Transcriptional regulation of lipid metabolism by fatty acids: a key determinant of pancreatic β-cell function

BACKGROUND: Optimal pancreatic β-cell function is essential for the regulation of glucose homeostasis in both humans and animals and its impairment leads to the development of diabetes. Type 2 diabetes is a polygenic disease aggravated by environmental factors such as low physical activity or a hypercaloric high-fat diet. RESULTS: Free fatty acids represent an important factor linking excess fat mass to type 2 diabetes. Several studies have shown that chronically elevated free fatty acids have a negative effect on β-cell function leading to elevated insulin secretion basally but with an impaired response to glucose. The transcription factors PPARα, PPARγ and SREBP-1c respond to changing fat concentrations in tissues, thereby coordinating the genomic response to altered metabolic conditions to promote either fat storage or catabolism. These transcription factors have been identified in β-cells and it appears that each may exert influence on β-cell function in health and disease. CONCLUSION: The role of the PPARs and SREBP-1c as potential mediators of lipotoxicity is an emerging area of interest

Expression of PPARα modifies fatty acid effects on insulin secretion in uncoupling protein-2 knockout mice

AIMS/HYPOTHESIS: In uncoupling protein-2 (UCP2) knockout (KO) mice, protection of beta cells from fatty acid exposure is dependent upon transcriptional events mediated by peroxisome proliferator-activated receptor-α (PPARα). METHODS: PPARα expression was reduced in isolated islets from UCP2KO and wild-type (WT) mice with siRNA for PPARα (siPPARα) overnight. Some islets were also cultured with oleic or palmitic acid, then glucose stimulated insulin secretion (GSIS) was measured. Expression of genes was examined by quantitative RT-PCR or immunoblotting. PPARα activation was assessed by oligonucleotide consensus sequence binding. RESULTS: siPPARα treatment reduced PPARα protein expression in KO and WT islets by >85%. In siPPARα-treated UCP2KO islets, PA but not OA treatment significantly decreased the insulin response to 16.5 mM glucose. In WT islets, siPPARα treatment did not modify GSIS in PA and OA exposed groups. In WT islets, PA treatment significantly increased UCP2 mRNA and protein expression. Both PA and OA treatment significantly increased PPARα expression in UCP2KO and WT islets but OA treatment augmented PPARα protein expression only in UCP2KO islets (p < 0.05). PA treatment induced carnitine palmitoyltransferase I, acyl CoA oxidase and malonyl CoA decarboxylase mRNA in UCP2KO islets. CONCLUSION: These data show that the negative effect of saturated fatty acid on GSIS is mediated by PPARα/UCP2. Knockout of UCP2 protects beta-cells from PA exposure. However, in the absence of both UCP2 and PPARα even a short exposure (24 h) to PA significantly impairs GSIS

Relationship between objective measures of physical activity and weather: a longitudinal study

BACKGROUND: The weather may be a barrier to physical activity but objective assessment of this hypothesis is lacking. Therefore we evaluated the effect of temperature, rain or snow, and wind speed on the daily physical activity of adults. METHODS: This report contains data from 25 males (BMI (mean ± SD): 28.7 ± 3.83 kg/m(2)) and 177 females (BMI: 29.2 ± 5.92 kg/m(2)) enrolled in an intervention to increase physical activity. Steps/day of the participants was measured by pedometer. Weather data were obtained from Environment Canada. A total of 8,125 observations were included in a mixed linear model analysis. RESULTS: Significant weather related variables (at the 5% level) impacting steps/day included: seasonal effects related to the interaction between weekday and month; mean temperature, total rainfall, interactions between gender, BMI and total snow, interactions between maximum wind speed and BMI, and the amount of snow on the ground. The estimated magnitudes for the various effects were modest, ranging from ~1% to ~20%. Thus for an average individual taking ~10,000 steps/day, weather-dependent changes in physical activity could reach 2,000 steps/day. CONCLUSION: We conclude that weather had modest effects on physical activity of participants in an intervention to increase their activity. It should be stressed that these effects may be different for less or more motivated people. With this in mind, we suggest that the effect of weather on physical activity in the general population needs to be objectively assessed to better understand the barrier it poses, especially as it relates to outdoor recreation or work activities

