Lack of FFAR1/GPR40 Does Not Protect Mice From High-Fat Diet–Induced Metabolic Disease
Hong Lan 1 ,
Lizbeth M. Hoos 1 ,
Li Liu 1 ,
Glen Tetzloff 1 ,
Weiwen Hu 2 ,
Susan J. Abbondanzo 2 ,
Galya ...Vassileva 2 ,
Eric L. Gustafson 2 ,
Joseph A. Hedrick 1 and
Harry R. Davis 1
1 Department of Cardiovascular and Metabolic Diseases, Schering-Plough Research Institute, Kenilworth, New Jersey
2 Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, New Jersey
Corresponding author: Hong Lan, hong.lan{at}spcorp.com
Abstract
OBJECTIVE— FFAR1/GPR40 is a G-protein–coupled receptor expressed predominantly in pancreatic islets mediating free fatty acid–induced
insulin secretion. However, the physiological role of FFAR1 remains controversial. It was previously reported that FFAR1 knockout
( Ffar1 −/− ) mice were resistant to high-fat diet–induced hyperinuslinemia, hyperglycemia, hypertriglyceridemia, and hepatic steatosis.
A more recent report suggested that although FFAR1 was necessary for fatty acid–induced insulin secretion in vivo, deletion
of FFAR1 did not protect pancreatic islets against fatty acid–induced islet dysfunction. This study is designed to investigate
FFAR1 function in vivo using a third line of independently generated Ffar1 −/− mice in the C57BL/6 background.
RESEARCH DESIGN AND METHODS— We used CL-316,243, a β3 adrenergic receptor agonist, to acutely elevate blood free fatty acids and to study its effect on
insulin secretion in vivo. Ffar1 +/+ (wild-type) and Ffar1 −/− (knockout) mice were placed on two distinct high-fat diets to study their response to diet-induced obesity.
RESULTS— Insulin secretion was reduced by ∼50% in Ffar1 −/− mice, confirming that FFAR1 contributes significantly to fatty acid stimulation of insulin secretion in vivo. However, Ffar1 +/+ and Ffar1 −/− mice had similar weight, adiposity, and hyperinsulinemia on high-fat diets, and Ffar1 −/− mice showed no improvement in glucose or insulin tolerance tests. In addition, high-fat diet induced comparable levels of
lipid accumulation in livers of Ffar1 +/+ and Ffar1 −/− mice.
CONCLUSIONS— FFAR1 is required for normal insulin secretion in response to fatty acids; however, Ffar1 −/− mice are not protected from high-fat diet–induced insulin resistance or hepatic steatosis.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 4 August 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted July 18, 2008.
Received May 1, 2008.
DIABETES
Abstract We present high-cadence ultraviolet through near-infrared observations of the Type Ia supernova (SN Ia) 2023bee at D = 32 ± 3 Mpc, finding excess flux in the first days after explosion, ...particularly in our 10 minutes cadence TESS light curve and Swift UV data. Compared to a few other normal SNe Ia with early excess flux, the excess flux in SN 2023bee is redder in the UV and less luminous. We present optical spectra of SN 2023bee, including two spectra during the period where the flux excess is dominant. At this time, the spectra are similar to those of other SNe Ia but with weaker Si ii , C ii, and Ca ii absorption lines, perhaps because the excess flux creates a stronger continuum. We compare the data to several theoretical models on the origin of early excess flux in SNe Ia. Interaction with either the companion star or close-in circumstellar material is expected to produce a faster evolution than observed. Radioactive material in the outer layers of the ejecta, either from double detonation explosion or from a 56 Ni clump near the surface, cannot fully reproduce the evolution either, likely due to the sensitivity of early UV observable to the treatment of the outer part of ejecta in simulation. We conclude that no current model can adequately explain the full set of observations. We find that a relatively large fraction of nearby, bright SNe Ia with high-cadence observations have some amount of excess flux within a few days of explosion. Considering potential asymmetric emission, the physical cause of this excess flux may be ubiquitous in normal SNe Ia.
