Abstract
BackgroundObesity is a growing global concern with strong associations with cardiovascular disease, cancer and type-2 diabetes. Although various genome-wide association studies have identified more than 40 genes associated with obesity, these genes cannot fully explain the heritability of obesity, suggesting there may be other contributing factors, including epigenetic effects.ResultsWe performed genome wide DNA methylation profiling comparing normal-weight and obese 9–13 year old children to investigate possible epigenetic changes correlated with obesity. Of note, obese children had significantly lower methylation levels at a CpG site located near coronin 7 (CORO7), which encodes a tryptophan-aspartic acid dipeptide (WD)-repeat containing protein most likely involved in Golgi complex morphology and function. Anatomical profiling of coronin 7 (Coro7) mRNA expression in mice revealed that it is highly expressed in appetite and energy balance regulating regions, including the hypothalamus, striatum and locus coeruleus, the main noradrenergic brain site. Interestingly, we found that food deprivation in mice downregulates hypothalamic Coro7 mRNA levels, and injecting ethanol, an appetite stimulant, increased the number of Coro7 expressing cells in the locus coeruleus. Finally, by employing the genetically-tractable Drosophila melanogaster model we were able to demonstrate an evolutionarily conserved metabolic function for the CORO7 homologue pod1. Knocking down the pod1 in the Drosophila adult nervous system increased their resistance to starvation. Furthermore, feeding flies a high-calorie diet significantly increased pod1 expression.ConclusionWe conclude that coronin 7 is involved in the regulation of energy homeostasis and this role stems, to some degree, from the effect on feeding for calories and reward.
Highlights
Obesity is a growing global concern with strong associations with cardiovascular disease, cancer and type-2 diabetes
DNA methylation profiling and analysis of genetic association to obesity To establish if there is a correlation between weight category and methylation levels of CpG sites/islands we investigated the genome-wide methylation profile using whole blood obtained from obese and normal-weight participants
A second linear model was used, adjusted for the same confounders and weight category, where we selected the top 15 sites/islands whose methylation levels correlated with the obesity-linked gene STK33 rs4929949 polymorphism (Table 2), which we previously demonstrated is associated with obesity in two independent children cohorts [25]
Summary
Obesity is a growing global concern with strong associations with cardiovascular disease, cancer and type-2 diabetes. Various genome-wide association studies have identified more than 40 genes associated with obesity, these genes cannot fully explain the heritability of obesity, suggesting there may be other contributing factors, including epigenetic effects. The coronin family encodes for actin-binding proteins that are divided into two evolutionarily conserved tryptophanaspartic acid dipeptide (WD)-40 repeat containing groups, short and long, based on their domain composition and structure [7]. This family has seven vertebrate classes where the human members are coronin 1A, 1B, 1C, 2A, 2B, 6 and 7. Overexpression of Pod greatly remodels the cytoskeleton to promote dynamic neurite-like actin-dependent projections [11]
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