Peroxisome Proliferator-activated Receptor Gene Research Articles

Elevated adipogenesis of marrow mesenchymal stem cells during early steroid-associated osteonecrosis development

BackgroundIncreased bone marrow lipid deposition in steroid-associated osteonecrosis (ON) implies that abnormalities in fat metabolism play an important role in ON development. The increase in lipid deposition might be explained by elevated adipogenesis of marrow mesenchymal stem cells (MSCs). However, it remains unclear whether there is a close association between elevated adipogenesis and steroid-associated ON development.ObjectiveThe present study was designed to test the hypothesis that there might be a close association between elevated adipogenesis and steroid-associated ON development.MethodsON rabbit model was induced based on our established protocol. Dynamic-MRI was employed for local intra-osseous perfusion evaluation in bilateral femora. Two weeks after induction, bone marrow was harvested for evaluating the ability of adipogenic differentiation of marrow MSCs at both cellular and mRNA level involving adipogenesis-related gene peroxisome proliferator-activated receptor gamma2 (PPARγ2). The bilateral femora were dissected for examining marrow lipid deposition by quantifying fat cell number, fat cell size, lipid deposition area and ON lesions. For investigating association among adipogenesis, lipid deposition and perfusion function with regard to ON occurrence, the rabbits were divided into ON+ (with at least one ON lesion) group and ON- (without ON lesion) group. For investigating association among adipogenesis, lipid deposition and perfusion function with regard to ON extension, the ON+ rabbits were further divided into sub-single-lesion group (SON group: with one ON lesion) and sub-multiple-lesion group (MON group: with more than one ON lesion).ResultsLocal intra-osseous perfusion index was found lower in either ON+ or MON group when compared to either ON- or SON group, whereas the marrow fat cells number and area were much larger in either ON+ or MON group as compared with ON- and SON group. The adipogenic differentiation ability of MSCs and PPARγ2 expression in either ON+ or MON group were elevated significantly as compared with either ON- or SON group.ConclusionThese findings support our hypothesis that there is a close association between elevated adipogenesis and steroid-associated osteonecrosis development.

The acyl-CoA thioesterase I is regulated by PPARα and HNF4α via a distal response element in the promoter

The cytosolic acyl-coenzyme A thioesterase I (Acot1) is an enzyme that hydrolyzes long-chain acyl-CoAs of C(12)-C(20)-CoA in chain length to the free fatty acid and CoA. Acot1 was shown previously to be strongly upregulated at the mRNA and protein level in rodents by fibrates. In this study, we show that Acot1 mRNA levels were increased by 90-fold in liver by treatment with Wy-14,643 and that Acot1 mRNA was also increased by 15-fold in the liver of hepatocyte nuclear factor 4alpha (HNF4alpha) knockout animals. Our study identified a direct repeat 1 (DR1) located in the Acot1 gene promoter in mouse, which binds the peroxisome proliferator-activated receptor alpha (PPARalpha) and HNF4alpha. Chromatin immunoprecipitation (ChIP) assay showed that the identified DR1 bound PPARalpha/retinoid X receptor alpha (RXRalpha) and HNF4alpha, whereas the binding in ChIP was abrogated in the PPARalpha and HNF4alpha knockout mouse models. Reporter gene assays showed activation of the Acot1 promoter in cells by the PPARalpha agonist Wy-14,643 after cotransfection with PPARalpha/RXRalpha. However, transfection with a plasmid containing HNF4alpha also resulted in an increase in promoter activity. Together, these data show that Acot1 is under regulation by an interplay between HNF4alpha and PPARalpha.

