Aims/hypothesis Phosphatidylinositol 3-kinase (PI3K) couples the leptin and insulin signalling pathways via the insulin receptor substrates IRS1 and IRS2. Hence, defective activation of PI3K could be a novel mechanism of peripheral leptin or insulin resistance. We investigated associations of tagging single-nucleotide polymorphisms (tSNPs) in the PI3K p85α regulatory subunit gene PIK3R1 with anthropometry, leptin, body fat and insulin sensitivity in a female twin population of European extraction. Materials and methods Eight tSNPs were genotyped in 2,778 women (mean age 47.4±12.5 years) from the St Thomas' UK Adult Twin Registry (Twins UK). Results SNP rs1550805 was associated with serum leptin (p=0.028), BMI (p=0.025), weight (p=0.019), total fat (p=0.004), total fat percentage (p=0.002), waist circumference (p=0.025), central fat (p=0.005) and central fat percentage (p=0.005). SNPs rs7713645 and rs7709243 were associated with BMI (p=0.020 and p=0.029, respectively), rs7709243 with weight, total and central fat (p=0.026, p=0.031 and p=0.023, respectively) and both SNPs with fasting glucose (p=0.003 and p=0.001, respectively) and glucose 2-h post OGTT (p=0.023 and p=0.007, respectively). Subjects with haplotype 222 (frequency 7.2%) showed higher serum leptin concentration (p=0.007) and body fat measures (p≤0.001 for all), and those with haplotype 221 (frequency 38.7%) showed higher fasting and 2-h glucose (p=0.035 and p=0.021, respectively) compared with subjects with the most common haplotype, 111 (frequency 45.5%). Conclusions/interpretation Association of the PIK3R1 SNP rs1550805 with serum leptin and body fat may reflect a diminished ability of PI3K to signal via IRS1 or IRS2 in response to leptin.

Aims/hypotheses We recently reported significant associations between BMI and three TUB single nucleotide polymorphisms (SNPs) in two Dutch cohorts enriched for type 2 diabetes. Here, we attempted a replication of these associations in a large population-based cohort of female twins comprehensively phenotyped for measures of general and central obesity.Methods Two TUB SNPs (rs2272382, rs2272383) and a third (rs1528133), 22 kb distal to RIC3, were genotyped in 2694 Europid women from the St Thomas' UK Adult Twin Registry (Twins UK) (mean age±SD: 47.6±12.7 years; 42.8% postmenopausal). We explored the hypothesis that TUB is a candidate gene for late-onset obesity in humans through testing the interaction of the SNPs by menopausal status. Results In the whole cohort, none of the three SNPs showed a significant main effect on measures of general or central obesity. However, for central obesity the rs2272382 SNP showed a significant interaction with menopausal status (p=0.036). Postmenopausal women homozygous for the minor allele of rs2272382 showed significantly more general obesity (p=0.022) and central obesity (p=0.009) than carriers of the major allele. Differences (beta [95% CI]) between the two genotype groups were 0.92 kg/m 2 (0.03-1.81) for BMI (p=0.036), 2.73 cm (0.62-4.84) for waist circumference (p=0.013) and 2.43% (0.27-4.60) for per cent central fat (p=0.027). These associations were confirmed by a sibling transmission disequilibrium test for central obesity, waist circumference and per cent central fat. Conclusions/interpretation We have replicated associations of TUB SNP rs2272382 with measures of general and central obesity in normal postmenopausal women. These findings confirm TUB as a candidate gene for late-onset obesity in humans.

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Carbon monoxide (CO) is endogenously produced from the degradation of heme, in a reaction that is catalyzed by heme oxygenase (HO). Systemic blockade of HO acutely decreases neural HO activity, and this increases arterial pressure in a manner that is reversed by CO microinjections into the nucleus tractus solitarii (NTS) of the brain stem; such findings are the original evidence that endogenous CO in the NTS serves as a tonic vasodepressor. Whilst the NTS coordinates the balance and distribution of sympathetic and parasympathetic influences on the cardiovascular system, the actions of the endogenous CO on these autonomic components have not been explored. The purpose of the current study was to identify the sympathetic and parasympathetic influences that contribute to the vasoregulatory actions of the endogenous CO system. Towards this end, male Sprague-Dawley rats were fitted with chronic femoral catheters and permitted four days recovery before conducting awake experiments. The acute blood pressure effects of an HO inhibitor, zinc deuteroporphyrin 2,4-bisglycol (ZnDPBG), were examined in animals pretreated with atropine, prazosine or propranolol to block the muscarinic, ␣1or ␤-adrenergic receptors, respectively. Administration of ZnDPBG (45 µmol/kg, IP) increased arterial pressure from 123 Ϯ 2 to 133 Ϯ 3 mm Hg (p < .05) but did not affect heart rate. The actions of ZnDPBG were not affected by pretreatment with atropine (50 mg/kg, IP) but were abolished by pretreatment with prazosine (5 mg/kg, IP). In addition, pretreatment with a beta-blocker, propranolol (15 mg/kg, IP), resulted in an abbreviated pressor response to ZnDPBG. Immunohistochemical staining and Western blot analysis confirmed that HO is present in both the NTS and adrenal medulla, but complementary experiments revealed that ZnDPBG treatment did not affect circulating levels of epinephrine. This study shows that HO is present in NTS and that the actions of ZnDPBG are independent of parasympathetic changes. While HO is present in the adrenal medulla and the pressor effect of ZnDPBG apparently arises from enhanced sympathetic tone, the HO inhibitor does not increase plasma levels of epinephrine. These findings suggest that inhibition of heme-derived CO in the NTS leads to activation of peripheral sympathetic neurons and that the consequent pressor effect arises from ␣1-adrenergic-mediated vasoconstriction and ␤1-adrenergic-mediated increases in cardiac performance.