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TRIENNIAL GROWTH SYMPOSIUM |
Departments of Food Science & Human Nutrition and Animal Science, Iowa State University, Ames 50011
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Abstract |
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, and creates a local environment by which these cytokines regulate both metabolic and immunological pathways. However, adipocytes are also the predominant source of the antiinflammatory hormone, adiponectin, which suppresses the activation of nuclear factor kappa B and the production of proinflammatory cytokines. The molecular ability to recognize antigens and produce regulatory molecules strategically positions adipocytes and myofibers to regulate growth locally and to reciprocally regulate metabolism in peripheral tissues.
Key Words: adipocyte • cytokine • growth • inflammation • myofiber
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INTRODUCTION |
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). This performance deficit poses an enormous economic opportunity for pork producers, and a similar scenario undoubtedly encompasses other production animal species. Perpetual immune stimulation in the rearing environment results in the production of potent proinflammatory cytokines, which antagonize anabolic growth factors and thus suppress growth (Johnson, 1997; Spurlock, 1997; Broussard et al., 2003) to insure adequate energy and nutrients are available for high priority immunological and homeostatic pathways. Consequently, there is considerable incentive to understand the regulation of proinflammatory cytokine production and, equally as important, that of the antiinflammatory factors which counter them. It is exciting that the adipocyte and myofiber are emerging as regulatory cells that produce cytokines and other molecules that influence energy metabolism, locally, and in peripheral tissues (Sethi and Hotamisligil, 1999; Chaldakov et al., 2003). Although typically viewed in the context of immune modulation, tumor necrosis factor- (TNF) and IL-6 antagonize insulin-mediated anabolic processes, including protein accretion in skeletal muscle and lipid accumulation in adipose tissue (Hotamisligil et al., 1993; de Alvaro et al., 2004). Adipocytes are known to be a significant contributors to pericellular and circulating concentrations of both of these cytokines (Chaldakov et al., 2003). Furthermore, both the adipocyte and myofiber respond to direct stimulation with Toll-like receptor (Tlr)-4 ligands by producing IL-6 and TNF. Thus, the regulation of cytokine production by adipocytes and myofibers may be very important to whole animal metabolic regulation, and local changes in concentrations of these molecules likely alter metabolism and growth, even in the absence of a clinically evident challenge. In this paper, metabolic and immunological functions of adipocytes and myofibers are considered. We hope to convey evidence for clear relationships between these newly discovered roles for adipocytes and myofibers and the regulation of cytokine production and energy metabolism at the cellular and whole-animal level. |
ADIPOCYTES AND MYOFIBERS EXPRESS TOLL-LIKE RECEPTORS AND PARTICIPATE IN THE INNATE IMMUNE RESPONSE |
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; Leclerc and Reichhart, 2004). The Toll receptors on cells of the fat body are responsible for recognition of these pathogens and initiation of the secretory response. In fact, mutations in the Toll receptor that preclude pathogen recognition are lethal (Lemaitre et al., 1996). Mammalian homologues of the Toll receptors are known as the Toll-like receptors and, as in drosophila, are critical to pathogen recognition and initiation of the innate immune response (Rock et al., 1998).
The immunological implications for adipocytes and myofibers are expanding rapidly. Experiments performed with cultured 3T3-L1 adipocytes (Lin et al., 2000), C2C12 myoblasts (Frost et al., 2003), or fused myotubes (Frost et al., 2002) indicate that adipocytes and skeletal muscle express Toll-like receptors and respond to bacterial lipopolysaccharide (LPS) by producing TNF and IL-6, classical proinflammatory cytokines. We have extended these findings to include primary pig adipocytes and determined that stimulation of adipocytes with LPS invokes activation, nuclear translocation, and transcriptional activity of the nuclear factor kappa B (NF
B) transcription factor (Ajuwon et al., 2004). Likewise, Frost et al. (2002) have shown that activation of NFB is pivotal to the innate immune response in skeletal muscle. These findings underscores the similarity between macrophages and adipocytes or myofibers in that this transcription factor is a major mediator of TNF and IL-6 production in classical immune cells, adipocytes, and myofibers.
