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* Departments of Animal Sciences and
and
Basic Medical Sciences, Center for Comparative Medicine, Purdue University, West Lafayette, IN 47907
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Abstract |
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 Top Abstract INTRODUCTIONADIPOCYTES AND MYOFIBERS EXPRESS...ADIPOCYTES AND MYOFIBERS EXPRESS...LEPTIN AND ADIPONECTIN AS...ADIPOKINES AND REGULATION OF...REGULATION OF PROTEIN METABOLISM...REGULATION OF GROWTH AND...LITERATURE CITED |
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). However, adipocytes are also the predominant source of the antiinflammatory hormone adiponectin, which regulates the nuclear factor kappa-B transcription factor. The ability to recognize antigens and produce regulatory molecules strategically positions adipocytes and myofibers to regulate growth locally, and to reciprocally regulate metabolism peripherally.
Key Words: adipocyte • cytokine • growth • inflammation • myofiber
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INTRODUCTION |
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TopAbstractINTRODUCTIONADIPOCYTES AND MYOFIBERS EXPRESS...ADIPOCYTES AND MYOFIBERS EXPRESS...LEPTIN AND ADIPONECTIN AS...ADIPOKINES AND REGULATION OF...REGULATION OF PROTEIN METABOLISM...REGULATION OF GROWTH AND...LITERATURE CITED |
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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 ensure that 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 counteracting antiinflammatory factors. 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-alpha (TNF) and interleukin-6 (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). The adipocyte is now known to be a significant contributor 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 4 (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, we will discuss metabolic and immunological aspects of the adipocyte and myofiber, and build specific linkages between these processes, 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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TopAbstractINTRODUCTIONADIPOCYTES AND MYOFIBERS EXPRESS...ADIPOCYTES AND MYOFIBERS EXPRESS...LEPTIN AND ADIPONECTIN AS...ADIPOKINES AND REGULATION OF...REGULATION OF PROTEIN METABOLISM...REGULATION OF GROWTH AND...LITERATURE CITED |
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; Leclerc and Reichhart, 2004). It is the Toll receptor on cells of the fat body that is 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 receptor 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) and 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. This finding in adipocytes and myofibers underscores the similarity between macrophages and adipocytes or myofibers in that NFB is a major mediator of TNF and IL-6 production in classical immune cells.
The adipocyte produces multiple adipokines and immune modulators, which 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 the excessive accumulation of triglycerides that occurs with the onset and progression of obesity, are now known to trigger an "inflammatory response," which 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 those 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 (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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ADIPOCYTES AND MYOFIBERS EXPRESS IL-15 |
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TopAbstractINTRODUCTIONADIPOCYTES AND MYOFIBERS EXPRESS...ADIPOCYTES AND MYOFIBERS EXPRESS...LEPTIN AND ADIPONECTIN AS...ADIPOKINES AND REGULATION OF...REGULATION OF PROTEIN METABOLISM...REGULATION OF GROWTH AND...LITERATURE CITED |
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-helix bundle family of cytokines that communicates immunological needs to T-cell and natural killer cell populations (Ranson et al., 2003; Ruckert et al., 2003). Though a clear participant in immune modulation cascades, this cytokine is 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 interferon-
(IFN-) induces IL-15 in primary pig adipocytes (Ajuwon et al., 2004), and prevents the upregulation of peroxisome proliferntor-activated receptor2 (PPAR2) by adiponectin (Ajuwon and Spurlock, 2005). 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, suppress lipogenesis (Ajuwon and Spurlock, 2004). Although the concentrations of IL-15 used in our experiments were higher than what is 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 that reflected in the circulation. The antilipogenic effect of IL-15 was quite small, and its biological significance is unclear. It may be that the small attenuation achieved after 2 h would have a greater impact in vivo, but longer-term experiments are 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 autocrine 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 to signaling molecules such as diacylglycerol 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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LEPTIN AND ADIPONECTIN AS REGULATORY ADIPOKINES |
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TopAbstractINTRODUCTIONADIPOCYTES AND MYOFIBERS EXPRESS...ADIPOCYTES AND MYOFIBERS EXPRESS...LEPTIN AND ADIPONECTIN AS...ADIPOKINES AND REGULATION OF...REGULATION OF PROTEIN METABOLISM...REGULATION OF GROWTH AND...LITERATURE CITED |
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Leptin
