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Abstract Milk is an evolutionary benefit for humans. For infants, it offers optimal nutrients for normal growth, neural development, and protection from harmful microbes. Humans are the only mammals who drink milk throughout their life. Lipids in colostrum originate mostly from milk fat globule membrane (MFGM) droplets extruded from the mammary gland. The MFGM gained much interest as a potential nutraceutical, due to their high phospholipid (PL), ganglioside (GD), and protein contents. In this review, we focused on health effects of MFGM ingredients and dairy food across the life span, especially on neurodevelopment, cardiometabolic health, and frailty in older adults. The MFGM supplements to infants and children reduced gastrointestinal and respiratory tract infections and improved neurodevelopment due to the higher content of protein, PL, and GD in MFGM. The MFGM formulas containing PL and GD improved brain myelination and fastened nerve conduction speed, resulting in improved behavioral developments. Administration of MFGM-rich ingredients improved insulin sensitivity and decreased inflammatory markers, LDL-cholesterol, and triglycerides by lowering intestinal absorption of cholesterol and increasing its fecal excretion. The MFGM supplements, together with exercise, improved ambulatory activities, leg muscle mass, and muscle fiber velocity in older adults. There are great variations in the composition of lipids and proteins in MFGM products, which make comparisons of the different studies impossible. In addition, investigations of the individual MFGM components are required to evaluate their specific effects and molecular mechanisms. Although we are currently only beginning to understand the possible health effects of MFGM products, the current MFGM supplementation trials as presented in this review have shown significant clinical health benefits across the human life span, which are worth further investigation.
Abstract Fat oxidation during exercise is associated with cardio-metabolic benefits, but the extent of which whole-body exercise modality elicits the greatest fat oxidation remains unclear. We investigated the effects of treadmill, elliptical and rowing exercise on fat oxidation in healthy individuals. Nine healthy males participated in three, peak oxygen consumption tests, on a treadmill, elliptical and rowing ergometer. Indirect calorimetry was used to assess maximal oxygen consumption (V̇O2peak), maximal fat oxidation (MFO) rates, and the exercise intensity MFO occurred (Fatmax). Mixed venous blood was collected to assess lactate and blood gases concentrations. While V̇O2peak was similar between exercise modalities, MFO rates were higher on the treadmill (mean ± SD; 0.61 ± 0.06 g·min-1) compared to both the elliptical (0.41 ± 0.08 g·min−1, p = 0.022) and the rower (0.40 ± 0.08 g·min−1, p = 0.017). Fatmax values were also significantly higher on the treadmill (56.0 ± 6.2 %V̇O2peak) compared to both the elliptical (36.8 ± 5.4 %V̇O2peak, p = 0.049) and rower (31.6 ± 5.0 %V̇O2peak, p = 0.021). Post-exercise blood lactate concentrations were also significantly lower following treadmill exercise (p = 0.021). Exercising on a treadmill maximizes fat oxidation to a greater extent than elliptical and rowing exercises, and remains an important exercise modality to improve fat oxidation, and consequently, cardio-metabolic health.
Abstract Purpose: Metabolic flexibility is compromised in individuals suffering from metabolic diseases, lipo- and glucotoxicity, and mitochondrial dysfunctions. Exercise studies performed in cold environments have demonstrated an increase in lipid utilization, which could lead to a compromised substrate competition, glycotoxic-lipotoxic state, or metabolic inflexibility. Whether metabolic flexibility is altered during incremental maximal exercise to volitional fatigue in a cold environment remains unclear. Methods: Ten young healthy participants performed four maximal incremental treadmill tests to volitional fatigue, in a fasted state, in a cold (0 °C) or a thermoneutral (22.0 °C) environment, with and without a pre-exercise ingestion of a 75-g glucose solution. Metabolic flexibility was assessed via indirect calorimetry using the change in respiratory exchange ratio (ΔRER), maximal fat oxidation (ΔMFO), and where MFO occurred along the exercise intensity spectrum (ΔFatmax), while circulating lactate and glucose levels were measured pre and post exercise. Results: Multiple linear mixed-effects regressions revealed an increase in glucose oxidation from glucose ingestion and an increase in lipid oxidation from the cold during exercise (p < 0.001). No differences were observed in metabolic flexibility as assessed via ΔRER (0.05 ± 0.03 vs. 0.05 ± 0.03; p = 0.734), ΔMFO (0.21 ± 0.18 vs. 0.16 ± 0.13 g min−1; p = 0.133) and ΔFatmax (13.3 ± 19.0 vs. 0.6 ± 21.3 %V̇O2peak; p = 0.266) in cold and thermoneutral, respectively. Conclusions: Following glucose loading, metabolic flexibility was unaffected during exercise to volitional fatigue in a cold environment, inducing an increase in lipid oxidation. These results suggest that competing pathways responsible for the regulation of fuel selection during exercise and cold exposure may potentially be mechanistically independent. Whether long-term metabolic influences of high-fat diets and acute lipid overload in cold and warm environments would impact metabolic flexibility remain unclear.
Abstract Circadian rhythms significantly affect metabolism, and their disruption leads to cardiometabolic diseases and fibrosis. The clock repressor Rev-Erb is mainly expressed in the liver, heart, lung, adipose tissue, skeletal muscles, and brain, recognized as a master regulator of metabolism, mitochondrial biogenesis, inflammatory response, and fibrosis. Fibrosis is the response of the body to injuries and chronic inflammation with the accumulation of extracellular matrix in tissues. Activation of myofibroblasts is a key factor in the development of organ fibrosis, initiated by hormones, growth factors, inflammatory cytokines, and mechanical stress. This review summarizes the importance of Rev-Erb in ECM remodeling and tissue fibrosis. In the heart, Rev-Erb activation has been shown to alleviate hypertrophy and increase exercise capacity. In the lung, Rev-Erb agonist reduced pulmonary fibrosis by suppressing fibroblast differentiation. In the liver, Rev-Erb inhibited inflammation and fibrosis by diminishing NF-κB activity. In adipose tissue, Rev- Erb agonists reduced fat mass. In summary, the results of multiple studies in preclinical models demonstrate that Rev-Erb is an attractive target for positively influencing dysregulated metabolism, inflammation, and fibrosis, but more specific tools and studies would be needed to increase the information base for the therapeutic potential of these substances interfering with the molecular clock.
Abstract Exogenous ketone supplementation and whole-body cooling (WBC) have shown to independently influence exercise metabolism. Whether readily available ketone salts, with and without WBC, would provide similar metabolic benefits during steady-state aerobic and time-trial performances was investigated. Nine active males (VO2peak: 56.3 ± 2.2 mL·kg−1·min−1) completed three single-blind exercise sessions preceded by: (1) ingestion of placebo (CON), (2) ketone supplementation (0.3 g·kg−1 β-OHB) (KET), and (3) ketone supplementation with WBC (KETCO). Participants cycled in steady-state (SS, 60% Wmax) condition for 30-min, immediately followed by a 15-min time trial (TT). Skin and core temperature, cardio-metabolic, and respiratory measures were collected continuously, whereas venous blood samples were collected before and after supplementation, after SS and TT. Venous β-OHB was elevated, while blood glucose was lower, with supplementation vs. CON (p < 0.05). TT power output was not different between conditions (p = 0.112, CON: 190 ± 43.5 W, KET: 185 ± 40.4 W, KETCO: 211 ± 50.7 W). RER was higher during KETCO (0.97 ± 0.09) compared to both CON (0.88 ± 0.04, p = 0.012) and KET (0.88 ± 0.05, p = 0.014). Ketone salt supplementation and WBC prior to short-term exercise sufficiently increase blood β-OHB concentrations, but do not benefit metabolic shifts in fuel utilization or improve time trial performance.
Abstract Introduction: Interest in human physiological responses to cold stress have seen a resurgence in recent years with a focus on brown adipose tissue (BAT), a mitochondria dense fat specialized for heat production. However, a majority of the work examining BAT has been conducted among temperate climate populations. Methods: To expand our understanding of BAT thermogenesis in a cold climate population, we measured, using indirect calorimetry and thermal imaging, metabolic rate and body surface temperatures of BAT-positive and BAT-negative regions at room temperature, and mild cold exposure of resting participants from a small sample of reindeer herders (N = 22, 6 females) from sub-Arctic Finland. Results: We found that most herders experienced a significant mean 8.7% increase in metabolic rates, preferentially metabolized fatty acids, and maintained relatively warmer body surface temperatures at the supraclavicular region (known BAT location) compared to the sternum, which has no associated BAT. These results indicate that the herders in this sample exhibit active BAT thermogenesis in response to mild cold exposure. Conclusions: This study adds to the rapidly growing body of work looking at the physiological and thermoregulatory significance of BAT and the important role it may play among cold stressed populations.