Effects of different dietary fatty acid on expression of nuclear receptor genes in breast cancer of rats

To study the effects of different dietary fatty acid on the expression of nuclear receptor genes in the breast cancer of rats. Fifty-day-old female Sprague-Dawley rats were fed on eight different diets containing following fatty acids: saturated fatty acid (SFA); monounsaturated fatty acid (MUFA); n-6 polyunsaturated fatty acid (PUFA); n-3 PUFA; 1:1 n-6/n-3; 5:1 n-6/n-3; 10:1 n-6/n-3; 1:2:1 S/M/P (n-6/n-3 at 1:1). The rats were given a single intraperitoneal injection of methyl-nitrosourea (MNU) at 50 mg/kg body weight to establish the rat model of mammary carcinogenesis, the ultrastructure changes of mammary gland cells in rats were observed by transmission electron microscope, the cell proliferation activity was detected by BrdU-labeled immunocytochemistry, and the expression of PPARbeta and PPARgamma mRNA were assayed by RT-PCR. There was no breast cancer occurring in control groups and the MNU-treated n-3 PUFA group, and the ultrastructure and proliferation activity of mammary gland cells in these groups were normal. In contrast, there appeared obvious marker of adenocarcinomas in mammary gland cells of MNU-induced breast cancer, and a high cell proliferation activity was found in tumor growth-enhancing groups (SFA, MUFA, n-6 PUFA, 5:1 n-6/n-3, 10:1 n-6/n-3 and S/M/P, 21% - 22% of BrdU-labeled cells), while a low cell proliferation activity was detected in rats fed with 1:1 n-6/n-3 diet (13% of BrdU-labeled cells, P < 0.05). Moreover, peroxisome proliferator-activated receptors (PPARs), as important nuclear receptor genes of relating lipid metabolism, the expressions of PPARbeta and PPARgamma mRNA were significantly up-regulated in mammary adipose tissues of MNU-induced breast cancer as compared with the control groups, but the expression levels of peroxisome proliferator-activated receptors (PPARs) in rats fed with 1:1 n-6/n-3 group were lowest (P < 0.05). The different dietary fatty acid compositions should diversely adjust the expression of PPARs gene in rats, which maybe have an important role in affecting incidence of breast cancer.

Epidemiology, genes and the environment: lessons learned from the Helsinki Birth Cohort Study

Nonoptimal growth during fetal life and infancy is associated with an increased risk of coronary heart disease and type 2 diabetes later in life. This early pattern of growth is associated with an increased disease risk especially when followed by a relative gain in body size later in childhood. Genetic factors are closely involved in growth and disease pathogenesis and gene-early life environmental interactions will be described affecting adult health outcomes. This overview will primarily focus upon findings from the Helsinki Birth Cohort Study consisting of 15846 subjects born 1924-1944 on whom growth data and information on adult health are available.

Complete replacement of dietary fish oil with a vegetable oil blend affect liver lipid and plasma lipoprotein levels in Atlantic salmon (Salmo salar L.)

To study how hepatic lipid turnover and lipid transport may be affected by complete replacement of dietary fish oil (FO) with a vegetable oil blend (VO) from start feeding until the adult stages, Atlantic salmon (Salmo salar L.) were fed either 100% FO- or 100% VO-based diets (55% rapeseed oil, 30% palm oil and 15% linseed oil) from start feeding until 22 months. Liver and plasma lipoprotein lipid class levels and lipoprotein fatty acid composition were analysed through the seawater phase, whereas liver fatty acid composition, plasma cholesterol, triacylglycerol (TAG) and protein levels were analysed through both freshwater and seawater stages. Further, enzyme activity of liver fatty acid synthetase (FAS), NADH-isocitrate dehydrogenase, malic enzyme, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase and expression of the gene Peroxisome proliferator-activated receptor γ (PPARγ) was analysed during both fresh water and seawater stages through the experiment. Dietary VO significantly increased salmon liver TAG and hence total liver lipid stores after 14 and 22 months of feeding. Further, after 22 months of feeding, plasma lipid levels and plasma low-density lipoprotein (LDL) levels were significantly decreased in VO-fed salmon compared with FO-fed fish. The same trend, although not statistically significant, was seen for plasma very low-density lipoprotein (VLDL). The activity of FAS was generally low throughout the experiment with the VO group having significantly lower activity after 16 months of feeding. The expression of PPARγ in livers increased prior to seawater transfer followed by a decrease, and then another increase towards the final sampling (22 months). Dietary vegetable oil replacement had no impact on PPARγ expression in salmon liver. In summary, liver TAG stores, plasma lipid and LDL levels were affected by dietary vegetable oil replacement in Atlantic salmon during a long–term feeding experiment. Current results indicate that high dietary vegetable oil inclusion increase hepatic TAG stores and decrease plasma lipid levels possible through decreased VLDL synthesis.