Abstract
The Hobby–Eberly Telescope Dark Energy Experiment (HETDEX) is an untargeted spectroscopic survey that aims to measure the expansion rate of the universe at
z
∼ 2.4 to 1% precision for both
H
...(
z
) and
D
A
(
z
). HETDEX is in the process of mapping in excess of one million Ly
α
emitting (LAE) galaxies and a similar number of lower-
z
galaxies as a tracer of the large-scale structure. The success of the measurement is predicated on the post-observation separation of galaxies with Ly
α
emission from the lower-
z
interloping galaxies, primarily O
ii
, with low contamination and high recovery rates. The Emission Line eXplorer (ELiXer) is the principal classification tool for HETDEX, providing a tunable balance between contamination and completeness as dictated by science needs. By combining multiple selection criteria, ELiXer improves upon the 20 Å rest-frame equivalent width cut commonly used to distinguish LAEs from lower-
z
O
ii
emitting galaxies. Despite a spectral resolving power,
R
∼ 800, that cannot resolve the O
ii
doublet, we demonstrate the ability to distinguish LAEs from foreground galaxies with 98.1% accuracy. We estimate a contamination rate of Ly
α
by O
ii
of 1.2% and a Ly
α
recovery rate of 99.1% using the default ELiXer configuration. These rates meet the HETDEX science requirements.
To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting ...enlargement.
Prospective cohort study within a controlled clinical trial.
Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50-85 years.
Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype.
(1) Presence or development of GA; (2) change in the square root of GA area over time.
At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27-0.30) and incident GA (0.28 mm/year; 0.27-0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P = 0.33) or smoking status (P = 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P = 0.0002), and APOE non-risk (P = 0.001) genotypes.
Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.
All components of the renin angiotensin system necessary for ANG II generation and action have been reported to be present in renal proximal convoluted tubules. Given the close relationship between ...renal sodium handling and blood pressure regulation, we hypothesized that modulating the action of ANG II specifically in the renal proximal tubules would alter the chronic level of blood pressure. To test this, we used a proximal tubule-specific, androgen-dependent, promoter construct (KAP2) to generate mice with either overexpression of a constitutively active angiotensin type 1A receptor transgene or depletion of endogenous angiotensin type 1A receptors. Androgen administration to female transgenic mice caused a robust induction of the transgene in the kidney and increased baseline blood pressure. In the receptor-depleted mice, androgen administration to females resulted in a Cre recombinase-mediated deletion of angiotensin type 1A receptors in the proximal tubule and reduced blood pressure. In contrast to the changes observed at baseline, there was no difference in the blood pressure response to a pressor dose of ANG II in either experimental model. These data, from two separate mouse models, provide evidence that ANG II signaling via the type 1A receptor in the renal proximal tubule is a regulator of systemic blood pressure under baseline conditions.
•We test the pollination module of InVEST in an urban environment (Chicago, USA).•The model predicts 46% of the native bee richness (p=0.008, n=14).•The model suggests that pollination supply is ...highly variable across Chicago.•We model various land cover change scenarios’ effect on pollination supply.•Of the scenarios tested, increasing floral resources around urban agriculture sites is best.
Although urban agriculture is growing in popularity, little is known about the distribution of insect pollinators across urbanized landscapes. We used the pollination module of InVEST (a suite of software models used to map and value ecosystem services), along with fine-scale land cover data and empirical data on bee distributions, to assess different scenarios of urban pollinator management in Chicago, Illinois (USA). Specifically, we simulated the partial conversion of lawn/turf-grass to floral resources in city parks only, in gardens managed by individual households only, and in any available turf grass within buffer distances of 250–1000m of urban farms, community gardens, and home gardens across Chicago. We found that the output of InVEST’s pollination model was significantly related to empirical measures of bee richness (explaining 46% of the variation) but not bee abundance in Chicago. To increase pollination supply at urban farms and community gardens, our results indicate that, out of the scenarios presented here, the best strategy for the City of Chicago would be to concentrate floral resources nearby (within a 250m buffer rather than within a 1km buffer). In contrast, for home gardens, the model indicates that it may be better to increase floral resources throughout the city. This discrepancy may be due to the smaller size of home gardens and their more dispersed spatial arrangement throughout the city. Generally, our results indicate that converting turf grass to a more florally-rich land cover would support increased supply of pollinators and urban agriculture.
•White matter microstructure is related to childhood cognitive control.•Tracts in a frontal–parietal–motor–striatal circuit relate to childhood cognitive control.•Children with higher FA are more ...accurate on a control task.•Children with lower RD are also more accurate on a control task.
Cognitive control, which involves the ability to pay attention and suppress interference, is important for learning and achievement during childhood. The white matter tracts related to control during childhood are not well known. We examined the relationship between white matter microstructure and cognitive control in 61 children aged 7–9 years using diffusion tensor imaging (DTI). This technique enables an in vivo characterization of microstructural properties of white matter based on properties of diffusion. Such properties include fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, measures thought to reflect specific biological properties of white matter integrity. Our results suggest that children with higher estimates of white matter integrity in the corona radiata, superior longitudinal fasciculus, posterior thalamic radiation, and cerebral peduncle were more accurate during incongruent (>><>>, <<><<) and neutral (-->--, --<--) trials of a task of cognitive control. Importantly, less interference during the task (i.e., incongruent and neutral difference scores) was associated with greater white matter microstructure in the posterior thalamic radiation and cerebral peduncle. Fiber tracts in a frontal–parietal–striatal–motor circuit seem to play a role in cognitive control in children.
