Cloud cover currently represents the single greatest source of uncertainty in General Circulation Models. Stable carbon isotope ratios (δ
13
C) from tree-rings, in areas of low moisture stress, are ...likely to be primarily controlled by photosynthetically active radiation (PAR), and therefore should provide a proxy record for cloud cover or sunshine; indeed this association has previously been demonstrated experimentally for Scots pine in Fennoscandia, with sunlight explaining ca 90% of the variance in photosynthesis and temperature only ca 4%. We present a statistically verifiable 1011-year reconstruction of cloud cover from a well replicated, annually-resolved δ
13
C record from Forfjord in coastal northwestern Norway. This reconstruction exhibits considerable variability in cloud cover over the past millennium, including extended sunny periods during the cool seventeenth and eighteenth centuries and warm cloudy periods during the eleventh, early fifteenth and twentieth centuries. We find that while a generally positive relationship persists between sunshine and temperature at high-frequency, at lower (multi-decadal) frequencies the relationship is more often a negative one, with cool periods being sunny (most notably the Little Ice Age period from 1600 to 1750 CE) and warm periods more cloudy (e.g. the mediaeval and the twentieth century). We conclude that these long-term changes may be caused by changes in the dominant circulation mode, likely to be associated with the Arctic Oscillation. There is also strong circumstantial evidence that prolonged periods of high summer cloud cover, with low PAR and probably high precipitation, may be in part responsible for major European famines caused by crop failures.
Peroxisome proliferator activated receptor gamma 2 (PPARg2) is the nutritionally regulated isoform of PPARg. Ablation of PPARg2 in the ob/ob background, PPARg2(-/-) Lep(ob)/Lep(ob) (POKO mouse), ...resulted in decreased fat mass, severe insulin resistance, beta-cell failure, and dyslipidaemia. Our results indicate that the PPARg2 isoform plays an important role, mediating adipose tissue expansion in response to positive energy balance. Lipidomic analyses suggest that PPARg2 plays an important antilipotoxic role when induced ectopically in liver and muscle by facilitating deposition of fat as relatively harmless triacylglycerol species and thus preventing accumulation of reactive lipid species. Our data also indicate that PPARg2 may be required for the beta-cell hypertrophic adaptive response to insulin resistance. In summary, the PPARg2 isoform prevents lipotoxicity by (a) promoting adipose tissue expansion, (b) increasing the lipid-buffering capacity of peripheral organs, and (c) facilitating the adaptive proliferative response of beta-cells to insulin resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutations in the melanocortin 4 receptor gene (MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We ...examined the MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss-of-function (LoF) mutations in MC4R was ~1 in 337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and noncarriers of LoF mutations were 17.76 kg (95% CI 9.41, 26.10), 4.84 kg m
(95% CI 2.19, 7.49) and 14.78 kg (95% CI 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity.
Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk
. More than 60% of this effect is attributable to the ability of ...metformin to lower body weight in a sustained manner
. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.
The intestine secretes a range of hormones with important local and distant actions, including the control of insulin secretion and appetite. A number of enteroendocrine cell types have been ...described, each characterized by a distinct hormonal signature, such as K-cells producing glucose-dependent insulinotropic polypeptide (GIP), L-cells producing glucagon-like peptide-1 (GLP-1), and I-cells producing cholecystokinin (CCK). To evaluate similarities between L-, K-, and other enteroendocrine cells, primary murine L- and K-cells, and pancreatic α- and β-cells, were purified and analyzed by flow cytometry and microarray-based transcriptomics. By microarray expression profiling, L cells from the upper small intestinal (SI) more closely resembled upper SI K-cells than colonic L-cells. Upper SI L-cell populations expressed message for hormones classically localized to different enteroendocrine cell types, including GIP, CCK, secretin, and neurotensin. By immunostaining and fluorescence-activated cell sorting analysis, most colonic L-cells contained GLP-1 and PeptideYY In the upper SI, most L-cells contained CCK, approximately 10% were GIP positive, and about 20% were PeptideYY positive. Upper SI K-cells exhibited approximately 10% overlap with GLP-1 and 6% overlap with somatostatin. Enteroendocrine-specific transcription factors were identified from the microarrays, of which very few differed between the enteroendocrine cell populations. Etv1, Prox1, and Pax4 were significantly enriched in L-cells vs. K cells by quantitative RT-PCR. In summary, our data indicate a strong overlap between upper SI L-, K-, and I-cells and suggest they may rather comprise a single cell type, within which individual cells exhibit a hormonal spectrum that may reflect factors such as location along the intestine and exposure to dietary nutrients.
