A hierarchical dynamic model used for investigating feed efficiency and its relationship with hepatic gene expression in APOE*3-Leiden.CETP mice

Background: Feed efficiency (FE) is an important trait for livestock and humans. While the livestock industry focuses on increasing FE, in the current obesogenic society it is more of interest to decrease FE. Hence, understanding mechanisms involved in the regulation of FE and particularly how it can be decreased would help tremendously in counteracting the obesity pandemic. However, it is difficult to accurately measure or calculate FE in humans. In this study, we aimed to address this challenge by developing a hierarchical dynamic model based on humanized mouse data. Methods: We analyzed existing experimental data derived from 105 APOE*3-Leiden.CETP (E3L.CETP) mice fed a high-fat high-cholesterol (HFHC) diet for 1 (N = 20), 2 (N = 19), 3 (N = 20), and 6 (N = 46) month. We developed an ordinary differential equation (ODE) based model to estimate the FE based on the longitudinal data of body weight and food intake. Since the liver plays an important role in maintaining metabolic homeostasis, we evaluated associations between FE and hepatic gene expression levels. Depending on the feeding duration, we observed different relationships between FE and hepatic gene expression levels. Results: After 1-month feeding of HFHC diet, we observed that FE was associated with vitamin A metabolism, arachidonic acid metabolism, and the PPAR signaling pathway. After 3- and 6-month feeding of HFHC diet, we observed that FE was associated most strongly with expression levels of Spink1 and H19, genes involved in cell proliferation and glucose metabolism, respectively. Conclusions: In conclusion, our analysis suggests that various biological processes such as vitamin A metabolism, hepatic response to inflammation, and cell proliferation associate with FE at different stages of diet-induced obesity.</p

Distribution of Brown Adipose Tissue Radiodensity in Young Adults: Implications for Cold [18F]FDG-PET/CT Analyses

Procedures: We measured 125 individuals after a personalized cooling protocol with a static [18F]FDG-PET/CT scan. We quantified BAT using different combination of threshold in every single HU for all participants. Results: We observed that the SUV threshold influences BAT quantification by [18F]FDG-PET/ CT scans more than the HU range. We found that the range from − 50 to − 10 HU had the highest proportion of total BAT volume (43.2 %), which represents 41.4 % of the total BAT metabolic activity in our cohort. We also observed that BAT volume was not different between categories of body mass index, as well as BAT activity (SUVmean). In addition, BAT was less dense in women than in men, although the BAT activity (SUVmean) was higher in all ranges of HU. We also observed that the radiodensity of BAT located in the cervical area was mainly in the range from − 50 to − 10 HU. Conclusion: Therefore, all future human studies using static [18F]FDG-PET/CT scans should include BAT in the radiodensity range from − 50 to − 10 HU.This study was supported by the Spanish Ministry of Economy and Competitiveness, Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI13/01393) and Retos de la Sociedad (DEP2016-79512-R), Fondos Estructurales de la Unión Europea (FEDER), by the Spanish Ministry of Education (FPU 13/04365), by the Fundación Iberoamericana de Nutrición (FINUT), the Redes Temáticas de Investigación Cooperativa RETIC (Red SAMID RD16/0022), the AstraZeneca HealthCare Foundation, the University of Granada Plan Propio de Investigación 2016 - Excellence actions: Unit of Excellence on Exercise and Health (UCEES) - and Plan Propio de Investigación 2018 - Programa Contratos-Puente, and the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades (FEDER, ref. SOMM17/6107/UGR)

Preoperative apolipoprotein CI levels correlate positively with the proinflammatory response in patients experiencing endotoxemia following elective cardiac surgery

Objective: Experimental models show that apolipoprotein CI (apoCI) binds and enhances the inflammatory response to endotoxin. We studied in patients undergoing cardiopulmonary bypass surgery (CPB) and experiencing endotoxemia during reperfusion whether plasma apoCI levels correlate with the inflammatory response and perioperative cytokine release. Design: Prospective, observational, clinical cohort study. Setting: Operating room (OR) and intensive care unit (ICU) of a university hospital. Patients: One hundred fifty-nine consecutive patients > 18 years of age (66% males (n = 105), median age 65 and 67 years for males and females, respectively) undergoing elective cardiothoracic surgery with cardiopulmonary bypass. Interventions: None. Measurements: Baseline apoCI, apoCIII, total cholesterol and triglyceride levels, and perioperative endotoxin and TNF-α levels were determined. Results: High preoperative plasma apoCI, but not apoCIII, levels were associated (p < 0.05) with increased perioperative levels of TNF-α in patients experiencing endotoxemia. This association was not observed in patients without endotoxemia. Conclusion: High plasma apoCI is positively related to proinflammatory response in patients experiencing endotoxemia and confirms the observations in animal models. © 2008 The Author(s)

Butyrate oxidation attenuates the butyrate-induced improvement of insulin sensitivity in myotubes