Estimates of species' vital rates and an understanding of the factors affecting those parameters over time and space can provide crucial information for management and conservation. We used ...mark–recapture, reproductive output, and territory occupancy data collected during 1985–2013 to evaluate population processes of Northern Spotted Owls (Strix occidentalis caurina) in 11 study areas in Washington, Oregon, and northern California, USA. We estimated apparent survival, fecundity, recruitment, rate of population change, and local extinction and colonization rates, and investigated relationships between these parameters and the amount of suitable habitat, local and regional variation in meteorological conditions, and competition with Barred Owls (Strix varia). Data were analyzed for each area separately and in a meta-analysis of all areas combined, following a strict protocol for data collection, preparation, and analysis. We used mixed effects linear models for analyses of fecundity, Cormack-Jolly-Seber open population models for analyses of apparent annual survival (φ), and a reparameterization of the Jolly-Seber capture–recapture model (i.e. reverse Jolly-Seber; RJS) to estimate annual rates of population change (λRJS) and recruitment. We also modeled territory occupancy dynamics of Northern Spotted Owls and Barred Owls in each study area using 2-species occupancy models. Estimated mean annual rates of population change (λ) suggested that Spotted Owl populations declined from 1.2% to 8.4% per year depending on the study area. The weighted mean estimate of λ for all study areas was 0.962 (± 0.019 SE; 95% CI: 0.925–0.999), indicating an estimated range-wide decline of 3.8% per year from 1985 to 2013. Variation in recruitment rates across the range of the Spotted Owl was best explained by an interaction between total winter precipitation and mean minimum winter temperature. Thus, recruitment rates were highest when both total precipitation (29 cm) and minimum winter temperature (−9.5°C) were lowest. Barred Owl presence was associated with increased local extinction rates of Spotted Owl pairs for all 11 study areas. Habitat covariates were related to extinction rates for Spotted Owl pairs in 8 of 11 study areas, and a greater amount of suitable owl habitat was generally associated with decreased extinction rates. We observed negative effects of Barred Owl presence on colonization rates of Spotted Owl pairs in 5 of 11 study areas. The total amount of suitable Spotted Owl habitat was positively associated with colonization rates in 5 areas, and more habitat disturbance was associated with lower colonization rates in 2 areas. We observed strong declines in derived estimates of occupancy in all study areas. Mean fecundity of females was highest for adults (0.309 ± 0.027 SE), intermediate for 2-yr-olds (0.179 ± 0.040 SE), and lowest for 1-yr-olds (0.065 ± 0.022 SE). The presence of Barred Owls and habitat covariates explained little of the temporal variation in fecundity in most study areas. Climate covariates occurred in competitive fecundity models in 8 of 11 study areas, but support for these relationships was generally weak. The fecundity meta-analysis resulted in 6 competitive models, all of which included the additive effects of geographic region and annual time variation. The 2 top-ranked models also weakly supported the additive negative effects of the amount of suitable core area habitat, Barred Owl presence, and the amount of edge habitat on fecundity. We found strong support for a negative effect of Barred Owl presence on apparent survival of Spotted Owls in 10 of 11 study areas, but found few strong effects of habitat on survival at the study area scale. Climate covariates occurred in top or competitive survival models for 10 of 11 study areas, and in most cases the relationships were as predicted; however, there was little consistency among areas regarding the relative importance of specific climate covariates. In contrast, meta-analysis results suggested that Spotted Owl survival was higher across all study areas when the Pacific Decadal Oscillation (PDO) was in a warming phase and the Southern Oscillation Index (SOI) was negative, with a strongly negative SOI indicative of El Niño events. The best model that included the Barred Owl covariate (BO) was ranked 4th and also included the PDO covariate, but the BO effect was strongly negative. Our results indicated that Northern Spotted Owl populations were declining throughout the range of the subspecies and that annual rates of decline were accelerating in many areas. We observed strong evidence that Barred Owls negatively affected Spotted Owl populations, primarily by decreasing apparent survival and increasing local territory extinction rates. However, the amount of suitable owl habitat, local weather, and regional climatic patterns also were related to survival, occupancy (via colonization rate), recruitment, and, to a lesser extent, fecundity, although there was inconsistency in regard to which covariates were important for particular demographic parameters or across study areas. In the study areas where habitat was an important source of variation for Spotted Owl demographics, vital rates were generally positively associated with a greater amount of suitable owl habitat. However, Barred Owl densities may now be high enough across the range of the Northern Spotted Owl that, despite the continued management and conservation of suitable owl habitat on federal lands, the long-term prognosis for the persistence of Northern Spotted Owls may be in question without additional management intervention. Based on our study, the removal of Barred Owls from the Green Diamond Resources (GDR) study area had rapid, positive effects on Northern Spotted Owl survival and the rate of population change, supporting the hypothesis that, along with habitat conservation and management, Barred Owl removal may be able to slow or reverse Northern Spotted Owl population declines on at least a localized scale.
