The genome of the naturally evolved obesity-prone Ossabaw miniature pig.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC8455653 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ossabaw swine fed excess kilocalorie diet develop metabolic syndrome (MS) characterized by obesity, hypertension, insulin resistance, and glucose intolerance with/without dyslipidemia. The purpose of this study was to test the hypothesis that MS would have a detrimental effect on skeletal muscle structure and cause changes in the expression of myosin heavy chains (MHCs). Adult male Ossabaw swine were fed for 24 wk high-fructose or high-fat/cholesterol/fructose diets to induce normolipidemic MS (MetS) or dyslipidemic MS (DMetS), respectively, and were compared with the lean swine on control diet. MetS swine showed mild MS, lacking increases in total and low density lipoprotein (LDL) cholesterol, both of which were highly upregulated in DMetS swine. There was an ?1.2-fold increase in the cross-sectional areas of muscle fibers in MetS and DMetS groups compared with control for biceps femoris and plantaris muscles. In plantaris muscles, DMetS diet caused an ?2-fold decrease in slow MHC mRNA and protein expression and an ?1.2- to 1.8-fold increase in the number of intramyocellular lipid (IMCL) droplets without large changes in the size of the droplets. There was a trend to the decrease in slow MHC expression in muscles of swine on MetS diet. The number of IMCL droplets in muscle fibers of the MetS group was comparable to controls. These data correlate well with the data on total plasma cholesterol (control = 60, MetS = 70, and DMetS = 298 mg/dl) and LDL (control = 29, MetS = 30, and DMetS = 232 mg/dl). We conclude that structural changes observed in skeletal muscle of obese Ossabaw swine correlate with those previously reported for obese humans.
| S-EPMC3093979 | biostudies-literature
Project description:Adenosine clearly regulates coronary blood flow (CBF); however, contributions of specific adenosine receptor (AR) subtypes (A(1), A(2A), A(2B), A(3)) to CBF in swine have not been determined. ARs generally decrease (A(1), A(3)) or increase (A(2A), A(2B)) cyclic adenosine monophosphate, a major mediator of vasodilation. We hypothesized that A(1) antagonism potentiates coronary vasodilation and coronary stent deployment in dyslipidemic Ossabaw swine elicits impaired vasodilation to adenosine that is associated with increased A(1)/A(2A) expression. The left main coronary artery was accessed with a guiding catheter allowing intracoronary infusions. After placement of a flow wire into the left circumflex coronary artery the responses to bolus infusions of adenosine were obtained. Steady-state infusion of AR-specific agents was achieved by using a small catheter fed over the flow wire in control pigs. CBF was increased by the A(2)-nonselective agonist 2-phenylaminoadenosine (CV1808) in a dose-dependent manner. Baseline CBF was increased by the highly A(1)-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), but not changed by other AR-specific agents. The nonselective A(2) antagonist 3,7-dimethyl-1-propargylxanthine and A(2A)-selective antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385) abolished adenosine-induced CBF, whereas A(2B) and A(3) antagonism had no effect. Dyslipidemia and stenting decreased adenosine-induced CBF ∼70%, whereas A(1), A(2A), and A(2B) mRNA were up-regulated in dyslipidemic versus control >5-fold and there was no change in the ratio of A(1)/A(2A) protein in microvessels distal to the stent. In control Ossabaw swine A(1) antagonism by DPCPX positively regulated basal CBF. Impaired adenosine-induced CBF after stenting in dyslipidemia is most likely caused by the altered balance between A(1) and A(2A) signaling, not receptor expression.
| S-EPMC2993551 | biostudies-literature
Project description:UnlabelledMiniature pigs residing in the Ossabaw Island (Ossabaw pigs) exhibit a thrifty genotype, and when fed a high-calorie diet they consistently develop metabolic syndrome defined by obesity, insulin resistance, hypertension, and dyslipidemia. We conducted a study to induce steatohepatitis in Ossabaw pigs by dietary manipulation. Pigs were fed standard chow (controls, n = 15), high-fructose diet (20% kcal from fructose and 10.5% kcal from fat) (fructose group, n = 9), atherogenic diet (20% kcal from fructose and 46% kcal from fat and 2% cholesterol and 0.7% cholate by weight) (atherogenic diet group, n = 13), and modified atherogenic diet (different source of fat and higher protein but lower choline content) (M-Ath diet group, n = 7). All animals were sacrificed at 24 weeks after dietary intervention. The high-fructose group had significant weight gain, hypertension, and insulin resistance but showed normal liver histology. The atherogenic diet group had metabolic syndrome and abnormal liver histology consisting of significant microvesicular steatosis and fatty Kupffer cells but no ballooning or fibrosis. The M-Ath diet group developed severe metabolic syndrome and markedly abnormal liver histology with macrovesicular and microvesicular steatosis, fatty Kupffer cells, extensive hepatocyte ballooning, and pericellular/perisinusoidal fibrosis. Compared with controls, the M-Ath diet group had significantly lower serum adiponectin but higher serum leptin and tumor necrosis factor (TNF) levels and higher hepatic triglyceride and malondialdehyde levels.ConclusionOssabaw pigs fed a modified atherogenic diet develop severe metabolic syndrome and abnormal liver histology with close resemblance to human nonalcoholic steatohepatitis (NASH).
