Abstract
An increased adipocyte size relative to the size of fat depots, also denoted hypertrophic adipose morphology, is a strong risk factor for the future development of insulin resistance and type 2 diabetes. The regulation of adipose morphology is poorly understood. We set out to identify genetic loci associated with adipose morphology and functionally evaluate candidate genes for impact on adipocyte development. We performed a genome-wide association study (GWAS) in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort comprising 948 participants who have undergone abdominal subcutaneous adipose biopsy with a determination of average adipose volume and morphology. The GWAS identified 31 genetic loci displaying suggestive association with adipose morphology. Functional evaluation of candidate genes by small interfering RNAs (siRNA)-mediated knockdown in adipose-derived precursor cells identified six genes controlling adipocyte renewal and differentiation, and thus of potential importance for adipose hypertrophy. In conclusion, genetic and functional studies implicate a regulatory role for ATL2, ARHGEF10, CYP1B1, TMEM200A, C17orf51, and L3MBTL3 in adipose morphology by their impact on adipogenesis.
Highlights
Excess adipose tissue plays a central role in the risk of developing insulin resistance (IR) and, thereby, the development of type 2 diabetes (T2D)
Among established risk alleles for T2D from genome-wide association study (GWAS), only 12 alleles were nominally associated with hypertrophic adipose morphology
The knockdown of either gene stimulated proliferation of adipose-derived human mesenchymal stem cells (hMSCs) accompanied by reduced expression of mRNA markers for adipogenesis, inhibited lipid accumulation, and reduced lipolysis in cells
Summary
Excess adipose tissue plays a central role in the risk of developing insulin resistance (IR) and, thereby, the development of type 2 diabetes (T2D). It is the size and the morphology of subcutaneous adipose tissue (SAT), which influences adipose function [1,2]. The number of fat cells differs substantially between individuals, even among those with the same total body fat, giving rise to hypertrophic, i.e., fewer but larger fat cells, or hyperplastic, i.e., more but smaller fat cells, adipose morphology [3,4]. Hypertrophic SAT has been linked to local IR and increased release of pro-inflammatory mediators and free fatty acids within SAT [5,6], which through systemic effects, contribute to systemic IR.
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