A Duplication CNV That Conveys Traits Reciprocal to Metabolic Syndrome and Protects against Diet-Induced Obesity in Mice and Men
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{"title"=>"A duplication CNV that conveys traits reciprocal to metabolic syndrome and protects against diet-induced obesity in mice and men", "type"=>"journal", "authors"=>[{"first_name"=>"Melanie", "last_name"=>"Lacaria", "scopus_author_id"=>"53063974400"}, {"first_name"=>"Pradip", "last_name"=>"Saha", "scopus_author_id"=>"35230709900"}, {"first_name"=>"Lorraine", "last_name"=>"Potocki", "scopus_author_id"=>"56877041300"}, {"first_name"=>"Weimin", "last_name"=>"Bi", "scopus_author_id"=>"7005294540"}, {"first_name"=>"Jiong", "last_name"=>"Yan", "scopus_author_id"=>"7403729299"}, {"first_name"=>"Santhosh", "last_name"=>"Girirajan", "scopus_author_id"=>"8973262400"}, {"first_name"=>"Brooke", "last_name"=>"Burns", "scopus_author_id"=>"37037018800"}, {"first_name"=>"Sarah", "last_name"=>"Elsea", "scopus_author_id"=>"7003860801"}, {"first_name"=>"Katherina", "last_name"=>"Walz", "scopus_author_id"=>"7005713813"}, {"first_name"=>"Lawrence", "last_name"=>"Chan", "scopus_author_id"=>"36907183000"}, {"first_name"=>"James R.", "last_name"=>"Lupski", "scopus_author_id"=>"7103394224"}, {"first_name"=>"Wenli", "last_name"=>"Gu", "scopus_author_id"=>"26326226500"}], "year"=>2012, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537390", "scopus"=>"2-s2.0-84863685348", "sgr"=>"84863685348", "pui"=>"365220731", "isbn"=>"1553-7404", "pmid"=>"22654670", "doi"=>"10.1371/journal.pgen.1002713"}, "id"=>"67b76cda-7538-337b-97db-e6d4918fa5ab", "abstract"=>"The functional contribution of CNV to human biology and disease pathophysiology has undergone limited exploration. Recent observations in humans indicate a tentative link between CNV and weight regulation. Smith-Magenis syndrome (SMS), manifesting obesity and hypercholesterolemia, results from a deletion CNV at 17p11.2, but is sometimes due to haploinsufficiency of a single gene, RAI1. The reciprocal duplication in 17p11.2 causes Potocki-Lupski syndrome (PTLS). We previously constructed mouse strains with a deletion, Df(11)17, or duplication, Dp(11)17, of the mouse genomic interval syntenic to the SMS/PTLS region. We demonstrate that Dp(11)17 is obesity-opposing; it conveys a highly penetrant, strain-independent phenotype of reduced weight, leaner body composition, lower TC/LDL, and increased insulin sensitivity that is not due to alteration in food intake or activity level. When fed with a high-fat diet, Dp(11)17/+ mice display much less weight gain and metabolic change than WT mice, demonstrating that the Dp(11)17 CNV protects against metabolic syndrome. Reciprocally, Df(11)17/+ mice with the deletion CNV have increased weight, higher fat content, decreased HDL, and reduced insulin sensitivity, manifesting a bona fide metabolic syndrome. These observations in the deficiency animal model are supported by human data from 76 SMS subjects. Further, studies on knockout/transgenic mice showed that the metabolic consequences of Dp(11)17 and Df(11)17 CNVs are not only due to dosage alterations of Rai1, the predominant dosage-sensitive gene for SMS and likely also PTLS. Our experiments in chromosome-engineered mouse CNV models for human genomic disorders demonstrate that a CNV can be causative for weight/metabolic phenotypes. Furthermore, we explored the biology underlying the contribution of CNV to the physiology of weight control and energy metabolism. The high penetrance, strain independence, and resistance to dietary influences associated with the CNVs in this study are features distinct from most SNP-associated metabolic traits and further highlight the potential importance of CNV in the etiology of both obesity and MetS as well as in the protection from these traits.", "link"=>"http://www.mendeley.com/research/duplication-cnv-conveys-traits-reciprocal-metabolic-syndrome-protects-against-dietinduced-obesity-mi", "reader_count"=>32, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Other"=>3, "Student > Master"=>2, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Other"=>3, "Student > Master"=>2, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>10, "Medicine and Dentistry"=>7, "Arts and Humanities"=>1, "Business, Management and Accounting"=>2, "Veterinary Science and Veterinary Medicine"=>1, "Psychology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Psychology"=>{"Psychology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>4}, "Arts and Humanities"=>{"Arts and Humanities"=>1}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"Romania"=>1, "Portugal"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/633791"], "description"=>"<p>(A) During IP-GTT, WT mice display more dramatically decreased glucose clearance rate (*p = 0.00011) after HF diet than <i>Dp(11)17/+</i> mice (*p = 0.03). (B) The insulin level of both genotypes are not impacted by HF diet. (C, D) During IP-ITT, <i>Dp(11)17/+</i> mice after HF diet demonstrate lower blood glucose concentration than WT mice, shown as both actual concentration in (C) (*p = 0.002, 0.007, 0.003 and 0.002) and percentage of the initial glucose concentration in (D) (*p = 0.00015, 0.00063, 0.0026, 0.041); whereas the differences are only partially significant under RC as shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002713#pgen-1002713-g003\" target=\"_blank\">Figure 3</a> (C, D). (E) Body weight of both genotypes after HF diet from 10 to 30 weeks. *: comparison for each genotype between HF and RC; $: comparison between the genotypes under the same diet condition. After HF feeding, both genotypes gain weight (WT: *p<0.001; <i>Dp(11)17/+</i>: *p = 0.048). <i>Dp(11)17/+</i> mice are still lighter than WT littermates after HF (<sup>$</sup>p<0.0005), similar to those fed with RC (<sup>$</sup>p<0.001). The curves for normal diet (data points without triangles) are the same as shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002713#pgen-1002713-g001\" target=\"_blank\">Figure 1B</a>. All comparisons were made with ANOVA with repeated measures (A, B, E) or two-tailed t-test (C, D); results are expressed as mean ± s.e.m. and obtained from measurements of n = 5 <i>Dp(11)17/+</i> and 7 WT after HF diet. <i>Dp</i>/WT mice after HF diet: red/gray solid line with triangle markers; <i>Dp</i>/WT mice with RC: red/gray dashed line without marker.</p>", "links"=>[], "tags"=>["mice", "greater", "insulin", "hf", "19", "22", "weeks"], "article_id"=>304269, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Melanie Lacaria", "Pradip Saha", "Lorraine Potocki", "Weimin Bi", "Jiong Yan", "Santhosh Girirajan", "Brooke Burns", "Sarah Elsea", "Katherina Walz", "Lawrence Chan", "James R. Lupski", "Wenli Gu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002713.g006", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_WT_mice_gray_display_a_greater_increase_in_insulin_resistance_than_Dp_11_17_mice_red_after_HF_diet_from_19_to_22_weeks_as_well_as_an_increased_weight_gain_after_a_long_term_HF_diet_/304269", "title"=>"WT mice (gray) display a greater increase in insulin resistance than <i>Dp(11)17/+</i> mice (red) after HF diet from 19 to 22 weeks as well as an increased weight gain after a long-term HF diet.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 01:11:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/633695"], "description"=>"<p>(A) Only WT, but not <i>Dp(11)17/+</i> mice have significant (*p = 0.00028) weight gain after three weeks of HF (19–22 wks) that is mainly due to fat mass increase (*p = 0.00030). (B) Body weight percentage of epididymal (EWAT), mesenteric (MWAT), retroperitoneal (RWAT) and inguinal (IWAT) white adipose tissues are all higher in WT mice post HF than <i>Dp(11)17/+</i> mice (*p = 0.000033 for EWAT, p = 0.00021 for MWAT, p = 0.000033 for RWAT, p = 0.000048 for IWAT). Liver and brown adipose tissues (BAT) remain similar. (C) Dissected EWAT, MWAT and liver are compared between WT and <i>Dp(11)17/+</i> mice post HF diet. EWAT and MWAT, but not the liver, are much smaller in <i>Dp(11)17/+</i> mice. (D) Histology of the EWAT adipocytes from <i>Dp(11)17/+</i> and WT mice, demonstrating smaller adipocytes in <i>Dp(11)17/+</i> mice after HF feeding. The measurements are from (A): 11 <i>Dp(11)17</i>/+ and 12 WT at 22 wks post HF feeding compared to 6 <i>Dp(11)17</i>/+ and 10 WT on RC at 21–22 wks (B) 8 <i>Dp(11)17</i>/+ and 9 WT post HF feeding. <i>Dp</i>/WT mice after HF diet: red/gray bars with dotted pattern; <i>Dp</i>/WT mice with RC: red/gray bars without pattern.