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Endocrinology, doi:10.1210/en.2006-0855
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Endocrinology Vol. 147, No. 11 5019-5022
Copyright © 2006 by The Endocrine Society

Adiponectin Deficiency Does Not Affect the Inflammatory Response to Endotoxin or Concanavalin A in Mice

Maria Pini, Joseph A. Sennello, Lawrence Chan and Giamila Fantuzzi

Department of Human Nutrition (M.P., J.A.S., G.F.), University of Illinois at Chicago, Chicago, Illinois 60612; and Department of Molecular and Cellular Biology (L.C.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Giamila Fantuzzi, Department of Human Nutrition, University of Illinois at Chicago, 1919 West Taylor Street, MC 517, Chicago, Illinois 60612. E-mail: giamila{at}uic.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Conclusions
 References
 
Adiponectin (APN) is an adipocyte-derived protein that regulates insulin sensitivity and displays antiinflammatory activities in a variety of experimental models. The present study aimed at investigating the effect of APN deficiency on the inflammatory response to endotoxin (lipopolysaccharide, LPS) and Concanavalin A (ConA) in vivo in mice. Administration of a high dose of LPS (100 µg/mouse) induced production of comparable amounts of IL-6, TNF{alpha}, and interferon-{gamma} in wild-type (WT) and APN knockout (KO) mice. Furthermore, LPS-induced hypoglycemia, anorexia, and body weight loss did not differ between WT and APN KO mice. Administration of a low dose of LPS (100 or 10 ng/g) in association with D-galactosamine induced equivalent mortality rates, hepatotoxicity, and serum IL-6 in WT and APN KO mice. Finally, ConA-induced cytokine production and hepatotoxicity were not significantly different between WT and APN KO mice. These data indicate that—despite its well-described role as an antiinflammatory molecule—endogenous APN does not play a critical role in modulating the inflammatory responses to LPS and ConA in mice.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Conclusions
 References
 
ADIPONECTIN (APN) IS a protein produced and secreted mainly by adipocytes and is therefore a member of the adipokine family (1). Adiponectin is present in blood of healthy individuals at concentrations of approximately 5–20 µg/ml (1) and shares structural homologies with complement factor C1q and with the cytokine TNF{alpha} (1). The APN monomer is composed of a collagenous and a globular domain: APN monomers assemble into trimers, which further polymerize to various degrees, leading to the presence of several molecular weight forms of APN in the circulation (2). Furthermore, APN can be cleaved by elastase, resulting in the generation of a free globular domain, which may have distinct biological functions (3).

APN exerts its activity by binding to specific seven-transmembrane domain receptors, which have been cloned and named ADIPOR1 and ADIPOR2 (4). These receptors are expressed by a variety of cell types and signal through multiple pathways, including AMP kinase and p38 MAPK (4). In addition to binding to its own receptors, APN can also act as a decoy for several growth factors (5), thus impeding them from binding and activating their respective receptors and therefore effectively preventing their bioactivity. Furthermore, APN binds to T cadherin, although the biological significance of this interaction is still unclear (6).

The biology of APN has mostly been investigated in the context of insulin sensitivity and atherosclerosis. A strong epidemiological relationship between low circulating APN and diabetes, metabolic syndrome, and cardiovascular disease has been reported (1). In accordance, several antiinflammatory effects have been described for APN, including inhibition of TNF{alpha} production and activity, inhibition of nuclear factor-{kappa}B activation, induction of antiinflammatory cytokines, and down-regulation of adhesion molecules (7). Based on these observations and on the protective role of APN in cardiovascular disease, this adipokine is generally considered as an antiinflammatory molecule. In particular, it has been suggested that APN might play a protective role in the experimental models of systemic inflammation induced by administration of endotoxin (lipopolysaccharide, LPS) or Concanavalin A (ConA) in mice. Administration of APN reduced liver damage in the model of hepatotoxicity induced by administration of D-galactosamine (GalN) and LPS to obese mice by inhibiting production of TNF{alpha} (8). A suggested mechanism by which this inhibition might occur is the ability of APN to bind and possibly inactivate LPS (9, 10). Recently, it has been demonstrated that APN deficiency exacerbates liver injury in the model of GalN and LPS administration (11). Furthermore, administration of APN is protective in the model of liver damage induced by administration of ConA, possibly by modulating production of IL-10 as well as TNF{alpha} bioactivity (12, 13).