We assess relationships among 192 species in all 12 monocot orders and 72 of 77 families, using 602 conserved single-copy (CSC) genes and 1375 benchmarking single-copy ortholog (BUSCO) genes ...extracted from genomic and transcriptomic datasets. Phylogenomic inferences based on these data, using both coalescent-based and supermatrix analyses, are largely congruent with the most comprehensive plastome-based analysis, and nuclear-gene phylogenomic analyses with less comprehensive taxon sampling. The strongest discordance between the plastome and nuclear gene analyses is the monophyly of a clade comprising Asparagales and Liliales in our nuclear gene analyses, versus the placement of Asparagales and Liliales as successive sister clades to the commelinids in the plastome tree. Within orders, around six of 72 families shifted positions relative to the recent plastome analysis, but four of these involve poorly supported inferred relationships in the plastome-based tree. In Poales, the nuclear data place a clade comprising Ecdeiocoleaceae+Joinvilleaceae as sister to the grasses (Poaceae); Typhaceae, (rather than Bromeliaceae) are resolved as sister to all other Poales. In Commelinales, nuclear data place Philydraceae sister to all other families rather than to a clade comprising Haemodoraceae+Pontederiaceae as seen in the plastome tree. In Liliales, nuclear data place Liliaceae sister to Smilacaceae, and Melanthiaceae are placed sister to all other Liliales except Campynemataceae. Finally, in Alismatales, nuclear data strongly place Tofieldiaceae, rather than Araceae, as sister to all the other families, providing an alternative resolution of what has been the most problematic node to resolve using plastid data, outside of those involving achlorophyllous mycoheterotrophs. As seen in numerous prior studies, the placement of orders Acorales and Alismatales as successive sister lineages to all other extant monocots. Only 21.2% of BUSCO genes were demonstrably single-copy, yet phylogenomic inferences based on BUSCO and CSC genes did not differ, and overall functional annotations of the two sets were very similar. Our analyses also reveal significant gene tree-species tree discordance despite high support values, as expected given incomplete lineage sorting (ILS) related to rapid diversification. Our study advances understanding of monocot relationships and the robustness of phylogenetic inferences based on large numbers of nuclear single-copy genes that can be obtained from transcriptomes and genomes.
Fluticasone furoate (FF) is a novel inhaled corticosteroid with 24 h activity. FF is being developed as a once-daily treatment in combination with the long-acting β(2) agonist vilanterol trifenatate ...for asthma and chronic obstructive pulmonary disease.
To determine the optimal dose(s) of FF for treating patients with asthma.
An 8-week multicentre, randomised, double-blind study. 627 patients with persistent moderate-to-severe asthma, symptomatic on medium-dose inhaled corticosteroid therapy, were randomised to placebo, FF 200, 400, 600 or 800 μg (once daily in the evening using a novel dry powder inhaler), or fluticasone propionate 500 μg twice daily (via Diskus™/Accuhaler™). The primary efficacy measure was mean change from baseline in pre-dose evening forced expiratory volume in one second (FEV(1)). Other endpoints included morning and evening peak expiratory flow, and rescue/symptom-free 24 h periods.
Each dose was significantly superior to placebo for the primary endpoint (p<0.001) with efficacy at least similar to that reported with fluticasone propionate. There was no dose-response relationship across the FF doses studied. Peak expiratory flow improved in all groups (p<0.001 vs placebo), and there were significant treatment effects on rescue/symptom-free 24 h periods with all active treatments. FF was generally well tolerated. The incidence of oral candidiasis was higher with FF 800 μg than placebo; pharmacokinetic and 24 h urinary cortisol analyses confirmed a higher systemic exposure of FF at this highest dose level.
FF doses <800 μg have a favourable therapeutic index. The absence of an efficacy dose response suggests that 200 μg is an appropriate dose in patients with moderate persistent asthma. CLINICALTRIALS.GOV IDENTIFIER: NCT00603746.
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