Genomic Variants Associated with Resistance to High Fat Diet Induced Obesity in a Primate Model

Abstract

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.

Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques

“…WSD-fed macaques exhibit weight gain and an increase in fat mass [44]. In addition, 3 treatment groups were established that mirrored the ‘window of opportunity’ hypothesis of HT.…”

Offspring from maternal nutrient restriction in mice show variations in adult glucose metabolism similar to human fetal growth restriction

“…Some individuals with extremely low birth weights (ELBW) although having three times greater risk will not develop glucose intolerance and type 2 diabetes. 3 In adults, genetic variation and differential expression contribute to obesity and metabolic disorder resistant and/or susceptible populations of nonhuman primates 27 and rodent models 28,29 in response to nutritional stress, such as a high fat diet. Offspring in models exposed to maternal high fat diet or nutrient restriction have metabolic, 7,30 gut microbe 31 and epigenomic changes, 32 but to our knowledge none of these models focus on changes specific to susceptible and resistant populations in these offspring.…”

Congenic mice demonstrate the presence of QTLs conferring obesity and hypercholesterolemia on chromosome 1 in the TALLYHO mouse

“…The hydroxysteroid (17-beta) dehydrogenase 7 ( Hsd17b7 ) gene encodes an enzyme required for the cholesterol biosynthesis in liver and is known to be downregulated in a hypocholesterolemic rodent model (Nemoto et al 2013). The phospholipase A2, group IVA (cytosolic, calcium-dependent) ( Pla2g4a ) gene encodes a calcium activated enzyme that catalyzes the hydrolysis of membrane phospholipids to release arachidonic acid, mediating eicosanoid-driven inflammation; polymorphism in Pla2g4a was associated with obesity resistant phenotype in a primate model (Harris et al 2016). The C-reactive protein ( Crp ) gene and serum amyloid P-component ( Apcs, also called Sap ) gene are located in close proximity on Chr 1.…”