Abstract
BackgroundObesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain.ResultsTo enrich for adipose tissue obesity genes a ‘snap-shot’ pooled-sample transcriptome comparison of key fat depots and non adipose tissues (muscle, liver, kidney) was performed. Known obesity quantitative trait loci (QTL) information for the model allowed us to further filter genes for increased likelihood of being causal or secondary for obesity. This successfully identified several genes previously linked to obesity (C1qr1, and Np3r) as positional QTL candidate genes elevated specifically in F line adipose tissue. A number of novel obesity candidate genes were also identified (Thbs1, Ppp1r3d, Tmepai, Trp53inp2, Ttc7b, Tuba1a, Fgf13, Fmr) that have inferred roles in fat cell function. Quantitative microarray analysis was then applied to the most phenotypically divergent adipose depot after exaggerating F and L strain differences with chronic high fat feeding which revealed a distinct gene expression profile of line, fat depot and diet-responsive inflammatory, angiogenic and metabolic pathways. Selected candidate genes Npr3 and Thbs1, as well as Gys2, a non-QTL gene that otherwise passed our enrichment criteria were characterised, revealing novel functional effects consistent with a contribution to obesity.ConclusionsA focussed candidate gene enrichment strategy in the unique F and L model has identified novel adipose tissue-enriched genes contributing to obesity.
Highlights
Obesity and its co-associated metabolic diseases result from a complex interaction between environmental and genetic factors [1,2,3]
Since the divergent adiposity of the model was selected using fat pad mass rather than food intake, and because several studies, including recent meta-genome wide association, link lipid metabolism and intrinsic molecular pathways within the adipose tissue to fat mass regulation [8,9,10,11,12] we reasoned that the F and L adipose tissue would be a rich resource for identifying obesity-susceptibility genes
Functional validation of key divergently expressed genes To further validate our stratified obesity gene enrichment approach we investigated the functional impact of 3 genes implicated in F-line obesity on fat cell function
Summary
Obesity and its co-associated metabolic diseases result from a complex interaction between environmental and genetic factors [1,2,3]. The polygenic Fat (F) and Lean (L) mouse models were selectively bred for divergent body fat mass [4] and model complex polygenic human obesity. Since the divergent adiposity of the model was selected using fat pad mass rather than food intake, and because several studies, including recent meta-genome wide association, link lipid metabolism and intrinsic molecular pathways within the adipose tissue to fat mass regulation [8,9,10,11,12] we reasoned that the F and L adipose tissue would be a rich resource for identifying obesity-susceptibility genes. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain
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