Project description:To pinpoint genes associated with trimethylamine-induced malodor modulation by Ecklonia cava, we conducted microarray hybridization using total RNA extracted from the liver of trimethylamine-treated ICR mice following oral administration of Ecklonia cava. Identification of genes associated with deodorizing effects through comparison of hepatic gene expression levels in trimethylamine-treated ICR mice following oral administration of Ecklonia cava.
Project description:Obesity results from a chronic imbalance between energy intake and energy expenditure, with excess calories stored as fat. As such, weight loss has long been considered as a primary goal of treatment for obesity. A surgical treatment of severe obesity such as gastric bypass provides the most dramatic reductions in body weight, and a well-known effect of weight loss is an improvement in insulin sensitivity. However, the molecular mechanism underlying this association remains unclear. Thus, we profiled skeletal muscle of morbidly obese patients before and after gastric bypass surgery. Results from this project will provide global patterns of gene expression with weight loss, which help to understand the pathogenesis of obesity at the molecular level. Experiment Overall Design: To identify responsive genes to weight loss.
Project description:Obesity results from a chronic imbalance between energy intake and energy expenditure, with excess calories stored as fat. As such, weight loss has long been considered as a primary goal of treatment for obesity. A surgical treatment of severe obesity such as gastric bypass provides the most dramatic reductions in body weight, and a well-known effect of weight loss is an improvement in insulin sensitivity. However, the molecular mechanism underlying this association remains unclear. Thus, we profiled skeletal muscle of morbidly obese patients before and after gastric bypass surgery. Results from this project will provide global patterns of gene expression with weight loss, which help to understand the pathogenesis of obesity at the molecular level. Keywords: Time-Series
Project description:Histamine receptor antagonists, commonly used to treat allergies, block histamine signalling and have been shown to impair acute and chronic adaptations to high-intensity and endurance-type exercise. Since it remains unclear whether this is a universal mechanism of muscle adaptation, this study investigated the effect of histamine receptor blockade on resistance training adaptations. Eighteen men performed 10 weeks of resistance training with either a placebo (n=9) or H1 receptor antihistamine (n=9, 180mg fexofenadine) intake before each training session. Outcomes assessed before and after the intervention included maximal strength (1RM), muscle volume (MRI), fat mass (skinfolds), fat free mass, whole-body glucose tolerance (OGTT), vascular function, dietary intake (self-reported food diaries) and muscle proteome remodelling. Both the placebo and antihistamine groups showed similar increases in muscle volume (+7% and +8%) and maximal strength (+14% and +20%) and reductions in diastolic blood pressure (-6 and -5 mmHg), total glucose level (-24% and -10%) and total insulin level (-10% and -9%) during the OGTT. Unexpectedly, the blockade group gained fat mass (+0.6 kg), while the placebo group did not (-0.3 kg), which could be related to increased dietary carbohydrate intake in the blockade, but not the placebo group (+29% vs -7%). In conclusion, histamine blockade did not impair resistance training-induced adaptations, suggesting that intercellular H1-histaminergic crosstalk is not a universal mechanism across training modalities. However, antihistamine intake led to increased habitual food intake and fat mass following 10 weeks of resistance training, possibly linked to a role of histamine in appetite regulation.
Project description:Tirzepatide is an anti-obesity drug based on dual agonism of the incretin receptors GLP-1R and GIPR. Its anti-obesity effect is largely based on its action of reducing food intake. However, there are suggestive indications that tirzeparide may exert effects on adipose tissues beyond those resulting from fat loss due to reduced intake. To investigate this, we treated mice that had previously been made obese through a high-fat diet with tirzepatide. Tzp group experienced a reduction in body weight. Glucose tolerance improved in tirzepatide-treated obese mice, independently of reduced food intake. Tirzepatide treatment also lowered the inflammatory status of obese mice, an effect that, in this case, was attributable to decreased food consumption. Tirzepatide exerted distinct effects on brown adipose tissue relative to white adipose tissues, significantly boosting thermogenic activity and modifying its gene expression pattern, including the upregulation of genes linked to thermogenesis and substrate oxidation. White adipose tissues responded differently, being primarily affected in their lipid metabolism. These effects were specific to tirzepatide treatment and not attributable to reduced food intake. Our results indicate that tirzepatide affects the function and metabolism of adipose tissues and especially induces activation of brown adipose tissue in mice, which may be relevant for future human studies to ascertain the mechanisms of tirzepatide metabolic benefits.
Project description:Many diseases, such as obesity, have systemic effects that impact multiple organ systems throughout the body. However, tools for comprehensive, high-resolution analysis of disease-associated changes at the whole-body scale have been lacking. Here, we developed a suite of deep learning-based image analysis algorithms (MouseMapper) and integrated it with tissue clearing and light sheet microscopy to enable a comprehensive quantitative analysis of diseases impacting diverse systems across the mouse body. This technological approach enables quantitative analysis of cellular and structural changes across the entire mouse body at unprecedented resolution and scale, including tracking nerves over several centimeters in whole animal bodies. To demonstrate its power, we applied MouseMapper to study nervous and immune systems in chow and high-fat diet (HFD)-induced obese mice. We uncovered widespread changes in both immune cell distribution and nerve structures, including alterations in the trigeminal nerve characterized by reduced nerve endings in obese mice. These structural abnormalities were associated with functional deficits of whiskers that they innervate and proteomic changes in their ganglion, primarily affecting pathways related to axon growth, and the complement system. Additionally, we revealed whole-body inflammation, which showed heterogeneity across different tissues in obese mice. Our study demonstrates MouseMapper's capability to discover and quantify pathological alterations at the whole-body level, offering a powerful new approach for investigating the systemic impacts of various diseases.