</p>", "links"=>[], "tags"=>["mice", "diet-induced", "obesity", "compared", "wt", "littermates", "high-fat", "feeding", "19", "22"], "article_id"=>304155, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Melanie Lacaria", "Pradip Saha", "Lorraine Potocki", "Weimin Bi", "Jiong Yan", "Santhosh Girirajan", "Brooke Burns", "Sarah Elsea", "Katherina Walz", "Lawrence Chan", "James R. Lupski", "Wenli Gu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002713.g005", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dp_11_17_mice_red_display_resistance_to_diet_induced_obesity_compared_to_WT_littermates_gray_after_a_high_fat_diet_HF_feeding_from_19_to_22_weeks_/304155", "title"=>"<i>Dp(11)17/+</i> mice (red) display resistance to diet-induced obesity compared to WT littermates (gray) after a high-fat diet (HF) feeding from 19 to 22 weeks.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 01:09:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/633578"], "description"=>"<p>(A) <i>Dp(11)17/+</i> mice have similar amount daily food intake to WT mice after 4 wks of age, although they consume less food at 3 wks (*p = 0.001) and 4 wks (*p = 0.048). (B) VersaMax system (Accuscan Inc., Ohio) using the beam block technique implemented in home cages revealed no difference in horizontal activity level between <i>Dp(11)17/+</i> and WT animals. (C, D) Oxygen consumption measured using the CLAMS system (Columbus Ins., Ohio) for over three days documented higher energy expenditure of <i>Dp(11)17/+</i> mice in the light phases alone (*p = 0.0095) and during the entire day (*p = 0.044). (E, F) Respiratory exchange ratio (RER) measured using the CLAMS system for over three days again confirmed higher metabolic activity of <i>Dp(11)17/+</i> mice (*p = 0.00151). (G) Western blot for UCP1 expression in BAT tissue of three <i>Dp(11)17/+</i> and three WT mice with antibody AB3036 (Millipore). The same blot was normalized to actin blotting using MAB1501 (Millipore). (H) Normalized intensity of UCP1 signals in <i>Dp(11)17/+</i> vs. WT mice (17.13±10.21 vs. 4.74±2.05, p = 0.35). The measurements are from (A) 5–13 <i>Dp(11)17</i>/+ and 5–11 WT at different time points (B) to (F) 12 <i>Dp(11)17</i>/+ and 7–10 WT at 25–32 wks (G) 3 <i>Dp(11)17</i>/+ and 3 WT at 30 wks.</p>", "links"=>[], "tags"=>["mice", "intake", "higher", "expenditure", "wt", "accounted", "levels", "ucp1"], "article_id"=>304044, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Melanie Lacaria", "Pradip Saha", "Lorraine Potocki", "Weimin Bi", "Jiong Yan", "Santhosh Girirajan", "Brooke Burns", "Sarah Elsea", "Katherina Walz", "Lawrence Chan", "James R. Lupski", "Wenli Gu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002713.g004", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dp_11_17_mice_red_have_similar_food_intake_and_activity_levels_but_higher_energy_expenditure_than_WT_mice_gray_which_may_be_partially_accounted_for_by_the_difference_in_expression_levels_of_UCP1_in_the_BAT_tissue_/304044", "title"=>"<i>Dp(11)17/+</i> mice (red) have similar food intake and activity levels, but higher energy expenditure than WT mice (gray), which may be partially accounted for by the difference in expression levels of UCP1 in the BAT tissue.