Abstract Exercise is shown to improve cognitive function in various human and animal studies. Laboratory mice are often used as a model to study the effects of physical activity and running wheels provide a voluntary and non-stressful form of exercise. The aim of the study was to analyze whether the cognitive state of a mouse is related to its wheel-running behavior. Twenty-two male C57BL/6NCrl mice (9.5 weeks old) were used in the study. The cognitive function of group-housed mice (n = 5–6/group) was first analyzed in the IntelliCage system followed by individual phenotyping with the PhenoMaster with access to a voluntary running wheel. The mice were divided into three groups according to their running wheel activity: low, average, and high runners. The learning trials in the IntelliCage showed that the high-runner mice exhibited a higher error rate at the beginning of learning trials but improved their outcome and learning performance more compared to the other groups. The high-runner mice ate more compared to the other groups in the PhenoMaster analyses. There were no differences in the corticosterone levels between the groups, indicating similar stress responses. Our results demonstrate that high-runner mice exhibit enhanced learning capabilities prior to access to voluntary running wheels. In addition, our results also show that individual mice react differently when introduced to running wheels, which should be taken into consideration when choosing animals for voluntary endurance exercise studies.
Abstract Regular physical activity (PA) improves cognitive functions, prevents brain atrophy, and delays the onset of cognitive decline, dementia, and Alzheimer’s disease. Presently, there are no specific recommendations for PA producing positive effects on brain health and little is known on its mediators. PA affects production and release of several peptides secreted from peripheral and central tissues, targeting receptors located in the central nervous system (CNS). This review will provide a summary of the current knowledge on the association between PA and cognition with a focus on the role of (neuro)peptides. For the review we define peptides as molecules with less than 100 amino acids and exclude myokines. Tachykinins, somatostatin, and opioid peptides were excluded from this review since they were not affected by PA. There is evidence suggesting that PA increases peripheral insulin growth factor 1 (IGF-1) levels and elevated serum IGF-1 levels are associated with improved cognitive performance. It is therefore likely that IGF-1 plays a role in PA induced improvement of cognition. Other neuropeptides such as neuropeptide Y (NPY), ghrelin, galanin, and vasoactive intestinal peptide (VIP) could mediate the beneficial effects of PA on cognition, but the current literature regarding these (neuro)peptides is limited.
Abstract Purpose: We investigated the effects of the macronutrient composition of diets with differing satiety values on fasting appetite-related hormone concentrations after weight loss and examined whether the hormone secretion adapted to changes in body fat mass (FM) and fat-free mass (FFM) during the weight maintenance period (WM). Methods: Eighty-two men and women with obesity underwent a 7-week very-low-energy diet (VLED) and were then randomised to a higher-satiety food (HSF) group or a lower-satiety food (LSF) group during 24-weeks of the WM. The groups consumed isoenergetic foods with different satiety ratings and macronutrient compositions. Results: During the WM, the HSF group consumed more protein and dietary fibre and less fat than the LSF group, but the groups showed similar changes in body weight and fasting appetite-related hormones. In the whole study sample, VLED induced 12 kg (p < 0.001) weight loss. At the end of the WM, weight regain was 1.3 kg (p = 0.004), ghrelin concentration increased, whereas leptin, insulin, and glucose concentrations decreased compared to pre-VLED levels (p < 0.001 for all). Peptide YY did not differ from pre-VLED levels. Changes in ghrelin levels were inversely associated with changes in FFM during weeks 0–12 of the WM (p = 0.002), while changes in leptin and insulin levels were positively associated with changes in FM during weeks 0–12 (p = 0.015 and p = 0.038, respectively) and weeks 12–24 (p < 0.001 and p = 0.022) of the WM. Conclusions: The macronutrient composition of an isoenergetic WM diet did not affect fasting appetite-related hormone concentrations. Leptin and insulin adjusted to the reduced FM, whereas ghrelin reflected FFM during the first months of the WM. Trial registration: isrctn.com, ID 67529475.
Abstract Our aim was to compare three research-grade accelerometers for their accuracy in step detection and energy expenditure (EE) estimation in a laboratory setting, at different speeds, especially in overweight/obese participants. Forty-eight overweight/obese subjects participated. Participants performed an exercise routine on a treadmill with six different speeds (1.5, 3, 4.5, 6, 7.5, and 9 km/h) for 4 min each. The exercise was recorded on video and subjects wore three accelerometers during the exercise: Sartorio Xelometer (SX, hip), activPAL (AP, thigh), and ActiGraph GT3X (AG, hip), and energy expenditure (EE) was estimated using indirect calorimetry for comparisons. For step detection, speed-wise mean absolute percentage errors for the SX ranged between 9.73–2.26, 6.39–0.95 for the AP, and 88.69–2.63 for the AG. The activPALs step detection was the most accurate. For EE estimation, the ranges were 21.41–15.15 for the SX, 57.38–12.36 for the AP, and 59.45–28.92 for the AG. All EE estimation errors were due to underestimation. All three devices were accurate in detecting steps when speed exceeded 4 km/h and inaccurate in EE estimation regardless of speed. Our results will guide users to recognize the differences, weaknesses, and strengths of the accelerometer devices and their algorithms.
Abstract Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a liver serine protease regulating LDL cholesterol metabolism. PCSK9 binds to LDL receptors and guides them to lysosomes for degradation, thus increasing the amount of circulating LDL cholesterol. The aim of the study was to investigate associations between physical activity and plasma PCSK9 in subjects with high risk for type 2 diabetes (T2D). Methods: Sixty-eight subjects from both genders with a high risk for T2D were included to a randomized controlled trial with a 3-month physical activity intervention. Physical activity intensities and frequencies were monitored throughout the intervention using a hip worn portable accelerometer. The plasma was collected before and after intervention for analysis of PCSK9 and cardiovascular biomarkers. Results: Plasma PCSK9 did not relate to physical activity although number of steps were 46% higher in the intervention group than in the control group (p < 0.029). Total cholesterol was positively correlated with plasma PCSK9 (R = 0.320, p = 0.008), while maximal oxygen uptake was negatively associated (R = −0.252, p = 0.044). After the physical activity intervention PCSK9 levels were even stronger inversely associated with maximal oxygen uptake (R = −0.410, p = 0.0008) and positively correlated with HDL cholesterol (R = 0.264, p = 0.030). Interestingly, plasma PCSK9 levels were higher in the beginning than at the end of the study. Conclusion: The low physical activity that our subjects with high risk for T2D could perform did not influence plasma PCSK9 levels. Intervention with higher physical activities might be more effective in influencing PCSK9 levels.
Abstract Paleogenetics has significantly changed since its inception almost forty years ago. Initially, molecular techniques available to the researchers offered minimal possibilities for ancient DNA analysis. The subsequent expansion of the scientific tool cabinet allowed for more remarkable achievements, combined has with the newfound popularity of this budding field of science. Finally, a breakthrough was made with the development of next-generation sequencing (NGS) technologies and the update of DNA isolation protocols, through which even very fragmented aDNA samples could be used to sequence whole genomes. In this paper, we review the achievements made thus far and compare the methodologies utilized in this field of science, discussing their benefits and challenges.