For comprehensive reviews of leptin in agriculturally important species, the reader is referred to Barb et al. (2001) and Liefers et al. (2005). Leptin is produced predominantly in the adipose tissue (Zhang et al., 1994; Bidwell et al., 1997; Ramsay et al., 1998), but is also produced by rodent skeletal muscle under some metabolic circumstances (Wang et al., 1998, 1999). It is secreted into the blood and thereafter reaches myriad target cells in the brain and peripheral tissues. Leptin acts acutely as a nutrient sensor, but circulating concentrations also reflect adipose mass in pigs (Ramsay et al., 1998; Jacobi et al., 2004), rodents (Friedrichs et al., 1995; Maffei et al., 1995), and humans (Maffei et al., 1995). Although leptin clearly functions through central mechanisms to regulate caloric intake and energy expenditure, there is convincing evidence of its direct effects on peripheral tissues. Exposure to leptin inhibits lipogenesis in primary porcine adipocytes and in adipocytes derived from stromal-vascular cells. Although the underlying mechanism is not known, it encompasses disruption of insulin-stimulated lipogenesis (Ramsay, 2003a). In some models, leptin also acts to suppress the inhibition of ß-receptor–mediated lipolysis by insulin (Ramsay, 2001), and reduces insulin-induced glucose transport and(or) lipogenesis (Muller et al., 1997; Ramsay, 2004). In the absence of insulin, leptin directly stimulates lipolysis in rodent and porcine adipocytes (Fruhbeck et al., 1997, 1998; Ajuwon et al., 2003). Mechanistically, lipolytic regulation by leptin is not well characterized. The adenylate cyclase-cyclic AMP (cAMP) system could be a key regulator of hormone-stimulated lipolysis. Leptin expression is down-regulated by cAMP (Slieker et al., 1996), but in the study of Wang et al. (1999) leptin stimulated lipolysis and decreased leptin expression. Nonetheless, induction of cAMP alone does not seem to be the action of leptin-mediated lipolysis. Others have investigated the interaction of leptin and adenosine. Frühbeck et al. (2001) provided evidence that leptin antagonizes the tonic inhibition of lipolysis by adenosine. Leptin, like growth hormone, is a member of the class-I family of helical cytokines (Madej et al., 1995); therefore, signaling through similar receptors (Tartaglia et al., 1995). It interesting that growth hormone alters the function of the G inhibitory coupled protein (Gi) in adipose tissue by diminished ADP ribosylation (Houseknecht and Bauman, 1997). The study demonstrated that the diminished functionality of Gi was associated with an enhancement of lipolysis by growth hormone. This is another potential pathway in which leptin may function to regulate lipolysis and adipose tissue mass in mammals.
Leptin also modulates adipose tissue composition by causing fatty acid oxidation, adipose ablation, and apoptosis. Early research with models of induced hyperleptinemia indicated that specific adipose depots were virtually eliminated (Chen et al., 1996; Shimabukuro et al., 1997). The recovery of body fat in these animals was much slower than in diet-matched controls (Higa et al., 2000). The implications of these results were that there was a prolonged impact of hyperleptinemia on the ability of adipocytes to accumulate and store lipid. This response in part may be due to an induction of apoptosis (Qian et al., 1998). However, the majority of change in composition is likely due to an induction of fatty acid release and the parallel upregulation of genes that regulate fatty acid oxidation driven by increased PPAR expression (Wang et al., 1999). In fact, using wild type and PPAR–/– mice, Lee et al. (2002) determined that the depletion of body fat in the null mice during hyperleptinemia is markedly lower than in wild-type mice. This effect was associated in part with the failure of hyperleptinemia to achieve an upregulation of carnitine palmitoyl transferase in adipose tissue due to the absence of PPAR.
The biochemical changes associated with hyperleptinemia shift the metabolic goal of adipocytes from lipid storage to lipid disposal. Also of considerable significance is that leptin ultimately results in a dedifferentiation of adipocytes (Zhou et al., 1999), as indicated by the loss of adipocyte marker (aP2) and concomitant appearance of the preadipocyte marker, Pref-1. Together, these findings indicate that leptin in high concentrations may be used to reduce adipose mass, but conclusions need further clarification (Higa et al., 2000). The mechanism for this critical role of leptin is such that there is a shift in metabolism from storage to oxidation of fatty acids.
Adiponectin
Adiponectin is a relatively new adipokine that was cloned independently by 4 separate groups in the mid-1990s (Scherer et al., 1995; Hu et al., 1996; Maeda et al., 1996; Nakano et al., 1996). Adipocytes and to a lesser extent, preadipocytes, are typically the only source of adiponectin in rodents (Scherer et al., 1995) and pigs (Ding et al., 2004; Jacobi et al., 2004), although recent publications indicate expression in avian (Maddineni et al., 2005) and human skeletal muscle (Punyadeera et al., 2005). The expression of this protein in rodent adipose tissue is upregulated by feed deprivation (Berg et al., 2001) and cold exposure (Yoda et al., 2001). Other investigations have been focused on the relationship among adiponectin, obesity, and insulin sensitivity in liver and skeletal muscle; adiponectin is clearly downregulated at the mRNA and (or) protein level in conditions of obesity in humans (Arita et al., 1999). Furthermore, fatter genetic lines of pigs have lower circulating adiponectin concentrations than do contemporary high-lean genotypes (Jacobi et al., 2004).
