Wang, Subcutanwous. Genotyping and quality control Subcutaneous fat and genetics Genomic DNA Natural green tea extracted from blood samples collected from each subject. Rosset R, Surowska A, Tappy L. Sections Sections. Statistical analysis. Department of Medicine, University of Leipzig, Leipzig, Germany.

Subcutaneous fat and genetics -

Of particular interest, three genomic regions located in BTA1, BTA13 and BTA24 showed purely non-additive recessive effects Figure 1 and Table 1. The region in BTA1 3. The region in BTA13 The significant region in BTA24 3. Figure 2 shows a set of terms that were significantly enriched with genes associated with visceral fat accumulation.

These functional terms are related to calcium signaling, cell arrangement, cell metabolism, cell proliferation, cell signaling, immune response, lipid metabolism, membrane permeability, and nervous signaling, among other functions.

FIGURE 2. Functional terms significantly enriched with genes associated with visceral fat accumulation. Six gene-set databases were analyzed: GO, KEGG, MeSH, InterPro, MSigDB, and Reactome.

The y -axis displays the name while the x -axis displays the percentage of significant genes in each functional enriched term.

The identification of genomic regions affecting displaced abomasum or ketosis was performed using the single-step genomic BLUP. This method combines all the available phenotypic, genotypic, and pedigree information, and fits all the SNP simultaneously.

Candidate regions were identified based on the amount of genetic variance explained by 2. Figure 3 shows the gene mapping results for displaced abomasum. Notably, the prominent peak in BTA20, which harbors gene ANKRD55 , was also significantly associated with visceral fat accumulation, suggesting a pleiotropic action.

On the other hand, there were not common regions between ketosis and visceral fat accumulation data not shown. FIGURE 3. Whole-genome scan for incidence of displaced abomasum: percentage of additive genetic variance explained by 2.

Candidate gene ANKRD55 is implicated in both visceral fat accumulation and displaced abomasum. Visceral fat is a highly active tissue involved in complex metabolic processes, such as energy supply, inflammation, and insulin sensitivity.

Dairy cows with excessive visceral fat are more susceptible to metabolic disorders Drackley et al. Although its importance on health and production traits, very few studies have investigated the genetic basis of visceral fat accumulation in dairy cattle.

As such, this study was specially conducted to identify individual genes, functional gene-sets and biological pathways associated with visceral fat accretion in Holstein cows. Two groups of cows with extreme differences in fat deposition in the omentum, one of the most important visceral fat depots, but with very similar subcutaneous fat deposition, were evaluated.

Note that omental fat is strongly correlated with total visceral fat. Furthermore, given the relationship between visceral fat and metabolic disorders, we also investigated the genetic link between visceral fat accumulation and the incidence of displaced abomasum and ketosis in early lactation.

Several pathways revealed in our study coincide with cell rearrangement of adipose tissue identified in other species in obesity studies.

In fact, our gene-set analysis detected biological pathways directly involved in the visceral fat expansion, such as cell arrangement, cell proliferation and cytoskeleton regulation.

Additionally, some of the most significant genes detected in our whole-genome scans are directly implicated in lipid accumulation and tissue rearrangement. For instance, gene PRNP encodes the cellular prior protein known to regulate visceral fat volume, body fat weight, adipocyte cell size, and body weight gain in mice Jeong et al.

Similarly, the significant gene ZADH2 , also known as PTGR-3, negatively modulates adipocyte differentiation through regulation of PPARγ, a major regulator of adipogenesis Yu et al. Regarding cell rearrangement, the significant gene YPEL2 is known to be involved in cell division Hosono et al.

Genes implicated in the cascade signaling due to the active release of NEFA on liver were also detected. Notably, gene SMAD7 , one of the most significant genes revealed in the association mapping, is associated with higher levels of circulating NEFA, lower expression of lipolytic genes, and more proinflammatory proteins in obese mice Seong et al.

While the action of SMAD7 occurs by downregulating TGF-β pathway, the significant gene CLTC stimulates this pathway while downregulate NADPH oxidase to protect against the negative effects of highly active NEFA oxidation Han, ; Caballero-Díaz et al. Additionally, our overrepresentation analysis detected pathways related to fibroblast growth factor receptors FGFR , calcium signaling, protein kinases and glutamate signaling.

The FGFR1 signaling pathway is related to lipid droplet dynamics, phospholipid homeostasis, protection against oxidative stress and to hypertrophy in obese individuals Ye et al. The FGFR2 signaling pathway, inhibited by the significant gene SMAD7 , indirectly promotes lipid biosynthesis by reducing cAMP pool and protein kinase A PKA activity Ornitz and Itoh, ; Huang et al.