Abstract Orexin-A (OXA) has been originally isolated from a precursor peptide prepro-orexin from the lateral hypothalamus. The orexin system has been attributed to important functions in sleep, arousal and regulation of energy homeostasis. In addition to its high levels in cerebrospinal fluid, OXA is present in blood. However, reported peptide concentrations in plasma vary significantly depending on the method used. Therefore, a specific and sensitive OXA radioimmunoassay (RIA) with solid phase extraction method was developed to determine whether plasma OXA concentrations is affected by acute feeding and/or wake and sleep in young healthy males. Blood samples were collected for 24 h from nine healthy males (aged 20–24 years; BMI 20.7–26.5) every 2 h starting at 11 a.m. Food was served at 12 p.m, 5:30 p.m, 8 p.m and 8 a.m and the sleep time was between 10 p.m and 7 a.m. Plasma samples were analyzed in addition for cortisol and melatonin levels. Blood pressure was monitored through the experimental period. OXA antibody was raised in rabbits. OXA antiserum had only minor cross-reactivity with prepro-orexin precursor (<0.001%), amino-terminal peptide (<0.001%), carboxy-terminal peptide (0.001%), and orexin-B (0.3%) with high sensitivity (0.15 pg/tube). Plasma OXA levels varied between 0.5 and 16 pg/ml in seven subjects and were undetectable (below 0.5 pg/ml) in two subjects. The OXA concentrations did not correlate to feeding nor wake/sleep, whereas cortisol, melatonin and mean arterial blood pressure presented a clear circadian rhythm in each subject. In conclusion, OXA is present in blood in low amounts and its levels do not follow autonomic nor neuroendocrine circadian rhythms. Thereby, studies examining regulatory mechanisms and influences of OXA from blood samples should interpret results very cautiously.
Abstract Alcoholic beverages stimulate pancreatic enzyme secretions by inducing cholecystokinin (CCK) release. CCK is the major stimulatory hormone of pancreatic exocrine secretions, secreted from enteroendocrine I-cells of the intestine. Fermentation products of alcoholic beverages, such as maleic and succinic acids, influence gastric acid secretions. We hypothesize that maleic and succinic acids stimulate pancreatic exocrine secretions during beer and wine ingestion by increasing CCK secretions. Therefore, the effects of maleic and succinic acids on CCK release were studied in duodenal mucosal cells and the enteroendocrine cell line STC-1. Mucosal cells were perfused for 30 min with 5 min sampling intervals, STC-1 cells were studied under static incubation for 15 min, and supernatants were collected for CCK measurements. Succinate and maleate-induced CCK release were investigated. Succinate and maleate doses dependently stimulated CCK secretions from mucosal cells and STC-1 cells. Diltiazem, a calcium channel blocker, significantly inhibited succinate and maleate-induced CCK secretions from mucosal cells and STC-1 cells. Maleate and succinate did not show cytotoxicity in STC-1 cells. Our results indicate that succinate and maleate are novel CCK-releasing factors in fermented alcoholic beverages and could contribute to pancreatic exocrine secretions and their pathophysiology.
Abstract Obesity is one of the major global threats to human health and risk factors for cardiometabolic diseases and certain cancers. Glucagon-like peptide-1 (GLP-1) plays a major role in appetite and glucose homeostasis and recently the USFDA approved GLP-1 agonists for the treatment of obesity and type 2 diabetes. GLP-1 is secreted from enteroendocrine L-cells in the distal part of the gastrointestinal (GI) tract in response to nutrient ingestion. Endogenously released GLP-1 has a very short half-life of <2 min and most of the nutrients are absorbed before reaching the distal GI tract and colon, which hinders the use of nutritional compounds for appetite regulation. The review article focuses on nutrients that endogenously stimulate GLP-1 and peptide YY (PYY) secretion via their receptors in order to decrease appetite as preventive action. In addition, various delivery technologies such as pH-sensitive, mucoadhesive, time-dependent, and enzyme-sensitive systems for colonic targeting of nutrients delivery are described. Sustained colonic delivery of nutritional compounds could be one of the most promising approaches to prevent obesity and associated metabolic diseases by, e.g., sustained GLP-1 release.
Abstract Physical activity (PA) is one of the most efficient ways to prevent obesity and its associated diseases worldwide. In the USA, less than 10% of the adult population were able to meet the PA recommendations when accelerometers were used to assess PA habituation. Accelerometers significantly differ from each other in step recognition and do not reveal raw data. The aim of our study was to compare a novel accelerometer, Sartorio Xelometer, which enables to gather raw data, with existing accelerometers ActiGraph GT3X+ and activPAL in terms of step detection and energy expenditure estimation accuracy. 53 healthy subjects were divided into 2 cohorts (cohort 1 optimization; cohort 2 validation) and wore 3 accelerometers and performed an exercise routine consisting of the following speeds: 1.5, 3, 4.5, 9 and 10.5 km/h (6 km/h for 2nd cohort included). Data from optimization cohort was used to optimize Sartorio step detection algorithm. Actual taken steps were recorded with a video camera and energy expenditure (EE) was measured. To observe the similarity between video and accelerometer step counts, paired samples t test and intraclass correlation were used separately for step counts in different speeds and for total counts as well as EE estimations. In speeds of 1.5, 3, 4.5, 6, 9 and 10.5 km/h mean absolute percentage error (MAPE) % were 8.1, 3.5, 4.3, 4.2, 3.1 and 7.8 for the Xelometer, respectively (after optimization). For ActiGraph GT3X+ the MAPE-% were 96.93 (87.4), 34.69 (23.1), 2.13 (2.3), 1.96 (2.6) and 2.99 (3.8), respectively and for activPAL 6.55 (5.6), 1.59 (0.6), 0.81 (1.1), 10.60 (10.3) and 15.76 (13.8), respectively. Significant intraclass correlations were observed with Xelometer estimates and actual steps in all speeds. Xelometer estimated the EE with a MAPE-% of 30.3, activPAL and ActiGraph GT3X+ with MAPE percentages of 20.5 and 24.3, respectively. The Xelometer is a valid device for assessing step counts at different gait speeds. MAPE is different at different speeds, which is of importance when assessing the PA in obese subjects and elderly. EE estimates of all three devices were found to be inaccurate when compared with indirect calorimetry.
Abstract Background: Oxidative stress results in lipid, protein, and DNA oxidation, resulting in telomere erosion, chromosomal damage, and accelerated cellular aging. Training promotes healthy metabolic and oxidative profiles whereas the effects of multi-day, prolonged, and continuous exercise are unknown. This study investigated the effects of multi-day prolonged exercise on metabolic and oxidative stress as well as telomere integrity in healthy adults. Methods: Fifteen participants performed a 14-day, 260-km, wilderness canoeing expedition (12 males) (EXP) (24 ± 7 years, 72 ± 6 kg, 178 ± 8.0 cm, 18.4 ± 8.4% BF, 47.5 ± 9.3 mlO2 kg−1 min−1), requiring 6–9 h of low- to moderate-intensity exercise daily. Ten controls participated locally (seven males) (CON) (31 ± 11 years, 72 ± 15 kg, 174 ± 10 cm, 22.8 ± 10.0% BF, 47.1 ± 9.0 mlO2 kg−1 min−1). Blood plasma, serum, and mononuclear cells were sampled before and after the expedition to assess hormonal, metabolic, and oxidative changes. Results: Serum cholesterol, high- and low-density lipoprotein, testosterone, insulin, sodium, potassium, urea, and chloride concentrations were not different between groups, whereas triglycerides, glucose, and creatinine levels were lower following the expedition (p < 0.001). Malondialdehyde and relative telomere length (TL) were unaffected (EXP: 4.2 ± 1.3 vs. CON: 4.1 ± 0.7 μM; p > 0.05; EXP: 1.00 ± 0.48 vs. CON: 0.89 ± 0.28 TS ratio; p = 0.77, respectively); however, superoxidase dismutase activity was greater in the expedition group (3.1 ± 0.4 vs. 0.8 ± 0.5 U ml−1; p < 0.001). Conclusion: These results indicate a modest improvement in metabolic and oxidative profiles with increased superoxidase dismutase levels, suggesting an antioxidative response to counteract the exercise-associated production of free radicals and reactive oxygen species during prolonged exercise, mimicking the effects from long-term training. Although improved antioxidant activity may lead to increased TL, the present exercise stimulus was insufficient to promote a positive cellular aging profile with concordant chromosomal changes in our healthy and young participants.
