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Wiemerslage, L., Islam, R., van der Kamp, C., Cao, H., Olivo, G., Ence-Eriksson, F., . . . Schiöth, H. B. (2017). A DNA methylation site within the KLF13 gene is associated with orexigenic processes based on neural responses and ghrelin levels. International Journal of Obesity, 41(6), 990-994.
Open this publication in new window or tab >>A DNA methylation site within the KLF13 gene is associated with orexigenic processes based on neural responses and ghrelin levels
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2017 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 41, no 6, 990-994 p.Article in journal (Refereed) Published
Abstract [en]

We investigated five methylation markers recently linked to body-mass index, for their role in the neuropathology of obesity. In neuroimaging experiments, our analysis involving 23 participants showed that methylation levels for the cg07814318 site, which lies within the KLF13 gene, correlated with brain activity in the claustrum, putamen, cingulate gyrus, and frontal gyri, some of which have been previously associated to food signaling, obesity, or reward. Methylation levels at cg07814318 also positively correlated with ghrelin levels. Moreover, expression of KLF13 was augmented in the brains of obese and starved mice. Our results suggest the cg07814318 site could be involved in orexigenic processes, and also implicate KLF13 in obesity. Our findings are the first to associate methylation levels in blood with brain activity in obesity-related regions, and further support previous findings between ghrelin, brain activity, and genetic differences.

National Category
Neurosciences Endocrinology and Diabetes Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-315855 (URN)10.1038/ijo.2017.43 (DOI)000402735900024 ()28194012 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2017-02-21 Created: 2017-02-21 Last updated: 2018-01-13Bibliographically approved
Ciuculete, D.-M., Bandstein, M., Benedict, C., Waeber, G., Vollenweider, P., Lind, L., . . . Mwinyi, J. (2017). A genetic risk score is significantly associated with statin therapy response in the elderly population. Clinical Genetics, 91(3), 379-385.
Open this publication in new window or tab >>A genetic risk score is significantly associated with statin therapy response in the elderly population
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2017 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 91, no 3, 379-385 p.Article in journal (Refereed) Published
Abstract [en]

The ability of statins to strongly reduce low-density lipoprotein cholesterol (LDL-C) varies interindividually and is partially influenced by genetic variants. Based on a comprehensive analysis of 23 single nucleotide polymorphisms (SNPs) known to be associated with pharmacokinetics and dynamics of statins, we developed a genetic risk score to study its impact on the therapy outcome in elderly individuals under at least 5 years statin therapy. The study was performed in a population-based cohort of 1016 elderly individuals, which comprised 168 statin users investigated at age 75 and 80. Using random forest models, the major variants influencing LDL-C levels were summarized in a weighted GRS (wGRS). The wGRS was tested with lipid and glucose outcomes and validated in an independent population-based cohort including 221 statin users. Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. The wGRS was significantly associated with lower LDL-C at age 75 and 80. This association was replicated displaying similar results. GRS analysis is a powerful tool to evaluate the additive effects of genetic variants on statin response and to estimate the magnitude of LDL-C reduction to a considerable extent in the older population.

Keyword
pharmacogenetics, polygenetic risk score, random forest analysis, single nucleotide polymorphism, statins
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-318494 (URN)10.1111/cge.12890 (DOI)000395007600004 ()27943270 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)Swedish Research CouncilGlaxoSmithKline (GSK)
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2018-01-13Bibliographically approved
Cedernaes, J., Osorio, R. S., Varga, A. W., Kam, K., Schiöth, H. B. & Benedict, C. (2017). Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease.. Sleep Medicine Reviews, 31, 102-111, Article ID S1087-0792(16)00018-6.
Open this publication in new window or tab >>Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease.
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2017 (English)In: Sleep Medicine Reviews, ISSN 1087-0792, E-ISSN 1532-2955, Vol. 31, 102-111 p., S1087-0792(16)00018-6Article, review/survey (Refereed) Published
Abstract [en]