Interestingly, both cAMP and PKA are affected by the gene MRAP , a significant gene detected in the non-additive scan. Of particular interest, this gene is associated with mitochondrial fatty acid oxidation and is essential for the lipolytic response to adrenocorticoid hormone, and consequently, insulin sensitivity Zhang et al.

Research has shown that inflammation is directly impacted by higher availability of glucose and NEFA Patel and Abate, Interestingly, our study revealed many genes and gene-sets associated with inflammation. For instance, the gene NOX4 , the main source of reactive oxygen species ROS , is highly expressed in adipocytes and is controlled by gene CLTC , which was detected as significantly associated with fat accumulation in our whole-genome scan Den Hartigh et al.

Our enrichment analysis detected calcium transport terms that are known to be affected by ROS in the form of impaired calcium homeostasis that can lead to cell death Dejos et al. Other adipose-related inflammation responses were also detected is this work. For instance, the significant gene SLC23A2 codes for SVCT1, a transporter of vitamin C, a well-known antioxidant that is able to inhibit adipocyte differentiation and lipid accumulation Rahman et al.

Significant functional terms such as protein kinase C, dendritic spine, and metalloproteinases may indicate the response to local inflammation via proliferation, activation and communication of T-cells, respectively Black and Black, ; Khokha et al.

Interestingly, the gene SKAP1 identified in the genomic scan is an immune cell adaptor responsible for regulating multiple functions of T-cells Raab et al. Enriched terms such as metalloproteases and bacterial humoral defense can also be related to systemic inflammation as the threshold between the beneficial acute inflammation and damaging effect of chronic inflammation is controlled by metalloproteinases via macrophage activity Khokha et al.

There is growing evidence that excessive visceral fat may lead to metabolic disorders. In fact, the significant genes and pathways identified in this study suggest a differential inflammatory response among cows with different levels of visceral fat.

It is known that cows with displaced abomasum have preferable mobilization of visceral over subcutaneous fat and present higher macrophage infiltration in the omental adipose tissue compared to healthy individuals Hostens et al.

Interestingly, our work revealed one region in chromosome 20 that has significant effects on both visceral fat accumulation and susceptibility to displaced abomasum. Notably, this region harbors the gene ANKRD55 , which encodes a scaffold protein related to proliferation of pre-adipocytes, insulin sensitivity, and even more important, higher visceral fat accumulation in human subjects Harder et al.

Gene ANKRD55 is highly active in immune diseases, which corresponds to the state of the clinically diagnosed displaced abomasum cows used in this study, as studies have shown that cows with displaced abomasum are under active lipolysis, negative energy balance, and under higher infiltration of macrophages in adipose tissues Hostens et al.

The whole-body insulin resistance possibly promoted by ANKRD55 would endorse the insulin resistance stimulated by cytokines release from visceral fat and the impaired glucose-stimulated insulin secretion in pancreatic β cells mediated by the significant gene TSHZ1 Raum et al. Changes in insulin concentration and blood calcium levels, two mechanisms identified in our gene-set analysis, are some of the causes for displaced abomasum in cows Van Winden et al.

This common peak in BTA20 for visceral fat accumulation and displaced abomasum suggests a genetic link between visceral fat levels and the incidence of metabolic diseases that deserves further investigation. In this study, we performed an integrative genomic analysis to better understand the genetic basis of visceral fat accumulation in Holstein cows.

Our analysis revealed several genomic regions with significant additive and non-additive genetic effects. Interestingly, these regions harbor genes, such as SMAD7 , SKAP1 , ANKRD55 , MRAP and MIS18A , that are directly implicated in adipocyte differentiation, lipid metabolism, immune response, and insulin tolerance.

We also performed a gene-set analysis to gain additional insights into the genetic architecture of visceral fat deposition. Our analysis revealed gene pathways and molecular mechanisms related to cell metabolism, cell signaling, and immune response, among others.

We also assessed the genetic link between visceral fat and metabolic disorders. Notably, one region on BTA20, which harbors the gene ANKRD55 , implicated in adipocyte differentiation and insulin resistance, showed significant effects on both visceral fat accumulation and displaced abomasum.

Overall, our study suggests that visceral fat deposition in dairy cows is controlled by both additive and non-additive genetic factors. The genetic link between visceral fat accumulation and metabolic disorders deserves further investigation.

The animal study was reviewed and approved by University of Missouri, protocol number FP, PM, and PP designed the study. PM performed the field study. LN, LC, and FP analyzed the data. LN, LC, PP, PM, and FP contributed to the interpretation of the results.