The adipocyte produces multiple adipokines and immune modulators that are potent regulators of energy and protein metabolism. Many cytokines exert powerful influences over metabolic and immunologic activities, locally and in skeletal muscle (Chaldakov et al., 2003). Proinflammatory cytokines are generally lipolytic and antilipogenic in adipocytes (Lyngso et al., 2002; van Hall et al., 2003; Trujillo et al., 2004). These results are of considerable interest in light of the new paradigm in which adipocytes are viewed as integral components of the immunoendocrine interface, and because of the metabolic actions of these cytokines, especially in relationship to energy metabolism and insulin signaling (Hotamisligil et al., 1993; Kern et al., 1995). Of great significance, metabolic perturbations, including excessive accumulation of triglycerides, which occurs with the onset and progression of obesity, are now known to trigger an inflammatory response that includes production of IL-6 and TNF, recruitment of macrophages into adipose tissue, and transmittal of the inflammatory state to these resident macrophages (Weisberg et al., 2003; Xu et al., 2003). Although circulating concentrations of TNF are sometimes not elevated, the local actions of this cytokine on the adipocyte are certain (Isomaa, 2003). Furthermore, the literature indicates that the adipocyte is responsible for 30% or more of the circulating IL-6, and that concentrations of IL-6 in the interstitial fluid of adipose tissues are markedly higher than that in the circulation (Sopasakis et al., 2004). Consequently, there is a clear link between the production of proinflammatory cytokines and physiologic cues to alter metabolism.
The significance of local actions of TNF on the adipocyte itself was recently documented in transcript profiling experiments in which treatment with this cytokine for as little as 4 h resulted in altered expression of some 200 genes in 3T3-L1 adipocytes (Ruan et al., 2002b). Similar results were obtained in vivo with adipose tissue in response to TNF infusion (Ruan et al., 2002a). Although the vast majority of the work with cytokines in the adipocyte has targeted TNF, it is very important to note that IL-6 has been recently associated with insulin resistance and altered metabolism in adipocytes and skeletal muscle (Path et al., 2001; Lagathu et al., 2003). Regarding the pig adipocyte, IL-6 is more highly expressed under basal conditions than is TNF, and is more responsive to LPS in terms of the accumulated concentration of this cytokine in stimulated cells than is TNF (Ajuwon et al., 2004). Given that IL-6 normally circulates at significant concentrations in the pig, whereas TNF is typically low (Webel et al., 1997; Wright et al., 2000), the regulation of IL-6 production and signaling in pig adipocytes is of considerable importance.
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SATURATED FATTY ACIDS ACTIVATE Tlr-4 AND PROMOTE INFLAMMATION IN ADIPOCYTES AND MYOFIBERS |
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; Bernstein et al., 2006). Consequently, it might be expected that some fatty acids would interact directly with the receptor to induce or antagonize proinflammatory signals. Furthermore, because adipocytes and myofibers would rarely encounter bacterial ligands for Tlr-4 under normal conditions, endogenous fatty acid ligands may be of equal or greater physiological significance than bacterial ligands. It is quite intriguing that palmitate and the n-3 fatty acid docosahexenoic acid (DHA) differentially regulate Tlr-4 signaling in vitro in RAW 264.7 macrophages and 293T cells (Lee et al., 2003b), human monocytes (Zhao et al., 2005), and dendritic cells (Weatherill et al., 2005). We have now shown that palmitate stimulates NFB activity and IL-6 production in 3T3-L1 adipocytes and that DHA antagonizes the ability of palmitate to activate NFB-driven reporter gene activity (Ajuwon and Spurlock, 2005b). Similar findings have been reported for cultured myocytes inthat palmitate mediates insulin resistance in C2C12 myotubes via a Tlr-2-dependent pathway that entails activation of protein kinase C and NFB (Pini et al., 2006).
