Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity.

The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress

The relationship of tobacco and alcohol use with ageing self-perceptions in older people in Ireland

Abstract Background Health behaviour patterns in older groups, including tobacco and alcohol use, are key factors in chronic disease prevention. We explore ageing self-perceptions as motivating factors behind smoking and drinking alcohol in older adults, and the complex reasons why individuals engage harmfully in these behaviours. Methods Cigarette and alcohol use was assessed in a large cross-sectional national sample aged 50 years and above from the Irish Longitudinal Study on Ageing (TILDA) (n = 6,576). The Brief Ageing Perceptions Questionnaire (BAPQ) assessed individual’s views of their own ageing across five domains. Study hypothesis that stronger beliefs on each of the BAPQ domains would be related to drinking and smoking was examined using multinomial logit models (MNLM). Regression parameter estimates for all variables were estimated relative risk ratios (RRR). Results More women were non-drinkers (30 % vs. 20 %) and men displayed significantly higher alcohol use patterns. One in five older Irish adults was a current smoker (16.8 % of women, 17 % of men), and smoking and harmful drinking were strongly associated (P < .001). Some domains of ageing perceptions were significantly associated with harmful drinking and smoking. While the risk of being be harmful drinker decreased with stronger beliefs about the positive consequences of ageing (RRR 0.89), it increased with higher scores on both emotional representation and control positive domains. Greater awareness of ageing and stronger emotional reaction to ageing increased likelihood of smoking. A greater sense of control over the outcomes of ageing was associated with increased risk of both harmful drinking (RRR control positive 1.16) and smoking (RRR control and consequences negative 1.25). This suggests optimistic bias in relation to perceived health risk from smoking and harmful drinking as a potential adverse effect of perceptions of control. Risks of concurrent smoking and harmful drinking increased with chronic awareness of ageing (RRR 1.24), and negative emotional responses to it (RRR 1.21), and decreased with stronger perceptions of the positive consequences of ageing (RRR 0.85). Conclusions The relationship between ageing perceptions, smoking and drinking is complex. Altering perceptions of ageing may be a useful intervention target aimed at facilitating engagement in preventative health behaviours in older people

Universal genetic screening uncovers a novel presentation of an sdhaf2 mutation

Context: Hereditary pheochromocytoma/paraganglioma (PC/PGL) accounts for up to 60% of previously considered sporadic tumors. Guidelines suggest that phenotype should guide genetic testing. Next-generation sequencing technology can simultaneously sequence 9 of the 18 known susceptibility genes in a timely, cost-efficient manner. Objective: Our aim was to confirm that universal screening is superior to targeted testing in patients with histologically confirmed PC and PGL. Methods: In two tertiary referral hospitals in Ireland, NGS was carried out on all histologically confirmed cases of PC/PGL diagnosed between 2004 and 2013. The following susceptibility genes were sequenced: VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. A multiplex ligation-dependent probe amplification analysis was performed in VHL, SDHB, SDHC, SDHD, and SDHAF2 genes to detect deletions and duplications. Results: A total of 31 patients were tested, 31% (n = 10) of whom were found to have a genetic mutation. Of those patients with a positive genotype, phenotype predicted genotype in only 50% (n = 5). Significant genetic mutations that would have been missed in our cohort by phenotypic evaluation alone include a mutation in TMEM127, two mutations in SDHAF2, and two mutations in RET. Target testing would have identified three of the latter mutations based on age criteria. However, 20% of patients (n = 2) would not have satisfied any criteria for targeted testing including one patient with a novel presentation of an SDHAF2 mutation. Conclusion: This study supports the value of universal genetic screening for all patients with PC/PGL

Iodine status of teenage girls on the island of Ireland

Purpose The trace element iodine is a vital constituent of thyroid hormones. Iodine requirements increase during pregnancy, when even mild deficiency may affect the neurocognitive development of the offspring. Urinary iodine concentration (UIC) is the means of assessing iodine status in population surveys; a median UIC of 100–199 µg/L is deemed sufficient in a non-pregnant population. Milk is the main dietary source of iodine in the UK and Ireland. Methods We surveyed the iodine status of 903 girls aged 14–15 years in seven sites across the island of Ireland. Urine iodine concentration was measured in spot-urine samples collected between March 2014 and October 2015. Food group intake was estimated from iodine-specific food-frequency questionnaire. Milk-iodine concentration was measured at each site in summer and winter. Results The median UIC overall was 111 µg/L. Galway was the only site in the deficient range (median UIC 98 µg/L). All five of the Republic of Ireland sites had UIC ≤ 105 µg/L. In the two sites surveyed twice, UIC was lower in summer vs winter months [117 µg/L (IQR 76–165) vs 130 µg/L (IQR 91–194) (p ˂ 0.01)]. Milk samples collected from Galway and Roscommon had a lower mean iodine concentration than those from Derry/Londonderry (p ˂ 0.05). Milk intake was positively associated with UIC (p ˂ 0.001). Conclusions This is the largest survey of its kind on the island of Ireland, which currently has no iodine-fortification programme. Overall, the results suggest that this young female population sits at the low end of sufficiency, which has implications if, in future, they enter pregnancy with borderline status.</p

CXC Ligand 5 Is an Adipose-Tissue Derived Factor that Links Obesity to Insulin Resistance

International audienceWe show here high levels of expression and secretion of the chemokine CXC ligand 5 (CXCL5) in the macrophage fraction of white adipose tissue (WAT). Moreover, we find that CXCL5 is dramatically increased in serum of human obese compared to lean subjects. Conversely, CXCL5 concentration is decreased in obese subjects after a weight reduction program, or in obese non-insulin-resistant, compared to insulin-resistant, subjects. Most importantly we demonstrate that treatment with recombinant CXCL5 blocks insulin-stimulated glucose uptake in muscle in mice. CXCL5 blocks insulin signaling by activating the Jak2/STAT5/SOCS2 pathway. Finally, by treating obese, insulin-resistant mice with either anti-CXCL5 neutralizing antibodies or antagonists of CXCR2, which is the CXCL5 receptor, we demonstrate that CXCL5 mediates insulin resistance. Furthermore CXCR2-/- mice are protected against obesity-induced insulin resistance. Taken together, these results show that secretion of CXCL5 by WAT resident macrophages represents a link between obesity, inflammation, and insulin resistance