The strongest BMI-associated GWAS locus in humans is the FTO gene. Rodent studies demonstrate a role for FTO in energy homeostasis and body composition. The phenotypes observed in loss of expression ...studies are complex with perinatal lethality, stunted growth from weaning, and significant alterations in body composition. Thus understanding how and where Fto regulates food intake, energy expenditure, and body composition is a challenge. To address this we generated a series of mice with distinct temporal and spatial loss of Fto expression. Global germline loss of Fto resulted in high perinatal lethality and a reduction in body length, fat mass, and lean mass. When ratio corrected for lean mass, mice had a significant increase in energy expenditure, but more appropriate multiple linear regression normalisation showed no difference in energy expenditure. Global deletion of Fto after the in utero and perinatal period, at 6 weeks of age, removed the high lethality of germline loss. However, there was a reduction in weight by 9 weeks, primarily as loss of lean mass. Over the subsequent 10 weeks, weight converged, driven by an increase in fat mass. There was a switch to a lower RER with no overall change in food intake or energy expenditure. To test if the phenotype can be explained by loss of Fto in the mediobasal hypothalamus, we sterotactically injected adeno-associated viral vectors encoding Cre recombinase to cause regional deletion. We observed a small reduction in food intake and weight gain with no effect on energy expenditure or body composition. Thus, although hypothalamic Fto can impact feeding, the effect of loss of Fto on body composition is brought about by its actions at sites elsewhere. Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is currently an unmet clinical need to develop better pharmacological treatments to improve glucose handling in Type II Diabetes patients with obesity. To this end, determining the effect of ...obesity-associated adipokines on skeletal muscle insulin sensitivity has emerged as an important area of drug discovery research. This review draws together the data on the functional role of adipokines on skeletal muscle insulin signalling, highlights several understudied novel adipokines and provides a perspective on the direction of future research.
The adipokines leptin, resistin, visfatin and adiponectin have all been shown to affect skeletal muscle insulin sensitivity by impacting on the activity of components within insulin signalling pathways, affecting GLUT4 translocation and modulating insulin-mediated skeletal muscle glucose uptake. Furthermore, proteomic analysis of the adipose tissue secretome has recently identified several novel adipokines including vaspin, chemerin and pref-1 that are associated with obesity and insulin resistance in humans and functionally impact on insulin signalling pathways. However, predominantly, these functional findings are the result of studies in rodents, with in vitro studies utilising either rat L6 or murine C2C12 myoblasts and/or myotubes. Despite the methodology to isolate and culture human myoblasts and to differentiate them into myotubes being established, the use of human muscle in vitro models for the functional validation of adipokines on skeletal muscle insulin sensitivity is limited.
Understanding the mechanism of action and function of adipokines in mediating insulin sensitivity in skeletal muscle may lead to the development of novel therapeutics for patients with type 2 diabetes. However, to date, studies conducted in human skeletal muscle cells and tissues are limited. Such human in vitro studies should be prioritised in order to reduce the risk of candidate drugs failing in the clinic due to the assumption that rodent skeletal muscle target validation studies will to translate to human.
The objective of this observational study was to assess the relationship between herd-level prevalence of hyperketolactia (HPH) with management practices of the transition period and herd milk ...production. Dairy herds (n = 71) were selected based on their inclusion in a herd management risk assessment study (August 2014–March 2018) using a Vital 90 (Elanco) Risk Assessment tool (one assessment per farm). Data from multiple milk recording test-days (Dairy Herd Improvement, DHI; Lactanet) were included in the analysis. Tests performed within ±6 mo relative to each farm's risk assessment date were included (10 ± 2 SD tests per farm). The majority of the farms were located in Ontario (83%). For each farm DHI test, the data set included herd average milk yield (kg/cow per day), average milk fat and protein (%), average somatic cell count (cells/mL), average days in milk (DIM), number of cows tested for ketosis, number of ketosis-positive tests (milk β-hydroxybutyrate ≥0.15 mmol/L), and proportion of cows by parity groups. Overall HPH (5–21 DIM) was calculated based on data available per farm (sum of all positive tests within 5–21 DIM/sum of all cows tested within 5–21 DIM). Each farm average was obtained by considering all test-days. A logit-transformation was applied to hyperketolactia prevalence. Linear regression models (PROC GLM and MIXED of SAS, Version 9.4) were used to predict herd HPH (milk β-hydroxybutyrate ≥0.15 mmol/L within 5 to 21 DIM; the outcome of interest). Four initial models (far-off, close-up, and fresh periods, and DHI) were separately built to assess associations between their variables and HPH; a final model considered variables selected in the initial models. Univariable (liberal P < 0.25) followed by multivariable models were used to build specific models for each period of the risk assessment. Herd prevalence of hyperketolactia was 27 ± 14%, with an average herd size of 141 ± 110 cows. The final HPH model (R2 = 24.8%) included weighted milk yield, the proportion of primiparous cows, water access in the close-up period, and access to rest areas or stall access in the fresh period. Herd prevalence of hyperketolactia was negatively associated with milk yield odds ratio, OR = 0.96 (95% confidence interval 0.92–0.99) and proportion of primiparous cows OR = 0.98 (0.96–0.99). The odds of hyperketolactia were greater with poor water access and quality (<5 cm of linear access per cow; dirty water; only 1 water location in pen) than with ≥10.2 cm of linear access per cow; clean water; >2 water locations in pen 1.23 (1.11–2.39) in the close-up period. The odds of hyperketolactia were greater in farms providing limited access to rest areas in the fresh period than in farms providing constant access to rest areas, without dead-ends 1.64 (1.03–2.80). In Canadian dairy herds, HPH in early lactation was associated with certain transition-period management practices and was negatively associated with herd productivity.
