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Department of Animal Science, University of Nebraska, Lincoln 68583-0908
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Abstract |
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 Top Abstract IntroductionLeptinResistinComplement-Related ProteinsSummary and ConclusionImplicationsLiterature Cited |
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, can also inhibit differentiation of preadipocytes. Adiponectin/Acrp30 secretion from adipocytes is diminished in obese states. This protein can enhance use of fatty acids in lean tissues, inhibit glucose production by liver, and consequently decrease both blood glucose and BW. Adiponectin may also be responsible for the effectiveness of thiazolidinediones, given that these drugs promote adiponectin secretion. Secretion of complement proteins has been observed in adipocytes, and these interact to generate a signal called acylation-stimulating protein, which can promote triacylglycerol synthesis. These signals seem to be largely unique to adipocytes. Other signals are derived from adipose tissue, and it is unlikely that all the adipocyte’s endocrine signals have been identified. Certainly, there is much to learn about how these signals function; however, it is clear that these biomedical research discoveries comprise a useful model for our study of growth and development in livestock.
Key Words: Acylation-Stimulating Protein • Adiponectin Hormone • Adipose Tissue • Leptin • Resistin
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Introduction |
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TopAbstractIntroductionLeptinResistinComplement-Related ProteinsSummary and ConclusionImplicationsLiterature Cited |
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), as are postpartum anestrus, age at puberty (Dziuk and Bellows, 1983), and general health. Numerous adipocyte-derived signals have recently been identified and significant progress has been made in understanding their specific functions in the mouse model. Several molecules that were previously established as signals from nonadipose tissues are now known to be secreted by adipose cells as well. These include renin-angiotensin components, IGF-1, adenosine, interleukin-1, interleukin-6, tumor necrosis factor-, plasminogen activator inhibitor, and fasting-induced adipose factor (Kim and Moustaid-Moussa, 2000). In addition, adipose tissue secretes leptin, resistin, and complement-related proteins. The latter group is distinguished from the former by the evidence that at least one major function of molecules in the latter group is both adipose-specific and endocrine. Consequently, this article focuses on the latter group. Among these, complement proteins D, B, and C3 constitute the well-established proximal alternate complement pathway in the immune system. These functions will not be addressed here because such information is readily available in textbooks and is not clearly related to complement proteins’ proposed function as adipocyte hormones (Volanakis and Frank, 1998). This paper is concerned with these molecules as adipose-derived signals. |
Leptin |
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TopAbstractIntroductionLeptinResistinComplement-Related ProteinsSummary and ConclusionImplicationsLiterature Cited |
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), knowledge of its existence had been established much earlier. Ingalls et al. (1950) reported the occurrence of a single gene mutation that disposed mice to become morbidly obese and diabetic at an early age. Associated with the phenotype were slow basal metabolic rate, increased feed intake, and infertility due to lack of gonadotropin secretion. These are characteristics exhibited by wild-type mice following feed restriction. Coleman (1973) used parabiosis to establish a link between the ob gene and production of a blood-born regulatory molecule. Blood from a normal mouse (containing leptin) can correct the aberrant feed intake and blood glucose of an ob/ob mouse.
Once cloned, leptin was quickly established as an endocrine signal (Zhang et al., 1994). It is produced specifically by adipocytes, secreted, and transported in blood to receptors in numerous tissues. Multiple receptor molecules are expressed (Tartaglia, 1997), including a long form with 303 residues of intracellular domain, and a short form with only 34 intracellular AA. These forms have identical extracellular domains. Another mouse mutation that causes obesity (db) is a mutation of the leptin receptor gene. The short form of leptin receptor is conspicuously expressed in choroid plexus, exhibits nanomolar affinity for leptin, and may function to regulate transport of serum leptin across the blood-brain barrier (Malik and Young, 1996). Schwartz et al. (1996) observed that cerebrospinal fluid leptin concentration is correlated with plasma leptin, which is correlated with body mass index in humans. Central administration of recombinant leptin has reliably reduced feed intake and body fatness in leptin-deficient mice. Peripheral administration is also effective, although a greater dosage is required (e.g., Pellymounter et al., 1995). This indicates that a major site of leptin action is within the brain. This model is supported by the finding of long-form leptin receptors associated with neuropeptide Y (NPY) neurons in the hypothalamus (Stephens et al., 1995). These authors further reported that leptin administration caused an inhibition of NPY production. Given that NPY is a potent feeding stimulant and an inhibitor of sympathetic tone, at least part of the function of leptin may be mediated through NPY. Consistent with this notion, Erickson et al. (1996) demonstrated that disruption of NPY expression could moderate effects of leptin deficiency. This putative action of leptin on NPY expression may further depend on an intermediate signal through melanocortin-4 receptors (Zemel, 1998). In spite of the preponderance of evidence that the central nervous system is a major site of leptin action, Huan et al. (2003) recently reported that inhibition of leptin receptor expression in adipocytes could produce many of the symptoms that accompany total leptin deficiency. It should be noted that although leptin administration can produce profound effects on energy expenditure and feed intake when compared with the leptin-deficient state, administration of leptin to normal or obese hyperleptinemic mice or people produces unremarkable effects. This has lead to the notion that leptin functions to guard against starvation rather than to prevent obesity (Rosenbaum et al., 2002).