Abstract Polydextrose (PDX) reduces subsequent energy intake (EI) when administered at midmorning in single-blind trials of primarily normal-weight men. However, it is unclear if this effect also occurs when PDX is given at breakfast time. Furthermore, for ecological validity, it is desirable to study a female population, including those at risk for obesity. We studied the effects of PDX, served as part of a breakfast or midmorning preload, on subsequent EI and other appetite-related parameters in healthy normal-weight and overweight females. Per earlier studies, the primary outcome was defined as the difference in subsequent EI when PDX was consumed at midmorning versus placebo. Thirty-two volunteers were enrolled in this acute, double-blind, placebo-controlled, randomized, and crossover trial to examine the effects of 12.5 g of PDX, administered as part of a breakfast or midmorning preload, on subsequent EI, subjective feelings of appetite, well-being, and mood. Gastric emptying rates and the blood concentrations of glucose, insulin, cholecystokinin, ghrelin, glucagon-like peptide 1 (GLP-1), and peptide tyrosine-tyrosine were measured in the group that received PDX as part of their breakfast. There were no differences in EI between volunteers who were fed PDX and placebo. PDX intake with breakfast tended to elevate blood glucose (P = 0.06) during the postabsorptive phase, significantly lowered insulin by 15.7% (P = 0.04), and increased GLP-1 by 39.9% (P = 0.02); no other effects on blood parameters or gastric emptying rates were observed. PDX intake at midmorning reduced hunger by 31.4% during the satiation period (P = 0.02); all other subjective feelings of appetite were unaffected. Volunteers had a uniform mood profile during the study. PDX was well tolerated, causing one mild adverse event throughout the trial.
Abstract Metabolic adaptation and signal integration in response to hypoxic conditions is mainly regulated by hypoxia-inducible factors (HIFs). At the same time, hypoxia induces ROS formation and activates the unfolded protein response (UPR), indicative of endoplasmic reticulum (ER) stress. However, whether ER stress would affect the hypoxia response remains ill-defined. Here we report that feeding mice a high fat diet causes ER stress and attenuates the response to hypoxia. Mechanistically, ER stress promotes HIF-1α and HIF-2α degradation independent of ROS, Ca2+, and the von Hippel-Lindau (VHL) pathway, involving GSK3β and the ubiquitin ligase FBXW1A/βTrCP. Thereby, we reveal a previously unknown function of the GSK3β/HIFα/βTrCP1 axis in ER homeostasis and demonstrate that inhibition of the HIF-1 and HIF-2 response and genetic deficiency of GSK3β affects proliferation, migration, and sensitizes cells for ER stress promoted apoptosis. Vice versa, we show that hypoxia affects the ER stress response mainly through the PERK-arm of the UPR. Overall, we discovered previously unrecognized links between the HIF pathway and the ER stress response and uncovered an essential survival pathway for cells under ER stress.
Abstract Background: A body of literature suggests a metabolically healthy phenotype in individuals with obesity. Despite important clinical implications, the early origins of metabolically healthy obesity (MHO) have received little attention. Objective: To assess the prevalence of MHO among the Northern Finland Birth Cohort 1966 (NFBC1966) at 31 years of age, examine its determinants in early life taking into account the sex specificity. Methods: We studied 3205 term-born cohort participants with data available for cardio-metabolic health outcomes at 31 years, and longitudinal height and weight data. After stratifying the population by sex, adult BMI and a strict definition of metabolic health (i.e., no risk factors meaning metabolic health), we obtained six groups. Repeated childhood height and weight measures were used to model early growth and early adiposity phenotypes. We employed marginal means adjusted for mother and child covariates including socio-economic status, birth weight and gestational-age, to compare differences between the groups. Results: The prevalence of adult MHO was 6% in men and 13.5% in women. Differences in adult metabolic status were linked to alterations in BMI and age at adiposity peak in infancy (p < 0.0003 in men and p = 0.027 in women), and BMI and age at adiposity rebound (AR) (p < 0.0001 irrespective of sex). Compared to MHO, metabolically unhealthy obese (MUO) women were five and a half months younger at AR (p = 0.007) with a higher BMI while MUO men were four months older ( p = 0.036) with no difference in BMI at AR. Conclusion: At the time of AR, MHO women appeared to be older than their MUO counterparts while MHO men were younger. These original results support potential risk factors at the time of adiposity rebound linked to metabolic health in adulthood. These variations by sex warrant independent replication.
Abstract Introduction: Vitamin D deficiency has been linked to the increased risk of several chronic diseases, especially in people living in the Northern Latitudes. The aim of this study was to assess the vitamin D status in older subjects born in 1945 in Northern Finland (latitude 65°North), and to examine its associations to components of metabolic syndrome (MetS). Methods: In this cross-sectional study, we invited 904 subjects born in 1945 from the Oulu region (Oulu45 cohort), out of an original cohort of 1332 subjects. In the cohort, plasma 25 hydroxyvitamin D (25OHD) levels were determined by an enzyme immunoassay of 263 men and 373 women, with a mean age baseline of 69±0.5 years old. We assessed the participants’ usage of vitamin D supplements, as well as their lifestyle factors, using a questionnaire. Results: Nearly 80% of the subjects had low vitamin D levels [either vitamin D deficient (<50 nmol/L) or insufficient (50–75 nmol/L)], and only 20% of the participants had sufficient vitamin D levels (>75 nmol/L) (based on the American Endocrine Society guidelines). The low vitamin D status was associated with a high prevalence of MetS; a significantly higher number of subjects with MetS (41%) had low vitamin D levels in comparison to the non-MetS subjects (38%) (p ≤ 0.05). The subjects under vitamin D supplementation had a significantly lower incidence of MetS (42.6% vs 57.4%) and its components in comparison to the non-supplemented subjects (p ≤ 0.05). Conclusions: Low vitamin D levels are a risk factor for MetS amongst other lifestyle factors, such as dietary habits and physical inactivity, among older subjects in the Northern Latitudes (65°North). Optimal supplementation of vitamin D, along with rich dietary sources of vitamin D, are highly recommended for older subjects as a means to positively affect, e.g., hypertension, insulin resistance, and obesity, as components of the MetS.
Abstract Obesity and dyslipidemia are hallmarks of metabolic and cardiovascular diseases. Polydextrose (PDX), a soluble fiber has lipid lowering effects. We hypothesize that PDX reduces triglycerides and cholesterol by influencing gut microbiota, which in turn modulate intestinal gene expression. C57BL/6 male mice were fed a Western diet (WD) ±75 mg PDX twice daily by oral gavage for 14 days. Body weight and food intake were monitored daily. Fasting plasma lipids, caecal microbiota and gene expression in intestine and liver were measured after 14 days of feeding. PDX supplementation to WD significantly reduced food intake (p < 0.001), fasting plasma triglyceride (p < 0.001) and total cholesterol (p < 0.05). Microbiome analysis revealed that the relative abundance of Allobaculum, Bifidobacterium and Coriobacteriaceae taxa associated with lean phenotype, increased in WD + PDX mice. Gene expression analysis with linear mixed-effects model showed consistent downregulation of Dgat1, Cd36, Fiaf and upregulation of Fxr in duodenum, jejunum, ileum and colon in WD + PDX mice. Spearman correlations indicated that genera enriched in WD + PDX mice inversely correlated with fasting lipids and downregulated genes Dgat1, Cd36 and Fiaf while positively with upregulated gene Fxr. These results suggest that PDX in mice fed WD promoted systemic changes via regulation of the gut microbiota and gene expression in intestinal tract.
Abstract Novel treatment methods for obesity are urgently needed due to the increasing global severity of the problem. Gastrointestinal hormones, such as GLP-1 and PYY, are secreted by the enteroendocrine cells, playing a critical role in regulating food intake. Digested nutrients trigger the secretion of these hormones, which have a very short half-life. α-Linolenic acid (αLA) has been shown to stimulate GLP-1 secretion, however, chemical instability and fast uptake in the small intestine hinder its use in body weight management. We developed a novel delivery system based on inorganic mesoporous particles for αLA to increase secretion of gastrointestinal peptides. αLA was loaded to thermally hydrocarbonized porous silicon particles (THCPSi). 47.9 ± 3.84% and 30.7 ± 2.86% of αLA was released during 6 h from 3.0% and 9.2% loading degree (w/w) samples in vitro, respectively. Native αLA (50 μM) significantly increased GLP-1 secretion from enteroendocrine STC-1 and GLUTag cell lines. αLA loaded THCPSi significantly and dose dependently stimulated GLP-1 secretion from STC-1 cells, whereas empty particles did not. We demonstrated in vitro that THCPSi particles have the potential to be used as a controlled delivery system for nutrients such as αLA, increasing GLP-1 secretion. Our results justify further in vivo investigations.