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 01:07:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/633977"], "description"=>"<p>(A) The growth curve of <i>Rai1<sup>+/−</sup></i> and WT littermates reveals increased body weights of <i>Rai1<sup>+/−</sup></i> mice (*p = 0.028 by ANOVA with repeated measures). (B) <i>Rai1<sup>+/−</sup></i> mice have increased body fat mass (*p = 0.014) and reduced lean mass (*p = 0.015). (C) <i>Rai1<sup>+/−</sup></i> mice demonstrate higher TC (*p = 0.036) and HDL (*p = 0.048), but unchanged TC/HDL ratio. In GTT experiments, <i>Rai1<sup>+/−</sup></i> mice have (D) higher blood glucose at 60 mins (*p = 0.042) and 120 mins (*p = 0.030 after glucose injection, and *p = 0.038 for total AUC) and (E) higher insulin levels throughout (*p = 0.0056, 0.0069, 0.029, 0.008 at 0, 15, 30 and 120 mins and #p = 0.058 at 60 mins after injection. For AUC, *p = 0.021). (F, G) IP-ITT resulted in similar glucose level change between <i>Rai1<sup>+/−</sup></i> and WT mice, as shown by both actual concentration (F) and percentage of the initial glucose concentration (G). All comparisons were made with two-tailed t-test except (A) that used ANOVA; results are expressed as mean ± s.e.m. from measurements of (A) 10–25 <i>Df(11)17/+</i> and 10–25 WT mice (B, C) 6 <i>Rai1<sup>+/−</sup></i> and 8 WT at 30–31 wks (D, E) 5 <i>Rai1<sup>+/−</sup></i> and 5 WT mice at 41–43 wks (F, G) n = 7 <i>Rai1<sup>+/−</sup></i> and 6 WT mice at 33–36 wks. All AUCs are computed until 120 minutes, for the entire length of the time curves.</p>", "links"=>[], "tags"=>["mice", "reduced", "insulin", "compared", "wt"], "article_id"=>304455, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Melanie Lacaria", "Pradip Saha", "Lorraine Potocki", "Weimin Bi", "Jiong Yan", "Santhosh Girirajan", "Brooke Burns", "Sarah Elsea", "Katherina Walz", "Lawrence Chan", "James R. Lupski", "Wenli Gu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002713.g008", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rai1_8722_mice_blue_are_obese_have_increased_TC_HDL_and_display_reduced_insulin_sensitivity_compared_to_WT_mice_gray_/304455", "title"=>"<i>Rai1<sup>+/−</sup></i> mice (blue) are obese, have increased TC, HDL, and display reduced insulin sensitivity compared to WT mice (gray).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 01:14:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/633331"], "description"=>"<p>(A) Less relative total fat mass (*p = 0.000088) and more relative lean mass (*p = 0.00012) was identified in <i>Dp(11)17/+</i> mice with ECHO-MRI system. (B) <i>Dp(11)17/+</i> animals also possess smaller epididymal white adipose tissue pad (EWAT) (*p = 0.0020). Fasting serum profile revealed (C) reduced TC (*p = 0.021), LDL (*p = 0.01), TC/HDL ratio (*p = 0.0007) and (D) reduced leptin (*p = 0.021) in <i>Dp(11)17/+</i> mice. All comparisons were made with two-tailed t-test; results are expressed as mean ± s.e.m. from measurements of (A) 6 <i>Dp(11)17/+</i> and 10 WT at 21–22 wks (B) 6 <i>Dp(11)17/+</i>, 7 WT at 41 wks (C) 5 <i>Dp(11)17/+</i> and 6 WT at 20–22 wks (D) 6 <i>Dp(11)17/+</i> and 4 WT of 20–21 wks.</p>", "links"=>[], "tags"=>["mice", "leaner", "reduced", "serum"], "article_id"=>303814, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Melanie Lacaria", "Pradip Saha", "Lorraine Potocki", "Weimin Bi", "Jiong Yan", "Santhosh Girirajan", "Brooke Burns", "Sarah Elsea", "Katherina Walz", "Lawrence Chan", "James R. Lupski", "Wenli Gu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002713.g002", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dp_11_17_mice_red_are_also_leaner_and_have_reduced_serum_TC_LDL_TC_HDL_ratio_and_leptin_/303814", "title"=>"<i>Dp(11)17/+</i> mice (red) are also leaner and have reduced serum TC, LDL, TC/HDL ratio, and leptin.