Dynamic regulation of adipose tissue metabolism in the domestic broiler chicken – an alternative model for studies of human obesity

Background The domestic chicken is an attractive, but underutilized, animal model for studies of adipose tissue biology, metabolism and obesity: 1.) like humans, chickens rely on liver rather than adipose tissue for the majority of de novo lipogenesis; 2.) quantitative trait loci (QTLs) linked to fatness in chickens contain genes implicated in human susceptibility to obesity and diabetes; 3.) chickens are naturally hyperglycemic and insulin resistant; and 4.) a broad selection of genetic models exhibiting a range of fatness are available. To date, however, little is known about regulation of adipose metabolism in this model organism. Materials and methods Affymetrix arrays were used to profile gene expression in abdominal adipose tissue from broiler chickens fed ad libitum or fasted for five hours and from three distinct genetic lines with low (Fayoumi and Leghorn) or high (broiler) levels of adiposity. QPCR was used to validate microarray results for select genes. Western blotting was used to assay levels of signaling proteins. Tissue levels of beta-hydroxybutyrate were measured as an index of fatty acid oxidation using a colorimetric assay. Multiple testing was controlled using q-value. Mixed linear model and multivariate clustering analysis were implemented in SAS. The Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.7 (http://david.abcc.ncifcrf.gov/ webcite) was used for Gene Ontology (GO) and KEGG pathway enrichment analyses. Results A total of 1780 genes were differentially expressed in fasted vs. ad libitum fed (p\u3c0.05) tissue after correction for multiple testing. Gene Ontology and pathway analyses, combined with Western blot validation, indicated significant effects on a broad selection of pathways related to metabolism, stress signaling and adipogenesis. In particular, fasting upregulated rate-limiting genes in both the mitochondrial and peroxisomal pathways of beta-oxidation. Enhanced fatty acid oxidation in white adipose tissue was further suggested by a significant increase in tissue content of the ketone beta-hydroxybutyrate. Expression profiles suggested that, despite the relatively brief duration of feed withdrawal, fasting suppressed adipogenesis; expression of key genes in multiple steps of adipogenesis, including lineage commitment from mesenchymal stem cells, were significantly down-regulated in fasted vs. fed adipose tissue. Interestingly, fasting increased expression of several inflammatory adipokines and components of the toll-like receptor 4 signaling pathway. Microarray analysis of Fayoumi, Leghorn and broiler adipose tissue revealed that genetic leanness shared molecular signatures with the effects of fasting. In supervised clustering analysis, fasted broiler chickens clustered with lean Fayoumi and Leghorn lines rather than with the fed broiler group, suggesting that fasting manipulated expression profiles to resemble those of the lean phenotype. Conclusions Collectively, these data suggest that leanness in chickens is associated with increased fat utilization which, given the similarities between avian and human adipose tissue with regard to lipid metabolism, may have relevance for humans. The paradoxical increase in some inflammatory markers with an acute fast suggests that the dynamic relationship between inflammation and adipose metabolism may differ from what is observed in obesity. These results highlight chicken as a useful model in which to study the interrelationships between food intake, adipose development, metabolism, and cell stress

Erratic movement disorders disclosing Graves’ disease and paralleling thyroid function but not autoantibody levels

Graves’ disease (GD) is an autoimmune pathology characterized by hyperthyroidism and the presence of specific anti-thyroid antibodies. Neurological symptoms such as seizures, cognitive impairment, and tremor can be observed during the course of GD, but more complex movement disorders such as chorea and myoclonus are less frequent. The mechanisms underlying movement disorders in GD are not fully understood. While some authors relate movement disorders to thyroid dysfunction, others claim an autoimmune origin. We herein report a case involving a 60-year-old woman who presented with erratic, intricate movement disorders for which a medical workup revealed GD. During the 2-year follow-up period, her neurological symptoms evolved in parallel with her thyroid function, but not with her autoimmune anti-thyroid antibody level. Her neurological symptoms completely disappeared when she became euthyroid. We herein discuss the complicated clinicobiological relationship between thyroid function and movement disorders. This relationship involves several factors, including the impact of radioactive treatment. The present case emphasizes the importance of including thyroid function screening in the workup of unexplained movement disorders

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Q&A: Trash talk: disposal and remote degradation of neuronal garbage

Abstract Caenorhabditis elegans neurons have recently been found to throw out cellular debris for remote degradation and/or storage, adding an “extracellular garbage elimination” option to known intracellular protein and organelle degradation pathways. This Q&A describes initial insights into the biology of seemingly selective protein and organelle elimination by challenged neurons, highlighting mysteries of how garbage is distinguished and sorted in the sending neuron, how the garbage-filled “exophers” appear to elicit degradative responses as they transit neighboring tissue, and how non-digestible materials get thrown out of cells again via processes that may be highly relevant to human neurodegenerative disease mechanisms