PPARα activators and fasting induce the expression of adipose differentiation-related protein in liver

The adipose differentiation-related protein (ADFP)/adipophilin belongs to a family of PAT (for perilipin, ADFP, and TIP47) proteins that associate on the surface of lipid droplets (LDs). Except for LD association, a clear role for ADFP has not been found. We demonstrate that ADFP is transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARalpha) in mouse liver and rat and human hepatoma cells through a highly conserved direct repeat-1(DR-1) element. Although the ADFP mRNA is highly increased by a synthetic PPARalpha agonist, the ADFP protein is only substantially increased in cells containing LDs, such as hepatocytes incubated with fatty acids, and in livers of fasted mice. ADFP is induced by fasting even in the absence of a functional PPARalpha, in marked contrast to the PPARalpha target gene acyl-coenzyme A oxidase-1. Activation of LXRs, which stimulates LD formation through the activation of lipogenesis, does not affect ADFP mRNA levels. TIP47, another PAT member known to be expressed in liver, was unaffected by all treatments. This constitutively expressed PAT member seems to be less transcriptionally regulated than ADFP. These observations suggest that ADFP is primarily a fasting-induced protein in liver that coats the newly synthesized triacylglycerol-containing LDs formed during fasting.

An Integrated Biological Approach to Nuclear Receptor Signaling in Physiological Control and Disease

The nuclear receptors (NRs)--vitamin D receptor (VDR); peroxisome proliferator-activated receptor (PPAR) alpha, delta, gamma; and pregnane X receptor (PXR)--act as sensors for various molecules encountered by the body on a daily basis. The effects of these ligands can be understood by the fact that numerous genes involved in the cellular processes, such as general homeostasis, growth, and defense against microbes, are under the control of these five NRs. The target gene and protein expression patterns of VDR, PPARs, and PXR; the resulting changes in metabolite levels; and their physiological consequences create a network that can be monitored by high-throughput methods and analyzed by multimodal approaches, such as systems biology. We suggest that the fine regulation of this NR network is specific to each human individual and depends, in part, on the constellation of regulatory small nucleotide polymorphisms (SNPs) in his or her genome. When regulatory SNPs affect NRs response elements, lifetime exposure to food components will have different accumulative consequences on the expression of the respective NR target genes. These differences will influence the individual's susceptibility to aging-related diseases, such as type 2 diabetes, atherosclerosis, cancer, and osteoporosis. Furthermore, it is anticipated that systems biology methods will also help to identify the most critical genes, proteins, or metabolites in the NR network that will serve as biomarkers for the early detection of these diseases.

The Peroxisome Proliferator-Activated Receptor- 2 P12A Polymorphism and Type 2 Diabetes in an Arab Population

The association of type 2 diabetes with the P12A polymorphism of the peroxisome proliferator–activated receptor gene ( PPAR-γ2 ) has been established in several populations (1). However, no studies have thus far been reported for Arab populations. While many variants have been identified in this gene, the most prevalent and best studied is the P12A polymorphism. There is considerable interpopulation variance in the incidence of the risk allele (P12). This ranges in frequency from a high of 0.96–0.98 in populations including the Japanese, Chinese, and African Americans to 0.91 in …

Single Nucleotide Polymorphisms on Peroxisome Proliferator-activated Receptor Genes Associated with Fatness Traits in Chicken