Mechanistically, the interaction between fatty acids and Tlr-mediated inflammation is complex and varies with cell type. Whereas n-3 fatty acids largely suppress the inflammatory response to LPS in classical immunocytes (Lee et al., 2003a,b, 2004), in adipocytes, DHA antagonizes the induction of NFB transcriptional activity when induced by palmitate, but has little impact on the stimulatory effect of LPS (Ajuwon and Spurlock, 2005b). Likewise, stimulation of IL-6 release from adipocytes into the culture media by LPS and palmitate is not attenuated by DHA. It is also important to note that intracellular metabolism of palmitate in adipocytes also impacts the inflammatory response. When fatty acyl CoA synthase activity is blocked chemically, the induction of NFB by palmitate is abrogated, but the accumulation of IL-6 in the culture media is markedly augmented (Ajuwon and Spurlock, 2005b). Finally, whereas the phosphoinositide-3 (PI3)-Akt kinase pathways are pivotal for activation of NFB by saturated fatty acids in macrophages (Lee et al., 2003b), inhibition of PI3 kinase with wortmannin in cultured adipocytes causes a marked increase in the proinflammatory effect of palmitate as reflected in the transcriptional activity of NFB activity and IL-6 accumulation in the media.
Collectively, the data relating fatty acids to inflammation indicate the feasibility of altering dietary lipid profiles to favor polyunsaturates (i.e., DHA) may provide an effective means of alleviating inflammation and insulin resistance in adipose tissue and systemically (Lee et al., 2001). This concept is supported by recent findings that n-3 fatty acid consumption is associated with improved insulin sensitivity and glucose tolerance in Eskimos (Ebbesson et al., 2005), and by epidemiologic and clinical studies that relate improvements in markers of atherosclerosis and coronary artery disease to n-3 fatty acid consumption (Brouwer et al., 2004; Zhao et al., 2004; Djousse et al., 2005). Furthermore, we have determined that dietary fatty acid profiles do indeed impact the inflammatory response in adipose tissue to LPS (Gabler et al., 2008). In this study, n-3 polyunsaturated fatty acids blocked the LPS-induced downregulation of Tlr-4 in adipose tissue, which is the classical homologous desensitization phenomenon that protects against an overzealous and prolonged immune response (Pedron et al., 2003). Thus, it seems that the n-3 fatty acids attenuated the activation of Tlr-4 by LPS, and if so, controlling inflammatory events at the tissue level by manipulating dietary fatty acid profiles may become an effective nutritional strategy for improving growth and efficiency in meat animals.
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ADIPOCYTES AND MYOFIBERS EXPRESS INTERLEUKIN-15 |
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helix bundle family of cytokines, which communicates immunological needs to T-cell and natural killer cell populations (Ranson et al., 2003; Ruckert et al., 2003). Although a clear participant in immune modulation cascades, this cytokine is also highly expressed in skeletal muscle (Satoh et al., 1998; Sugiura et al., 2002), where it promotes protein accretion (Quinn et al., 1995) and antagonizes muscle wasting in some disease models (Carbo et al., 2000). Busquets et al. (2005) have now excluded the regulation of protein synthesis, amino acid transport, and alanine metabolism as components of the mechanism by which IL-15 promotes muscle accretion but have shown strong evidence that this cytokine acts directly to suppress protein degradation.
We recently showed for the first time in any species that that interferon (IFN)-
induces IL-15 in primary pig adipocytes (Ajuwon et al., 2004), and prevents the up-regulation of peroxisome proliferator-activated receptor (PPAR)2 by adiponectin (Ajuwon and Spurlock, 2005a). It is not yet known whether a similar response to IFN- occurs in myofibers, or if IL-15 production is regulated in myofibers activated with LPS. However, it seems possible that acute regulation of IL-15 influences the metabolic changes in muscle during clinical and even subclinical challenges.
In addition to its enhancement of muscle growth, there is strong evidence that IL-15 suppresses fat accretion in rodent models, perhaps through a direct effect on the adipocyte. Recently, Alvarez et al. (2002) provided conclusive evidence of the expression of the IL-15 receptor in adipose tissue of rodents. Furthermore, the reduction in adiposity achieved with IL-15 in lean Zucker rats was precluded in fa/fa rats, in which adipose expression of the (c) signaling receptor subunit is also markedly lower than in lean controls. Based on these findings, and on the indications that IL-15 might act directly on the adipocyte to regulate fat accretion (Alvarez et al., 2002), we hypothesized that IL-15 would enhance lipolysis and suppress lipogenesis. Indeed, IL-15 does target the adipocyte directly. It acts acutely to stimulate lipolysis, and to a lesser extent, suppresses lipogenesis (Ajuwon and Spurlock, 2004). Although the concentrations of IL-15 used in our experiments were higher than typically reported in the systemic circulation (Gonzalez-Alvaro et al., 2003; Jang et al., 2003), secretion of IL-15 by the adipocyte may present these cells with a substantially higher concentration than what is reflected in the circulation. The antilipogenic effect of IL-15 was quite small, and its biological significance is unclear. Albeit, the small attenuation achieved after 2 h may have a greater impact in vivo, but longer term experiments will be required to address this issue.