During wakefulness, extracellular levels of metabolites in the brain increase. These include amyloid beta (Aβ), which contributes to the pathogenesis of Alzheimer's disease (AD). Counterbalancing their accumulation in the brain, sleep facilitates the removal of these metabolites from the extracellular space by convective flow of the interstitial fluid from the para-arterial to the para-venous space. However, when the sleep-wake cycle is disrupted (characterized by increased brain levels of the wake-promoting neuropeptide orexin and increased neural activity), the central nervous system (CNS) clearance of extracellular metabolites is diminished. Disruptions to the sleep-wake cycle have furthermore been linked to increased neuronal oxidative stress and impaired blood-brain barrier function - conditions that have also been proposed to play a role in the development and progression of AD. Notably, recent human and transgenic animal studies have demonstrated that AD-related pathophysiological processes that occur long before the clinical onset of AD, such as Aβ deposition in the brain, disrupt sleep and circadian rhythms. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted sleep-wake cycles, which is able to accelerate the development and progression of this disease.

Keyword
Aging, Amyloid beta, Blood brain barrier, Circadian misalignment, Neurodegeneration, Orexin, Oxidative stress, Sleep disruption, Slow-wave sleep, Tau
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-318575 (URN)10.1016/j.smrv.2016.02.002 (DOI)26996255 (PubMedID)
Available from: 2017-03-26 Created: 2017-03-26 Last updated: 2018-01-13
Thienel, M., Wilhelm, I., Benedict, C., Born, J. & Hallschmid, M. (2017). Intranasal insulin decreases circulating cortisol concentrations during early sleep in elderly humans. Neurobiology of Aging, 54, 170-174, Article ID 170e174.
Open this publication in new window or tab >>Intranasal insulin decreases circulating cortisol concentrations during early sleep in elderly humans
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2017 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 54, 170-174 p., 170e174Article in journal (Refereed) Published
Abstract [en]

Aging is associated with increases in hypothalamic-pituitary-adrenal (HPA) axis activity that can predispose to metabolic and cognitive impairments. We investigated in elderly and young subjects whether intranasal insulin administration to the human brain reduces early-sleep nadir concentrations of adrenocorticotropin and cortisol, that is, indicators of baseline HPA axis activity. In within-subject comparisons, intranasal insulin (160 IU) or placebo was administered to 14 elderly (mean age 70.0 years) and 30 young (23.6 years) healthy subjects before bedtime. Sleep was polysomno-graphically assessed and blood samples were repeatedly collected. Elderly compared with young participants displayed increased early-sleep cortisol concentrations (p < 0.04) and reductions in slow wave and REM sleep (p < 0.001). Insulin administration reduced cortisol levels between 2300 hours and 0020 hours in the elderly (p = 0.03) but not young participants (p = 0.56; p = 0.003 for interaction). Findings indicate that central nervous insulin acts as an inhibitory signal in basal HPA axis activity regulation and suggest that intranasal insulin may normalize sleep-associated stress axis activity in older age.

Keyword
Insulin, Brain, Sleep, Aging, Hypothalamic-pituitary-adrenal axis, Cortisol
National Category
Neurosciences Geriatrics
Identifiers
urn:nbn:se:uu:diva-322080 (URN)10.1016/j.neurobiolaging.2017.03.006 (DOI)000399501800018 ()28385552 (PubMedID)
Funder
German Research Foundation (DFG), SFB 654
Available from: 2017-05-19 Created: 2017-05-19 Last updated: 2018-01-13Bibliographically approved
Rångtell, F. H., Karamchedu, S., Andersson, P., van Egmond, L., Hultgren, T., Broman, J.-E., . . . Benedict, C. (2017). Learning performance is linked to procedural memory consolidation across both sleep and wakefulness. Scientific Reports, 7, Article ID 10234.
Open this publication in new window or tab >>Learning performance is linked to procedural memory consolidation across both sleep and wakefulness
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 10234Article in journal (Refereed) Published
Abstract [en]