The role of leptin in reproduction was first indicated by the observation that homozygous ob/ob mice are sterile (Ingalls et al., 1950). It was later determined that exogenous leptin can correct sterility and furthermore can speed the onset of puberty (Chehab et al., 1996; Cheung et al., 1997). Based on push-pull perfusion experiments, it seems likely that leptin acts on, or very close to, GnRH neurons to facilitate secretion of gonadotropins (Watanobe, 2002).
To briefly summarize, in the mouse, leptin seems to be a major signal from adipocytes that indicates increased body fatness to the brain and consequently promotes basal metabolism, inhibits feeding, and permits gonadotropin secretion. These three actions are relevant to animal agriculture, and there is accumulating evidence that leptin performs a related role in livestock species as well.
Serum concentration of leptin in sheep and cattle varies according to the model that this protein is a signal of body energy stores. A 65-d feed restriction caused reductions in both body fat and serum leptin concentration in ovariectomized ewes (Delavaud et al., 2000). Similarly, a 48-h fast decreased leptin mRNA content in adipose and protein in serum of prepubertal heifers (Amstalden et al., 2000). Pregnant cows exhibited a decline in serum leptin at parturition and during the negative energy balance associated with lactation (Liefers et al., 2003). Furthermore, Garcia et al. (2002) reported a rise in serum leptin concentration that correlated with onset of puberty in heifers. Thus, in at least these two ruminant species, it appears that the leptin signal reflects energy status. There is also evidence that the action of leptin in ruminants parallels that in rodents. Central infusion of leptin can suppress feeding in ewes and was also shown to increase LH secretion in cows (Henry et al., 1999; Amstalden et al., 2002). Perhaps leptin acts via the long form of the leptin receptor, which has been detected in the hypothalamus, anterior pituitary, and adipose tissue of ewes (Dyer et al., 1997). In the pig, leptin expression responded to an acute fast, but not to a moderate long-term feed restriction (Spurlock et al., 1998; McNeel et al., 2000). McNeel et al. (2000) observed a greater concentration of leptin mRNA in adipose tissue of obese vs. lean pigs. This is consistent with the model that leptin expression reflects body fatness. Injection of leptin in pigs caused modest elevation of serum free fatty acid concentration (Ajuwon et al., 2003).
That adipocytes function as endocrine cells in the rodent models is clear, although much is still to be learned about how leptin mediates its functions. Similarly, evidence derived from studies of livestock species encourages an interpretation that leptin is a signal of energy status in farm animals. Whether leptin protein will ever be applied clinically is uncertain. However, our understanding of how growth and reproductive traits are controlled has improved as a result of investigating leptin. This is taking us closer to novel methods of improving livestock management. Perhaps it is possible to use leptin’s gonadotropin-stimulating effect to facilitate reproduction in spite of marginal nutritional status. In addition to the technical hurdles of finding means of delivering a leptin-like stimulation, the stimulation of gonadotropin secretion will need to be distinguished from the additional leptin effects of sympathetic stimulation (which increases energy expenditure) and its depressing effect on feed consumption. This will require further understanding of leptin signaling in the central nervous system.