Project description:Prolonged intervention studies investigating molecular metabolism are necessary for a deeper understanding of dietary effects on health. Here we provide mechanistic information about metabolic adaptation to fat-rich diets. Healthy men ingested saturated (SFA) or poly unsaturated (PUFA) fat-rich diets for six weeks during weight maintenance. Hyperinsulinemic clamps combined with leg balance technique revealed unchanged peripheral insulin sensitivity, independent of fatty acid type. Both diets increased fat oxidation potential in muscle. Hepatic insulin clearance increased, while glucose production, de novo lipogenesis and plasma triacylglycerol decreased. High fat intake changed the plasma proteome in immune-supporting direction and the gut microbiome displayed changes at taxonomical and functional level with PUFA. In mice, eucaloric feeding of human PUFA and SFA diets lowered hepatic triacylglycerol content compared to low-fat fed control mice, and induced adaptations in the liver supportive of decreased gluconeogenesis and lipogenesis. Intake of fat-rich diets thus induces extensive metabolic adaptations enabling disposition of dietary fat without metabolic complications.
Project description:Low-carbohydrate, high-fat diets under eucaloric conditions are associated with several health-beneficial metabolic effects in humans, particularly in the liver. We recently observed that apolipoprotein A-IV (apoA-IV), a highly abundant apolipoprotein, was among the most upregulated proteins in the circulation after six weeks of high fat intake in humans. However, the dietary regulation of apoA-IV and the potential effects of apoA-IV on regulation of glucose- and lipid metabolism remain to be fully established. We here demonstrate in healthy human individuals that both short- and long-term high-fat intake increased fasting plasma apoA-IV concentrations by up to 54%, while high carbohydrate intake suppressed plasma apoA-IV concentrations. In mice, administration of apoA-IV acutely lowered blood glucose levels in lean and obese mice. Interestingly, this was related to a dual mechanism, involving both inhibition of hepatic glucose production and increased glucose uptake into white and brown adipose tissues. In addition to an effect on hepatic glucose production, the apoA-IV-induced liver proteome revealed increased capacity for lipoprotein clearance. The effects of apoA-IV in the liver and adipose tissues were obtained concomitant with increased whole-body fatty acid oxidation. Upon glucose stimulation, an improvement in glucose tolerance by apoA-IV administration was related to potentiation of glucose-induced insulin secretion, while apoA-IV inhibited glucagon secretion ex vivo in islets. In conclusion, we find that ApoA-IV is potently increased by the intake of fat in humans, and that several beneficial metabolic effects, previously associated with high fat intake in humans, are mimicked by administration of apoA-IV protein to mice.
Project description:This study used untargeted proteomics to compare blood proteomic profiles in two groups of adults that differed widely in lifestyle habits. The goal was to identify a core list of proteins that were either upregulated or downregulated based on adherence to recommended lifestyle habits in adults. A total of 52 subjects in the lifestyle group (LIFE) (28 males, 24 females) and 52 in the control group (CON) (27 males, 25 females) participated in this cross-sectional study. Age, education level, marital status, and height did not differ significantly between LIFE and CON groups. The LIFE and CON groups differed markedly in body composition and fat mass-related anthropometric measurements including waist circumference, body mass index (BMI), sagittal abdominal diameter (SAD), and body composition (body fat percentage and fat mass index or FMI) (p<0.001). LIFE and CON groups were also widely disparate in physical activity patterns and maximal aerobic fitness, dietary intake patterns, disease risk factor prevalence, blood measures of inflammation, triglycerides, HDL-cholesterol, glucose, and insulin, weight-adjusted leg/back and handgrip strength, and mood states. The proteomics analysis showed strong group differences for 39 of 725 proteins identified in the dried blood spot samples. Of these, 18 were downregulated in the LIFE group and collectively indicated a lower innate immune activation signature. A total of 21 proteins were upregulated in the LIFE group and supported greater lipoprotein metabolism and HDL remodeling. Lifestyle-related habits and biomarkers were probed and the variance (>50%) in downregulated and upregulated proteins was best explained by group contrasts in indicators of body composition and visceral fat including FMI and SAD. This cross-sectional study established that a relatively small number of upregulated and downregulated proteins are associated with good lifestyle habits. A targeted “lifestyle” proteomic panel based on these data could be used in future studies to determine the efficacy of various prevention and treatment strategies.
Project description:Exogenous glucocorticoids regulate the muscl-fat axis communication, but little attention is paid to their frequency of intake. Here we investigated the transcriptional effects of prednisone in muscle and adipose tissue when dosed as intermittent once-weekly 1mg/kg i.p. versus once-daily 1mg/kg in WT obese mice. Prior to treatment, mice were fed a high-fat diet for 12 weeks. After 12 weeks of treatment, we performed RNA-seq analysis in muscle (quadriceps) and white adipose tissue (ventral fat pad) to quantitate gene expression at isoform level.