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- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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- Gallo-Payet, Nicole, et al.
(författare)
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AT2 Receptor Agonists : Exploiting the Beneficial Arm of Ang II Signaling
- 2012
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Ingår i: current hypertension reviews. - : bentham science publishers. - 1573-4021. ; 8:1, s. 47-59
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Forskningsöversikt (refereegranskat)abstract
- In the classical view, the hormone angiotensin II (Ang II) mediates its action via two major receptors, namely the Ang II type-1 receptor (AT1R) and the type-2 receptor (AT2R). Several recent reviews implicate the renin-angiotensin system (RAS) in various aspects of adipose tissue physiology and dysfunction. Research on AT2R has long been hampered by at least three potential challenges, (i) the low expression level of the AT2R in the adult, (ii) the atypical signaling pathways of AT2R and (iii) the absence of appropriate selective ligands. Indeed, apart a few exceptions, the role of the AT2R was in fact revealed by the results of simultaneous treatment with Ang II and AT1R blockers or in AT2Rdeficient mice. The first aim of this review is to summarize current paradigms concerning the role of the AT2R in adipocyte differentiation and in metabolic disorders related to insulin resistance and type 2 diabetes. Secondly, we will highlight the potential utility of selective AT2R agonists in clarifying potential roles of the AT2R in adipocyte physiology. We summarized our findings using a selective and high affinity nonpeptide ligand of the AT2R and demonstrate that AT2R is involved in adipocyte differentiation and may improve insulin sensitivity in a model of insulin resistance, in addition to increase vasodilation and reduce inflammation in adipose tissue. Thus the recent development of orally active, selective AT2R agonists should facilitate efforts to elucidate the distinct roles of the AT2R in physiology, including adipocyte physiology.
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- Leblanc, Samuel, et al.
(författare)
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Angiotensin II Type 2 Receptor Stimulation Improves Fatty Acid Ovarian Uptake and Hyperandrogenemia in an Obese Rat Model of Polycystic Ovary Syndrome
- 2014
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 155:9, s. 3684-3693
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Tidskriftsartikel (refereegranskat)abstract
- Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[F-18]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 mu U/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g.min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km(P = .009), which were strongly correlated together in all PCOS/cp rats (rho = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.
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- Shum, Michael, et al.
(författare)
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Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats
- 2013
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 304:2, s. E197-E210
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Tidskriftsartikel (refereegranskat)abstract
- Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats. Am J Physiol Endocrinol Metab 304: E197-E210, 2013. First published November 13, 2012; doi:10.1152/ajpendo.00149.2012.-This study was aimed at establishing whether specific activation of angiotensin II (ANG II) type 2 receptor (AT2R) modulates adipocyte differentiation and function. In primary cultures of subcutaneous (SC) and retroperitoneal (RET) preadipocytes, both AT2R and AT1R were expressed at the mRNA and protein level. Cells were stimulated with ANG II or the AT2R agonist C21/M24, alone or in the presence of the AT1R antagonist losartan or the AT2R antagonist PD123,319. During differentiation, C21/M24 increased PPA gamma expression in both RET and SC preadipocytes while the number of small lipid droplets and lipid accumulation solely increased in SC preadipocytes. In mature adipocytes, C21/M24 decreased the mean size of large lipid droplets. Upon abolishment of AT2R expression using AT2R-targeted shRNAs, expressions of AT2R, aP2, and PPAR gamma remained very low, and cells were unable to differentiate. In Wistar rats fed a 6-wk high-fat/high-fructose (HFHF) diet, a significant shift toward larger adipocytes was observed in RET and SC adipose tissue depots. C21/M24 treatments for 6 wk restored normal adipocyte size distribution in both these tissue depots. Moreover, C21/M24 and losartan decreased hyperinsulinemia and improved insulin sensitivity impaired by HFHF diet. A strong correlation between adipocyte size area and glucose infusion rate during euglycemic-hyperinsulinemic clamp was observed. These results indicate that AT2R is involved in early adipocyte differentiation, while in mature adipocytes and in a model of insulin resistance AT2R activation restores normal adipocyte morphology and improves insulin sensitivity.
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