SNPs in the first intron of FTO (fat mass and obesity associated) are strongly associated with human obesity. While it is not yet formally established that this effect is mediated through the actions ...of the FTO protein itself, loss of function mutations in FTO or its murine homologue Fto result in severe growth retardation, and mice globally overexpressing FTO are obese. The mechanisms through which FTO influences growth and body composition are unknown. We describe a role for FTO in the coupling of amino acid levels to mammalian target of rapamycin complex 1 signaling. These findings suggest that FTO may influence body composition through playing a role in cellular nutrient sensing.
Genome-wide association studies have identified SNPs within FTO, the human fat mass and obesity-associated gene, that are strongly associated with obesity. Individuals homozygous for the at-risk ...rs9939609 A allele weigh, on average, ~3 kg more than individuals with the low-risk T allele. Mice that lack FTO function and/or Fto expression display increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet. Our results suggest that increased body mass results primarily from increased food intake. Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Highlights • Standardized use of EVGS is helpful in optimizing the visual scoring. • Reliability is higher for distal pathology and lower for proximal pathology. • Reliability is higher with greater ...gait analysis experience. • Reliability is higher with EVGS practice. • Reliability is higher with higher functioning children.
Human FTO gene variants are associated with body mass index and type 2 diabetes. Because the obesity-associated SNPs are intronic, it is unclear whether changes in FTO expression or splicing are the ...cause of obesity or if regulatory elements within intron 1 influence upstream or downstream genes. We tested the idea that FTO itself is involved in obesity. We show that a dominant point mutation in the mouse Fto gene results in reduced fat mass, increased energy expenditure, and unchanged physical activity. Exposure to a high-fat diet enhances lean mass and lowers fat mass relative to control mice. Biochemical studies suggest the mutation occurs in a structurally novel domain and modifies FTO function, possibly by altering its dimerisation state. Gene expression profiling revealed increased expression of some fat and carbohydrate metabolism genes and an improved inflammatory profile in white adipose tissue of mutant mice. These data provide direct functional evidence that FTO is a causal gene underlying obesity. Compared to the reported mouse FTO knockout, our model more accurately reflects the effect of human FTO variants; we observe a heterozygous as well as homozygous phenotype, a smaller difference in weight and adiposity, and our mice do not show perinatal lethality or an age-related reduction in size and length. Our model suggests that a search for human coding mutations in FTO may be informative and that inhibition of FTO activity is a possible target for the treatment of morbid obesity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Analyzed five three-dimensional multi-segmented foot-models (3DMSFMs).•Found repeatability and kinematics similarities and differences between each model.•All models showed moderate ...repeatability.•duPont and Oxford models show most similar kinematic values.•Use of model specific normative data recommended.
Many skin-mounted three-dimensional multi-segmented foot models are currently in use for gait analysis. Evidence regarding the repeatability of models, including between trial and between assessors, is mixed, and there are no between model comparisons of kinematic results.
This study explores differences in kinematics and repeatability between five three-dimensional multi-segmented foot models. The five models include duPont, Heidelberg, Oxford Child, Leardini, and Utah.
Hind foot, forefoot, and hallux angles were calculated with each model for ten individuals. Two physical therapists applied markers three times to each individual to assess within and between therapist variability. Standard deviations were used to evaluate marker placement variability. Locally weighted regression smoothing with alpha-adjusted serial T tests analysis was used to assess kinematic similarities.
All five models had similar variability, however, the Leardini model showed high standard deviations in plantarflexion/dorsiflexion angles. P-value curves for the gait cycle were used to assess kinematic similarities. The duPont and Oxford models had the most similar kinematics.
All models demonstrated similar marker placement variability. Lower variability was noted in the sagittal and coronal planes compared to rotation in the transverse plane, suggesting a higher minimal detectable change when clinically considering rotation and a need for additional research. Between the five models, the duPont and Oxford shared the most kinematic similarities. While patterns of movement were very similar between all models, offsets were often present and need to be considered when evaluating published data.