Collisionally Activated Dissociation and Electron Capture Dissociation Provide Complementary Structural Information for Branched Permethylated Oligosaccharides

Doubly charged sodiated and permethylated linear malto-oligosaccharides ({Glc}6-{Glc}9), branched N-linked glycans (high-mannose type GlcNAc2Man5-9, and complex asialo- and disialylated-biantennary glycans) were analyzed by tandem mass spectrometry using collisionally-activated dissociation (CAD) and “hot” electron capture dissociation (ECD) available in a custom-built ESI FTICR mass spectrometer. For linear permethylated malto-oligosaccharides, both CAD and “hot” ECD produced glycosidic cleavages (B, Y, C, and Z ions), cross-ring cleavages (A- and X-type), and internal cleavages (B/Y and C/Y type) to provide sequence and linkage information. For the branched N-linked glycans, CAD and “hot” ECD provided complementary structural information. CAD generated abundant B and Y fragment ions by glycosidic cleavages, whereas “hot” ECD produced dominant C and Z ions. A-type cross-ring cleavages were present in CAD spectra. Complementary A- and X-type cross-ring fragmentation pairs were generated by “hot” ECD, and these delineated the branching patterns and linkage positions. For example, 0, 4An and 3, 5An ions defined the linkage position of the major branch as the 6-position of the central core mannose residue. The internal fragments observed in CAD were more numerous and abundant than in “hot” ECD spectra. Since the triply charged (sodiated) molecular ion of the permethylated disialylated-biantennary N-linked glycan has relatively high abundance, it was isolated and fragmented in a “hot” ECD experiment and extensive fragment ions (glycosidic and complementary pairs of cross-ring cleavages) were generated to fully confirm the sequence, branching, and linkage assignments for this glycan

Uncoupling protein-2 increases nitric oxide production and TNFAIP3 pathway activation in pancreatic islets

Mutations in the uncoupling protein 2 (Ucp2) gene are linked to type-2 diabetes. Here, a potential mechanism by which lack of UCP2 is cytoprotective in pancreatic β-cells was investigated. Nitric oxide (NO) production was elevated in Ucp2−/− islets. Proliferation (cyclin D2, Ccnd2) and anti-apoptosis (Tnfaip3) genes had increased expression in Ucp2−/− islets, whereas the mRNA of pro-apoptosis genes (Jun, Myc) was reduced. TNFAIP3 cellular localization was detected in both α- and β-cells of Ucp2−/− islets but in neither α- nor β-cells of UCP2+/+ islets, where it was detected in pancreatic polypeptide-expressing cells. TNFAIP3 distribution was not markedly altered 14 days after streptozotocin treatment. Basal apoptosis was attenuated in Ucp2−/− β-cells, while the nuclear factor κB (NF-κB) pathway was transactivated after islet isolation. Ucp2+/+ and Ucp2−/− islets were treated with cytokines for 24 h. Cytokines did not increase NF-κB transactivation or apoptosis in Ucp2−/− islets and TNFAIP3 was more strongly induced in Ucp2−/− islets. Inhibition of NO production strongly reduced NF-κB activation and apoptosis. These data show that null expression of Ucp2 induces transactivation of NF-κB in isolated islets, possibly due to NO-dependent up-regulation of inhibitor of κB kinase β activity. NF-κB transactivation appears to result in altered expression of genes that enhance a pro-survival phenotype basally and when β-cells are exposed to cytokines. TNFAIP3 is of particular interest because of its ability to regulate NF-κB signaling pathways