The peroxisome proliferator-activated receptors (PPARs) are members of a superfamily of nuclear hormone receptors. Lots of studies in rodents and humans have shown that PPARs were involved in lipid metabolism and adipocyte differentiation. The main objective of this work was to detect the single nucleotide polymorphisms (SNPs) in whole coding regions of peroxisome proliferator-activated receptor alpha (PPAR-α) and gamma (PPAR-γ) genes with approach of single strand conformation polymorphism (SSCP) in the chicken population of Arber Acres broiler, Hyline layer and three Chinese native breeds (Shiqiza, Beijing You, Bai'er). Two SNPs of C1029T and C297T were found in chicken PPAR-α and PPAR-γ genes respectively and each SNP found three genotypes in the experimental populations. The results showed that the distribution frequency of 3 genotypes in Arber Acres broiler, Hyline layer and Chinese native breeds had significant differences on the PPAR-α and PPAR-γ gene respectively (p<0.01). Furthermore, in the PPAR-α gene, the results of least square estimation for genotypes and body composition traits showed the BB genotype birds had higher abdominal fat weight (AFW) and percentage of abdominal fat (AFP) than AA genotype birds (p<0.05). From these we conjecture the PPAR-α and PPAR-γ genes were suffered intensive selection during the long term commercial breeding and the PPAR-α gene may be a major gene or linked to the major genes that impact chicken fat metabolism and the SNPs could be used in molecular assistant selection (MAS) as a genetic marker for the chicken fatness traits. (Asian-Aust. J. Anim. Sci. 2005. Vol 18, No. 9 : 1221-1225)

The PPAR genes, cardiovascular disease and the emergence of PPAR pharmacogenetics

The peroxisome proliferator-activated receptors (PPARs) comprise a group of related transcription factors that serve to regulate a number of cellular processes that are central to cardiovascular health and disease. Two large bodies of work strongly implicate the PPARs as key factors in normal cardiovascular physiology and in cardiovascular pathophysiology: i) studies demonstrating associations between PPAR and abnormal cardiovascular phenotypes; and ii) pharmacological studies assessing the effects of specific PPAR agonists in clinical trials. With the abundance of data available from these studies as a background, PPAR pharmacogenetics has become a promising and rapidly-advancing field. This review summarises the current state of understanding of PPAR pharmacogenetics and its profound implications for the individualisation of therapy for patients with a diverse group of cardiovascular diseases.

Low‐ and High‐Carbohydrate Diets: Body Composition Differences in Rats

To determine differences in adipose tissue mass, cell size, and lipid metabolism transcripts and differences in composition of body weight loss and energy expenditure (EE) after isoenergetic, energy-restricted intake of low-carbohydrate/high-fat/high-protein (LC) and high-carbohydrate/low-fat/moderate-protein (HC) diets. Ten-week old female Sprague-Dawley rats were fed a high-fat diet ad libitum for 8 weeks to induce weight gain and fat deposition. Weight-matched rats were then assigned to isoenergetic LC (Atkins) and HC (American Dietary Association Exchange) diets for 10 weeks at 65% of ad libitum energy intake. There was no significant difference in the serum lipid profiles or amount of body weight lost between the HC and LC groups, whereas a higher insulin sensitivity index (p < 0.01) resulted from the HC compared with the LC diet. Compared with the post-restriction LC group, the HC group demonstrated (p < 0.05) higher EE during active hours, lower mRNA levels for the lipogenic genes peroxisome proliferator-activated receptor gamma2, lipoprotein lipase, and, adipocyte fatty acid binding protein, decreased adipocyte cell volume, and decreased fat mass. Results indicated down-regulation of lipogenic genes, decreased fat mass, and, therefore, improved body composition in the post-restriction HC compared with the LC group. The small mean differences between the two diet groups (p = 0.11) in 24-hour EE over the 10 weeks of diet intervention would account for the majority of the lower mean body weights in the post-restriction HC group. These data suggest that macronutrient composition of the diet influences body composition and indicate a distinction between HC and LC diets.

Genomic effect of vitamin ‘C’ and statins within human mononuclear cells involved in atherogenic process

Deregulated crosstalk within nuclear receptor/transcription factor family, comprising of peroxisome proliferator-activated receptors (PPARs) and liver X receptor-alpha (LXR-alpha), can give rise to cooperativity between lipid peroxidation and inflammation leading to atherogenic process. The present study addressed to explore the effect of statins and vitamin 'C' on transcriptional expression of genes coding for this nuclear receptor/transcription factor family within mononuclear cells revealed for the first time that both mevastatin and vitamin 'C' have common action in that they significantly downregulate the expression of PPARs (alpha, gamma) genes and upregulate LXR-alpha gene expression as compared to the control. The similar phenomenon was observed in mononuclear cells obtained from coronary heart disease (CHD) patients who were receiving atorvastatin treatment (20 mg HS). Further, the observed upregulatory effect of LXR-alpha gene expression was in conformity with the downregulatory effect of LXR-alpha on its effector gene matrix metalloproteinase-9. Based on these results, we propose that LXR-alpha-dependent signaling pathway may be a crucial target for the therapeutic intervention in human CHD, and in addition to statins, vitamin 'C' deserves a close scrutiny for the treatment of CHD.