Fruebis et al. (2001) provided the first evidence that adiponectin regulates lipid metabolism and body composition. These researchers used recombinant adiponectin and a carboxyl terminal peptide (gAdn) produced by trypsin cleavage of the recombinant protein to identify metabolic implications of adiponectin. First, mice consuming a high-fat sucrose diet, or infused with a fat emulsion had suppressed postprandial surges in plasma triglyceride, free fatty acids, and glucose concentrations when infused with gAdn compared with control animals. Secondly, muscle preparations and C2C12 myotubes cultured with gAdn show increased free fatty acid oxidation. Lastly, the authors examined the effect of adiponectin on growth and weight change in mice. Immature mice and mature mice were fed a high-fat sucrose diet and body weight was monitored. Immature mice infused with gAdn had suppressed weight gain compared with control immature mice. The mature mice infused with gAdn showed appreciable and sustained weight loss. Using the pig primary adipocyte model, Jacobi et al. (2004) determined that adiponectin suppresses lipogenesis, and that this occurs well within physiological concentrations of the intact protein. The mechanisms underlying the metabolic functions of adiponectin are being identified quickly. Collectively, these findings indicate that adiponectin works to promote fat use rather than storage, and that adiponectin deficiency may either facilitate the development of excess adipose mass, or fail to maintain the adiposity set point.
Our laboratory recently showed that adiponectin works directly on porcine primary adipocytes to suppress lipogenesis (Jacobi et al., 2004), and other researchers have provided insight into the mechanism by which this may occur. 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). Activated AMPK phosphorylates acetyl CoA carboxylase (ACC) and thereby deactivates it. Consequently, cytosolic malonyl CoA is depleted and its allosteric repression of carnitine palmitoyltransferase (CPT-1) is alleviated to facilitate mitochondrial fatty acid transport and oxidation. Furthermore, our preliminary results show that porcine adipocytes treated with adiponectin have increased PPAR protein compared with untreated adipocytes. This is of particular interest considering that the PPAR transcription factor is a central regulator of fatty acid metabolism in adipocytes and skeletal muscle. We have also shown that adiponectin attenuates the translocation of NFB to the nucleus of adipocytes stimulated with LPS (Ajuwon and Spurlock, 2005). This is of significance, because recent studies show that a chemical activator of AMPK, 5-aminoimidazole-4-carboximide 1-ß-D-ribofuranoside (AICAR; Ido et al., 2002), or expression of constitutively active AMPK (Ruderman et al., 2003), disrupts NFB-mediated gene expression in some cell types. Accordingly, if adiponectin activates the AMPK, a reduction in NFB-mediated gene expression, presumably due to disrupted translocation to the nucleus, would be expected and the expression of PPAR would be increased to support increased fatty acid oxidation.
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ADIPOKINES AND REGULATION OF THE IMMUNE SYSTEM |
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TopAbstractINTRODUCTIONADIPOCYTES AND MYOFIBERS EXPRESS...ADIPOCYTES AND MYOFIBERS EXPRESS...LEPTIN AND ADIPONECTIN AS...ADIPOKINES AND REGULATION OF...REGULATION OF PROTEIN METABOLISM...REGULATION OF GROWTH AND...LITERATURE CITED |
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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/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 exemplars 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 also to 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 Toll-like receptor 4 and 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 bacteria 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; this may be relevant in the fight against disease. Interestingly, there is evidence that fat cells 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 crosstalk between adipocytes and the tissue-resident macrophages that may be critical in immune and inflammatory responses.
Currently, the relative contribution of adipocytes to the elevated cytokines that accompany disease challenge is unknown and the resultant depression in animal growth performance under typical farm conditions is unclear. However, the roles of inflammatory cytokines, some of which are of adipocyte origin, in regulation of protein synthesis and efficiency of feed use are clearly recognized (Webel et al., 1997; Wright et al., 2000) and it is necessary to determine the extent to which breeding for the reduction of adipose mass has modified adipose biology in this respect.
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REGULATION OF PROTEIN METABOLISM IN MUSCLE (MYOTUBES) BY ADIPONECTIN AND LEPTIN |
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TopAbstractINTRODUCTIONADIPOCYTES AND MYOFIBERS EXPRESS...ADIPOCYTES AND MYOFIBERS EXPRESS...LEPTIN AND ADIPONECTIN AS...ADIPOKINES AND REGULATION OF...REGULATION OF PROTEIN METABOLISM...REGULATION OF GROWTH AND...LITERATURE CITED |
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, Kokta et al. (2004), Szendrodi and Roden (2004), Arner (2005), and Lihn et al. (2005).