The present study was performed to investigate the effect of APN deficiency on the inflammatory response to LPS and ConA. Based on the previously available evidence of APN acting as an antiinflammatory molecule, we hypothesized that APN-deficient [APN knockout (KO)] mice would develop a more severe inflammatory response compared with their wild-type (WT) littermates. However, in contrast to our expectations, the results obtained indicate that APN deficiency does not significantly alter the in vivo inflammatory response to LPS or ConA in mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Conclusions
 References
 
Materials
LPS (a phenol-extracted preparation from Escherichia coli), GalN, and ConA were purchased from Sigma Chemical Co. (St. Louis, MO).

Animals and treatments
Care of mice followed institutional guidelines under protocols approved by the Institutional Animal Care and Use Committee at the University of Illinois at Chicago. Adiponectin KO mice were generated as previously described (14). Mice were in a C57BL6 background. Mice heterozygous for APN were mated and 8- to 10-wk-old littermates used for each experiment. Mice were genotyped by PCR of tail DNA, and APN deficiency was confirmed in each mouse by measuring serum APN using a specific ELISA (R&D Systems, Minneapolis, MN). No significant differences in terms of serum APN levels were observed between +/+ and +/– mice. Therefore, mice of both genotypes were used and are collectively defined as WT throughout the remaining of the report.

LPS was administered ip at either 100 µg/mouse alone or at 10 or 100 ng/g body weight in association with GalN (800 µg/g body weight). ConA was administered iv at a dose of 100 µg/mouse. Serum samples were obtained from the retroorbital plexus at various times after administration of LPS or ConA. For evaluation of survival, anorexia and body weight, mice received injections of LPS or LPS + GalN and were monitored every 24 h without any further intervention.

Serum alanine aminotransferase (ALT), glucose, and cytokine measurement
Serum levels of ALT were determined using a colorimetric method (TECO Diagnostics, Anaheim, CA). Glucose levels were measured using a glucometer (Bayer, Leverkusen Germany). Levels of IL-6, TNF{alpha}, and interferon (IFN) {gamma} were determined using commercially available ELISA kits, specific for murine cytokines, according to the manufacturer’s protocol. Kits for IL-6 were from BD Biosciences (San Jose, CA), whereas kits for TNF{alpha}, and IFN{gamma} were from e-Biosciences (San Diego, CA).

Statistical analysis
ANOVA using Fisher’s least significant difference was used. Data are expressed as the mean ± SEM. Differences were considered significant for P < 0.05.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Conclusions
 References
 
Evaluation of mouse genotype and confirmation by ELISA of serum APN levels
Each of the mice used in the experiments described below was genotyped for the presence or absence of WT and mutated alleles of the APN gene by PCR of tail DNA. Because the strain of APN KO mice we used does not display an obvious phenotype, genotype was confirmed in each mouse by evaluating serum APN levels by ELISA. On average, serum APN levels were 9.10 ± 1.72 µg/ml (mean ± SEM, n = 35) in WT mice and were always below detection limit (30 pg/ml) in each APN KO mouse, thus confirming the absence of APN production in each of the APN KO mice used.

Response of WT and APN KO mice to high-dose LPS
To investigate the role of endogenous APN in the response to a high dose of LPS, WT and APN KO mice were injected with 100 µg/mouse of LPS and their response evaluated in terms of cytokine production, glycemia, anorexia, and body weight loss.

As shown in Table 1Go, LPS induced a marked increase in serum levels of IL-6, TNF{alpha}, and IFN-{gamma} in both WT and APN KO mice. In contrast to our hypothesis that APN deficiency would lead to an enhanced inflammatory response, no significant differences were observed between WT and APN KO mice for any of the cytokines measured. Thus, endogenous APN does not appear to be a critical modulator of cytokine production in response to LPS in vivo.


