Systems genetic analysis of brown adipose tissue function

Abstract

Brown adipose tissue (BAT) has been suggested to play an important role in lipid and glucose metabolism in rodents and possibly also in humans. In the current study, we used genetic and correlation analyses in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), to identify genetic determinants of BAT function. Linkage analyses revealed a quantitative trait locus (QTL) associated with interscapular BAT mass on chromosome 4 and two closely linked QTLs associated with glucose oxidation and glucose incorporation into BAT lipids on chromosome 2. Using weighted gene coexpression network analysis (WGCNA) we identified 1,147 gene coexpression modules in the BAT from BXH/HXB rats and mapped their module eigengene QTLs. Through an unsupervised analysis, we identified modules related to BAT relative mass and function. The Coral4.1 coexpression module is associated with BAT relative mass (includes Cd36 highly connected gene), and the Darkseagreen coexpression module is associated with glucose incorporation into BAT lipids (includes Hiat1, Fmo5, and Sort1 highly connected transcripts). Because multiple statistical criteria were used to identify candidate modules, significance thresholds for individual tests were not adjusted for multiple comparisons across modules. In summary, a systems genetic analysis using genomic and quantitative transcriptomic and physiological information has produced confirmation of several known genetic factors and significant insight into novel genetic components functioning in BAT and possibly contributing to traits characteristic of the metabolic syndrome.

Estimation of inbreeding and identification of regions under heavy selection based on runs of homozygosity in a Large White pig population

“…SIRT1 may downregulate pig preadipocyte proliferation and differentiation [23]. FMO5 plays a role in increasing glucose metabolism and insulin sensitivity in brown adipose tissue [49]. SIM1 is involved in the regulation of energy homeostasis [50], and KIF1BP and MCHR2 are involved in the regulation of food intake [51,52], which in turn affects obesity risk [53].…”

Mutant Wars2 Gene in Spontaneously Hypertensive Rats Impairs Brown Adipose Tissue Function and Predisposes to Visceral Obesity

“…Statistical significance was defined as P<0.05. Statistical analysis of gene expression data was performed using the REST XL program, which tests for significance using a randomization procedure (Pfaffl et al 2002). Correlation analysis of glucose oxidation and incorporation into BAT lipids (Pravenec et al 2017) with parameters of glucose and lipid metabolism in the BXH/HXB RI strains were performed using GeneNetwork database and online software (www.genenetwork.org) (Mulligan et al 2017).…”

“…The SHR/OlaIpcv strain (referred to as the SHR), SHR.BN-D2Rat171/D2Arb24 congenic strain with wild type Wars2 (referred to as SHR-2) (Pravenec et al 2001) and the new SHR transgenic strain expressing wild type Wars2 gene were housed in a facility with constant temperature 23 °C and 12 h light/dark cycle and allowed free access to standard laboratory chow and water. Transgenic SHR/Ola-Tg(EF1a-Wars2) (referred to as the transgenic SHR-Wars2) strain was derived by microinjecting fertilized eggs with a mix of the Sleeping Beauty construct containing BN Wars2 cDNA under control of the universal EF-1α promoter and mRNA of the SB100X transposase (Ivics et al 2014).…”

Endogenous Roles of Mammalian Flavin-Containing Monooxygenases

“…A combined quantitative trait locus and transcriptomic approach in rats identified FMO5 as being important for the functioning of brown adipose tissue [105].…”