A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPARα-dependent and -independent pathways

Branched-chain fatty acids (such as phytanic and pristanic acid) are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha) in vitro. To investigate the effects of these physiological compounds in vivo, wild-type and PPARalpha-deficient (PPARalpha-/-) mice were fed a phytol-enriched diet. This resulted in increased plasma and liver levels of the phytol metabolites phytanic and pristanic acid. In wild-type mice, plasma fatty acid levels decreased after phytol feeding, whereas in PPARalpha-/- mice, the already elevated fatty acid levels increased. In addition, PPARalpha-/- mice were found to be carnitine deficient in both plasma and liver. Dietary phytol increased liver free carnitine in wild-type animals but not in PPARalpha-/- mice. Investigation of carnitine biosynthesis revealed that PPARalpha is likely involved in the regulation of carnitine homeostasis. Furthermore, phytol feeding resulted in a PPARalpha-dependent induction of various peroxisomal and mitochondrial beta-oxidation enzymes. In addition, a PPARalpha-independent induction of catalase, phytanoyl-CoA hydroxylase, carnitine octanoyltransferase, peroxisomal 3-ketoacyl-CoA thiolase, and straight-chain acyl-CoA oxidase was observed. In conclusion, branched-chain fatty acids are physiologically relevant ligands of PPARalpha in mice. These findings are especially relevant for disorders in which branched-chain fatty acids accumulate, such as Refsum disease and peroxisome biogenesis disorders.

Three Peroxisome Proliferator-Activated Receptor Isotypes from Each of Two Species of Marine Fish

The cloning and characterization of cDNAs and genes encoding three peroxisome proliferator-activated receptor (PPAR) isotypes from two species of marine fish, the plaice (Pleuronectes platessa) and the gilthead sea bream (Sparus aurata), are reported for the first time. Although differences in the genomic organization of the fish PPAR genes compared with their mammalian counterparts are evident, sequence alignments and phylogenetic comparisons show the fish genes to be homologs of mammalian PPARalpha, PPARbeta/delta, and PPARgamma. Like their mammalian homologs, fish PPARs bind to a variety of natural PPAR response elements (PPREs) present in the promoters of mammalian or piscine genes. In contrast, the mRNA expression pattern of PPARs in the two fish species differs from that observed in other vertebrates. Thus, PPARgamma is expressed more widely in fish tissues than in mammals, whereas PPARalpha and beta are expressed similarly in profile to mammals. Furthermore, nutritional status strongly influences the expression of all three PPAR isotypes in liver, whereas it has no effect on PPAR expression in intestinal and adipose tissues. Fish PPARalpha and beta exhibit an activation profile similar to that of the mammalian PPAR in response to a variety of activators/ligands, whereas PPARgamma is not activated by mammalian PPARgamma-specific ligands. Amino acid residues shown to be critical for ligand binding in mammalian PPARs are not conserved in fish PPARgamma and therefore, together with the distinct tissue expression profile of this receptor, suggest potential differences in the function of PPARgamma in fish compared with mammals.

Microarray analysis of early adipogenesis in C3H10T1/2 cells: Cooperative inhibitory effects of growth factors and 2,3,7,8-tetrachlorodibenzo- p-dioxin

