Project description:Exposure to cold temperatures is known to mimic the effects of exercise, protecting against obesity and improving metabolic health. Cold is known to act through the sympathetic nervous systems and -adrenergic signaling, but here we report that cold temperature can directly activate a variety of gene programs in muscle independent of -adrenergic signaling.
Project description:<p>Emerging evidence that the gut microbiota may contribute in important ways to human health and disease has led us and others to hypothesize that both symbiotic and pathological relationships between gut microbes and their host may be key contributors to obesity and the metabolic complications of obesity. Our "Thrifty Microbiome Hypothesis" poses that gut microbiota play a key role in human energy homeostasis. Specifically, constituents of the gut microbial community may introduce a survival advantage to its host in times of nutrient scarcity, promoting positive energy balance by increasing efficiency of nutrient absorption and improving metabolic efficiency and energy storage. However, in the presence of excess nutrients, fat accretion and obesity may result, and in genetically predisposed individuals, increased fat mass may result in preferential abdominal obesity, ectopic fat deposition (liver, muscle), and metabolic complications of obesity (insulin resistance, hypertension, hyperlipidemia). Furthermore, in the presence of excess nutrients, a pathological transition of the gut microbial community may occur, causing leakage of bacterial products into the intestinal lymphatics and portal circulation, thereby inducing an inflammatory state, further aggravating metabolic syndrome traits and accelerating atherosclerosis. This pathological transition and the extent to which antimicrobial leakage occurs and causes inflammatory and other maladaptive sequelae of obesity may also be influenced by host factors, including genetics. In the proposed study, we will directly test the Thrifty Microbiome Hypothesis by performing detailed genomic and functional assessment of gut microbial communities in intensively phenotyped and genotyped human subjects before and after intentional manipulation of the gut microbiome. To address these hypotheses, five specific aims are proposed: (1) enroll three age- and sex-matched groups from the Old Order Amish: (i) 50 obese subjects (BMI > 30 kg/m2) with metabolic syndrome, (ii) 50 obese subjects (BMI > 30 kg/m2) without metabolic syndrome, and (iii) 50 non-obese subjects (BMI < 25 kg/m2) without metabolic syndrome and characterize the architecture of the gut microbiota from the subjects enrolled in this study by high-throughput sequencing of 16S rRNA genes; (2) characterize the gene content (metagenome) to assess the metabolic potential of the gut microbiota in 75 subjects to determine whether particular genes or pathways are correlated with disease phenotype; (3) characterize the transcriptome in 75 subjects to determine whether differences in gene expression in the gut microbiota are correlated with disease phenotype, (4) determine the effect of manipulation of the gut microbiota with antibiotics on energy homeostasis, inflammation markers, and metabolic syndrome traits in 50 obese subjects with metabolic syndrome and (5) study the relationship between gut microbiota and metabolic and cardiovascular disease traits, weight change, and host genomics in 1,000 Amish already characterized for these traits and in whom 500K Affymetrix SNP chips have already been completed. These studies will provide our deepest understanding to date of the role of gut microbes in terms of 'who's there?', 'what are they doing?', and 'how are they influencing host energy homeostasis, obesity and its metabolic complications? PUBLIC HEALTH RELEVANCE: This study aims to unravel the contribution of the bacteria that normally inhabit the human gastrointestinal tract to the development of obesity, and its more severe metabolic consequences including cardiovascular disease, insulin resistance and Type II diabetes. We will take a multidisciplinary approach to study changes in the structure and function of gut microbial communities in three sets of Old Order Amish patients from Lancaster, Pennsylvania: obese patients, obese patients with metabolic syndrome and non-obese individuals. The Old Order Amish are a genetically closed homogeneous Caucasian population of Central European ancestry ideal for genetic studies. These works have the potential to provide new mechanistic insights into the role of gut microflora in obesity and metabolic syndrome, a disease that is responsible for significant morbidity in the adult population, and may ultimately lead to novel approaches for prevention and treatment of this disorder.</p>
Project description:Carnitine is a water soluble quaternary amine which is essential for normal function of all tissues. Besides improving performance characteristics of livestock animals carnitine has attracted scientific interest due to several health-related effects, like protection against neurodegeneration, mitochondrial decay, and oxidative stress, improvement of glucose tolerance and insulin sensitivity as well as reduction of hepatic steatosis. To gain insight into mechanisms through which carnitine exerts its beneficial metabolic effects, we fed piglets either a control or a carnitine supplemented diet, and analyzed the transcriptome in the liver, which plays a central role in whole body metabolism. Total RNA was isolated from pig liver samples for hybridization on Affymetrix GeneChip porcine genome arrays. Two RNA pools, each for the control group and the carnitine group, were used. Each RNA pool comprised RNA from 4 pigs.
Project description:This trial studies how well weight management and health behavior intervention works in helping patients with hereditary breast and ovarian cancer and Lynch syndrome mutation carriers lose or maintain a healthy weight and lower their risk for cancer. Lifestyle behaviors such as physical activity, diet, and weight management may play a key role in preventing cancers and improving outcomes even in those with hereditary cancer syndromes.
Project description:The interaction of genetics and environment play a major role in health and disease. Therefore, modeling experiments to investigate gene-environment interaction in a laboratory setting would provide the opportunity to gain mechanistic insight under controlled conditions. In laboratory research it is unclear if the gene-environment interaction of a sedentary lifestyle predisposes laboratory animals to hypokinetic diseases. Keywords: repeat sample
Project description:The interaction of genetics and environment play a major role in health and disease. Therefore, modeling experiments to investigate gene-environment interaction in a laboratory setting would provide the opportunity to gain mechanistic insight under controlled conditions. In laboratory research it is unclear if the gene-environment interaction of a sedentary lifestyle predisposes laboratory animals to hypokinetic diseases. Experiment Overall Design: We are seeking to compare gene expression and physiological markers of health and wellness in animals with: i. a sedentary lifestyle in a standard cage (CSS1-4); ii. access to twice-weekly physical activity in a large box outside a standard cage (CSA1-4); and iii. access to regular exercise in cages with running wheels (CSR1-4).
Project description:Ectomycorrhizal (ECM) fungi are crucial for tree nitrogen (N) nutrition, however, mechanisms governing N transfer from fungal tissues to the host plant are not well understood. ECM fungal isolates, even from the same species, vary considerably in their ability to support tree N nutrition resulting in a range of often unpredictable symbiotic outcomes. In this study, we used isotopic labelling to quantify the transfer of N to the plant host by isolates from the ECM genus Pisolithus known to have significant variability in colonisation and transfer of nutrients to a host. We considered the metabolic fate of N acquired by the fungi and found that the percentage of plant N acquired through symbiosis significantly correlated to the concentration of free amino acids present in the ECM extra-radical mycelium. Transcriptomic analyses complemented these findings with isolates having high amino acid content and N transfer showing increased expression of genes in amino acid transport and catabolic pathways. These results suggest that fungal N metabolism drives transfer to the host plant in this interaction and that relative N transfer may be possible to predict through basic biochemical analyses.
Project description:Carnitine is a water soluble quaternary amine which is essential for normal function of all tissues. Besides improving performance characteristics of livestock animals carnitine has attracted scientific interest due to several health-related effects, like protection against neurodegeneration, mitochondrial decay, and oxidative stress, improvement of glucose tolerance and insulin sensitivity as well as reduction of hepatic steatosis. To gain insight into mechanisms through which carnitine exerts its beneficial metabolic effects, we fed piglets either a control or a carnitine supplemented diet, and analyzed the transcriptome in the liver, which plays a central role in whole body metabolism.