Tracing PAHs and Warm Dust Emission in the Seyfert Galaxy NGC 1068

We present a study of the nearby Seyfert galaxy NGC 1068 using mid- and far- infrared data acquired with the IRAC, IRS, and MIPS instruments aboard the Spitzer Space Telescope. The images show extensive 8 um and 24 um emission coinciding with star formation in the inner spiral approximately 15" (1 kpc) from the nucleus, and a bright complex of star formation 47" (3 kpc) SW of the nucleus. The brightest 8 um PAH emission regions coincide remarkably well with knots observed in an Halpha image. Strong PAH features at 6.2, 7.7, 8.6, and 11.3 um are detected in IRS spectra measured at numerous locations inside, within, and outside the inner spiral. The IRAC colors and IRS spectra of these regions rule out dust heated by the AGN as the primary emission source; the SEDs are dominated by starlight and PAH emission. The equivalent widths and flux ratios of the PAH features in the inner spiral are generally consistent with conditions in a typical spiral galaxy ISM. Interior to the inner spiral, the influence of the AGN on the ISM is evident via PAH flux ratios indicative of a higher ionization parameter and a significantly smaller mean equivalent width than observed in the inner spiral. The brightest 8 and 24 um emission peaks in the disk of the galaxy, even at distances beyond the inner spiral, are located within the ionization cones traced by [O III]/Hbeta, and they are also remarkably well aligned with the axis of the radio jets. Although it is possible that radiation from the AGN may directly enhance PAH excitation or trigger the formation of OB stars that subsequently excite PAH emission at these locations in the inner spiral, the orientation of collimated radiation from the AGN and star formation knots in the inner spiral could be coincidental. (abridged)Comment: 20 pages, 11 figures; AJ, accepted; full resolution version available at http://spider.ipac.caltech.edu/staff/jhhowell/astro/howelln1068.pd

HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis

Penile verrucous carcinoma is a rare disease and little is known of its aetiology or pathogenesis. In this study we examined cell-cycle proteins expression and correlation with human papillomavirus infection in a series of 15 pure penile verrucous carcinomas from a single centre. Of 148 penile tumours, 15 (10%) were diagnosed as pure verrucous carcinomas. The expression of the cell-cycle-associated proteins p53, p21, RB, p16INK4A and Ki67 were examined by immunohistochemistry. Human papillomavirus infection was determined by polymerase chain reaction to identify a wide range of virus types. The expression of p16INK4A and Ki67 was significantly lower in verrucous carcinoma than in usual type squamous cell carcinoma, whereas the expression of p53, p21 and RB was not significantly different. p53 showed basal expression in contrast to usual type squamous cell carcinoma. Human papillomavirus infection was present in only 3 out of 13 verrucous carcinomas. Unique low-risk, high-risk and mixed viral infections were observed in each of the three cases. In conclusion, lower levels of p16INK4A and Ki67 expressions differentiate penile verrucous carcinoma from usual type squamous cell carcinoma. The low Ki67 index reflects the slow-growing nature of verrucous tumours. The low level of p16INK4A expression and human papillomavirus detection suggests that penile verrucous carcinoma pathogenesis is unrelated to human papillomavirus infection and the oncogenes and tumour suppressor genes classically altered by virus infection.Peer reviewedFinal Accepted Versio

Mapping evolutionary process: a multi-taxa approach to conservation prioritization

Human-induced land use changes are causing extensive habitat fragmentation. As a result, many species are not able to shift their ranges in response to climate change and will likely need to adapt in situ to changing climate conditions. Consequently, a prudent strategy to maintain the ability of populations to adapt is to focus conservation efforts on areas where levels of intraspecific variation are high. By doing so, the potential for an evolutionary response to environmental change is maximized. Here, we use modeling approaches in conjunction with environmental variables to model species distributions and patterns of genetic and morphological variation in seven Ecuadorian amphibian, bird, and mammal species. We then used reserve selection software to prioritize areas for conservation based on intraspecific variation or species-level diversity. Reserves selected using species richness and complementarity showed little overlap with those based on genetic and morphological variation. Priority areas for intraspecific variation were mainly located along the slopes of the Andes and were largely concordant among species, but were not well represented in existing reserves. Our results imply that in order to maximize representation of intraspecific variation in reserves, genetic and morphological variation should be included in conservation prioritization