J. Anim Sci. 2008. 86:3377-3384. doi:10.2527/jas.2008-0971
© 2008 American Society of Animal Science
ANIMAL GROWTH, PHYSIOLOGY, AND REPRODUCTION |
Fasting regulates the expression of adiponectin receptors in young growing pigs1
B. H. Liu*,2,
P. H. Wang*,2,
Y. C. Wang*,
W. M. Cheng*,
H. J. Mersmann
,3 and
S. T. Ding*,,4
* Department of Animal Science and Technology, and
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan
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Abstract
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Adiponectin is an adipocyte-derived hormone that can improve insulin sensitivity. Its functions in regulating glucose utilization and fatty acid metabolism in mammals are mediated by 2 subtypes of adiponectin receptors (AdipoR1 and AdipoR2). This study was conducted to determine the effect of fasting on the expression of adiponectin and its receptors. The expression of adiponectin was not affected in s.c. adipose tissue, but adiponectin expression increased in visceral adipose tissue after fasting. In contrast, expression of both AdipoR mRNA was increased in the liver and s.c. adipose tissue of 24-h-fasted pigs compared with fed pigs, but the mRNA in muscle and visceral adipose tissue was not affected by fasting. A third putative adiponectin receptor, T-cadherin, was cloned and the mRNA expression was determined. T-Cadherin has been recognized to act as a vascular adiponectin receptor in vascular endothelial and smooth muscle cells. Our data showed that the expression of T-cadherin was decreased in the muscle of fasted pigs, suggesting that the expression of T-cadherin can be regulated by feeding status. In summary, in young pigs, adiponectin mRNA was up-regulated by fasting in visceral, but not s.c., adipose tissue, whereas AdipoR1 and AdipoR2 mRNA were increased in s.c., but not visceral, adipose tissue. The adiponectin receptor, T-cadherin, was expressed in s.c. and visceral adipose tissue and in muscle, but only muscle mRNA expression was decreased by fasting.
Key Words: adiponectin • adiponectin receptor • pig • T-cadherin
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INTRODUCTION
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Adiponectin is an adipokine abundantly produced by adipocytes (Scherer et al., 1995
; Hu et al., 1996). Administration of adiponectin to mice decreases plasma glucose, FFA, and triacylglycerols, increases muscle fatty acid oxidation and induces BW loss (Fruebis et al., 2001). Decreased circulating adiponectin concentrations are associated with insulin resistance, obesity, and type 2 diabetes (Yamauchi et al., 2001; Spranger et al., 2003). Moreover, exogenous adiponectin can be detected in cerebrospinal fluid (Qi et al., 2004; Kusminski et al., 2007), and can increase AMP-activated protein kinase (AMPK) activity through adiponectin receptors to stimulate food intake in adiponectin-deficient mice (Kadowaki et al., 2008). Therefore, adiponectin has been recognized as one of the key adipokines in the regulation of glucose and lipid metabolism.
The adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2) are widely expressed in many tissues, including the liver, muscle, heart, adipose tissue, and hypothalamus (Yamauchi et al., 2003; Ding et al., 2004; Kubota et al., 2007). A third receptor, T-cadherin, binds high molecular weight (HMW) adiponectin in vascular endothelial and smooth muscle cells (Hug et al., 2004). To clarify the nutritional regulation of adiponectin receptors in pigs, we cloned the full-length cDNA for porcine AdipoR genes (Ding et al., 2004) and found that fasting for 8 h increases the expression of AdipoR2 in s.c. adipose tissue (Ding et al., 2004). In this study, we cloned the full-length porcine T-cadherin and determined the expression of adiponectin and its receptors after 24 h of fasting in young, growing pigs.
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MATERIALS AND METHODS
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The animal protocol was approved by the Experimental Animal Care and Use Committee at National Taiwan University.
Fasting and Feeding Animals
Four male and 4 female crossbred pigs (Sus domesticus; sows were predominantly Landrace-Yorkshire crossbreds mated to a Duroc boar) were weaned at 28 d of age and fed a commercial diet (a corn, soybean meal-based diet containing 18% CP and 4% fat on an as-fed basis) ad libitum and raised to 60 d of age for the experiment. Before the experiment, crossbred pigs were randomly divided into fasting and feeding groups, and there was no significant difference between average BW in the 2 genders. Young pigs were studied to produce data that amplified the results of many previous studies from this laboratory regarding adipose tissue growth and metabolism in young pigs (Ding et al., 2004; Liu et al., 2005a,b). Furthermore, based on the work of Kyriazakis and Emmans, (1992) with pigs of a similar age to pigs in the current study, the effect of sex on growth and body composition was expected to be minimal. Fed pigs were killed by electrical stunning coupled with exsanguination at 1000 h after feeding at 0800 h, whereas the fasted group was killed after fasting for 24 h. This fasting time was selected because plasma metabolites (Pond and Mersmann, 2001) and adipose tissue lipogenic rates are stabilized (Mersmann et al., 1981; McNeel and Mersmann, 2000). Liver, LM, visceral adipose tissue from the greater omentum, and s.c. adipose tissue from the dorsal shoulder region were dissected, frozen in liquid N2, and stored at –80°C until RNA extraction. The average BW of pigs for both treatments was 20.4 ± 0.66 kg when killed.