Quinn et al. (2005) proposed an intriguing muscle-to-fat endocrine communication axis for IL-15, and our findings seemingly extend this to include an adipose-to-muscle axis that may be of particular importance during immune challenge scenarios in which energy must be mobilized and glucose spared. It seems possible that in this case, adipose-derived IL-15 could help protect muscle against an overzealous immune response by limiting muscle protein degradation. Regarding adipose tissue, these findings indicate a potential auto-crine regulatory axis with respect to immune challenge, one in which IL-15 is induced by IFN-, with the metabolic effects of mobilizing fatty acids for use as energy or as precursors for signaling molecules, such as diacyl glycerol or phosphoinositides. Although it will be necessary to confirm that the IL-15 protein is actually synthesized and released by the adipocyte to substantiate the existence of such an autocrine loop, it is already apparent that serum IL-15 is elevated in many inflammatory states (Gonzalez-Alvaro et al., 2003; Jang et al., 2003). Thus, the adipocyte may contribute to the increased circulating concentrations and thereby modify peripheral tissue metabolism.
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ADIPONECTIN EXEMPLIFIES THE INTEGRATION OF METABOLIC AND INFLAMMATORY PATHWAYS |
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; Hu et al., 1996; Maeda et al., 1996; Nakano et al., 1996). Adiponectin is secreted primarily by adipocytes, typically the only tissue source of adiponectin in rodents (Scherer et al., 1995) and pigs (Ding et al., 2004; Jacobi et al., 2004). However, more recent publications indicate expression and secretion in avian (Maddineni et al., 2005) and human skeletal muscle (Punyadeera et al., 2005) and by murine and human cardiomyocytes (Pineiro et al., 2005).
Adiponectin circulates at relatively high (µg/mL) serum concentrations (Hotta et al., 2000; 2001) and exhibits structural homology with collagens VIII and X and complement factor C1q. The basic structure of adiponectin is a 247-amino acid protein with 4 domains: 1) an amino-terminal signal sequence; 2) a variable region; 3) a collagenous domain, and 4) a carboxyl terminal globular domain (Scherer et al., 1995). Circulating adiponectin is present in a wide range of full length multimers, varying form trimers, hexamers, and high molecular weight multimers or as a globular form generated by the cleaved C-terminal domains of a trimer adiponectin (Fruebis et al., 2001; Kobayashi et al., 2004). It remains unclear whether these different forms have different effects on tissues and metabolism. However, knockout and knockdown studies are shedding light on this issue.
Recently, 2 different isomers of the adiponectin receptor, AdipoR1 and AdipoR2, have been found and cloned (Yamauchi et al., 2003). These membrane receptors are structurally and topologically distinct from G-protein coupled receptors, but are predicted to contain 7 transmembrane domains. Both receptors are expressed in numerous cell types, including adipocytes, with AdipoR1 mainly expressed in skeletal muscle and AdipoR2 predominately expressed in the liver (Yamauchi et al., 2003). Interestingly, these 2 receptors exhibit different binding affinities for the globular and full length adiponectin. AdipoR1 has a high affinity for the globular adiponectin and a very low affinity for the full length form, whereas AdipoR2 has an intermediate affinity for both the full length and globular forms of adiponectin (Yamauchi et al., 2003).
Metabolism
Adipokines, such as leptin, IL6, TNF, resistin, and adiponectin, are strongly associated with metabolic disease and are modulators of insulin action and maintaining overall energy balance (Fantuzzi, 2005). Adiponectin plays an important role in the regulation of glucose and fatty acid metabolism (Fang and Sweeney, 2006). This fundamental link has focused research on the potential ability of adiponectin signaling to elevate insulin resistance and diabetes. Our laboratory recently showed that full-length adiponectin works directly on porcine primary adipocytes to suppress lipogenesis (Jacobi et al., 2004). Mechanistically, Yamauchi et al. (2002) and Tomas et al. (2002) independently provided evidence that adiponectin works to control fatty acid oxidation and triglyceride storage in skeletal muscle by activation of 5'AMP-activated protein kinase (AMPK). Phosphorylation of AMPK activates it and, in turn, phosphorylates and thereby deactivates acetyl CoA carboxylase. Consequently, cytosolic malonyl CoA is depleted and its allosteric repression of carnitine palmitoyltransferase is alleviated to facilitate mitochondrial fatty acid transport and oxidation (Li et al., 2007).