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Resistin |
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TopAbstractIntroductionLeptinResistinComplement-Related ProteinsSummary and ConclusionImplicationsLiterature Cited |
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). Steppan et al. (2001) identified resistin mRNA by selectively cloning cDNA from a mouse adipocyte clonal cell line (3T3-L1) that was differentially expressed following treatment with a TZD. This group then demonstrated that resistin mRNA directs synthesis of a 94-residue mature protein that is secreted. Resistin mRNA was found predominantly in white adipose tissue of mice, and at a lower level in brown adipose and mammary tissues, although not in any other tissue. Its expression is markedly reduced by the TZD rosiglitazone. Hartman et al. (2002) subsequently shed light on how this is mediated. They described and supported a mechanism involving CCAAT/enhancer-binding protein (C/EBP). Resistin expression can be attained in nonadipocytes simply by ectopic expression of C/EBP. The C/EBP recruits coactivators p300 and a ligand of cAMP-response element binding protein (CREB) called CREB-binding protein. This sequence leads to histone acetylation, which is apparently a prerequisite to resistin expression because the interaction of TZD with PPAR- prevents histone acetylation and resistin gene expression. Others have reported that expression of resistin is rapidly induced by growth hormone (Delhanty et al., 2002). Perhaps systemic, insulin-antagonistic effects of growth hormone are in part mediated by resistin.
Resistin-like molecules (RELM)- and -ß, with 29 and 37% sequence identity to resistin, are also expressed by adipose (RELM-) and various (RELM-ß) tissues. Blagoev et al. (2002) reported that resistin can dimerize with itself or with RELM-, and that this oligomerization is requisite to biological activity. Biological activities of resistin known thus far include: 1) impairment of glucose tolerance in mice in vivo, 2) antagonism of glucose uptake by cultured 3T3-L1 adipocytes, 3) inhibition of C2C12 myoblast differentiation into myotubes, and 4) inhibition of 3T3-L1 differentiation into adipocytes (Kim et al., 2001). Resistin’s effect on adipocyte differentiation is probably not related to proliferation because resistin did not promote cell division (Blagoev et al., 2002). No studies of resistin in livestock species have as yet been published. However, given that resistin inhibits differentiation of myoblasts, it will likely receive significant attention.
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Complement-Related Proteins |
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TopAbstractIntroductionLeptinResistinComplement-Related ProteinsSummary and ConclusionImplicationsLiterature Cited |
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first linked adipose tissue with complement proteins by ascertaining that complement factor D (adipsin) is expressed specifically by differentiated adipocytes, and to some extent, in lung and sciatic nerve. They established that adipsin is constitutively secreted, and they stimulated interest by reporting the serum concentration of adipsin is severely reduced in most rodent models of obesity (Cook et al., 1987; Flier et al., 1987). Adipsin is expressed in other mammals, including the pig, although its expression is not limited to adipose. High levels of adipsin mRNA were also found in all regions of the digestive tract and spleen (Miner et al., 2001). Unfortunately, convincing support for early speculation that adipsin may be causative to obesity has not been forthcoming. However, a closely related complement protein has emerged as a candidate regulator of lipid accumulation in adipocytes.
Complement Factor C3a-desArg (Acylation-Stimulating Protein)
In a search for causes of hyperapobetalipoproteinemia in humans, Cianflone et al. (1990) purified a 9-kD protein from serum, which is as potent as insulin at stimulating fatty acid esterification. This protein is a product of complement D enzymatic activity (complement C3a) less its N-terminal arginine, which is almost certainly removed by the ubiquitous carboxypeptidase N (Baldo et al., 1993). Adipocytes secrete complement proteins B, C3, and adipsin (Choy et al., 1992). Complement proteins B and C3 can form a complex, and once formed, this complex is cut by adipsin. Products of the adipsin-catalyzed reaction include complement C3a, which is rapidly dearginated to form acylation-stimulating protein (ASP). Formation rate of C3a seems to be determined by secretion of C3. Secretion of C3 is stimulated by chylomicrons (Maslowska et al., 1997).
