Genomic Variants Associated with Resistance to High Fat Diet Induced Obesity in a Primate Model.
Maternal obesity contributes to an increased risk of lifelong morbidity and mortality for both the mother and her offspring. In order to better understand the molecular mechanisms underlying these risks, we previously established and extensively characterized a primate model in Macaca fuscata (Japanese macaque). In prior studies we have demonstrated that a high fat, caloric dense maternal diet structures the offspring's epigenome, metabolome, and intestinal microbiome. During the course of this work we have consistently observed that a 36% fat diet leads to obesity in the majority, but not all, of exposed dams. In the current study, we sought to identify the genomic loci rendering resistance to obesity despite chronic consumption of a high fat diet in macaque dams. Through extensive phenotyping together with exon capture array and targeted resequencing, we identified three novel single nucleotide polymorphisms (SNPs), two in apolipoprotein B (APOB) and one in phospholipase A2 (PLA2G4A) that significantly associated with persistent weight stability and insulin sensitivity in lean macaques. By application of explicit orthogonal modeling (NOIA), we estimated the polygenic and interactive nature of these loci against multiple metabolic traits and their measures (i.e., serum LDL levels) which collectively render an obesity resistant phenotype in our adult female dams.
Department of Obstetrics &Gynecology, Division of Maternal-Fetal Medicine at Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.|Department of Molecular and Human Genetics at Baylor College of Medicine, Houston, TX, USA.
R Alan
RA
Harris
Developmental Biology Interdisciplinary Program at Baylor College of Medicine, Houston, TX, USA.
Callison E
CE
Alcott
Oregon National Primate Research Center, Oregon Health &Science University (OHSU), Beaverton, OR, USA.|Department of Biology, University of Portland, USA.
Elinor L
EL
Sullivan
Oregon National Primate Research Center, Oregon Health &Science University (OHSU), Beaverton, OR, USA.
Diana
D
Takahashi
Department of Human Physiology, University of Oregon, Eugene, OR, USA.
Carrie E
CE
McCurdy
Department of Biology, Corban University, Salem, OR, USA.
Sarah
S
Comstock
Oregon National Primate Research Center, Oregon Health &Science University (OHSU), Beaverton, OR, USA.
Karalee
K
Baquero
Oregon National Primate Research Center, Oregon Health &Science University (OHSU), Beaverton, OR, USA.
Peter
P
Blundell
Oregon National Primate Research Center, Oregon Health &Science University (OHSU), Beaverton, OR, USA.|Department of Obstetrics &Gynecology, Division of Maternal-Fetal Medicine, OHSU, Portland, OR, USA.
Antonio E
AE
Frias
Department of Obstetrics &Gynecology, Division of Maternal-Fetal Medicine at Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
Maike
M
Kahr
Department of Obstetrics &Gynecology, Division of Maternal-Fetal Medicine at Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
Melissa
M
Suter
Departments of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Stephanie
S
Wesolowski
Departments of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Jacob E
JE
Friedman
Oregon National Primate Research Center, Oregon Health &Science University (OHSU), Beaverton, OR, USA.
Kevin L
KL
Grove
Department of Obstetrics &Gynecology, Division of Maternal-Fetal Medicine at Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.|Department of Molecular and Human Genetics at Baylor College of Medicine, Houston, TX, USA.|Developmental Biology Interdisciplinary Program at Baylor College of Medicine, Houston, TX, USA.|Oregon National Primate Research Center, Oregon Health &Science University (OHSU), Beaverton, OR, USA.|Department of Molecular and Cell Biology at Baylor College of Medicine, Houston, TX, USA.
Kjersti M
KM
Aagaard
D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D016678:Genome; D005838:Genotype; D007333:Insulin Resistance / Q000235:genetics; D008251:Macaca; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy
D001055:Apolipoproteins B