Single-nucleotide polymorphisms in the first intron of the ubiquitously expressed FTO gene are associated with obesity. Although the physiological functions of FTO remain unclear, food intake is ...often altered when Fto expression levels are manipulated. Furthermore, deletion of FTO from neurones alone has a similar effect on food intake to deletion of FTO in all tissues. These results indicate that FTO expression in the brain is particularly important. Considerable focus has been placed on the dynamic regulation of Fto mRNA expression in the hypothalamus after short-term (16-48 hour) fasting, but results have been controversial. There are no studies that quantify FTO protein levels across the brain, and assess its alteration following short-term fasting. Using immunohistochemistry, we found that FTO protein is widely expressed in mouse brain, and present in the majority of neurones. Using quantitative Western blotting and RT-qPCR we show that FTO protein and mRNA levels in the hypothalamus, cerebellum and rostral brain are relatively uniform, and levels in the brain are higher than in skeletal muscles of the lower limbs. Fasting for 18 hours does not alter the expression pattern, or levels, of FTO protein and mRNA. We further show that the majority of POMC neurones, which are critically involved in food intake regulation, also express FTO, but that the percentage of FTO-positive POMC neurones is not altered by fasting. In summary, we find no evidence that Fto/FTO expression is regulated by short-term (18-hour) fasting. Thus, it is unlikely that the hunger and increased post-fasting food intake caused by such food deprivation is driven by alterations in Fto/FTO expression. The widespread expression of FTO in neurones also suggests that physiological studies of this protein should not be limited to the hypothalamus.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction:
The transition from pediatric health care and school systems presents enormous challenges for young adults with cerebral palsy (CP). The lack of strong societal support during this ...seminal life event is well-documented and leads many adults with CP to struggle with independence, higher education, and employment. Despite the relatively high prevalence of CP, information about the experiences and function of adults with CP in our society continues to be limited. The purpose of this project was to describe well-being by assessing education, employment, physical function, walking activity, and utilization of health care in an ambulatory adult cohort with CP who received specialized pediatric care at our center.
Method:
In this Institutional Review Board-approved prospective study, we invited former patients from our tertiary care pediatric CP center to complete a set of patient-reported outcomes including (1) the Patient-Reported Outcomes Measurement Information System domains of physical function and pain interference, (2) the Satisfaction with Life Scale, and a project-specific demographic questionnaire about education, employment, income, independence, pain, and health care utilization. Participants also wore a pedometer for 8 days to monitor community walking activity. Chi-squared pairwise or
t
-tests were used as appropriate to compare survey responses and walking activity data between three groups: participants who self-reported, those who reported by proxy, and published normative data from age-matched typically developing adult (TDA) samples.
Results:
One hundred twenty-six adults with CP consented to participate; 85 self-reported age 29.7 ± 4.3 years; Gross Motor Function Classification System: I (28%), II (47%), and III, (25%) and 41 reported by proxy age 29.7 ± 4.1 years; Gross Motor Function Classification System: I (10%), II (68%), and III (22%). For the group who self-reported, high school graduation rate (99%) was similar to TDA (92%;
p
= 0.0173) but bachelor's degree achievement rate (55%) was higher than TDA (37%;
p
< 0.001). Despite more advanced education, the unemployment rate in this group was higher than national levels at 33% and was associated with high utilization of Social Security Disability Insurance (33%). Within the self-reporting group, 13% required a caregiver. For the group who reported by proxy, educational levels (73% high school graduates, 0 bachelor's degree) were lower than the general population (
p
< 0.001) and unemployment was higher than the national level, at 64%. Unemployment in this group was associated with high utilization of Social Security Disability Insurance (85%). Within the proxy-reporting group, 71% required a caregiver. The full cohort demonstrated lower levels of physical function according to the Patient-Reported Outcomes Measurement Information System and less community walking activity compared with TDA references (
p
< 0.001). This cohort of adults with CP reported significantly higher frequency of chronic pain (48 vs. 12% for TDA;
p
< 0.001), but less pain interference with daily activities than TDA based on Patient-Reported Outcomes Measurement Information System results (
p
< 0.001). This cohort reported good to excellent overall health (93%) and high utilization of primary care (98%), but limited utilization of specialty care, specifically orthopedic care (21%) and physical therapy (15%).
Discussion:
This cohort of adults with CP had similar levels of education as the general population, but had relatively high rates of unemployment, caretaker need, and Social Security Disability Insurance utilization. Although chronic pain was frequent, the impact of pain on work and independent living did not exceed reports from a typically developing reference. Better targeted societal resources for adults with physical disabilities are urgently needed to allow equitable access to employment, promote opportunities for independence, and enable full participation in community life.
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