C3H10T1/2 mouse embryo fibroblasts differentiate into adipocytes when stimulated by a standard hormonal mixture (IDMB). 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD), via the aryl hydrocarbon receptor (AhR), inhibits induction of the key adipogenic gene peroxisome proliferator-activated receptor γ (PPARγ) and subsequent adipogenesis. This TCDD-mediated inhibition requires activation of the extracellular signal-regulated kinase (ERK) pathway, which can be accomplished by serum, epidermal growth factor (EGF), or fibroblast growth factor (FGF). In the absence of serum or growth factors, IDMB induced adipogenesis without mitosis. Microarray analysis identified 200 genes that exhibited expression changes of at least twofold after 24 h of IDMB treatment. This time precedes most PPARγ stimulation but follows the period of TCDD/ERK cooperation and periods of increased cell contraction and DNA synthesis. Functionally related gene clusters include genes associated with cell structure, triglyceride and cholesterol metabolism, oxidative regulation, and secreted proteins. In the absence of growth factors TCDD inhibited 30% of these IDMB responses without inhibiting the process of differentiation. A combination of EGF and TCDD that blocks differentiation cooperatively blocked a further 44 IDMB-responsive genes, most of which have functional links to differentiation, including PPARγ. Cell cycle regulators that are stimulated by EGF were substantially inhibited by IDMB but these responses were unaffected by TCDD. By contrast, TCDD and EGF cooperatively reversed IDMB-induced changes in cell adhesion complexes immediately prior to increases in PPARγ1 expression. Changes in adhesion-linked signaling may play a key role in TCDD affects on differentiation.

Release of Endogenous Glutamate by AMPA Receptors Expressed in Cultured Rat Costal Chondrocytes

We have previously demonstrated the release of endogenous glutamate by activation of DL-alpha-amino-3-hydroxy-5-methylisoxasole-4-propionate (AMPA) receptors expressed by bone, while there is no information available on the possible functional expression of glutamatergic signaling molecules in cartilage to date. In rat costal chondrocytes cultured for 4 to 28 d, expression of mRNA was seen for several chondral marker genes including sox9, runt-related gene 2/core binding factor alpha-1 (Runx-2/Cbfa-1), type II collagen and aggrecan, but not for the adipocyte marker gene peroxisome proliferator-activated receptor gamma (PPARgamma). Expression of mRNA was drastically increased for Runx-2/Cbfa-1 during culturing from 7 to 14 d with a gradual increase thereafter up to 28 d, while a transient increase was seen in mRNA expression for both type-II collagen and sox-9 on 14 d and for aggrecan on 7 d respectively, in chondrocytes cultured for a period up to 28 d. Irrespective of the culture period up to 21 d, marked expression was seen by cultured chondrocytes with mRNA for GluR3 subunit of AMPA receptors, in addition to vesicular glutamate transporter-1 (VGLUT1) required for the condensation and subsequent exocytotic release of glutamate in the glutamatergic neurotransmission in the brain. Cultured rat costal chondrocytes underwent spontaneous release of endogenous glutamate, while an inhibitor of AMPA receptor desensitization significantly prolonged the duration of endogenous glutamate release stimulated by AMPA. These results suggest that endogenous glutamate could be released from intracellular vesicular constituents associated with VGLUT1 through activation of AMPA receptors expressed by cultured rat costal chondrocytes.

Differential expression of peroxisome proliferator-activated receptors alpha and gamma gene in various chicken tissues

The peroxisome proliferator-activated receptors (PPARs) are the members of superfamily of nuclear hormone receptors. A great number of studies in rodent and human have shown that PPARs were involved in the lipids metabolism. The goal of the current study was to investigate the expression pattern of PPAR genes in various tissues of chicken. The tissue samples (heart, liver, spleen, lung, kidney, stomach, intestine, brain, breast muscle and adipose) were collected from six Arber Acres broilers (8 weeks old, male and female birds are half and half). Semi-quantitative RT-PCR and Northern blot were used to characterize the expression of PPAR-α and PPAR-γ genes in the above tissues. By semi-quantitative RT-PCR, the results showed the expression level of PPAR-α gene was higher in brain, lung, kidney, heart and intestine, medium in stomach, liver and adipose than in spleen, and it did not express in breast muscle. The expression level of PPAR-γ gene was higher in adipose, medium in brain and kidney than in spleen, heart, lung, stomach and intestine, but it did not express in liver and breast muscle. Northern blot results showed that PPAR-α gene expressed in heart, liver, kidney and stomach, and the intensity of hybridization signal was the stronger in liver and kidney than in other tissues, however, PPAR-γ gene only expressed in adipose and kidney tissues. The results of this study showed the profile of PPAR gene expression in the chicken was similar to that in rodent, human and pig. However the expression profile of chicken also have its own specific trait, i.e. compared with mammals, PPAR-α gene can not be detected in skeletal muscle and PPAR-γ gene can be stronger expressed in kidney tissues. This work will provide some basic data for the PPAR genes expression and lipids metabolism of birds.