The 2 adiponectin receptors differ in their signaling pathways (Yamauchi et al., 2007). Adenovirus-mediated expression of AdipoR1 and AdipoR2 in the liver of leptin –/– mice, increased the activation of AMPK and PPAR signaling, respectively (Yamauchi et al., 2007). The AMPK activation decreased gluconeogenesis and increased expression of the receptors in both cases, and increased fatty acid oxidation, resulting in the attenuation of insulin resistance in leptin –/– mice. Alternatively, simultaneous disruption of both receptors in these mice abolished adiponectin binding and actions, thus leading to increased insulin resistance and triglyceride content, glucose intolerance, and inflammation (Yamauchi et al., 2007). Furthermore, these mouse knockout studies have linked AdipoR1 more to the activation of the AMPK pathway and increased fatty acid oxidation, whereas AdipoR2 is more tightly involved in the regulation of PPAR pathway, which in turn, stimulates energy dissipation through fatty acid oxidation.
Similar knockdown adiponectin receptor studies were conducted by Yamauchi et al., (2007), but contradictions of some aspects of their work were reported (Bjursell et al., 2007). In this study, AdipoR1-deleted mice became obese, had decreased energy expenditure and locomotion activity, and were glucose intolerant, as expected. However, AdipoR2 deficiency surprisingly resulted in a lean mouse phenotype with resistance to diet-induced obesity, improved glucose tolerance, and improved plasma cholesterol levels (Bjursell et al., 2007). Enhanced PPAR or AMPK phosphorylation in the AdipoR2–/– mice was not observed and, therefore, could not explain these results. Taken together, these papers indicate that AdipoR1 and AdipoR2 have different roles in glucose and lipid metabolism. However, more studies are needed on different genetic backgrounds to clarify the contradictory results.
Because AMPK phosphorylation is known to increase glucose transporter 4 (GLUT4) translocation and stimulate glucose uptake (Ojuka et al., 2002), it seems feasible that adiponectin-dependent increase in glucose uptake is mediated, in part, through AMPK. This was first shown in rat skeletal muscle, in which globular adiponectin increased AMPK phosphorylation, GLUT4 translocation, and glucose uptake (Ceddia et al., 2005). Therefore, because skeletal muscle accounts for approximately 80% of the insulin-stimulated glucose disposal (DeFronzo et al., 1985), adiponectin treatments may be a viable means of enhancing insulin sensitivity and glucose disposal, thereby reducing diabetes.
Adiponectin significantly enhances glucose and fatty acid uptake in cardiomyocytes and induces the phosphorylation of AMPK (Shibata et al., 2004; Fujioka et al., 2006; Tao et al., 2007). This is of great significance to cardiac dysfunction and remodeling. Pathological cardiac remodeling characterized by myocardial hypertrophy can ultimately lead to heart failure. The activation of AMPK causes an inhibition of protein synthesis via the mammalian target of rampamycin (mTOR) pathway (Bolster et al., 2002; Horman et al., 2002). Here, AMPK activation of eukaryotic translation elongation factor 2 (eEF2) kinase results in reduced phosphorylation of protein kinase B on Ser(473), mTOR on Ser(2448), ribosomal protein S6 kinase at Thr(389), and eukaryotic initiation factor 4E-binding protein on Thr(37), as well as the phosphorylation and inactivation of eEF2. Ultimately, this causes reduced signaling through the mTOR pathway, accumulating in the inhibition of protein synthesis. In cardiomyocytes, adiponectin protects against the development of systolic dysfunction after myocardial infarction through its abilities to suppress cardiac hypertrophy and interstitial fibrosis (Shibata et al., 2007). However, to animal industries in which skeletal muscle protein synthesis is important, attenuation of mTOR signaling is not desirable if adiponectin is upregulated. Results from research currently being conducted in our laboratory using C2C12 myotubes indicate that adiponectin is having no effect on the mTOR pathway and protein synthesis, but is attenuating the degradation of skeletal muscle protein and its ubiquination (M. E. Spurlock, unpublished results).