Northern Blot Analysis
Total RNA was extracted by the guanidinium-phenol-chloroform extraction method (Chomczynski and Sacchi, 1987). The integrity of RNA was determined by examination of the 18S and 28S ribosomal RNA bands after electrophoresis. The RNA was quantified spectrophotometrically at 260 nm (NanoDrop, Wilmington, DE) and stored at –80°C. Total RNA (10 µg of each sample) was electrophoresed and transferred to nylon membranes for Northern blot analysis. The porcine adiponectin, AdipoR1, AdipoR2, and β-actin probe sequences were described previously (Ding et al., 2004; Liu et al., 2005a), whereas the T-cadherin probe (primer pairs 3) is described below and in Table 1. The probes were labeled by deoxycytidine 5'-triphosphate (
-32P) with PCR amplification. Hybridization blotting images were quantified by using a Typhon 9200 phosphorimage scanner and ImageQuant TL v2005 software (GE Healthcare, Piscataway, NJ). The densitometric value for an individual transcript in a sample lane was normalized to the densitometric value for the β-actin mRNA in the same lane. All procedures were described previously (Liu et al., 2005a).
Cloning of the Porcine T-Cadherin
Skeletal muscle total RNA (10 µg) from a crossbred pig was reverse transcribed by using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA). The resulting single-strand DNA was amplified by PCR for 35 cycles, using primer pairs 1 and 2 (Table 1
). The conditions for PCR were denaturation at 98°C for 6 s (30 s in the first cycle), annealing for 25 s, and extension at 72°C for 75 s (5 min in the last cycle). Phusion High-Fidelity DNA Polymerase (Finnzymes, Espoo, Finland) was used to amplify the cDNA. The PCR product for each partial T-cadherin was cloned using the by Zero Blunt TOPO PCR Cloning kit (Invitrogen, Carsbad, CA). The full-length T-cadherin gene was constructed by cleavage with the BglII enzyme and ligated by using the Zero Blunt TOPO PCR Cloning kit. The sequence of the T-cadherin gene was determined (GenBank EU140561).
Statistical Analysis
Data are presented as mean ± SEM. A Student t-test was used to test the effect of fasting on the gene expression of adiponectin, AdipoR1, AdipoR2, and T-cadherin. A significant difference was indicated at P 
0.05.
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RESULTS AND DISCUSSION
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The complete mRNA sequence for porcine adiponectin, AdipoR1, and AdipoR2, as well as tissue distributions and the effect of a short-term fast (8 h) in young pigs have been reported (Ding et al., 2004). Partial mRNA sequences and tissue distributions in relatively mature female pigs of several breeds were subsequently reported (Lord et al., 2005). Porcine adiponectin mRNA is primarily expressed in adipose tissue, whereas the AdipoR1 and AdipoR2 mRNA are expressed in many tissues (Ding et al., 2004; Lord et al., 2005; Dai et al., 2006).
Expression of Adiponectin mRNA
In various mammalian species, adiponectin is expressed in numerous tissues, including heart (Ding et al., 2007), muscle (Lord et al., 2005), pituitary (Rodriguez-Pacheco et al., 2007), osteoblast (Berner et al., 2004), testis (Caminos et al., 2008), placenta (Caminos et al., 2005), ovary (Chabrolle et al., 2007), oviduct (Archanco et al., 2007), and adipose tissues (Ding et al., 2004). In young (Ding et al., 2004) and older (Lord et al., 2005) pigs, adiponectin is expressed primarily in s.c. and visceral adipose tissues. The expression of adiponectin in porcine skeletal muscle was less than in other tissues and may represent expression from intramuscular adipocytes (Lord et al., 2005).