We investigated whether learning performance in a procedural finger tapping task before nocturnal sleep would predict performance gains after sleep in 60 young adults. Gains were defined as change in correctly tapped digit sequences between learning (12 trials administered in the evening) and retesting (3 trials administered in the morning after sleep). The same task was also administered to a separate wake group (N = 54 young adults), which learned in the morning and was retested in the evening. Learning performance was determined by either using the average performance on the last three learning trials or the average performance on the best three learning trials. Our results demonstrated an inverse association between learning performance and gains in procedural skill, i.e., good learners exhibited smaller performance gains across both wakefulness and sleep than poor learners. Regardless of learning performance, gains in finger tapping skills were greater after sleep than daytime wakefulness. Importantly, some of our findings were influenced by how learning performance was estimated. Collectively, these results suggest that learning performance and the method through which it is estimated may influence performance gains in finger tapping skills across both sleep and wakefulness.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-334935 (URN)10.1038/s41598-017-09263-5 (DOI)000408781200093 ()28860592 (PubMedID)
Funder
AFA InsuranceLars Hierta Memorial FoundationNovo NordiskSwedish Society for Medical Research (SSMF)Swedish Society of MedicineThe Swedish Brain FoundationSwedish Research CouncilÅke Wiberg Foundation
Available from: 2017-12-01 Created: 2017-12-01 Last updated: 2018-01-13Bibliographically approved
Olivo, G., Zhou, W., Sundbom, M., Zhukovsky, C., Hogenkamp, P., Nikontovic, L., . . . Schiöth, H. B. (2017). Resting-state brain connectivity changes in obese women after Roux-en-Y gastric bypass surgery: A longitudinal study. Scientific Reports, 7(1), Article ID 6616.
Open this publication in new window or tab >>Resting-state brain connectivity changes in obese women after Roux-en-Y gastric bypass surgery: A longitudinal study
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, 6616Article in journal (Refereed) Published
Abstract [en]

Bariatric surgery is an effective method to rapidly induce weight loss in severely obese people, however its impact on brain functional connectivity after longer periods of follow-up is yet to be assessed. We investigated changes in connectivity in 16 severely obese women one month before, one month after and one year after Roux-en-Y gastric bypass surgery (RYGB). 12 lean controls were also enrolled. Resting-state fMRI was acquired for all participants following an overnight fast and after a 260 kcal load. Connectivity between regions involved in food-related saliency attribution and reward-driven eating behavior was stronger in presurgery patients compared to controls, but progressively weakened after follow-up. At one year, changes in networks related to cognitive control over eating and bodily perception also occurred. Connectivity between regions involved in emotional control and social cognition had a temporary reduction early after treatment but had increased again after one year of follow-up. Furthermore, we could predict the BMI loss by presurgery connectivity in areas linked to emotional control and social interaction. RYGBP seems to reshape brain functional connectivity, early affecting cognitive control over eating, and these changes could be an important part of the therapeutic effect of bariatric surgery.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-327249 (URN)10.1038/s41598-017-06663-5 (DOI)000406366400024 ()28747648 (PubMedID)
Funder
The Swedish Brain FoundationSwedish Research CouncilSwedish Society for Medical Research (SSMF)
Available from: 2017-08-07 Created: 2017-08-07 Last updated: 2017-12-05Bibliographically approved
Chapman, C. D., Benedict, C. & Schiöth, H. B. (2017). Sex matters: Report experimenter gender [Letter to the editor]. Science, 356(6341), 916-917.
Open this publication in new window or tab >>Sex matters: Report experimenter gender
2017 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 356, no 6341, 916-917 p.Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-333634 (URN)10.1126/science.aan5448 (DOI)000402552300024 ()28572358 (PubMedID)
Available from: 2017-12-07 Created: 2017-12-07 Last updated: 2017-12-07Bibliographically approved
Cedernaes, J., Lampola, L., Axelsson, E. K., Liethof, L., Hassanzadeh, S., Yeganeh, A., . . . Benedict, C. (2016). A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men. Journal of Sleep Research, 25(1), 5-10.
Open this publication in new window or tab >>A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men
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2016 (English)In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, no 1, 5-10 p.Article in journal (Refereed) Published
Abstract [en]