Abstract Background: Conflicting evidence supports a role for vitamin D in women with reproductive disorders such as polycystic ovary syndrome (PCOS) but studies on large, unselected populations have been lacking. Methods: We conducted a general population-based study from the prospective Northern Finland Birth Cohort 1966 (NFBC1966). Serum 25-hydroksyvitamin D (25(OH)D) levels were evaluated in women with self-reported PCOS (n = 280) versus non-symptomatic controls (n = 1573) at the age of 31 with wide range of endocrine and metabolic confounders. Results: The levels of 25(OH)D were similar among women with and without self-reported PCOS (50.35 vs. 48.30 nmol/L, p = 0.051). Women with self-reported PCOS presented with a higher body mass index (BMI), increased insulin resistance, and low-grade inflammation and testosterone levels compared to controls. The adjusted linear regression model showed a positive association between total 25(OH)D levels in self-reported PCOS (β = 2.46, 95% confidence interval (CI) 0.84 to 4.08, p = 0.003). The result remained after adjustment for BMI, testosterone, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hs-CRP) levels. Conclusion: In this population-based setting, PCOS was associated with higher vitamin D levels when adjusting for confounding factors, without distinct beneficial effects on metabolic derangements.
Abstract Background: Although tissue perfusion is often decreased in patients with sepsis, the relationship between macrohemodynamics and microcirculatory blood flow is poorly understood. We hypothesized that alterations in retinal blood flow visualized by angiography may be related to macrohemodynamics, inflammatory mediators, and retinal microcirculatory changes. Methods: Retinal fluorescein angiography was performed twice during the first 5 days in the intensive care unit to observe retinal abnormalities in patients with sepsis. Retinal changes were documented by hyperfluorescence angiography; retinal blood flow was measured as retinal arterial filling time (RAFT); and intraocular pressure was determined. In the analyses, we used the RAFT measured from the eye with worse microvascular retinal changes. Blood samples for inflammation and cerebral biomarkers were collected, and macrohemodynamics were monitored. RAFT was categorized as prolonged if it was more than 8.3 seconds. Results: Of 31 patients, 29 (93%) were in septic shock, 30 (97%) required mechanical ventilation, 22 (71%) developed delirium, and 16 (51.6%) had retinal angiopathies, 75% of which were bilateral. Patients with prolonged RAFT had a lower cardiac index before (2.1 L/kg/m2 vs. 3.1 L/kg/m2, P = 0.042) and during angiography (2.1 L/kg/m2 vs. 2.6 L/kg/m2, P = 0.039). They more frequently had retinal changes (81% vs. 20%, P = 0.001) and higher intraocular pressure (18 mmHg vs. 14 mmHg, P = 0.031). Patients with prolonged RAFT had lower C-reactive protein (139 mg/L vs. 254 mg/L, P = 0.011) and interleukin-6 (39 pg/ml vs. 101 pg/ml, P < 0.001) than those with shorter RAFT. Conclusions: Retinal angiopathic changes were more frequent and cardiac index was lower in patients with prolonged RAFT, whereas patients with shorter filling times had higher levels of inflammatory markers.
Abstract Background: Infertility and fecundability problems have been linked with lower 25-hydroxyvitamin D (25(OH)D) concentrations, but studies conducted with small, heterogenous or selected populations have shown inconsistent results. Methods: This study included women at age 31 from prospective population-based Northern Finland Birth Cohort 1966. Serum 25(OH)D concentrations were evaluated between women with or without previous infertility examinations or treatments (infertility group, n = 375, reference group, n = 2051) and time to pregnancy (TTP) of over 12 months (decreased fecundability group, n = 338) with a wide range of confounders. Furthermore, 25(OH)D concentrations were also compared among reproductive outcomes. Results: The mean 25(OH)D concentration was lower and 25(OH)D < 30 nmol/L was more frequent in women with a history of infertility compared to reference group. Moreover, 25(OH)D > 75 nmol/L was more frequent in the reference group. The mean 25(OH)D concentration was lower in women who had had multiple miscarriages. Both history of infertility (β = −2.7, 95% confidence interval (CI) −4.6, −0.7) and decreased fecundability associated with lower 25(OH)D concentration (β = −4.1, 95% CI −7.4, −0.8) after adjustments. In conclusion, this population-based study demonstrated that previous infertility and decreased fecundability were associated with lower 25(OH)D.
Abstract Introduction: Physical activity (PA) has been associated with telomere shortening. The association of PA intensity or volume with telomere length (TL) is nonetheless unclear. The aim of our study was to investigate the associations of exercise intensity and volume with TL in elderly adults from Northern Finland (65° latitude North). Methods: Seven hundred elderly subjects born in 1945 in the Oulu region were investigated. PA was measured during a 2-week period with a wrist-worn accelerometer. In addition, a questionnaire was used to assess sedentary time and to achieve a longitudinal PA history and intensity. Relative telomere lengths (RTL) were determined from frozen whole blood samples using a qPCR-based method. Results: Relative telomere lengths were significantly longer in women than men and negatively correlated with age in both genders (men r = -0.210, p = 0.000, women r = -0.174, and p = 0.000). During the 2-week study period, women took more steps than men (p = 0.001), but the association between steps and RTL was only seen in men (p = 0.05). Total steps taken (r = 0.202 and p = 0.04) and sedentary time (r = -0.247 and p = 0.007) significantly correlated with RTLs in 70-year old subjects. Moderate PA was associated with RTL in subjects with the highest quartile of moderate PA compared to the three lower quartiles (p-values: 0.023 between 4th and 1st, 0.04 between 4th and 2nd, and 0.027 between 4th and 3rd) in the 70-year old subjects. Conclusion: Women had longer RTL and a higher step count compared to men. However, exercise volume and RTL correlated positively only in men. Surprisingly, age correlated negatively with RTL already within an age difference of 2 years. This suggests that telomere attrition rate may accelerate in older age. Moderate physical activity at the time of study was associated with RTL.
Abstract Investigations into the mechanisms regulating obesity are frantic and novel translational approaches are needed. The raccoon dog (Nyctereutes procyonoides) is a canid species representing a promising model to study metabolic regulation in a species undergoing cycles of seasonal obesity and fasting. To understand the molecular mechanisms of metabolic regulation in seasonal adaptation, we analyzed key central nervous system and peripheral signals regulating food intake and metabolism from raccoon dogs after autumnal fattening and winter fasting. Expressions of neuropeptide Y (NPY), orexin-2 receptor (OX2R), pro-opiomelanocortin (POMC) and leptin receptor (ObRb) were analyzed as examples of orexigenic and anorexigenic signals using qRT-PCR from raccoon dog hypothalamus samples. Plasma metabolic profiles were measured with 1H NMR-spectroscopy and LC-MS. Circulating hormones and cytokines were determined with canine specific antibody assays. Surprisingly, NPY and POMC were not affected by the winter fasting nor autumn fattening and the metabolic profiles showed a remarkable equilibrium, indicating conserved homeostasis. However, OX2R and ObRb expression changes suggested seasonal regulation. Circulating cytokine levels were not increased, demonstrating that the autumn fattening did not induce subacute inflammation. Thus, the raccoon dog developed seasonal regulatory mechanisms to accommodate the autumnal fattening and prolonged fasting making the species unique in coping with the extreme environmental challenges.
Abstract Scope: Nutrients stimulate the secretion of glucagon-like peptide-1 (GLP-1), an incretin hormone, secreted from enteroendocrine L-cells which decreases food intake. Thus, GLP-1 analogs are approved for the treatment of obesity, yet cost and side effects limit their use. L-cells are mainly localized in the distal ileum and colon, which hinders the utilization of nutrients targeting GLP-1 secretion. This study proposes a controlled delivery system for nutrients, inducing a prolonged endogenous GLP-1 release which results in a decrease food intake. Methods and Results: α-Linolenic acid (αLA) was loaded into thermally hydrocarbonized porous silicon (THCPSi) particles. In vitro characterization and in vivo effects of αLA loaded particles on GLP-1 secretion and food intake were studied in mice. A total of 40.4 ± 3.2% of loaded αLA is released from particles into biorelevant buffer over 24 h, and αLA loaded THCPSi significantly increased in vitro GLP-1 secretion. Single-dose orally given αLA loaded mesoporous particles increased plasma active GLP-1 levels at 3 and 4 h and significantly reduced the area under the curve of 24 h food intake in mice. Conclusions: αLA loaded THCPSi particles could be used to endogenously stimulate sustain gastrointestinal hormone release and reduce food intake.