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 01:03:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/633889"], "description"=>"<p>(A) ECHO-MRI identified elevated fat mass (*p = 0.0041) and reduced lean mass (*p = 0.0034) in <i>Df(11)17/+</i> animals. (B) <i>Df(11)17/+</i> animals have lower serum TC (*p = 0.033) and lower HDL (*p = 0.039), but no significantly change in TC/HDL ratio. IP-GTT documented (C) similar blood glucose levels but (D) significantly higher insulin levels (*p = 0.015, 0.028, 0.012 and 0.013 at 0, 30, 60, 120 mins post injection and *p = 0.011 for AUC) in <i>Df(11)17/+</i> animals. During IP-ITT, <i>Df(11)17/+</i> mice retain higher blood glucose concentration, shown as both (E) actual concentration (*p = 0.026 and 0.008 for 60 and 120 mins post insulin injection and *p = 0.018 for AUC) and (F) percentage of the initial glucose concentration (*p = 0.01 for both 60 and 120 min after injection and *p = 0.0086 for AUC). All comparisons were made with two-tailed t-test; results are expressed as mean ± s.e.m. from measurements of (A) 5 <i>Df(11)17/+</i> and 7 WT mice at 32–36 wks (B) 6 <i>Df(11)17/+</i> and 6 WT mice at 34–37 wks (C, D) 5 <i>Df(11)17/+</i> and 5 WT mice at 37–41 wks (E, F) 5 <i>Df(11)17/+</i> and 6 WT mice at 33–37 wks. All AUCs are computed until 120 minutes, for the entire length of the time curves.</p>", "links"=>[], "tags"=>["mice", "reduced", "insulin", "wt"], "article_id"=>304369, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Melanie Lacaria", "Pradip Saha", "Lorraine Potocki", "Weimin Bi", "Jiong Yan", "Santhosh Girirajan", "Brooke Burns", "Sarah Elsea", "Katherina Walz", "Lawrence Chan", "James R. Lupski", "Wenli Gu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002713.g007", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Df_11_17_mice_green_are_obese_have_reduced_TC_HDL_and_display_reduced_insulin_sensitivity_in_comparison_to_WT_mice_gray_/304369", "title"=>"<i>Df(11)17/+</i> mice (green) are obese, have reduced TC, HDL, and display reduced insulin sensitivity in comparison to WT mice (gray).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 01:12:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/633233"], "description"=>"<p>(A) A <i>Dp(11)17/+</i> male (23 weeks old) and its WT littermate are shown, both on isogenic C57BL/6<i><sup>Tyr</sup></i><sup>c<i>-Brd</i></sup> background. <i>Dp(11)17/+</i> mice appear gray because of a coat color marker in the construct used to chromosome engineer this strain <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002713#pgen.1002713-Walz1\" target=\"_blank\">[20]</a>. (B) Growth curve of <i>Dp(11)17/+</i> (red) and WT littermates (gray) reveal decreased weights for the duplication CNV mutants throughout their life span (*p<0.001 for by ANOVA with repeated measures). (C) A <i>Df(11)17/+</i> male (32 weeks old) and its WT littermate on pure 129S5 background (D) Growth curve of <i>Df(11)17/+</i> (green) and WT littermates (gray) reveal increased weights for the deletion CNV mutants (*p<0.05 by ANOVA). (B, D): n = 10–25 mice for each data point, results are expressed as mean ± s.e.m.</p>", "links"=>[], "tags"=>["mice", "reduced"], "article_id"=>303714, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Melanie Lacaria", "Pradip Saha", "Lorraine Potocki", "Weimin Bi", "Jiong Yan", "Santhosh Girirajan", "Brooke Burns", "Sarah Elsea", "Katherina Walz", "Lawrence Chan", "James R. Lupski", "Wenli Gu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002713.g001", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dp_11_17_mice_have_reduced_and_Df_11_17_mice_have_increased_body_weight_/303714", "title"=>"<i>Dp(11)17/+</i> mice have reduced and <i>Df(11)17/+</i> mice have increased body weight.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 01:01:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/327570", "https://ndownloader.figshare.com/files/327623", "https://ndownloader.figshare.com/files/327677", "https://ndownloader.figshare.com/files/327741", "https://ndownloader.figshare.com/files/327796"], "description"=>"<div><p>The functional contribution of CNV to human biology and disease pathophysiology has undergone limited exploration. Recent observations in humans indicate a tentative link between CNV and weight regulation. Smith-Magenis syndrome (SMS), manifesting obesity and hypercholesterolemia, results from a deletion CNV at 17p11.2, but is sometimes due to haploinsufficiency of a single gene, <em>RAI1</em>. The reciprocal duplication in 