The molecular clock.

Sea squirts ( Ciona sp. ), flies, ascidians and human beings all have vitamin D receptor and retinoid X receptor genes. However, thyroid hormone receptor, retinoic acid receptor, and peroxisome proliferator-activated receptor genes are found in sea squirts and Man, but not in flies, implying that these genes are an invention of the chordates. Similarly, sea squirts do not have oestrogen receptor genes, genes for androgen, glucocorticoid or mineralcorticoid receptors: these appear to be associated with the appearance of the vertebrates. Such steps may be of evolutionary significance, and their identification is part of a redefinition of taxonomy, much as new disease classifications (in oncology, say) depend on new genetic information. A measure of the genetic distance between species (now often known with great accuracy) can be converted to a time estimate for their separation from a common ancestor by using a calibration factor applied to the number of genetic changes expected in a given time. Though this methodology may seem cumbersome, and to be of only theoretical value, it is worth looking at more closely; it has helped to show that the last common ancestor of the main pandemic strain of the Human Immunodeficiency Virus was around in the 1930s, and thus could not have arisen from the use of primate cell cultures in polio vaccines, as has been suggested. Rates of molecular evolution are much less variable than rates of change of body form and function. The study of amino acid sequences in a given protein in different species shows that around one amino acid substitution per 1×109 years has occurred in haemoglobins. Of course, this rate of change per amino acid codon does not have to be divided by three to get the rate …

Generation and functional confirmation of a conditional null PPARgamma allele in mice.

Generation and functional confirmation of a conditional null PPARgamma allele in mice.

Nutritionally induced adipose hypertrophy in young pigs is transient and independent of changes in the expression of the obese and peroxisome proliferator activated receptor genes

Previous studies have shown that piglets weaned to a liquid milk replacer (MR), rather than a typical dry diet (DD) regimen, have improved growth rates and deposit more energy as body fat. In the present study, we used this model to determine whether changes in the expression of genes linked to the regulation of adiposity were related to the accelerated fat accretion. We also determined whether the increase in body fat was sustained throughout a substantial proportion of the growth curve. At weaning (19 ± 2 days of age), 96 piglets were placed in 12 replicate pens per diet (4 pigs per pen, 2 barrows and 2 gilts), and fed a liquid MR or conventional DD regimen for 5 weeks. Thereafter, 6 barrows and 6 gilts pigs from each diet were killed for determination of whole body chemical composition (less gastrointestinal contents). The remaining pigs were assigned randomly to weight target groups (60, 85, and 110 kg), placed in individual pens, and fed a conventional dietary regimen until killed at their respective weight targets for tissue sampling and determination of whole body chemical composition. Over the 5-week period in which the MR was fed, the growth rate of the pigs consuming the MR exceeded that of the pigs fed the DD by 36% (P < .05). Fat gain in these pigs was increased to 1.8 times that of the pigs fed the DD, and percentage body fat was 45% greater (P < .05). Acetyl Co-A carboxylase (ACC) activity (per mg of adipose extract protein) was not different between the two diet groups at the conclusion of the 5-week period, or at 110 kg body weight. During the MR period, actual protein gain was increased (P < .05) 22% in the pigs fed the MR as well. By 110 kg of body weight, body fat was reduced (P < .05) by 7.7% (total fat mass) and 8.3% (percentage of body weight basis) in the pigs fed MR vs. the DD group. The expression of the peroxisome proliferator activated receptors (PPAR) α and γ was not influenced by diet or by body weight. Expression of the obese gene was independent of diet, but was greater (P < .09) in pigs at 110 kg body weight than at 60 kg. These data provide additional evidence that piglets weaned to liquid diets have greater rates of growth and deposit more body fat, but that this difference subsides quickly when a typical dry dietary regimen is imposed. Furthermore, the biochemical changes responsible for the increased adiposity are independent of changes in the expression of the obese or PPAR genes, at least at the mRNA level.