In young pigs, the expression of adiponectin was less in visceral than in s.c. adipose tissue (Figure 1). The result was similar to that observed in humans (Fisher et al., 2002; Lihn et al., 2004). However, in older, relatively mature female pigs, there was no difference in expression between adipose tissue depots (Lord et al., 2005). It is not clear whether the divergent expression in young and older pigs resulted from age or sexual maturity. There may be sexual dimorphism in depot expression of adiponectin after puberty (Xu et al., 2005; Zhang et al., 2007), and testosterone can decrease the secretion of HMW adiponectin in mice and humans (Xu et al., 2005). Lord et al. (2005) determined gene expression in a relatively fat breed and in 2 thinner breeds. Visceral, but not s.c., adipose tissue adiponectin and AdipoR2 mRNA expressions were negatively correlated with body fat. There was no correlation between AdipoR1 and body fat.
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Figure 1. The effect of fasting on adiponectin gene expression in pigs. Samples of liver, LM, visceral adipose tissue (VAT), and subcutaneous adipose tissue (AT) were taken 2 h after feeding (Fed) or 24 h after feeding (Fasted). The total RNA from each tissue of each pig (10 µg) was electrophoresed and transferred to a nylon membrane. The membranes were hybridized with cDNA probes for adiponectin and β-actin. The mRNA abundance was determined by phosphorimage technology and the densitometric value for each gene was normalized to β-actin. The data represent the means of 4 crossbred pigs (2 males and 2 females) per treatment. Data were analyzed by Student’s t-test to evaluate the differences from the fed AT value (set to 100). Each bar represents the mean ± SEM; a value of P 0.05 was considered significant. The asterisk (*) indicates a significant treatment effect.
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An 8-h (Ding et al., 2004) or 24-h (Figure 1) fast did not affect the expression of adiponectin in s.c. adipose tissue. However, the 24-h fast increased expression of visceral adipose tissue adiponectin. The increased adiponectin expression in visceral adipose tissues would be expected to modify lipid and glucose metabolism in the pig. The expression of adiponectin in LM was not affected by fasting (Figure 1). Although not measured in this study, insulin was expected to decrease during fasting (Davis et al., 1997). Insulin decreases plasma adiponectin in patients with type I diabetes (Imagawa et al., 2002) and inhibits the secretion of HMW adiponectin from adipocytes to decrease the function of plasma adiponectin (Basu et al., 2007; Fujikawa et al., 2008). Insulin suppresses the expression of adiponectin in 3T3-L1 adipocytes and porcine primary adipocytes (Fasshauer et al., 2002; Liu et al., 2008).
Expression of AdipoR1 and AdipoR2 Genes
The adiponectin receptors, AdipoR1 and AdipoR2, are expressed in numerous porcine tissues (Ding et al., 2004; Lord et al., 2005), including adipose tissues. There is considerable support for the concept that visceral adipose tissue is a greater contributor to obesity-related pathologies than is s.c. adipose tissue in humans (Fukuhara et al., 2005). Obesity-related insulin resistance is closely associated with visceral fat accumulation and affects the expression of various adipokines in humans and rats (Milan et al., 2002; Fukuhara et al., 2005). Expression of adiponectin and its receptors in human visceral adipose tissue is negatively related to obesity (Nannipieri et al., 2007). The expression of AdipoR2, but not AdipoR1, mRNA is negatively correlated with the amount of porcine visceral, but not s.c., adipose tissue (Lord et al., 2005). Hence, the data suggest differential regulation of AdipoR1 and AdipoR2 by nutritional status in various tissues, even in different adipose tissue depots. Perhaps the regulation of the adiponectin receptors in s.c. adipose tissue and not in visceral adipose tissue in our young pigs reflects the minimal development of visceral adipose tissue at this stage of development.
In rodents, expression of both AdipoR1 and AdipoR2 genes is up-regulated after 48 h of fasting in the liver and muscle (Tsuchida et al., 2004). After an 8-h fast, only the AdipoR2 gene expression was increased in porcine s.c. adipose tissue (Ding et al., 2004), whereas after a 24-h fast, the mRNA for both receptors was increased (Figures 2 and 3). The hepatic mRNA for both receptors was increased after a 24-h fast, but there was no change in either mRNA from muscle or visceral adipose tissue (Figures 2 and 3). We speculate that the 48-h fast in the mouse is more extreme than the 24-h fast in the pig, thus leading to the observed species difference. Serum adiponectin concentration remained stable during a 72-h fast in normal-weight and overweight humans (Merl et al., 2005). Consequently, hormonal regulation of the feeding-fasting status on adiponectin function may act mainly through regulating the expression of AdipoR.
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Figure 2. The effect of fasting on adiponectin receptor 1 (AdipoR1) gene expression in pigs. Samples of liver, LM, visceral adipose tissue (VAT), and subcutaneous adipose tissue (AT) were taken 2 h after feeding (Fed) or 24 h after feeding (Fasted). All sampling, RNA analysis, and statistical analysis were as indicated in Figure 1, except that the cDNA probe was for AdipoR1. The asterisk (*) indicates a significant treatment effect (P < 0.05).