Abstract This article studies how an individual’s physical wellbeing contributes to one’s online user experience. The study subjects were elderly people at high risk for type 2 diabetes. The results suggest that the web usage experience of these pre-diabetic individuals is related to their physical health status and level of physical activity. Those with a better physical health status were more likely to feel ease of orientation in their web usage, and those with more frequent regular physical activity were more likely to perceive pleasure in navigating the web. In practice, variation in physical health and activity levels between individuals could, and should. be addressed in designing systems and services. In more general, studying user experience on par with biochemical measurements provides an exciting combination of research methods and paves the way for new design practices.
Abstract Epigenetic changes have been identified as a major driver of fundamental metabolic pathways. More specifically, the importance of epigenetic regulatory mechanisms for biological processes like speciation and embryogenesis has been well documented and revealed the direct link between epigenetic modifications and various diseases. In this review, we focus on epigenetic changes in animals with special attention on human DNA methylation utilizing ancient and modern genomes. Acknowledging the latest developments in ancient DNA research, we further discuss paleoepigenomic approaches as the only means to infer epigenetic changes in the past. Investigating genome-wide methylation patterns of ancient humans may ultimately yield in a more comprehensive understanding of how our ancestors have adapted to the changing environment, and modified their lifestyles accordingly. We discuss the difficulties of working with ancient DNA in particular utilizing paleoepigenomic approaches, and assess new paleoepigenomic data, which might be helpful in future studies.
Abstract Objective: Evidence from randomised controlled trials suggests that vitamin D may reduce multimorbidity, but very few studies have investigated specific determinants of vitamin D2 and D3 (two isoforms of 25-hydroxyvitamin D). The aim of the study was to investigate the determinants of vitamin D2 and D3 and to identify the risk factors associated with hypovitaminosis D. Design: Cross-sectional study. Setting: Northern Finland Birth Cohort 1966. Participants: 2374 male and 2384 female participants with data on serum 25(OH)D2 and 25(OH)D3 concentrations measured at 31 years of age (1997), together with comprehensive measures of daylight, anthropometric, social, lifestyle and contraceptive cofactors. Methods: We assessed a wide range of potential determinants prior to a nationwide fortification programme introduced in Finland. The determinants of 25(OH)D2, 25(OH)D3 and 25(OH)D concentrations were analysed by linear regression and risk factors for being in lower tertile of 25(OH)D concentration by ordinal logistic regression. Results: At the time of sampling, 72% of the participants were vitamin D sufficient (≥50 nmol/L). Low sunlight exposure period (vs high) was associated positively with 25(OH)D2 and negatively with 25(OH)D3 concentrations. Use of oral contraceptives (vs nonusers) was associated with an increase of 0.17 nmol/L (95% CI 0.08 to 0.27) and 0.48 nmol/L (95% CI 0.41 to 0.56) in 25(OH)D2 and 25(OH)D3 concentrations. Sex, season, latitude, alcohol consumption and physical activity were the factors most strongly associated with 25(OH)D concentration. Risk factors for low vitamin D status were low sunlight exposure defined by time of sampling, residing in northern latitudes, obesity, higher waist circumference, low physical activity and unhealthy diet. Conclusions: We demonstrate some differential associations of environmental and lifestyle factors with 25(OH)D2 and 25(OH)D3 raising important questions related to personalised healthcare. Future strategies could implement lifestyle modification and supplementation to improve vitamin D2 and D3 status, accounting for seasonal, lifestyle, metabolic and endocrine status.
Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades low-density lipoprotein cholesterol (LDL-C) receptors, and thus regulates the LDL-C levels in the circulation. Type 2 diabetics often have elevated LDL-C levels. However, the functions of PCSK9 in patients with alterations of glu-cose metabolism and statin therapy are still unclear. Method: we investigated a large cohort of 608 subjects, born in 1945 in Oulu, Finland (Oulu Cohort 1945). We studied the effects of PSCK9 lev-els with different glucose tolerances (normal glucose tolerance (NGT), prediabetes (PreDM) or type 2 diabetes (T2D)) with and without statin medication, and analyzed clinical data, NMR metabolomics and PCSK9 plasma levels. Results: PCSK9 plasma levels did not significantly differ between the three groups. Statin therapy significantly increased the PCSK9 levels in NGT, PreDM and T2D groups compared with subjects with no statins. In the NGT group, negative associations between PCSK9 and LDL-C, intermediate-density lipoprotein cholesterol (IDL-C), very low-density lipoprotein cholesterol (VLDL-C), total cholesterol and LDL and IDL triglycerides were observed under statin medication. In contrast, in the PreDM and T2D groups, these associa-tions were lost. Conclusions: our data suggest that in subjects with abnormal glucose metabolism and statin therapy, the significant PCSK9-mediated effects on the lipid metabolites are lost com-pared to NGT subjects, but statins reduced the LDL-C and VLDL-C levels.
Abstract Polydextrose (PDX) is a branched glucose polymer, utilized as a soluble dietary fiber. Recently, PDX was found to have hypolipidemic effects and effects on the gut microbiota. To investigate these findings more closely, a non-targeted metabolomics approach, was exploited to determine metabolic alterations in blood and epididymal adipose tissue samples that were collected from C57BL/6 mice fed with a Western diet, with or without oral administration of PDX. Metabolomic analyses revealed significant differences between PDX- and control mice, which could be due to differences in diet or due to altered microbial metabolism in the gut. Some metabolites were found in both plasma and adipose tissue, such as the bile acid derivative deoxycholic acid and the microbiome-derived tryptophan metabolite indoxyl sulfate, both of which increased by PDX. Additionally, PDX increased the levels of glycine betaine and l-carnitine in plasma samples, which correlated negatively with plasma TG and positively correlated with bacterial genera enriched in PDX mice. The results demonstrated that PDX caused differential metabolite patterns in blood and adipose tissues and that one-carbon metabolism, associated with glycine betaine and l-carnitine, and bile acid and tryptophan metabolism are associated with the hypolipidemic effects observed in mice that were given PDX.
Abstract Anemia is common in colorectal cancer (CRC) but its relationships with tumor characteristics, systemic inflammation, and survival have not been well characterized. In this study, blood hemoglobin levels and erythrocyte mean corpuscular volume (MCV) levels were measured in two independent cohorts of 148 CRC patients and 208 CRC patients, and their correlation with patient and tumor characteristics, systemic inflammatory markers (modified Glasgow Prognostic Score: mGPS; serum levels of thirteen cytokines, C-reactive protein, albumin), and survival were analyzed. We found that anemia, most frequently normocytic, followed by microcytic, was present in 43% of the patients. Microcytic anemia was most commonly associated with proximal colon tumor location. Average MCV and blood hemoglobin levels were lower in tumors with high T-class. Low blood hemoglobin associated with systemic inflammation, including high mGPS and high serum levels of C-reactive protein and IL-8. Particularly, normocytic anemia associated with higher mGPS. Normocytic anemia associated with a tendency towards worse overall survival (multivariate hazard ratio 1.61, 95% confidence interval 1.07–2.42, p = 0.023; borderline statistical significance considering multiple hypothesis testing). In conclusion, anemia in CRC patients is most frequently normocytic. Proximal tumor location is associated with predominantly microcytic anemia and systemic inflammation is associated with normocytic anemia.
