Abstract
Genetic variants in the fat mass- and obesity-associated gene Fto are linked to the onset of obesity in humans. The causal role of the FTO protein in obesity is supported by evidence obtained from transgenic mice; however, the underlying molecular pathways pertaining to the role of FTO in obesity have yet to be established. In this study, we investigate the Fto gene in mouse brown adipose tissue and in the browning process of white adipose tissue. We analyze distinct structural and molecular factors in brown and white fat depots of Fto-deficient mice under normal and obesogenic conditions. We report significant alterations in the morphology of adipose tissue depots and the expression of mRNA and microRNA related to brown adipogenesis and metabolism in Fto-deficient mice. Furthermore, we show that high-fat feeding does not attenuate the browning process of Fto-deficient white adipose tissue as observed in wild-type tissue, suggesting a triggering effect of the FTO pathways by the dietary environment.
Highlights
Common genetic variants in the fat mass- and obesity-associated gene Fto are the most prevalent variants linked to higher body mass index (BMI)
Fto-KO mice do not develop the diet-induced obese phenotype and the white adipocytes do not become hypertrophic in response to a high-fat diet (HFD) despite unchanged eating behavior, respiratory exchange ratio, and activity in comparison to wild-type (WT) mice. This led to the question of whether Fto participates in White Adipose Tissue (WAT) development and/or metabolism, and interestingly, we found altered in vivo expression of genes related to adipogenesis in Fto-KO epididymal WAT [17]
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Summary
Common genetic variants in the fat mass- and obesity-associated gene Fto are the most prevalent variants linked to higher body mass index (BMI). While genetic factors are estimated to account for 40%–70% of BMI variation, only a fraction of it is explained by presently known genetic variants [6] This may in part be due to the limited amount of genetic variants yet identified, but there is growing evidence of a gene-environment interaction, which needs to be fully established when the genetics of obesity is under investigation (reviewed in [7]). Individuals homozygous for the obesity-risk allele of Fto variant rs9939609 showed improved weight loss and metabolic markers after low-fat, but not low-carbohydrate, hypocaloric dietary intervention, while the improvement was evident on both diets in the group of the protective allele carriers [8]. A cohort-based study showed a different effect of genetic variants on the risk of obesity depending on the person’s year of birth
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