Obesity is the most common nutritional disorder in Western society. Uncoupling protein-2 (UCP2) is a recently identified member of the mitochondrial transporter superfamily that is expressed in many tissues, including adipose tissue. Like its close relatives UCP1 and UCP3, UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis and is therefore a candidate gene for obesity. We show here that a common G/A polymorphism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a reporter gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, we found a modest but significant reduction in obesity prevalence associated with the less-common allele. We confirmed this association in a population-based sample of 791 middle-aged subjects from the same geographic area. Despite its modest effect, but because of its high frequency (approximately 63%), the more-common risk allele conferred a relatively large population-attributable risk accounting for 15% of the obesity in the population studied.
The associations of the adiponectin (APM1) gene with parameters of the metabolic syndrome are inconsistent. We performed a systematic investigation based on fine-mapped single nucleotide polymorphisms (SNPs) highlighting the genetic architecture and their role in modulating adiponectin plasma concentrations in a particularly healthy population of 1,727 Caucasians avoiding secondary effects from disease processes. Genotyping 53 SNPs (average spacing of 0.7 kb) in the APM1 gene region in 81 Caucasians revealed a two-block linkage disequilibrium (LD) structure and enabled comprehensive tag SNP selection. We found particularly strong associations with adiponectin concentrations for 11 of the 15 tag SNPs in the 1,727 subjects (five P values <0.0001). Haplotype analysis provided a thorough differentiation of adiponectin concentrations with 9 of 17 haplotypes showing significant associations (three P values <0.0001). No significant association was found for any SNP with the parameters of the metabolic syndrome. We observed a two-block LD structure of APM1 pointing toward at least two independent association signals, one including the promoter SNPs and a second spanning the relevant exons. Our data on a large number of healthy subjects suggest a clear modulation of adiponectin concentrations by variants of APM1, which are not merely a concomitant effect in the course of type 2 diabetes or coronary artery disease. Diabetes 55: [375][376][377][378][379][380][381][382][383][384] 2006
Mild cognitive impairment has frequently been reported for patients in the early stages of multiple sclerosis. The aim of the present study was to measure whether altered cortical activation during a sustained attention task occurs along with limited extent of neuropsychological problems. Expanded brain activation of multiple sclerosis patients with normal motor function compared with healthy controls during a finger tapping paradigm has previously been reported. Compensatory brain activation in patients with multiple sclerosis compared with normal controls may also be observed when the subjects are performing cognitive functions. In 21 patients with clinically definite relapsing-remitting multiple sclerosis, a psychometric assessment was performed using the Wechsler Memory Scale (WMS) and the Multiple Sclerosis Functional Composite Score (MSFC). In addition, functional MRI was performed during a Paced Visual Serial Addition Task (PVSAT), a visual analogue of the Paced Auditory Serial Addition Task (PASAT). All patients were within 3 years of diagnosis and were not suffering from a relapse at the time of investigation. The multiple sclerosis patients were compared with a control group of 21 healthy volunteers matched for handedness, age, years of education and sex. With regard to psychometric results, the WMS general memory score showed statistically significant differences between patients and controls. We did not find differences for either the MSFC or the PASAT scores. A group analysis of the functional imaging data during the PVSAT revealed different activation patterns for patients compared with control subjects. In healthy volunteers, the main activation was found in the frontal part of the right gyrus cinguli (Brodmann area 32). In patients, the main activation was detected at the right hemispheric frontal cortex (Brodmann areas 6, 8 and 9). In addition, the left hemispheric Brodmann area 39 was activated. We interpret the different patterns of activation, accompanied with intact performance in a sustained attention task of our multiple sclerosis sample compared with healthy controls, as the consequence of compensatory mechanisms. This is an expression of neuronal plasticity during early stages of a chronic disease.
The importance of the left occipitotemporal cortex for visual word processing is highlighted by numerous functional neuroimaging studies, but the precise function of the Visual Word Form Area (VWFA) in this brain region is still under debate. The present fMRI study varied orthographic familiarity independent from phonological-semantic familiarity by presenting orthographically familiar and orthographically unfamiliar forms (pseudohomophones) of the same words in a phonological lexical decision task. Consistent with orthographic word recognition in the VWFA, we found lower activation for familiar compared to unfamiliar forms, but no difference between pseudohomophones and pseudowords. This orthographic familiarity effect in the VWFA differed from the phonological familiarity effect in left frontal regions, where phonologically unfamiliar pseudowords led to higher activation than phonologically familiar pseudohomophones. We suggest that the VWFA not only computes letter string representations but also hosts word specific orthographic representations. These representations function as recognition units with the effect that letter strings, which readily match with stored representations lead to less activation than letter strings which do not.
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