Abstract This study compared subjective and objective methods of measuring different categories of physical activity in non-depressed middle-aged subjects with normal cognitive function (NCF) and mild cognitive impairment (MCI). In total, 75 participants (NCF: n = 48, MCI: n = 27) were recruited and physical activity was assessed for seven days using the ActiGraph and the International Physical Activity Questionnaire (IPAQ). Anthropometric parameters, body compositions, resting metabolic rate, and energy expenditure were also assessed. ActiGraph data indicated that subjects with NCF were more active than MCI subjects. A comparison of the IPAQ and the ActiGraph data revealed a significant correlation between these methods for total (r = 0.3315, p < 0.01) and moderate (r = 0.3896, p < 0.01) physical activity in the total population and moderate activity (r = 0.2893, p < 0.05) within the NCF group. No associations between these methods were found within the MCI group. Independent predictors of subjectively evaluated total physical activity were alcohol consumption (p = 0.0358) and socio-professional status (p = 0.0288), while weight (p = 0.0285) and the Montreal Cognitive Assessment results (p = 0.0309) were independent predictors of objectively measured physical activity. In conclusion, the long version of IPAQ is a more reliable tool to assess PA in subjects with NCF than those with MCI. More studies are needed to confirm this finding.
Abstract Our objectives were to determine if there are quantitative associations between amounts and intensities of physical activities (PA) on NMR biomarkers and changes in skeletal muscle gene expressions in subjects with high risk for type 2 diabetes (T2D) performing a 3-month PA intervention. We found that PA was associated with beneficial biomarker changes in a factor containing several VLDL and HDL subclasses and lipids in principal component analysis (P = <0.01). Division of PA into quartiles demonstrated significant changes in NMR biomarkers in the 2nd – 4th quartiles compared to the 1st quartile representing PA of less than 2850 daily steps (P = 0.0036). Mediation analysis of PA-related reductions in lipoproteins showed that the effects of PA was 4–15 times greater than those of body weight or fat mass reductions. In a subset study in highly active subjects’ gene expressions of oxidative fiber markers, Apo D, and G0/G1 Switch Gene 2, controlling insulin signaling and glucose metabolism were significantly increased. Slow walking at speeds of 2–3 km/h exceeding 2895 steps/day attenuated several circulating lipoprotein lipids. The effects were mediated rather by PA than body weight or fat loss. Thus, lower thresholds for PA may exist for long term prevention of cardio-metabolic diseases in sedentary overweight subjects.
Abstract Background: Cancer cachexia is a complex wasting syndrome affecting patients with advanced cancer, with systemic inflammation as a key component in pathogenesis. Protein degradation and release of amino acids (AAs) in skeletal muscle are stimulated in cachexia. Here, we define factors contributing to serum AA levels in colorectal cancer (CRC). Methods: Serum levels of nine AAs were characterised in 336 CRC patients and their relationships with 20 markers of systemic inflammatory reaction, clinicopathological features of cancers and patient survival were analysed. Results: Low serum glutamine and histidine levels and high phenylalanine levels associated with indicators of systemic inflammation, including high modified Glasgow Prognostic Score, high blood neutrophil/lymphocyte ratio and high serum levels of CRP, IL-6 and IL-8. Low levels of serum glutamine, histidine, alanine and high glycine levels also associated with advanced cancer stage and with poor cancer-specific survival in univariate analysis. Conclusions: In CRC, serum AA levels are associated with systemic inflammation and disease stage. These findings may reflect muscle catabolism induced by systemic inflammation in CRC.
Abstract Background: Sepsis delays wound re-epithelialization. In this study we explored the effect of human sepsis sera as well as the effects of cytokines, growth factors and exosomes of sepsis sera treated normal fibroblasts (NF) on keratinocyte migration and proliferation in vitro. Methods: Serum samples were taken on days 1, 4, and 9 from 44 patients diagnosed with severe sepsis, and from 14 matching healthy controls. We evaluated the effects of sepsis serum with or without TNF-α, EGF, EGF receptor inhibitor or exosomes of sepsis sera treated NF on human keratinocyte (HaCaT) proliferation (BrdU assay), viability (MTT assay), and migration (horizontal wound healing model). Cytokine levels of sepsis and healthy sera were measured by multiplex assay. Comparisons between groups were carried out using SPSS statistics and P < 0.05 was considered significant. Results: Severe-sepsis sera collected on days 1, 4, and 9 reduced keratinocyte proliferation by 6% (P = 0.005), 20% (P = 0.001), and 18% (P = 0.002), respectively, compared to control sera. Cell viability in cultures exposed to sepsis sera from days 4 and 9 was reduced by 38% (P = 0.01) and 58% (P < 0.001), respectively. Open-surface wounds exposed to sepsis sera from days 1 and 4 were larger than those exposed to sera from healthy controls (60 vs. 31%, P = 0.034 and 66 vs. 31%, P = 0.023, respectively). Exosomes of sepsis or healthy sera treated NF inhibited keratinocyte migration. We detected higher serum levels of cytokines TNF-α (5.7 vs. 0.7 pg/ml, P < 0.001), IL-6 (24.8 vs. 3.8 pg/ml, P < 0.001), IL-10 (30.0 vs. 11.9 pg/ml, P = 0.040), and VEGF (177.9 vs. 48.1 pg/ml, P = 0.018) in sepsis sera. Levels of EGF were significantly lower in sepsis sera than in that of healthy controls (6.5 vs. 115.6 pg/ml, P < 0.001). Sepsis serum supplemented with EGF 5 ng/ml and TNF-α in all concentrations improved keratinocyte migration. Conclusions: Keratinocyte viability, proliferation and migration were reduced in severe sepsis in vitro. Exosomes from NF added in healthy or sepsis serum media inhibited keratinocyte migration. Decreased levels of EGF in sepsis sera may partially explain the delay of wound healing with severe-sepsis patients. Increased levels of TNF-α in sepsis sera do not explain diminished keratinocyte migration.
Abstract Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2gt/gt) mice to a high-fat, high-fructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, the Hif-p4h-2gt/gt mice gained less weight and had less white adipose tissue (WAT) and its inflammation, lower serum cholesterol levels, and lighter livers with less steatosis and lower serum ALT levels than the wild type (WT). The intake of fructose in majority of the Hif-p4h-2gt/gt tissues, including the liver, was 15–35% less than in the WT. We found upregulation of the key fructose transporter and metabolizing enzyme mRNAs, Slc2a2, Khka, and Khkc, and higher ketohexokinase activity in the Hif-p4h-2gt/gt small intestine relative to the WT, suggesting enhanced metabolism of fructose in the former. On the HF-MCD diet, the Hif-p4h-2gt/gt mice showed more browning of the WAT and increased thermogenesis. A pharmacological pan-HIF-P4H inhibitor protected WT mice on both diets against obesity, metabolic dysfunction, and liver damage. These data suggest that HIF-P4H-2 inhibition could be studied as a novel, comprehensive treatment strategy for NAFLD.
Abstract Associations between adverse childhood experiences (ACEs) and cholesterol in depressed patients are unclear. Therefore, we compared 78 adult outpatients with major depressive disorder (MDD) with (n = 24) or without (n = 54) experiences of physical violence in childhood. Background data were collected with questionnaires, and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured from fasting blood samples. Patients with a history of childhood physical violence had lower levels of TC than the control group. No differences were observed in HDL-C, LDL-C, or low-grade inflammation levels between the two groups. In multivariate models, decreased levels of TC were associated with childhood physical violence, and these associations remained significant after adjustments for age, gender, lifestyle, metabolic condition, socioeconomic situation, psychiatric status, suicidality, low-grade inflammation, the chronicity of depression, medications used and somatic diseases. At the 8-month follow-up, the results were essentially the same when the Trauma and Distress Scale (TADS) was used as the measure of ACEs. The specific mechanisms underlying cholesterol alterations associated with ACEs are a topic for future studies. Better understanding of these mechanisms might lead to possible new interventions in the prevention of adverse health effects resulting from ACEs.
Abstract Background: Adequate protein intake among older adults is associated with better health outcomes such as immune function and metabolic regulation of skeletal muscle, but conflicting results make it difficult to define the optimal intake. To further understand the impact of protein intake on metabolic processes, the aim of the study was to explore genome-wide gene expression changes in peripheral blood mononuclear cells (PBMCs) in home-dwelling old subjects after increased protein intake for 12 weeks. Method: In a parallel double-blind randomized controlled intervention study, subjects (≥ 70 years) received a protein-enriched milk (2 × 20 g protein/day, n = 14, mean (±SD) age 76.9 ± 4.9 years) or an isocaloric carbohydrate drink (n = 17, mean (±SD) age 77.7 ± 4.8 years) for breakfast and evening meal for 12 weeks. PBMCs were isolated before and after the intervention. Microarray analysis was performed using Illumina technology. Serum levels of gut peptides and insulin growth factor (IGF)-1 were also measured. Results: In total 758 gene transcripts were regulated after increased protein intake, and 649 gene transcripts were regulated after intake of carbohydrates (p < 0.05). Forty-two of these genes were overlapping. After adjusting for multiple testing, 27 of the 758 gene transcripts were regulated (FDR, q-value < 0.25) after protein intake. Of these 25 were upregulated and two downregulated. In particular, genes and signaling pathways involved in pro-opiomelanocortin (POMC) processing, immune function, and IGF signaling were significantly altered. Conclusions: PBMCs can be used to study gene expression changes after long-term protein intake, as many signaling pathways were regulated after increased protein intake. The functional significance of these findings needs to be further investigated.