17p11.2 causes Potocki-Lupski syndrome (PTLS). We previously constructed mouse strains with a deletion, <em>Df(11)17</em>, or duplication, <em>Dp(11)17</em>, of the mouse genomic interval syntenic to the SMS/PTLS region. We demonstrate that <em>Dp(11)17</em> is obesity-opposing; it conveys a highly penetrant, strain-independent phenotype of reduced weight, leaner body composition, lower TC/LDL, and increased insulin sensitivity that is not due to alteration in food intake or activity level. When fed with a high-fat diet, <em>Dp(11)17/+</em> mice display much less weight gain and metabolic change than WT mice, demonstrating that the <em>Dp(11)17</em> CNV protects against metabolic syndrome. Reciprocally, <em>Df(11)17/+</em> mice with the deletion CNV have increased weight, higher fat content, decreased HDL, and reduced insulin sensitivity, manifesting a bona fide metabolic syndrome. These observations in the deficiency animal model are supported by human data from 76 SMS subjects. Further, studies on knockout/transgenic mice showed that the metabolic consequences of <em>Dp(11)17</em> and <em>Df(11)17</em> CNVs are not only due to dosage alterations of <em>Rai1</em>, the predominant dosage-sensitive gene for SMS and likely also PTLS. Our experiments in chromosome-engineered mouse CNV models for human genomic disorders demonstrate that a CNV can be causative for weight/metabolic phenotypes. Furthermore, we explored the biology underlying the contribution of CNV to the physiology of weight control and energy metabolism. The high penetrance, strain independence, and resistance to dietary influences associated with the CNVs in this study are features distinct from most SNP–associated metabolic traits and further highlight the potential importance of CNV in the etiology of both obesity and MetS as well as in the protection from these traits.</p> </div>", "links"=>[], "tags"=>["duplication", "cnv", "conveys", "traits", "reciprocal", "metabolic", "protects", "diet-induced", "obesity", "mice", "men"], "article_id"=>124654, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Melanie Lacaria", "Pradip Saha", "Lorraine Potocki", "Weimin Bi", "Jiong Yan", "Santhosh Girirajan", "Brooke Burns", "Sarah Elsea", "Katherina Walz", "Lawrence Chan", "James R. Lupski", "Wenli Gu"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1002713.s001", "https://dx.doi.org/10.1371/journal.pgen.1002713.s002", "https://dx.doi.org/10.1371/journal.pgen.1002713.s003", "https://dx.doi.org/10.1371/journal.pgen.1002713.s004", "https://dx.doi.org/10.1371/journal.pgen.1002713.s005"], "stats"=>{"downloads"=>24, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Duplication_CNV_That_Conveys_Traits_Reciprocal_to_Metabolic_Syndrome_and_Protects_against_Diet_Induced_Obesity_in_Mice_and_Men/124654", "title"=>"A Duplication CNV That Conveys Traits Reciprocal to Metabolic Syndrome and Protects against Diet-Induced Obesity in Mice and Men", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-05-24 01:17:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/634085"], "description"=>"<p>Genomotypes are shown similar to <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002713#pgen.1002713-Lupski5\" target=\"_blank\">[57]</a>. The segments flanked by brackets that encompass the <i>Rai1</i> gene represent the CNV region, duplicated in <i>Dp(11)17/+</i> or deleted in <i>Df(11)17/+</i>. *: <i>TgRai1</i> strain has the insertion of <i>Rai1</i> outside of chromosome 11; it gives similar <i>Rai1</i> expression levels to those of the <i>Dp(11)17/+</i> strain although the copy number has been determined as four <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002713#pgen.1002713-Girirajan1\" target=\"_blank\">[35]</a>. Underlined results are from published reports.