Chylomicrons transport triacylglycerol from the intestine to peripheral tissues. In addition, chylomicrons transport vitamin A in complex with transthyretin, which presumably facilitates uptake of vitamin A into adipocytes (Scantlebury et al., 2001). Oxidation of vitamin A within an adipocyte yields retinoic acid, which is a ligand for nuclear receptors including retinoic acid receptors (RAR) and retinoid X receptors (RXR; Villaroya et al., 1999). Dependent on ligand binding, RXR can heterodimerize with RAR and interact with gene regulatory regions. Furthermore, RXR can heterodimerize with other nuclear receptors, including thyroid hormone receptor, vitamin D receptor, and multiple PPAR (reviewed by Kersten et al., 2000). Thus, depending on its concentration, retinoic acid can influence transcription of numerous genes in adipose cells. It can promote adipocyte differentiation at low doses and block differentiation at high doses (Scantlebury et al., 2001). Interestingly, manipulation of RXR and RAR activity by dietary vitamin A has been proposed as a means for influencing marbling in cattle (Ohyama et al., 1998). In keeping with the current discussion, though, acylation stimulating protein production is apparently regulated by chylomicrons by virtue of the vitamin A in these particles. This mechanism also seems to account for the observation that consumption of a high-fat meal by humans can increase production of ASP in adipose tissue, whereas a fast causes plasma ASP concentration to decrease (Cianflone et al., 1989, 1995).
The decrease in plasma ASP caused by fasting may partly account for the elevation of circulating FFA in this metabolic state. Acylation-stimulating protein is a potent stimulant of fatty acid esterification in adipocytes, whereas net uptake or release of fatty acids is determined by the rates of both esterification and lipolysis. To stimulate esterification, ASP must bind a specific receptor (C5L2), to which its affinity is approximately 70 nM (Kalant et al., 2003). Although the mechanism of ASP-stimulated signaling by this receptor has not been definitively described, there is evidence of protein kinase C involvement (Baldo et al., 1995). Binding of ASP to adipocytes leads to enhanced activity of diacylglycerol acyltransferase, which catalyzes the presumed rate-limiting step in fatty acid esterification to form triacylglycerol (Yasruel et al., 1991). Mice mutated to preclude ASP synthesis exhibit reduced body fat, reduced serum leptin concentration, and delayed triglyceride clearance. Genetic knockout of ASP in the leptin deficient ob/ob mouse can produce these effects as well as an increase in energy expenditure (Xia et al., 2002). Apparently, treatments that limit fatty acid storage consequently promote fuel oxidation, as observed in other models, such as the diacylglycerol acyltransferase knockout mouse (Smith et al., 2000) and the acetyl CoA carboxylase knockout mouse (Abu-Elheiga et al., 2003).
In addition to stimulating fatty acid esterification, ASP may function in regulation of both insulin secretion and feed intake. Ahren et al. (2003) observed that ASP causes an increase in glucose-stimulated insulin secretion by the INS-1 clone of islet beta cells. Schupf et al. (1983) found that C3a could enhance the hyperphagic response to hypothalamic norepinephrine injection. Given that C3a can bind the ASP receptor (C5L2) and that C3a is rapidly converted to ASP in vivo, it can be reasonably postulated that the hyperphagic response to C3a was, or could be, mediated by ASP as well. Although any conclusions concerning the role of ASP in regulation of insulin secretion or feed intake should be tentative, these putative functions indicate an endocrine action of ASP.
In summary of the alternate complement protein/adipocyte story, adipsin, factor B, and factor C3 are each secreted by adipocytes. Following secretion, adipsin and carboxypeptidase N enzymatic activities generate ASP. Production of ASP is stimulated by chylomicrons, which also supply fatty acids to adipose tissue. Esterification of fatty acids in adipocytes is potently stimulated by ASP. This function of ASP is probably autocrine or paracrine, but may be endocrine as well. The concentration of ASP in blood rises following fat consumption. It may further have a role in stimulation of insulin secretion and perhaps in feed intake regulation, although evidence for these latter roles is weak. Most of what we know about ASP is based on the mouse and human studies; however, the available evidence indicates a similar role for ASP in livestock. Porcine ASP, purified from serum, stimulates esterification in human adipocytes with a potency equal to that of human ASP (Zhang et al., 2001). Human ASP can stimulate esterification in bovine adipose explants, although this effect is not as great as that observed using isolated human adipocytes (Jacobi et al., 2002). However, this variation can probably be attributed to technical differences between tissue explants and isolated cells given that mouse adipose explants are similarly unresponsive despite the fact that mouse adipocyte monolayers are quite responsive.