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  		TABLE 1. Serum cytokine levels after administration of high-dose LPS

 
TNF{alpha} is an essential mediator of LPS toxicity, and we previously reported that APN modulates TNF{alpha} bioactivity in vitro (13). Therefore, even in the presence of comparable amounts of TNF{alpha} in WT and APN KO mice, these latter could be more susceptible to the toxic effects of TNF{alpha}. To clarify this issue, we investigated whether the cytokine-mediated effects of LPS toxicity were influenced by the absence of APN. As shown in Fig. 1Go, serum glucose levels were not significantly different between vehicle-injected (non-LPS treated) WT and APN KO mice, as previously reported for this strain of APN KO mice (14). A significant decrease in serum glucose levels was observed 2 and 6 h after injection of LPS in both WT and APN KO mice, with no significant difference in the magnitude of the response between the two groups. Similar results were obtained when the effect of LPS in inducing anorexia and body weight loss was evaluated. Initial body weight was not significantly different between WT and APN KO mice (27.90 ± 1.80 and 26.52 ± 2.61 g in WT and APN KO mice, respectively). As shown in Fig. 2Go, APN KO and WT mice lost a similar percent of body weight following an overlapping kinetics in response to LPS administration. Baseline food intake was not significantly different between WT and APN KO mice (3.3 ± 0.38 and 3.0 ± 0.14 g/mouse·d, respectively). Administration of LPS led to a 52% decrease in food intake in the following 24 h in both WT and APN KO mice. By 48 h after LPS injection, food intake had completely recovered to baseline levels in both groups of mice.


Figure 1
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  		FIG. 1. Effects of high-dose LPS on glycemia in WT and APN KO mice. WT (closed bars) and APN KO (open bars) mice were injected ip with 100 µg/mouse of LPS or vehicle and blood obtained 2 or 6 h thereafter for glucose evaluation. Data are mean ± SEM of five to eight mice per group. *, P < 0.05; **, P < 0.01 vs. respective vehicle.

 

Figure 2
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  		FIG. 2. Effects of high-dose LPS on body weight in WT and APN KO mice. WT (closed symbols) and APN KO (open symbols) mice were weighed daily, injected ip with 100 µg/mouse of LPS on d 4 (arrow), and followed until d 7, when their body weight had fully recovered to levels not significantly different from d 1. Data are mean ± SEM of five to eight mice per group. **, P < 0.01 vs. respective d 1.

 
Our data demonstrate that APN is not a pivotal mediator of the inflammatory response to high doses of LPS. Deficiency in APN does not result in altered cytokine production or responsiveness to the effects of endogenously produced cytokines in this model. Furthermore, although APN has been proposed to act as an LPS-binding protein, our data suggest that interaction between APN and LPS does not significantly modulate LPS bioactivity when LPS is administered in vivo at high doses.

Response of WT and APN KO mice to low-dose LPS
To investigate whether APN deficiency is associated with alterations in the response to low doses of LPS, we used the well-characterized model of injection of very low doses of LPS in association with GalN. This model has previously been used to demonstrate a beneficial effect of administration of exogenous APN in obese mice (8). Recently, Matsumoto et al. (11) used this model to demonstrate increased lethality and hepatotoxicity and altered cytokine production in a strain of APN KO mice that was generated independently from the one we used.

WT and APN KO mice received an ip injection of GalN immediately followed by administration of LPS at either 100 or 10 ng/g, and survival was evaluated. One hundred percent lethality (7/7 in WT and 6/6 in APN KO mice) was observed in both WT and APN KO mice 5–6 h after administration of LPS at 100 ng/g. When the lower dose of 10 ng/g was used, lethality was 0% in both groups. Using this lower dose, the effect of LPS + GalN on liver damage and IL-6 production was evaluated. As shown in Fig. 3Go, LPS-induced serum ALT and IL-6 levels were not significantly different between the two groups.