Inflammation
Several clinical studies have linked low circulating adiponectin levels with high proinflammatory cytokine concentrations in disease states, such as diabetes and obesity (Matsushita et al., 2006a,b; Bahceci et al., 2007). Therefore, much of adiponectin’s antiinflammatory role has focused on inflammation-induced insulin resistance. However, the exact mechanism(s) by which adiponectin potentates this antiinflammatory action remains elusive. Our laboratory has previously shown that adiponectin attenuates the translocation of NFB to the nucleus of adipocytes stimulated with LPS (Ajuwon and Spurlock, 2005a). Additionally, the antiinflammatory actions of adiponectin include suppression of IL-6 and induction of the antiinflammatory IL-10, mediated in part by suppression of NFB signaling and extracellular signal-regulated kinase 1/2 activity in macrophages (Wulster-Radcliffe et al., 2004).
Neumeier et al. (2006) used low-molecular-weight and high-molecular-weight adiponectin to induce apoptosis in nondifferentiated human acute monocytic leukemia (THP-1) cells, reduce macrophage scavenger receptor A gene expression, and activate the phosphorylation of AMPK. In agreement with Wulster-Radcliffe et al. (2004), who used the full length adiponectin, the low molecular weight adiponectin isomer reduced LPS-mediated IL-6 secretion and stimulated IL-10 secretion through reducing the abundance of inhibitor of NFB and therefore diminishing the nuclear translocation of NFB p65. However, the high molecular weight adiponectin was shown to induce IL-6 secretion and did not attenuate LPS induced proinflammatory secretion in their human monocytes and THP-1 cell model (Neumeier et al., 2006). Therefore Neumeier et al. (2006) concluded that different adiponectin isoforms induce isoform-specific responses (low-molecular-weight adiponectin displaying antiinflammatory attributes) but share common effects, such as increasing apoptosis, activating AMPK, and reducing macrophage scavenger receptor expression.
The importance of AdipoR1 and AdipoR2 in inflammation was identified recently by Yamauchi et al. (2007). They showed that simultaneous disruption of AdipoR1 and AdipoR2 in leptin –/– mice significantly increased the expression of genes encoding for chemokines, decreased the expression of genes encoding molecules that reduce oxidative stress, and increased the expression of genes that increase oxidative stress in white adipose tissue. Furthermore, the adenovirus-mediated overexpression of AdipoR2 reduced the inflammatory and oxidative stress genes, TNF and chemokine (C–C motif) ligand 2, and increased catalase and super-oxide dismutase 1 through increased PPAR expression. Both PPAR and PPAR have the ability to antagonize NFB and activator protein 1 pathways and inhibit proinflammatory gene expression (Fujii, 2005). In contrast to AdipoR2 overexpression, adenovirus-mediated overexpression of AdipoR1 had no effect on these inflammatory gene expression pathways (Yamauchi et al., 2007). However, AdipoR1 overexpression in these leptin –/– mice did cause an increase in the activation of AMPK in the liver by adiponectin, which was not observed by AdipoR2 overexpression.
Adiponectin is a known activator of AMPK in numerous cell types (Giri et al., 2004; Neumeier et al., 2006; Yamauchi et al., 2007), and similar to PPAR, AMPK may be a part of the antiinflammatory process of adiponectin. Recent studies show that a chemical activator of AMPK, 5-aminoimidazole-4-carboximide 1-β-D-ribo-furanoside (Ido et al., 2002), or expression of constitutively active AMPK (Ruderman et al., 2003) disrupts NFB-mediated gene expression in some cell types. Furthermore, AMPK regulates the transcriptional activity of NFB and CCAAT/enhancer binding protein 
through inhibiting their nuclear translocation, as well as the transcriptional activity of NFB, by inhibiting LPS-induced I-kappa kinase /β activity and phosphorylation/degradation of IB (Giri et al., 2004). The CCAAT/enhancer binding protein is known to regulate the expression of TNF, IL-1β, IL-6, inducible nitric oxide synthase, IL-8, and IL-12 (Poli, 1998). Together, through adiponectin’s ability to upregulate AMPK and PPAR, disruption of NFB transcriptional activity, and downstream proinflammatory gene expression, attenuation of inflammation may be achieved by adiponectin.