Cue-directed axon guidance depends partly on local translation in growth cones. Many mRNA transcripts are known to reside in developing axons, yet little is known about their subcellular distribution ...or, specifically, which transcripts are in growth cones. Here laser capture microdissection (LCM) was used to isolate the growth cones of retinal ganglion cell (RGC) axons of two vertebrate species, mouse and Xenopus, coupled with unbiased genomewide microarray profiling. An unexpectedly large pool of mRNAs defined predominant pathways in protein synthesis, oxidative phosphorylation, cancer, neurological disease, and signaling. Comparative profiling of "young" (pathfinding) versus "old" (target-arriving) Xenopus growth cones revealed that the number and complexity of transcripts increases dramatically with age. Many presynaptic protein mRNAs are present exclusively in old growth cones, suggesting that functionally related sets of mRNAs are targeted to growth cones in a developmentally regulated way. Remarkably, a subset of mRNAs was significantly enriched in the growth cone compared with the axon compartment, indicating that mechanisms exist to localize mRNAs selectively to the growth cone. Furthermore, some receptor transcripts (e.g., EphB4), present exclusively in old growth cones, were equally abundant in young and old cell bodies, indicating that RNA trafficking from the soma is developmentally regulated. Our findings show that the mRNA repertoire in growth cones is regulated dynamically with age and suggest that mRNA localization is tailored to match the functional demands of the growing axon tip as it transforms into the presynaptic terminal.
Fish farming in coastal marine environments results in the deposition of waste products on the seafloor and can cause changes in sediment chemistry and community structure. Rapid growth in the ...industry and an increased awareness and sensitivity to the environmental impacts over the last decade have resulted in more stringent compliance requirements for aquaculture producers. However, the selection of monitoring parameters is surrounded by uncertainty, which impedes the development of cost-effective monitoring procedures. Studies examining benthic impacts of fish farms have come to different conclusions concerning the severity of impacts. Previous attempts to quantitatively review these studies have had only limited success due to the uncertainty in the data originating from discrepancies in sampling and analytical protocols as well as different temporal and spatial scales covered in the studies. The main objective of this study was to review publications on fish farm benthic impacts and to develop a Bayesian network (BN) for the quantitative assessment of the relationships between impact parameters and site and farm characteristics. A BN was constructed based on parameters relationships obtained from 64 studies. It showed that benthic impact was a function of fish density, farm volume, food conversion ratio, water depth, current strength and sediment mud content. To examine the sensitivity of benthic impact variables to changes in these parameters, the BN was used to calculate three scenarios representing low, moderate and high impact. Porewater sulphide, acid volatile sulphide (AVS-S), water content, redox potential, sediment oxygen consumption, sediment NH4 release and macrofauna diversity showed the most certain and sensitive responses in these scenarios but methodological limitations have to be taken into consideration before characterising them as reliable monitoring parameters for a specific application. An examination of spatial trends in benthic impact parameters suggested that fish farm impacts were confined to a radius of about 40 to 70 m around the farms studied. The inability to satisfactorily model parameters as a function of distance from farms demonstrated the complexity of their spatial distribution and highlighted the need to improve our understanding of farm footprints to avoid detrimental environmental effects as a consequence of culture intensification. The BN approach successfully identified reliable monitoring parameters based on reviewed impact studies and has potential to support cost-effective monitoring. For use at specific farms, site-specific data should be integrated into the BN and additional variables could easily be added. BNs enable the synthesis of scientific and industry research data, practical experience and stakeholders’ perspectives, which are important in the development of monitoring guidelines that meet the needs of all parties.
Genome-wide association studies have revealed that single-nucleotide polymorphisms in the first intron of the gene encoding fat mass and obesity-associated protein (FTO) are robustly associated with ...BMI and obesity. Subsequently, this association with body weight, which is replicable across multiple populations and different age groups, has been unequivocally linked to increased food intake. Although evidence from a number of animal models with perturbed FTO expression indicates a role for FTO in energy homeostasis, to date, no conclusive link has been made between the risk alleles and FTO expression or its physiological role. FTO is a nucleic acid demethylase, and a deficiency in FTO leads to a complex phenotype highlighted by postnatal growth retardation, pointing to some fundamental developmental role. Recent emerging data now points to a role for FTO in the sensing of nutrients and the regulation of translation and growth. In this review, we explore the in vivo and in vitro evidence detailing the complex biology of FTO and discuss how these might link to the regulation of body weight.
At one level, obesity is clearly a problem of simple physics, a result of eating too much and not expending enough energy. The more complex question, however, is why do some people eat more than ...others? Studies of human and mouse genetics over the past two decades have uncovered a number of pathways within the brain that play a key role in the control of food intake. A prime example is the leptin–melanocortin pathway, which we now know greatly contributes to mammalian appetitive behaviour. However, genetic disruption of this pathway remains rare and does not represent the major burden of the disease that is carried by those of us with ‘common obesity’. In recent years, genome-wide association studies have revealed more than 100 different candidate genes linked to BMI, with most (including many components of the melanocortin pathway) acting in the central nervous system and influencing food intake. So while severe disruption of the melanocortin pathway results in severe obesity, subtle variations in these genes influence where you might sit in the normal distribution of BMI. As we now enter this ‘post-genomics’ world, can this new information influence our treatment and management of obese patients?
Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with ...Fe(II)- and 2-oxoglutarate-dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.
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