The present study sought to investigate whether a single night of partial sleep deprivation (PSD) would alter fasting insulin sensitivity and cephalic phase insulin release (CPIR) in humans. A rise in circulating insulin in response to food-related sensory stimulation may prepare tissues to break down ingested glucose, e.g. by stimulating rate-limiting glycolytic enzymes. In addition, given insulin's anorexigenic properties once it reaches the brain, the CPIR may serve as an early peripheral satiety signal. Against this background, in the present study 16 men participated in two separate sessions: one night of PSD (4.25 h sleep) versus one night of full sleep (8.5 h sleep). In the morning following each sleep condition, subjects' oral cavities were rinsed with a 1-molar sucrose solution for 45 s, preceded and followed by blood sampling for repeated determination of plasma glucose and serum insulin concentrations (-3, +3, +5, +7, +10 and +20 min). Our main result was that PSD, compared with full sleep, was associated with significantly higher peripheral insulin resistance, as indicated by a higher fasting homeostasis model assessment of insulin resistance index (+16%, P = 0.025). In contrast, no CPIR was observed in any of the two sleep conditions. Our findings indicate that a single night of PSD is already sufficient to impair fasting insulin sensitivity in healthy men. In contrast, brief oral cavity rinsing with sucrose solution did not change serum insulin concentrations, suggesting that a blunted CPIR is an unlikely mechanism through which acute sleep loss causes metabolic perturbations during morning hours in humans.

Keyword
HOMA-IR; cephalic phase insulin response; curtailed sleep
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-275287 (URN)10.1111/jsr.12340 (DOI)000367618900002 ()26361380 (PubMedID)
Funder
The Swedish Brain FoundationAFA InsuranceNovo NordiskMagnus Bergvall FoundationSwedish Research Council
Available from: 2016-02-02 Created: 2016-02-02 Last updated: 2017-11-30Bibliographically approved
Wiemerslage, L., Nilsson, E. K., Dahlberg, L. S., Ence-Eriksson, F., Castillo, S., Larsen, A. L., . . . Schiöth, H. B. (2016). An obesity-associated risk allele within the FTO gene affects human brain activity for areas important for emotion, impulse control and reward in response to food images. European Journal of Neuroscience, 43(9), 1173-1180.
Open this publication in new window or tab >>An obesity-associated risk allele within the FTO gene affects human brain activity for areas important for emotion, impulse control and reward in response to food images
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2016 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 43, no 9, 1173-1180 p.Article in journal (Refereed) Published
Abstract [en]

Understanding how genetics influences obesity, brain activity and eating behaviour will add important insight for developing strategies for weight-loss treatment, as obesity may stem from different causes and as individual feeding behaviour may depend on genetic differences. To this end, we examined how an obesity risk allele for the FTO gene affects brain activity in response to food images of different caloric content via functional magnetic resonance imaging (fMRI). Thirty participants homozygous for the rs9939609 single nucleotide polymorphism were shown images of low-or high-calorie food while brain activity was measured via fMRI. In a whole-brain analysis, we found that people with the FTO risk allele genotype (AA) had increased activity compared with the non-risk (TT) genotype in the posterior cingulate, cuneus, precuneus and putamen. Moreover, higher body mass index in the AA genotype was associated with reduced activity to food images in areas important for emotion (cingulate cortex), but also in areas important for impulse control (frontal gyri and lentiform nucleus). Lastly, we corroborate our findings with behavioural scales for the behavioural inhibition and activation systems. Our results suggest that the two genotypes are associated with differential neural processing of food images, which may influence weight status through diminished impulse control and reward processing.

Keyword
fMRI, food, FTO, obesity, SNP
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-297286 (URN)10.1111/ejn.13177 (DOI)000375134800007 ()26797854 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2016-06-22 Created: 2016-06-22 Last updated: 2018-01-10Bibliographically approved
Benedict, C. (2016). Antihypertensive medication prior to nocturnal sleep reduces the risk of new-onset type 2 diabetes in hypertensive patients: a role for slow-wave sleep? [Letter to the editor]. Diabetologia, 59(2), 390-391.
Open this publication in new window or tab >>Antihypertensive medication prior to nocturnal sleep reduces the risk of new-onset type 2 diabetes in hypertensive patients: a role for slow-wave sleep?
2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 2, 390-391 p.Article in journal, Letter (Refereed) Published
Keyword
Antihypertensive medication; Chronotherapy; Sleep; Type 2 diabetes
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-275767 (URN)10.1007/s00125-015-3791-5 (DOI)000377302400021 ()26471900 (PubMedID)
Available from: 2016-02-05 Created: 2016-02-05 Last updated: 2018-01-10Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/000-0002-8911-4068

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