Receptors for both leptin and adiponectin are localized in many peripheral tissues. The long form of the leptin receptor is located in the hypothalamus (Szanto and Kahn, 2000), whereas the short form is expressed in many peripheral tissues (Maamra et al., 2001; Margetic et al., 2002). Adiponectin has at least 2 receptors, adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2). AdipoR1 has a high affinity for the globular form of adiponectin and is abundantly expressed in both mouse and human skeletal muscle (Yamauchi et al., 2003). Human muscle also expresses a high abundance of AdipoR2, which binds both the long and globular forms of adiponectin (Yamauchi et al., 2003).
Short-term administration of recombinant human leptin (100 µg/kg of BW) to female Wistar rats did not result in changes in muscle protein degradation, synthesis, or proteolytic rates based on 3H-amino acid exchange and 14C tracer methodology (Carbo et al., 2000). Similarly, Ramsay (2003b), also using the amino acid exchange method, found that murine C2C12 myotubes treated with 0 to 500 ng/mL of recombinant porcine leptin were unresponsive in terms of protein synthesis as measured by 3H-tyrosine incorporation. However, in this same study, administration of leptin diminished protein degradation by 3.5%. The effect of leptin was apparent at 5.0 ng/mL and leptin at 50 ng/mL showed maximal inhibition of 3H-tyrosine (Ramsay, 2003a).
In another study, primary chick embryonic liver and muscle cells responded to recombinant murine leptin in a dose-dependent manner (Lamosova and Zeman, 2001); 100 ng/mL of leptin increased protein synthesis in muscle cells by approximately 32%. Contrary to these data, Lamosova and Zeman (2001) reported no improvement in hepatocyte protein synthesis with 10 to 100 ng/mL of leptin, but reported a 40% inhibition of 3H-leucine incorporation with 1,000 ng/mL of leptin. However, one must consider that this concentration of leptin is supraphysiological.
To date, there are no published data addressing the regulation of protein metabolism by adiponectin in any tissue or cell type. However, initial studies in our laboratory indicate that the myosin/myofibril protein fraction was 18% higher in the adiponectin treatments vs. the control (Gabler et al., 2005). However, this adiponectin effect was not reflected in the total protein fraction.
Collectively, these studies have only alluded to the mechanism by which protein metabolism may be altered. However, the phosphatidylinositol 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) pathway, which plays a pivotal role in skeletal muscle protein synthesis, may be a potential mechanism. Intermediates such as Akt (or protein kinase B) promote activation of the mTOR cascade leading to the downstream initiation of protein synthesis (Coffer et al., 1998; Scott et al., 1998; Ueki et al., 1998). Therefore, the insulin-like effects of leptin and adiponectin in muscle and myotubes may be responsible for the protein metabolism response. In myotube cultures, leptin activates the PI3-K kinase signaling pathway (Kellerer et al., 1997), and stimulates glucose transport (Berti et al., 1997), therefore mimicking the anabolic activity of insulin. However, in vitro studies in rat skeletal muscle failed to support the concept of a direct insulin-mimicking or desensitizing effect of leptin, at least following 1 to 6 h of exposure (Furnsinn et al., 1998). Additionally, preliminary data in our laboratory indicate that adiponectin is potentially upregulating the phosphorylation of Akt (Gabler et al., 2005).
In this exciting area of adipose-derived proteins, many questions remain to be answered with regard to the roles that leptin and adiponectin play in muscle protein metabolism. These hormones may play a role in maintaining skeletal muscle protein health and mass, and thus have application in human health and domestic animal production.
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REGULATION OF GROWTH AND METABOLISM BY INTEGRATED ADIPOKINE AND CYTOKINE SIGNALING |
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TopAbstractINTRODUCTIONADIPOCYTES AND MYOFIBERS EXPRESS...ADIPOCYTES AND MYOFIBERS EXPRESS...LEPTIN AND ADIPONECTIN AS...ADIPOKINES AND REGULATION OF...REGULATION OF PROTEIN METABOLISM...REGULATION OF GROWTH AND...LITERATURE CITED |
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), and thus they 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 proinflammatory cytokines, TNF and IL-6, in response to antigen challenge. Secondly, these cytokines have a notable history of inducing insulin- and growth hormone-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 in the pig that 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 protein synthesis in the liver (Reeds et al., 1994).
Based on this model of growth depression, it is 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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Footnotes |
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2 Corresponding author: mspurloc{at}iastate.edu
Received for publication August 25, 2005. Accepted for publication November 15, 2005.
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LITERATURE CITED |
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B kinase in a p38 MAPK-dependent manner. J. Biol. Chem. 279:17070–17078.