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Figure 3. The effect of fasting on adiponectin receptor 2 (AdipoR2) gene expression in pigs. Samples of liver, LM, visceral adipose tissue (VAT), and subcutaneous adipose tissue (AT) were taken 2 h after feeding (Fed) or 24 h after feeding (Fasted). All sampling, RNA analysis, and statistical analysis were as indicated in Figure 1, except that the cDNA probe was for AdipoR2. The asterisks (**) indicate a significant treatment effect (P < 0.01).
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Adiponectin can activate AdipoR1 to promote the activity of the AMPK (a major activating signal pathway of adiponectin) and activate AdipoR2 to increase the expression of peroxisome proliferator-activated receptor- activated genes in mouse liver (Yamauchi et al., 2007). Because peroxisome proliferator-activated receptor- is a key transcription factor for fatty acid oxidation (Berger and Moller, 2002) and the AMPK pathway is involved in glucose uptake (McGee and Hargreaves, 2008), we speculate that AdipoR1 may regulate glucose metabolism and AdipoR2 may regulate lipid metabolism. Insulin resistance was present in AdipoR1 and AdipoR2 knockout mice, suggesting that AdipoR1 and AdipoR2 act as major receptors for mediating the function of adiponectin in insulin-sensing pathways (Yamauchi et al., 2007). Liu et al. (2008) showed that expression of porcine AdipoR2 was inhibited by insulin through the PI3 kinase pathway. Thus, the fasted pig, with a decreased insulin concentration, would be expected to have increased expression of AdipoR2.
Expression of the T-Cadherin Gene
Homology of the porcine T-cadherin cDNA sequence (EU140561) to the human sequence (NM_001257) was 91% (Figure 4). The high homology of T-cadherin sequences suggests that gene function is conserved between these species. T-Cadherin was highly expressed in muscle and less so in adipose tissue in pigs (Figure 5). We did not detect the existence of T-cadherin mRNA in liver by Northern blot analysis. Fasting did not affect the expression of T-cadherin mRNA in adipose tissue, but decreased the expression in muscle. These results suggest that the regulation of T-cadherin differs from that of AdipoR1 and AdipoR2. The T-cadherin acts as a vascular adiponectin receptor positively regulating angiogenesis and is abundantly expressed in vascular endothelial and smooth muscle cells in atherosclerotic regions (Wyder et al., 2000; Adachi et al., 2006). The T-cadherin is up-regulated by estradiol, progesterone, and other factors in serum through transcriptional and posttranscriptional mechanisms (Bromhead et al., 2006). We do not know why T-cadherin expression decreased in porcine muscle after a 1-d fast, but perhaps hormonal changes during fasting are central factors. The results suggest that the function of adiponectin during fasting can be modulated by modifying the expression of T-cadherin in muscles.
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Figure 4. Porcine T-cadherin (T-cad) sequence. This full-length open reading frame was obtained from reverse transcription-PCR of mRNA from porcine muscle. The dots indicate the same nucleotide, and the arrows are primer binding sites (hollow arrows = primer pairs 1, dotted arrows = primer pairs 2, and full arrows including solid line = primer pairs 3). The homology between pigs and humans (GenBank NM_001257) was 91%.
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Figure 5. The effect of fasting on T-cadherin gene expression in pigs. Samples of liver, LM, visceral adipose tissue (VAT), and subcutaneous adipose tissue (AT) were taken 2 h after feeding (Fed) or 24 h after feeding (Fasted). All sampling, RNA analysis, and statistical analysis were as indicated in Figure 1, except that the cDNA probe was for T-cadherin. The asterisk (*) indicates a significant treatment effect (P < 0.05).
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In conclusion, we successfully cloned the full-length cDNA sequence of T-cadherin, a third putative adiponectin receptor, from porcine muscle. We found that fasting differentially regulated the AdipoR1, AdipoR2, and T-cadherin mRNA in various porcine tissues. These findings provide new gene sequence and expression information for T-cadherin and suggest additional functions of adiponectin and its receptors. The expression of adiponectin and its receptors to regulate energy metabolism may be an important mechanism for modulation of body composition.
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Footnotes
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1 This work was supported in part by a National Science Council grant (NSC96-2313-B-002-005) in Taiwan. 
2 The first 2 authors contributed equally to this work.
3 Visiting professor.
4 Corresponding author: sding{at}ntu.edu.tw
Received for publication February 20, 2008.
Accepted for publication July 22, 2008.
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Abstract
INTRODUCTION