</p>", "links"=>[], "tags"=>["findings", "variations"], "article_id"=>304568, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Melanie Lacaria", "Pradip Saha", "Lorraine Potocki", "Weimin Bi", "Jiong Yan", "Santhosh Girirajan", "Brooke Burns", "Sarah Elsea", "Katherina Walz", "Lawrence Chan", "James R. Lupski", "Wenli Gu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002713.g009", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Experimental_findings_for_specific_genetic_genomic_variations_in_this_report_/304568", "title"=>"Experimental findings for specific genetic/genomic variations in this report.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 01:16:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/633443"], "description"=>"<p>During IP-GTT (6 hr fasting, 1.5 mg glucose/g body weight), <i>Dp(11)17/+</i> mice demonstrate (A) lower blood glucose (*p = 0.006 for 120 minutes post injection; # p = 0.052 for the area under curve (AUC)) and (B) lower blood insulin level (*p = 0.0037, 0.0026, 0.0051, 0.0031 and 0.0015 for the time points 0, 15, 30, 60 and 120 minutes; *p = 0.002 for AUC). During IP-ITT (4–6 hrs fasting, 1 mU insulin/g body weight), <i>Dp(11)17/+</i> mice also demonstrate lower blood glucose concentration, shown as both actual concentration (C) (*p = 0.011, 0.004 and 0.037 for 0, 15 and 30 mins post insulin injection) and percentage of the initial glucose concentration (D) (*p = 0.038 for 15 mins post insulin injection). All comparisons were made with two-tailed t-test; results are expressed as mean ± s.e.m. from measurements of (A, B) n = 5 <i>Dp(11)17/+</i> and 6 WT at 30 wks (C, D) 4 <i>Dp(11)17/+</i> and 4 WT mice at 20–22 wks. All AUCs are computed until 120 minutes, for the entire length of the time curves.</p>", "links"=>[], "tags"=>["mice", "insulin", "compared", "wt"], "article_id"=>303916, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Melanie Lacaria", "Pradip Saha", "Lorraine Potocki", "Weimin Bi", "Jiong Yan", "Santhosh Girirajan", "Brooke Burns", "Sarah Elsea", "Katherina Walz", "Lawrence Chan", "James R. Lupski", "Wenli Gu"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002713.g003", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dp_11_17_mice_red_display_improved_insulin_sensitivity_compared_to_WT_mice_gray_/303916", "title"=>"<i>Dp(11)17/+</i> mice (red) display improved insulin sensitivity compared to WT mice (gray).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-24 01:05:16"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"22", "full-text"=>"24", "pdf"=>"9", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2012", "month"=>"9"}
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  • {"unique-ip"=>"31", "full-text"=>"32", "pdf"=>"11", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"4"}
  • {"unique-ip"=>"28", "full-text"=>"27", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"12", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2012", "month"=>"11"}
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  • {"unique-ip"=>"17", "full-text"=>"15", "pdf"=>"7", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"2"}
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  • {"unique-ip"=>"10", "full-text"=>"10", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"6"}
  • {"unique-ip"=>"13", "full-text"=>"14", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"7"}
  • {"unique-ip"=>"13", "full-text"=>"17", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"8"}
  • {"unique-ip"=>"18", "full-text"=>"19", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"9"}
  • {"unique-ip"=>"13", "full-text"=>"15", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"1", "year"=>"2015", "month"=>"10"}
  • {"unique-ip"=>"17", "full-text"=>"17", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"11"}
  • {"unique-ip"=>"11", "full-text"=>"14", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"12"}
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  • {"unique-ip"=>"8", "full-text"=>"5", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"2"}
  • {"unique-ip"=>"1", "full-text"=>"1", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"3"}
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Relative Metric

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