Figure 3
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  		FIG. 3. Effect of low-dose LPS + GalN on ALT (A) and IL-6 (B) levels in WT and APN KO mice. WT (closed bars) and APN KO (open bars) mice were injected ip with LPS and GalN. Serum was obtained 5 h later for evaluation of ALT and IL-6 levels. Data are mean ± SEM of five to eight mice per group.

 
Our results are in stark contrast with data reported by Matsumoto et al. (11) and briefly discussed above. The same type of LPS and similar doses of LPS and GalN were used in both studies; mice were in the C57BL6 strain in both cases. Therefore, it is unlikely that differences in the experimental procedures could account for the results’ discrepancy. These two strains of APN KO mice differ in terms of insulin sensitivity: the strain used by Matsumoto et al. develops severe insulin resistance in response to a high-fat diet (15), in agreement with data more recently reported on a third strain of APN KO mice (16). A fourth strain of APN KO mice displays yet a different phenotype, with development of insulin resistance under a regular chow diet (17). In contrast, in the strain of APN KO mice we used, no significant differences in terms of insulin resistance are observed between WT and KO mice in response to high-fat feeding or under regular chow feeding (14). Thus, a potential explanation for the discrepancy between our current data and those recently reported by Matsumoto et al. (11) may lie in the putative confounding effect of metabolic alterations present in their strain of APN KO mice but absent in the mice we used. Altered response to LPS and GalN administration have been reported in the NOD model of type I diabetes, indicating the possibility that different patterns of insulin sensitivity might influence the inflammatory response in this experimental model (18).

Response of WT and APN KO Mice to ConA
Data previously reported by our group as well as by Wolf et al. (12, 13) indicated that APN—possibly produced locally in the liver—plays a protective effect against ConA-induced hepatotoxicity by modulating production of IL-10 and the response to the hepatotoxic effects of TNF{alpha}. To investigate the role of endogenous APN in the response to ConA, WT and APN KO mice were injected with 100 µg of ConA or vehicle and their response evaluated at 2, 6, and 24 h in terms of serum ALT levels as well as production of various cytokines. As indicated in Table 2Go, no significant differences between WT and APN KO mice were observed for any of the parameters evaluated. Similar results were obtained when mice received a lower dose of ConA, 50 µg/mouse (serum ALT were 1856 ± 1144 and 1295 ± 964 IU/liter in WT and APN KO at 24 h, respectively).


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  		TABLE 2. Serum ALT and cytokine levels after administration of ConA

 
Thus, in agreement with data reported above for the LPS models, APN appears to play a nonessential role also in the model of ConA-induced hepatotoxicity.


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Conclusions
References
 
The present report demonstrates that APN deficiency is not associated with significant alterations in the inflammatory response to LPS or ConA in mice. Although we cannot exclude the possibility that an alternative antiinflammatory mechanism might be up-regulated in APN KO mice, these data indicate that APN is not an essential modulator of inflammation in the models used. It is important to note that contrasting results have recently been obtained with one of the models we employed (LPS + GalN) using a different strain of APN KO mice. Given the variability in the phenotype of APN KO mice reported by the four groups that have currently independently developed them, it will be important in future studies to perform side-by-side comparisons of the various strains to better clarify the mechanisms for the observed discrepancies. Despite these caveats, our current data indicate the importance of using a variety of models to dissect the role of APN in the modulation of the inflammatory response.


   Footnotes
 
This work was supported by National Institutes of Health Grants DK061483 (to G.F.) and DK68037 and HL51586 (to L.C.).

Disclosure statement: The authors have nothing to disclose.

First Published Online August 10, 2006

Abbreviations: ALT, Alanine aminotransferase; APN, adiponectin; ConA, Concanavalin A; GalN, D-galactosamine; KO, knockout; LPS, lipopolysaccharide; WT, wild type.

Received June 23, 2006.

Accepted for publication August 1, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Conclusions
 References
 

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