Although the antiinflammatory actions of adiponectin are in part due to the counteractions of NFB and proinflammatory cytokine production, the antiinflammatory effects may be mediated additionally through its general feature of binding chemokines with varying affinities via the globular head domain (Masaie et al., 2007). However, the dose of full-length recombinant adiponectin used here did not influence chemokine-receptor interactions.
Another mechanistic action of adiponectin, in relation to inflammation, is to promote the clearance of early apoptotic debris. This activity is mediated not by the adiponectin receptors, but through calreticulin expressed on the phagocytic cell surface (Takemura et al., 2007). The accumulation of cell debris can cause inflammation and immune system dysfunction, and this is observed in adiponectin-deficient mice (Takemura et al., 2007). However, adiponectin deficiency in itself is not sufficient to produce an autoimmune phenotype.
Contradictory to its protective antiinflammatory role in obesity, diabetes, and cardiovascular disease, adiponectin, together with resistin, was positively correlated with inflammatory markers of osteoarthritis and rheumatoid arthritis (Schaffler et al., 2003). It has since been shown that adiponectin can also exert significant proinflammatory and matrix-degrading effects by upregulating 2 major mediators of rheumatoid arthritis pathophysiology, IL-6, and matrix metalloproteinase 1 (Ehling et al., 2006). Furthermore, endogenous adiponectin has been shown not to play a critical role in attenuating LPS or concanavalin A-induced inflammation between wild type and adiponectin knockout mice (Pini et al., 2006).
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ADIPOKINES AND REGULATION OF THE IMMUNE SYSTEM |
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; Nova et al., 2002) and excessive adipose accumulation lead to impairment in immune function and disease susceptibility (Norgan, 1997; Klasing, 1998; Marti et al., 2001). In "higher" animals, adipose tissue is a source of cytokines and adipokines of immunological importance, including TNF (Xu et al., 2002), IL-6 (Lin et al., 2000), adipsin (Cook et al., 1985), haptoglobin (Friedrichs et al., 1995), leptin (Zhang et al., 1994), adiponectin (Scherer et al., 1995; Maeda et al., 1996), and IL-15 (Ajuwon and Spurlock, 2004). Because many immunological processes are mediated by cytokines, the adipocyte can directly regulate these processes via the cytokines it secretes. Leptin and adiponectin are exemplary of the importance of these molecules in that impaired T cell function in obese mice is only rescued by exogenous leptin treatment (Lord et al., 1998), and adiponectin modulates the growth of myelomonocytic progenitors and mature macrophage phagocytic activity and suppresses LPS-induced production of TNF in humans (Yokota et al., 2000). In porcine macrophages and THP-1 monocytes, adiponectin antagonizes the activation of NFB and induction of inflammatory cytokines, whereas it induces the expression of IL-10, an antiinflammatory cytokine (Wulster-Radcliffe et al., 2004; Wulster-Radcliffe and Spurlock, 2005). Thus, the adipocyte is clearly linked with immune function via the production of leptin and adiponectin.
Anatomically, the adipocyte is uniquely positioned around organs and represents a physical line of defense against pathogens. As a reservoir of fatty acids, adipose tissue serves as an energy source for the growth of surrounding lymphoid tissue (Pond and Mattacks, 1998). Both IL-6 and TNF have demonstrated lipolytic activity and may serve not only to provide fatty acids for energy, but may also provide fatty acids as regulatory molecules (Feingold et al., 1992; van Hall et al., 2003). Structurally, the adipocyte is equipped with receptors and intracellular signaling machinery to respond to pathogen-associated molecular patterns. The work of Lin et al. (2000) provided the first evidence of the presence of Tlr-4 and Tlr-2 in the adipocyte, making it able to respond to bacterial LPS and fungal components, respectively. We have provided evidence of the activation of the NFB signaling pathway in pig adipocytes and induction of IL-6 expression in response to bacterial endotoxin (Ajuwon et al., 2004). Therefore, by being able to respond to pathogen structures, the adipocyte is capable of acting in a similar fashion as an immune cell, and this may be relevant in the fight against disease. Interestingly, there is evidence that adipocytes may also work with specialized immune cells, such as macrophages, to orchestrate the immune response. Xu et al. (2003) and Weisberg et al. (2003) have shown that many inflammation- and macrophage-specific genes are dramatically upregulated in white adipose tissue in mouse models of genetic and high-fat diet-induced obesity. In addition, obesity leads to an inflammatory state that results in the recruitment of macrophages into adipose tissue (Weisberg et al., 2003; Xu et al., 2003), perhaps setting a premise for a crosstalk between adipocytes and the tissue-resident macrophages that may be critical in immune and inflammatory responses.