Recent dioxin contamination from Agent Orange in residents of a southern Vietnam city

Marked elevation of dioxin associated with the herbicide Agent Orange was recently found in 19 of 20 blood samples from persons living in Bien Hoa, a large city in southern Vietnam. This city is located near an air base that was used for Agent Orange spray missions between 1962 and 1970. A spill of Agent Orange occurred at this air base more than 30 years before blood samples were collected in 1999. Samples were collected, frozen, and sent to a World Health Organization-certified dioxin laboratory fm congener-specific analysis as part of a Vietnam Red Cross project. Previous analyses of more than 2200 pooled blood samples collected in the 1990s identified Bien Hoa as one of several southern Vietnam areas with persons having elevated blood dioxin levels from exposure to Agent Orange. In sharp contrast to this study, our previous research showed decreasing tissue dioxin levels over time since 1970. Only the dioxin that contaminated Agent Orange, 2,3, 7, 8-tetrachlmodibenzo-p-dioxin (TCDD), was elevated in the blood of 19 of 20 persons sampled from Bien Hoa. A comparison pooled sample from 100 residents of Hanoi, where Agent Orange was not used, measured blood TCDD levels of 2 parts per trillion (ppt). TCDD levels of up to 271 ppt, a 135-fold increase, were found in Bien Hoa residents. TCDD contamination was also found in some nearby soil and sediment samples. Persons new to this region and children born after Agent Orange spraying ended also had elevated TCDD levels. This TCDD uptake was recent and occurred decades after spraying ended. We hypothesize that a major route of current and past exposures is from the movement of dioxin from soil into river sediment, then into fish, and from fish consumption into people

Transcriptomic and metabolomic profiling of chicken adipose tissue in response to insulin neutralization and fasting

Abstract Background Domestic broiler chickens rapidly accumulate adipose tissue due to intensive genetic selection for rapid growth and are naturally hyperglycemic and insulin resistant, making them an attractive addition to the suite of rodent models used for studies of obesity and type 2 diabetes in humans. Furthermore, chicken adipose tissue is considered as poorly sensitive to insulin and lipolysis is under glucagon control. Excessive fat accumulation is also an economic and environmental concern for the broiler industry due to the loss of feed efficiency and excessive nitrogen wasting, as well as a negative trait for consumers who are increasingly conscious of dietary fat intake. Understanding the control of avian adipose tissue metabolism would both enhance the utility of chicken as a model organism for human obesity and insulin resistance and highlight new approaches to reduce fat deposition in commercial chickens. Results We combined transcriptomics and metabolomics to characterize the response of chicken adipose tissue to two energy manipulations, fasting and insulin deprivation in the fed state. Sixteen to 17 day-old commercial broiler chickens (ISA915) were fed ad libitum, fasted for five hours, or fed but deprived of insulin by injections of anti-insulin serum. Pair-wise contrasts of expression data identified a total of 2016 genes that were differentially expressed after correction for multiple testing, with the vast majority of differences due to fasting (1780 genes). Gene Ontology and KEGG pathway analyses indicated that a short term fast impacted expression of genes in a broad selection of pathways related to metabolism, signaling and adipogenesis. The effects of insulin neutralization largely overlapped with the response to fasting, but with more modest effects on adipose tissue metabolism. Tissue metabolomics indicated unique effects of insulin on amino acid metabolism. Conclusions Collectively, these data provide a foundation for further study into the molecular basis for adipose expansion in commercial poultry and identify potential pathways through which fat accretion may be attenuated in the future through genetic selection or management practices. They also highlight chicken as a useful model organism in which to study the dynamic relationship between food intake, metabolism, and adipose tissue biology.</p

Intermediate filaments associate with aggresome-like structures in proteostressed C. elegans neurons and influence large vesicle extrusions as exophers

Abstract Toxic protein aggregates can spread among neurons to promote human neurodegenerative disease pathology. We found that in C. elegans touch neurons intermediate filament proteins IFD-1 and IFD-2 associate with aggresome-like organelles and are required cell-autonomously for efficient production of neuronal exophers, giant vesicles that can carry aggregates away from the neuron of origin. The C. elegans aggresome-like organelles we identified are juxtanuclear, HttPolyQ aggregate-enriched, and dependent upon orthologs of mammalian aggresome adaptor proteins, dynein motors, and microtubule integrity for localized aggregate collection. These key hallmarks indicate that conserved mechanisms drive aggresome formation. Furthermore, we found that human neurofilament light chain (NFL) can substitute for C. elegans IFD-2 in promoting exopher extrusion. Taken together, our results suggest a conserved influence of intermediate filament association with aggresomes and neuronal extrusions that eject potentially toxic material. Our findings expand understanding of neuronal proteostasis and suggest implications for neurodegenerative disease progression