A duplication CNV that conveys traits reciprocal to metabolic syndrome and protects against diet-induced obesity in mice and men

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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish
Article numbere1002713
JournalPLoS Genetics
Volume8
Issue number5
DOIs
StatePublished - May 1 2012

Fingerprint

obesity
Smith-Magenis Syndrome
metabolic syndrome
Obesity
diet
Diet
mice
Weights and Measures
insulin resistance
fat
Insulin Resistance
phenotype
genomics
animal models
Phenotype
Haploinsufficiency
Biological Sciences
penetrance
Gene Dosage
Penetrance

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

A duplication CNV that conveys traits reciprocal to metabolic syndrome and protects against diet-induced obesity in mice and men. / Lacaria, Melanie; Saha, Pradip; Potocki, Lorraine; Bi, Weimin; Yan, Jiong; Girirajan, Santhosh; Burns, Brooke; Elsea, Sarah; Walz, Katherina; Chan, Lawrence; Lupski, James R.; Gu, Wenli.

In: PLoS Genetics, Vol. 8, No. 5, e1002713, 01.05.2012.

Research output: Contribution to journalArticle

Lacaria, M, Saha, P, Potocki, L, Bi, W, Yan, J, Girirajan, S, Burns, B, Elsea, S, Walz, K, Chan, L, Lupski, JR & Gu, W 2012, 'A duplication CNV that conveys traits reciprocal to metabolic syndrome and protects against diet-induced obesity in mice and men', PLoS Genetics, vol. 8, no. 5, e1002713. https://doi.org/10.1371/journal.pgen.1002713
Lacaria, Melanie ; Saha, Pradip ; Potocki, Lorraine ; Bi, Weimin ; Yan, Jiong ; Girirajan, Santhosh ; Burns, Brooke ; Elsea, Sarah ; Walz, Katherina ; Chan, Lawrence ; Lupski, James R. ; Gu, Wenli. / A duplication CNV that conveys traits reciprocal to metabolic syndrome and protects against diet-induced obesity in mice and men. In: PLoS Genetics. 2012 ; Vol. 8, No. 5.
@article{5d1a7a625d7c454bbaed008a46f29b30,
title = "A duplication CNV that conveys traits reciprocal to metabolic syndrome and protects against diet-induced obesity in mice and men",
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.",
author = "Melanie Lacaria and Pradip Saha and Lorraine Potocki and Weimin Bi and Jiong Yan and Santhosh Girirajan and Brooke Burns and Sarah Elsea and Katherina Walz and Lawrence Chan and Lupski, {James R.} and Wenli Gu",
year = "2012",
month = "5",
day = "1",
doi = "10.1371/journal.pgen.1002713",
language = "English",
volume = "8",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - A duplication CNV that conveys traits reciprocal to metabolic syndrome and protects against diet-induced obesity in mice and men

AU - Lacaria, Melanie

AU - Saha, Pradip

AU - Potocki, Lorraine

AU - Bi, Weimin

AU - Yan, Jiong

AU - Girirajan, Santhosh

AU - Burns, Brooke

AU - Elsea, Sarah

AU - Walz, Katherina

AU - Chan, Lawrence

AU - Lupski, James R.

AU - Gu, Wenli

PY - 2012/5/1

Y1 - 2012/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863685348&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863685348&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1002713

DO - 10.1371/journal.pgen.1002713

M3 - Article

C2 - 22654670

AN - SCOPUS:84863685348

VL - 8

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 5

M1 - e1002713

ER -