Abstract Purpose: Populations living in the Nordic countries are at high risk for vitamin D (VitD) deficiency or insufficiency. To reduce the risk, nationwide interventions based on food fortification and supplementation are being implemented. However, there is limited evidence about the impact of such public health campaigns on target populations. Methods: We studied an unselected sample of 3650 participants (56.2% females) from the longitudinal Northern Finland Birth Cohort 1966 with repeated measures of serum 25-hydroxyvitamin D [25(OH)D] at ages 31 (1997) and 46 (2012–2013). Timepoints corresponded to the period before and during the food fortification. We examined the effect of VitD intake from the diet and supplementation, body mass index and previous 25(OH)D concentration on 25(OH)D concentration at 46 years using a multivariable linear regression analysis. A 25(OH)D z score adjusted for sex, season, latitude and technical effect was used in the analysis. Results: We observed an increase of 10.6 nmol/L in 25(OH)D, when the baseline 25(OH)D was 54.3 nmol/L. The prevalence of serum 25(OH)D below < 50 nmol/L was halved. The changes were found for both sexes and were more pronounced in winter compared to summer months. Regular VitD supplementation had a significant positive effect on 25(OH)D at the age of 46, as well as had the dietary intake of fortified dairy products and fish, and the previous 25(OH)D concentration. However, the intake of fat-spreads albeit VitD-fortified, did not predict 25(OH)D. Conclusions: Our results demonstrated the positive impact of the fortification programme on VitD status in middle-aged population.
Abstract Systemic inflammation is a stage-independent marker of poor prognosis in colorectal cancer (CRC), activated in a complex, multifactorial process. It has been proposed that one of the main factors driving systemic inflammation may be tumor necrosis. Keratin 18 (KRT18) fragments are released from dead cells and their serum levels are markers for apoptotic and necrotic cell death. In CRC, high KRT18 levels associate with advanced disease, but their relationship with tumor necrosis and systemic inflammation is unknown. In this study, serum total soluble KRT18 (tKRT18) and apoptosis-related, caspase-cleaved fragment (aKRT18) levels were measured preoperatively from 328 CRC patients, and their difference was calculated to assess necrosis related KRT18 (nKRT18) levels. The relationships of these markers with tumor necrosis, clinicopathologic features, systemic inflammation markers (C-reactive protein, albumin, and 13 cytokines), and survival were analyzed. High serum tKRT18, aKRT18, and nKRT18 levels showed association with a higher extent of tumor necrosis, distant metastasis, and increased levels of several markers of systemic inflammation, including CXCL8. High serum tKRT18 (multivariable HR 1.94, 95% CI 1.28–2.95, p = 0.002) and nKRT18 (multivariable HR 1.87, 95% CI 1.24–2.82, p = 0.003) levels were associated with poor overall survival independent of potential confounding factors. Our results show that tumor necrosis in CRC contributes to serum levels of KRT18 fragments, and both necrosis and KRT18 levels associate with systemic inflammation. Moreover, we show that serum tKRT18 and nKRT18 levels have independent prognostic value in CRC. Our observations confirm the link between cell death and systemic inflammation.
Abstract The dietary lignan metabolite, enterolactone, has been suggested to have anti-cancer functions, and high serum enterolactone concentrations have been associated with decreased risk of breast and prostate cancers. We hypothesized that serum enterolactone concentrations as a marker of plant-based foods are associated with decreased risk in colorectal cancer (CRC). We measured serum enterolactone glucuronide and sulfate concentrations by liquid chromatography-tandem mass spectrometry in 115 CRC patients and 76 sex- and age-matched controls and analyzed the results with respect to tumor parameters, clinical parameters, and systemic inflammatory markers. Patients with colon cancer had significant lower serum enterolactone glucuronide and sulfate concentrations than controls (glucuronide: median 3.14 nM vs. 6.32 nM, P < 0.001; sulfate: median 0.13 nM vs. 0.17 nM, P = 0.002), whereas rectal cancer patients had similar enterolactone levels as controls (glucuronide: median 5.39 nM vs. 6.32 nM, P = 0.357; sulfate: median 0.19 nM vs. 0.17 nM, P = 0.452). High serum enterolactone concentrations were associated with low tumor grade, high serum creatinine levels, and concomitant diabetes. In summary, our results suggest that serum enterolactone concentrations are decreased in colon but not in rectal cancer. Further investigations are required to assess whether this reflects an altered lignan metabolism by the colon microbiome.
Abstract Background: Platelets not only contribute to hemostasis but also to the regulation of inflammatory reactions and cancer pathogenesis. We hypothesized that blood platelet count would be associated with systemic inflammation, the densities of tumor infiltrating immune cells, and survival in colorectal cancer (CRC), and these relationships could be altered by aspirin use. Methods: We measured blood platelet count in a cohort of 356 CRC patients and analyzed its relationships with tumor and patient characteristics including aspirin use, markers of systemic inflammation (modified Glasgow Prognostic Score, mGPS; serum levels of CRP, albumin, and 13 cytokines), blood hemoglobin levels, five types of tumor infiltrating immune cells (CD3, CD8, FoxP3, Neutrophil elastase, mast cell tryptase), and survival. Results: Platelet count inversely correlated with blood hemoglobin levels (p < 0.001) and positively correlated with serum levels of CRP and multiple cytokines including IL-1RA, IL-4, IL-6, IL-7, IL-8, IL-12, IFNγ, and PDGF-BB (p < 0.001 for all), while aspirin use was not associated with the levels of systemic inflammatory markers. High platelet count was also associated with high mGPS (p < 0.001) but did not show statistically significant multivariable adjusted associations with the densities of tumor infiltrating immune cells. Higher platelet counts were observed in higher tumor stage (p < 0.001), but platelet count or aspirin use were not associated with patient survival. Conclusions: High platelet count is associated with systemic inflammation in CRC. This study could not demonstrate statistically significant associations between platelet count, aspirin use, and the densities of tumor infiltrating immune cells.
Abstract We hypothezied that telomere length is considerably altered in cystic fibrosis (CF) patients compared to healthy subjects (HS), and that leukocyte telomere length variation reflects the severity of CF. Relative telomere length (RTL) was assessed by qPCR in 70 children aged 5–10 (34 CF; 36 HS) and 114 adults aged 18–45 (53 CF; 61 HS). Telomere length was similar in CF and HS (median (interquartile range): 0.799 (0.686–0.950) vs. 0.831 (0.707–0.986); p = 0.5283) both in children and adults. In adults, women had longer telomeres than men (0.805 (0.715–0.931) vs. 0.703 (0.574–0.790); p = 0.0002). Patients treated with inhaled corticosteroids had a shorter RTL compared to those without steroid therapy (0.765 (0.664–0.910) vs. 0.943 (0.813–1.191); p = 0.0007) and this finding remained significant after adjusting for gender, age, BMI, and child/adult status (p = 0.0003). Shorter telomeres were independently associated with the presence of comorbidities (0.763 (0.643–0.905) vs. 0.950 (0.783–1.130); p = 0.0006) and antibiotic treatment at the moment of blood sampling (0.762 (0.648–0.908) vs. 0.832 (0.748–1.129); p = 0.0172). RTL correlated with number of multiple-day hospitalizations (rho = −0.251; p = 0.0239), as well as number of hospitalization days (rho = −0.279; p = 0.0113). Leukocyte RTL in children and adults with CF was not shorter than in healthy controls, and did not seem to have any potential as a predictor of CF survival. However, it inversely associated with the investigated clinical characteristics.