, Ogawa D, Gizard F, Zhao Y, Heywood EB, Jones KL, Kawamori R, Cassis LA, Tschöp MH, Bruemmer D. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J Clin Invest. 2007;117(10):2877–88.
Curat CA, Miranville A, Sengenès C, Diehl M, Tonus C, Busse R, Bouloumié A. From blood monocytes to adipose tissue resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes. 2004;53(5):1285–92.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Science+Business Media New York
About this chapter
Cite this chapter
Jahansouz, C. (2016). Adipocyte Dysfunction, Inflammation, and Insulin Resistance in Obesity. In: Kurian, M., Wolfe, B., Ikramuddin, S. (eds) Metabolic Syndrome and Diabetes. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3220-7_5
Download citation
DOI: https://doi.org/10.1007/978-1-4939-3220-7_5
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4939-3219-1
Online ISBN: 978-1-4939-3220-7
eBook Packages: MedicineMedicine (R0)