| S-EPMC3254146 | biostudies-literature
Project description:BackgroundOssabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet) develop metabolic syndrome and nonalcoholic steatohepatitis (NASH) characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model.MethodsOssabaw swine were fed standard chow (control group; n = 6) or NASH diet (n = 6) for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24.ResultsThe NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a) hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (>90% hepatocytes), (b) hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c) Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides.ConclusionsThis report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a) hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b) hepatocyte ballooning generally precedes the development of fibrosis; (c) there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides.
| S-EPMC4433111 | biostudies-literature
Project description:Studies in human and non-human primates have confirmed the compensatory enlargement or positive remodeling (Glagov phenomenon) of coronary vessels in the presence of focal stenosis. To our knowledge, this is the first study to document arterial enlargement in a metabolic syndrome animal model with diffuse coronary artery disease (DCAD) in the absence of severe focal stenosis. Two different groups of Ossabaw miniature pigs were fed a high fat atherogenic diet for 4 months (Group I) and 12 months (Group II), respectively. Group I (6 pigs) underwent contrast enhanced computed tomographic angiography (CCTA) and intravascular ultrasound (IVUS) at baseline and after 4 months of high fat diet, whereas Group II (7 pigs) underwent only IVUS at 12 months of high fat diet. IVUS measurements of the left anterior descending (LAD), left circumflex (LCX) and right coronary (RCA) arteries in Group I showed an average increase in their lumen cross-sectional areas (CSA) of 25.8%, 11.4%, and 43.4%, respectively, as compared to baseline. The lumen CSA values of LAD in Group II were found to be between the baseline and 4 months values in Group I. IVUS and CCTA measurements showed a similar trend and positive correlation. Fractional flow reserve (FFR) was 0.91±0.07 at baseline and 0.93±0.05 at 4 months with only 2.2%, 1.6% and 1% stenosis in the LAD, LCX and RCA, respectively. The relation between percent stenosis and lumen CSA shows a classical Glagov phenomenon in this animal model of DCAD.
| S-EPMC4341907 | biostudies-other
Project description:DNA methylation is a crucial epigenetic modification involved in diverse biological processes. There is significant phenotypic variance between Chinese indigenous and western pig breeds. Here, we surveyed the genome-wide DNA methylation profiles of blood leukocytes from three pig breeds (Tongcheng, Landrace, and Wuzhishan) by methylated DNA immunoprecipitation sequencing. The results showed that DNA methylation was enriched in gene body regions and repetitive sequences. LINE/L1 and SINE/tRNA-Glu were the predominant methylated repeats in pigs. The methylation level in the gene body regions was higher than in the 5' and 3' flanking regions of genes. About 15% of CpG islands were methylated in the pig genomes. Additionally, 2,807, 2,969, and 5,547 differentially methylated genes (DMGs) were identified in the Tongcheng vs. Landrace, Tongcheng vs. Wuzhishan, and Landrace vs. Wuzhishan comparisons, respectively. A total of 868 DMGs were shared by the three contrasts. The DMGs were significantly enriched in development- and metabolism-related biological processes and pathways. Finally, we identified 32 candidate DMGs associated with phenotype variance in pigs. Our research provides a DNA methylome resource for pigs and furthers understanding of epigenetically regulated phenotype variance in mammals.
| S-EPMC4957084 | biostudies-literature
Project description:Ossabaw miniature swine were fed an excess calorie, atherogenic diet for 6, 9, or 12 months. Increased body weight, hypertension, and increased plasma cholesterol and triglycerides are described in Table 1. For more detailed interpretations and conclusions about the data, see our associated research study, "Biphasic alterations in coronary smooth muscle Ca(2+) regulation during coronary artery disease progression in metabolic syndrome" McKenney-Drake, et al. (2016) [1].