LN wrote the first draft of the manuscript. All authors have read and approved this manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

LN was supported by the Fulbright Brazil Commission and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior — Brasil CAPES — Finance Code Aguilar, I.

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It is unknown whether there is an interaction between lifestyle and other variants on fat distribution. Second, we tested the one SNP of each locus obtained from the top signals of GWAS in varied populations, which may lead to negative findings for the lack of good coverage of the regions in Chinese.

Moreover, despite the multiple comparisons performed in the study, the possibility of a spurious association still cannot be excluded. We replicated the impacts of the loci associated with BMI, waist circumference, and waist-to-hip ratio on fat distribution in a Chinese population and demonstrated that MC4R , LYPLAL1 , and ALDH2 may modulate visceral and subcutaneous fat distribution.

Our findings highlight the importance of considering direct and precise fat distribution traits in obesity-related loci investigations. From —, we recruited up to subjects from a community-based population with Chinese Han ancestry and excluded the subjects with cancer, severe disability, or severe psychiatric disturbances.

The remaining subjects provided informed consent and completed a questionnaire on their medical histories; they also underwent anthropometric measurements and laboratory examinations.

BMI was calculated as weight kilograms divided by height 2 meters. Waist circumference was measured at the level of the umbilicus, and hip circumference was measured around the buttocks.

The waist-to-hip ratio was calculated as the ratio between the waist and hip circumferences in centimetres. Each subject underwent abdominal MRI Archive, Philips Medical System, Amsterdam, Netherlands at the level of the umbilicus between L4 and L5 in the supine position for quantification of body fat distribution.

Two trained observers used SLICE-O-MATIC image analysis software version 4. As for alcohol consumption, briefly, each subject was asked whether they had ever consumed alcohol in their lifetime chance drunk less than three times in every week and regularly drunk equal or more than three times in every week and individuals who gave a positive answer were defined as drinkers, whereas those who gave a negative answer were non-drinkers.

Genomic DNA was extracted from blood samples collected from each subject. A total of 57 SNPs associated with BMI, waist circumference, and waist-to-hip ratio from previous literature as shown in Supplementary Table 1 and Supplementary Figure 1 were selected to be genotyped using the MassARRAY Compact Analyzer Sequenom, San Diego, CA, USA.

The Hardy-Weinberg equilibrium test was performed prior to the analysis. Haploview version4. All analyses were adjusted for covariates, such as age, sex, and other variables, if appropriate. Waist circumference, waist-to-hip ratio, VFA, SFA, and VFA-SFA ratio were logtransformed.

Since no accurate data on type and amount of alcohol consumption, alcohol consumption was converted into a dichotomous variable that includes drinkers and non-drinkers. Multiple testing based on permutations was performed with PLINK. The statistical analyses were performed using SAS software version 8.

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Zhonghua nei ke za zhi 45 , — Association analyses of , individuals reveal 18 new loci associated with body mass index. Download references. This work was supported by Program of China CB , program from Shanghai Municipality for Basic Research 11JC , National Natural Science Foundation of China grants , Shanghai Rising Star Program 12QH , Excellent Young Medical Expert of Shanghai XYQ , Shanghai Talent Development Grant and National Program for Support of Top-notch Young Professionals.

We thank all the research volunteers for their participation and gratefully acknowledge the skillful technical support of all the nursing and medical staff at the Shanghai Clinical Center for Diabetes.

You can also search for this author in PubMed Google Scholar. and W. conceived and designed the research. and R. performed the experiments. and C. analysed the data. and Y. drafted the manuscript. All authors contributed to the writing of this manuscript, and read and approved the final version.

Correspondence to Cheng Hu or Weiping Jia. This work is licensed under a Creative Commons Attribution 4. Reprints and permissions. Wang, T. Sci Rep 6 , Download citation. Received : 21 August Accepted : 05 January Published : 05 February Anyone you share the following link with will be able to read this content:.

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Subxutaneous fat is related to important Subcutaneous fat and genetics processes, including insulin Subvutaneous and lipid mobilization. The goal of adn study was to identify individual genes, pathways, and molecular processes implicated Subcutameous visceral fat deposition in Subcutaneous fat and genetics cows. The identification Germ-repelling surfaces regions with significant additive and non-additive genetic effects was performed using a two-step mixed model-based approach. Genomic scans were followed by gene-set analyses in order to reveal the genetic mechanisms controlling abdominal obesity. The association mapping revealed four regions located on BTA19, BTA20 and BTA24 with significant additive effects. These regions harbor genes, such as SMAD7ANKRD55and the HOXB family, that are implicated in lipolysis and insulin tolerance. Three regions located on BTA1, BTA13, and BTA24 showed marked non-additive effects.

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