Adipocyte Complement-Related Protein (Adiponectin)
Adiponectin was first described by Scherer et al. (1995). Although not truly a complement protein, the critical globular domain of adiponectin has much homology to complement protein C1q. It is secreted only by differentiated adipocytes and circulates in blood. Many insulin resistance models exhibit reduced serum adiponectin and mutations that preclude adiponectin expression can lead to insulin resistance (Kubota et al., 2002). Adiponectin monomers can form trimers, hexamers, and even higher-order multimers, and these oligomerizations influence its biological activity (Tsao et al., 2002). Exogenous adiponectin can stimulate fatty acid oxidation by muscle and can inhibit glucose output by hepatocytes (Berg et al., 2001). Stimulation of fatty acid oxidation in muscle can be achieved by monomers of the globular adiponectin domain (Tsao et al., 2002). However, inhibition of glucose output by hepatocytes is achieved by only hexamer, or higher order, complexes of adiponectin. These multimers activate a transcription factor called NF-
B by triggering degradation of its inhibitor (Tsao et al., 2002). Yamauchi et al. (2003) identified two adiponectin receptors. The first, called AdipoR1, is specifically expressed in muscle. The second, called AdipoR2, is specifically expressed in liver. The muscle receptor responds to adiponectin globular domain fragments. The liver receptor, on the other hand, is only stimulated by full-length adiponectin oligomers and it activates the nuclear receptor PPAR-. Adiponectin secretion is stimulated by exposure of adipocytes to PPAR- agonists and thereby may account for the insulin-sensitizing effect of such ligands, including the TZD (Combs et al., 2002).
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Summary and Conclusion |
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TopAbstractIntroductionLeptinResistinComplement-Related ProteinsSummary and ConclusionImplicationsLiterature Cited |
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stimulate adiponectin production and inhibit resistin production. Both actions serve to enhance peripheral insulin sensitivity. Retinoic acid can inhibit PPAR- activation, presumably by enhancing heterodimerization of RAR with RXR, thereby making RXR unavailable for dimerization with PPAR-. Retinoic acid can inhibit production of both leptin and adiponectin (Zhang et al., 2002). Retinoic acid also can stimulate production of ASP. Seemingly counterproductive effects of retinoic acid may be a function of the concentrations of retinoic acid used in experiments, given that this ligand can have opposing actions, depending on its concentration. Regardless, the connection of ASP, leptin, adiponectin, and resistin to nuclear receptors that are known to cross talk and to be modulated by nutrients is intriguing. In addition to probable roles in regulation of adipose metabolism, some of these adipocyte-derived molecules have been directly linked to other physiologies of interest to animal scientists. Resistin can inhibit differentiation of muscle cells. Leptin can inhibit feed intake and its absence inhibits gonadotropin production. To the extent that the function of these signaling molecules in livestock species parallels their apparent function in mice, they represent targets for manipulation. It is hoped that investigating the function of these molecules will reveal other biological mechanisms that ultimately form the basis of agricultural applications. |
Implications |
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TopAbstractIntroductionLeptinResistinComplement-Related ProteinsSummary and ConclusionImplicationsLiterature Cited |
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Footnotes |
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2 Correspondence—phone: 402-472-0518; e-mail: jminer1{at}unl.edu.
Received for publication July 11, 2003. Accepted for publication December 11, 2003.
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Literature Cited |
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TopAbstractIntroductionLeptinResistinComplement-Related ProteinsSummary and ConclusionImplicationsLiterature Cited |
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agonists: A potential mechanism of insulin sensitization.Endocrinology 143:998–1007.B signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J. Biol. Chem. 277:29359–29362.This article has been cited by other articles:
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 N Salma, H Xiao, and A N Imbalzano Temporal recruitment of CCAAT/enhancer-binding proteins to early and late adipogenic promoters in vivo J. Mol. Endocrinol., February 1, 2006; 36(1): 139 - 151. [Abstract] [Full Text] [PDF]
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 J. Novakofski Adipogenesis: Usefulness of in vitro and in vivo experimental models J Anim Sci, March 1, 2004; 82(3): 905 - 915. [Abstract] [Full Text] [PDF]
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