At present, the relative contribution of adipocytes to the elevated cytokines that accompany disease challenge and the resultant depression in animal growth performance under the nonsterile conditions of the typical farm is unknown. However, the roles of inflammatory cytokines, some of which are of adipocyte origin, in the regulation of protein synthesis and efficiency of feed utilization are clearly recognized (Webel et al., 1997; Wright et al., 2000). It is necessary to determine the extent to which genetic selection for the reduction of adipose mass has modified adipose biology in this respect.
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REGULATION OF GROWTH AND METABOLISM BY INTEGRATED ADIPOKINE AND CYTOKINE SIGNALING |
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), and thus, these principles will not be developed fully herein. However, in the context of this review, several pivotal changes are foundational. First, it is important to recognize that adipocytes and myofibers produce the proinflammatory cytokines, TNF and IL-6, in response to antigen challenge. Secondly, these cytokines have a notable history of inducing insulin and GH resistance in adipose tissue and skeletal muscle. Furthermore, evidence is mounting that the signaling potential of certain cytokines is intensified in skeletal muscle during the immune response in that expression of their receptors is markedly upregulated (Zhang et al., 2000). Consequently, muscle and liver production of IGF-I is reduced, and circulating concentrations of IGF-I decrease. In fact, we have determined that in the pig, LPS challenge has a more dramatic effect on skeletal muscle IGF-I expression than on liver (Spurlock et al., 1998). The loss in anabolic stimuli, coupled with the mobilization and repartitioning of energy and amino acids away from adipose and skeletal muscle depots, results in a diminution of growth in favor of higher priority immunological functions. In particular, the need for acute phase proteins in the midst of immune challenge imposes a considerable need for amino acid nitrogen to support acute phase proteins synthesis in the liver (Reeds et al., 1994).
Based on this model of growth depression, it seems of utmost importance to establish the immunological and metabolic roles of adiponectin in adipocytes and myofibers, and to determine how adiponectin receptors are regulated in these cells. As noted above, we have shown that adiponectin attenuates proinflammatory cytokine production in primary pig adipocytes and in 3T3-L1 adipocytes, and that the regulation of NFB is central to this effect. Whether adiponectin performs a similar role in muscle is under investigation. Furthermore, it is imperative to determine whether adipocyte or muscle-derived IL-15 influences metabolic and immunological pathways in challenged adipocytes and myofibers.
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CONCLUSIONS |
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Footnotes |
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2 This work was supported by National Research Initiative Competitive Grant no. 2004-35206-14182 and 2004-35206-17867 from the USDA Cooperative State Research, Education, and Extension Service.
3 Corresponding author: mspurloc{at}iastate.edu
Received for publication July 26, 2007. Accepted for publication September 18, 2007.
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  L. A. Gonzalez, K. S. Schwartzkopf-Genswein, N. A. Caulkett, E. Janzen, T. A. McAllister, E. Fierheller, A. L. Schaefer, D. B. Haley, J. M. Stookey, and S. Hendrick Pain mitigation after band castration of beef calves and its effects on performance, behavior, Escherichia coli, and salivary cortisol J Anim Sci, February 1, 2010; 88(2): 802 - 810. [Abstract] [Full Text] [PDF]
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 Yulan Liu, Junxia Shi, Jing Lu, Guoquan Meng, Huiling Zhu, Yongqing Hou, Yulong Yin, Shengjun Zhao, and Binying Ding Activation of peroxisome proliferator-activated receptor-{gamma} potentiates pro-inflammatory cytokine production, and adrenal and somatotropic changes of weaned pigs after Escherichia coli lipopolysaccharide challenge Innate Immunity, June 1, 2009; 15(3): 169 - 178. [Abstract] [PDF]
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Abstract
INTRODUCTION