{ "items": [ "\n\n
<jats:p> Two recent, large whole-genome association studies (GWAS) in European populations have associated a \u223c47-kb region that contains part of the FTO gene with high body mass index (BMI). The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to underfeeding/overfeeding, and to 4\u00b0C. Fto/ Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the A<jats:sup> y</jats:sup> , Lep<jats:sup> ob</jats:sup>, Lepr<jats:sup> db</jats:sup> , Cpe<jats:sup> fat</jats:sup>, or tub mutations, and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be coregulated. The putative overlapping regulatory region contains at least two canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 associated with lower body mass than the C allele preferentially bound CUTL1 in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65%, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed \u201cciliopathy.\u201d FTM has recently been shown to be a ciliary basal body protein. </jats:p>
\n \n\n \n \n<jats:sec><jats:title>Objective</jats:title><jats:p>Abnormal ghrelin regulation may influence the development of obesity-associated conditions including polycystic ovary syndrome (PCOS). Our aim was to compare ghrelin regulation between PCOS cases and controls.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>We compared serum ghrelin (total) levels, fasting and 30-min post-oral (75\u200ag) glucose load, between 50 PCOS cases and 28 female controls, including 22 body mass index (BMI)/fat mass-matched pairs. All subjects were of UK British/Irish origin.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Measurements included serum ghrelin (RIA technique (LINCO Research, St Charles MO, USA)), fat mass, serum testosterone, fasting serum insulin and plasma glucose levels. Insulin sensitivity was calculated as the homeostasis model assessment of insulin resistance (HOMA2 IR).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Fasting serum ghrelin levels were significantly lower in PCOS cases versus BMI/fat mass-matched controls (geometric mean (<jats:sc>s.d</jats:sc>. range), 1104\u200apg/ml (764\u20131595) vs 1756\u200apg/ml (1314\u20132347) respectively; <jats:italic>P</jats:italic>=2.3\u00d710<jats:sup>\u22124</jats:sup>). Ghrelin suppression following oral glucose load was significantly blunted in PCOS cases versus BMI/fat mass-matched controls (geometric mean ghrelin suppression (<jats:sc>s.d</jats:sc>. range), 160\u200apg/ml (88\u2013289) vs 424\u200apg/ml (220\u2013818) respectively; <jats:italic>P</jats:italic>=2.0\u00d710<jats:sup>\u22124</jats:sup>). Whole-group comparisons (50 PCOS cases versus 28 controls) adjusted for fat mass and age revealed similar results. In PCOS cases, there was a significant negative correlation between fasting serum ghrelin and HOMA2 IR (<jats:italic>r</jats:italic><jats:sup>2</jats:sup>=\u22120.40, <jats:italic>P</jats:italic>=5.7\u00d710<jats:sup>\u22123</jats:sup>). Following adjustment for HOMA2 IR, fat mass and age, comparisons between the whole groups of PCOS cases and controls revealed attenuated but significant differences in fasting serum ghrelin (<jats:italic>P</jats:italic>=1.3\u00d710<jats:sup>\u22123</jats:sup>) and ghrelin suppression (<jats:italic>P</jats:italic>=1.8\u00d710<jats:sup>\u22123</jats:sup>).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In women with PCOS, serum ghrelin levels are suppressed, showing a negative relationship with HOMA2 IR and a blunted response to oral glucose.</jats:p></jats:sec>
\n \n\n \n \n