| S-EPMC4845153 | biostudies-literature
Project description:We recently developed a nutritional model of steatohepatitis and metabolic syndrome in Ossabaw pigs. Here we describe changes in the serum proteome of pigs fed standard chow (control group; n = 7), atherogenic diet (n = 5), or modified atherogenic diet (M-ath diet group; n = 6). Pigs fed atherogenic diet developed metabolic syndrome and mildly abnormal liver histology, whereas pigs fed M-ath diet exhibited severe metabolic syndrome and liver injury closely resembling human nonalcoholic steatohepatitis (NASH). Using a label-free mass spectrometry-based proteomics approach, we identified 1,096 serum proteins, 162 of which changed significantly between any two diet groups (false discovery rate <5%). Biological classification of proteins with significant changes revealed functions previously implicated in development of NASH in humans, including immune system regulation and inflammation (orosomucoid 1, serum amyloid P component, paraoxonase 1, protein similar to alpha-2-macroglobulin precursor, beta-2-microglobulin, p101 protein, and complement components 2 and C8G), lipid metabolism (apolipoproteins C-III, E, E precursor, B, and N), structural and extracellular matrix proteins (transthyretin and endopeptidase 24.16 type M2), and coagulation [carboxypeptidase B2 (plasma)]. Several proteins with significant differential expression in pigs were also identified in our recent human proteomics study as changing significantly in serum from patients across the spectrum of nonalcoholic fatty liver disease, including apolipoproteins C-III and B, orosomucoid 1, serum amyloid P component, transthyretin, paraoxonase 1, and a protein similar to alpha-2-macroglobulin precursor. This serum proteomic analysis provides additional information about the pathogenesis of NASH and further characterizes our large animal model of diet-induced steatohepatitis and metabolic syndrome in Ossabaw pigs.
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Project description:Simple sequence repeats (SSRs) are commonly used as molecular markers in research on genetic diversity and discrimination among taxa or breeds because polymorphisms in these regions contribute to gene function and phenotypically important traits. In this study, we investigated genome-wide characteristics, repeat units, and polymorphisms of SSRs using sequencing data from SSR-enriched libraries created from Wuzhishan (WZS), Bama (BM), inbred Luchuan (LC) and Zangxiang (ZX) miniature pig breeds. The numbers and types of SSRs, distributions of repeat units and polymorphic SSRs varied among the four breeds. Compared to the Duroc pig reference genome, 2518 polymorphic SSRs were unique and common to all four breeds and functional annotation revealed that they may affect the coding and regulatory regions of genes. Several examples, such as FGF23, MYF6, IGF1R, and LEPROT, are associated with growth and development in pigs. Three of the polymorphic SSRs were selected to confirm the polymorphism and the corresponding alleles through fluorescence polymerase chain reaction (PCR) and capillary electrophoresis. Together, this study provides useful insights into the discovery, characteristics and distribution of SSRs in four pig breeds. The polymorphic SSRs, especially those common and unique to all four pig breeds, might affect associated genes and play important roles in growth and development.
| S-EPMC7600727 | biostudies-literature
Project description:We adopted a transcriptome-wide microarray analysis approach to determine the extent to which vascular gene expression is altered as a result of juvenile obesity and identify obesity-responsive mRNAs. We examined transcriptional profiles in the left anterior descending coronary artery (LAD), perivascular fat adjacent to the LAD, and descending thoracic aorta between obese (n = 5) and lean (n = 6) juvenile Ossabaw pigs (age = 22 wk). Obesity was experimentally induced by feeding the animals a high-fat/high-fructose corn syrup/high-cholesterol diet for 16 wk. We found that expression of 189 vascular cell genes in the LAD and expression of 165 genes in the thoracic aorta were altered with juvenile obesity (false discovery rate ? 10%) with an overlap of only 28 genes between both arteries. Notably, a number of genes found to be markedly upregulated in the LAD of obese pigs are implicated in atherosclerosis, including ACP5, LYZ, CXCL14, APOE, PLA2G7, LGALS3, SPP1, ITGB2, CYBB, and P2RY12. Furthermore, pathway analysis revealed the induction of proinflammatory and pro-oxidant pathways with obesity primarily in the LAD. Gene expression in the LAD perivascular fat was minimally altered with juvenile obesity. Together, we provide new evidence that obesity produces artery-specific changes in pretranslational regulation with a clear upregulation of proatherogenic genes in the LAD. Our data may offer potential viable drug targets and mechanistic insights regarding the molecular precursors involved in the origins of overnutrition and obesity-associated vascular disease. In particular, our results suggest that the oxidized LDL/LOX-1/NF-?B signaling axis may be involved in the early initiation of a juvenile obesity-induced proatherogenic coronary artery phenotype.
| S-EPMC3680784 | biostudies-literature