Skeletal muscle insulin resistance is a key pathophysiological process that precedes the development of type 2 diabetes. Whereas an overload of long-chain fatty acids can induce muscle insulin resistance, butyrate, a short -chain fatty acid (SCFA) produced from dietary fibre fermentation, prevents it. This preventive role of butyrate has been attributed to histone deacetylase (HDAC)-mediated transcription regulation and activation of mito-chondrial fatty-acid oxidation. Here we address the interplay between butyrate and the long-chain fatty acid palmitate and investigate how transcription, signalling and metabolism are integrated to result in the butyrate -induced skeletal muscle metabolism remodelling. Butyrate enhanced insulin sensitivity in palmitate-treated, insulin-resistant C2C12 cells, as shown by elevated insulin receptor 1 (IRS1) and pAKT protein levels and Slc2a4 (GLUT4) mRNA, which led to a higher glycolytic capacity. Long-chain fatty-acid oxidation capacity and other functional respiration parameters were not affected. Butyrate did upregulate mitochondrial proteins involved in its own oxidation, as well as concentrations of butyrylcarnitine and hydroyxybutyrylcarnitine. By knocking down the gene encoding medium-chain 3-ketoacyl-CoA thiolase (MCKAT, Acaa2), butyrate oxidation was inhibited, which amplified the effects of the SCFA on insulin sensitivity and glycolysis. This response was associated with enhanced HDAC inhibition, based on histone 3 acetylation levels. Butyrate enhances insulin sensitivity and induces glycolysis, without the requirement of upregulated long-chain fatty acid oxidation. Butyrate catabolism functions as an escape valve that attenuates HDAC inhibition. Thus, inhibition of butyrate oxidation indirectly prevents insulin resistance and stimulates glycolytic flux in myotubes treated with butyrate, most likely via an HDAC-dependent mechanism.Diabetes mellitus: pathophysiological changes and therap

Relationship between the Daily Rhythm of Distal Skin Temperature and Brown Adipose Tissue 18F-FDG Uptake in Young Sedentary Adults

The present study examines whether the daily rhythm of distal skin temperature (DST) is associated with brown adipose tissue (BAT) metabolism as determined by 18F-fluorodeoxyglucose (18F-FDG) uptake in young adults. Using a wireless thermometer (iButton) worn on the nondominant wrist, DST was measured in 77 subjects (26% male; age 22 ± 2 years; body mass index 25.2 ± 4.8 kg/m2) for 7 consecutive days. The temperatures to which they were habitually exposed over the day were also recorded. The interday stability of DST was calculated from the collected data, along with the intraday variability and relative amplitude; the mean temperature of the 5 and 10 consecutive hours with the maximum and minimum DST values, respectively; and when these hours occurred. Following exposure to cold, BAT volume and mean and peak standardized 18F-FDG uptake (SUVmean and SUVpeak) were determined for each subject via static 18F-FDG positron emission tomography/computed tomography scanning. Relative amplitude and the time at which the 10 consecutive hours of minimum DST values occurred were positively associated with BAT volume, SUVmean, and SUVpeak (p ≤ 0.02), whereas the mean DST of that period was inversely associated with the latter BAT variables (p ≤ 0.01). The interday stability and intraday variability of the DST were also associated (directly and inversely, respectively) with BAT SUVpeak (p ≤ 0.02 for both). All of these associations disappeared, however, when the analyses were adjusted for the ambient temperature to which the subjects were habitually exposed. Thus, the relationship between the daily rhythm of DST and BAT activity estimated by 18F-FDG uptake is masked by environmental and likely behavioral factors. Of note is that those participants exposed to the lowest ambient temperature showed 3 to 5 times more BAT volume and activity compared with subjects who were exposed to a warmer ambient temperature

LDL aggregation susceptibility is higher in healthy South Asian compared with white Caucasian men

BACKGROUND: South Asians are more prone to develop atherosclerotic cardiovascular disease (ASCVD) compared with white Caucasians, which is not fully explained by classical risk factors. We recently reported that the presence of aggregation-prone low-density lipoprotein (LDL) in the circulation is associated with increased ASCVD mortality. OBJECTIVE: We hypothesized that LDL of South Asians is more prone to aggregate, which may be explained by differences in their LDL lipid composition. METHODS: In this cross-sectional hypothesis-generating study, LDL was isolated from plasma of healthy South Asians (n = 12) and age- and BMI-matched white Caucasians (n = 12), and its aggregation susceptibility and lipid composition were analyzed. RESULTS: LDL from South Asians was markedly more prone to aggregate compared with white Caucasians. Among all measured lipids, sphingomyelin 24:0 and triacylglycerol 56:8 showed the highest positive correlation with LDL aggregation. In addition, LDL from South Asians was enriched in arachidonic acid containing phosphatidylcholine 38:4 and had less phosphatidylcholines and cholesteryl esters containing monounsaturated fatty acids. Interestingly, body fat percentage, which was higher in South Asians (+26%), positively correlated with LDL aggregation and highly positively correlated with triacylglycerol 56:8, sphingomyelin 24:0, and total sphingomyelin. CONCLUSIONS: LDL aggregation susceptibility is higher in healthy young South Asians compared with white Caucasians. This may be partly explained by the higher body fat percentage of South Asians, leading to sphingomyelin enrichment of LDL. We anticipate that the presence of sphingomyelin-rich, aggregation -prone LDL particles in young South Asians may increase LDL accumulation in the arterial wall and thereby contribute to their increased risk of developing ASCVD later in life. (C) 2019 National Lipid Association. Published by Elsevier Inc.Peer reviewe

Hematopoietic upstream stimulating factor 1 deficiency is associated with increased atherosclerosis susceptibility in LDL receptor knockout mice

Total body upstream stimulatory factor 1 (USF1) deficiency in mice is associated with brown adipose tissue activation and a marked protection against the development of obesity and atherosclerotic lesions. Functional expression of USF1 has also been detected in monocytes and monocyte-derived macrophages. In the current study we therefore tested whether selective hematopoietic USF1 deficiency can also beneficially impact the development of atherosclerosis. For this purpose, LDL receptor knockout mice were transplanted with bone marrow from USF1 knockout mice or their wild-type littermate controls and subsequently fed a Western-type diet for 20 weeks to stimulate atherosclerotic lesion development. Strikingly, absence of USF1 function in bone marrow-derived cells was associated with exacerbated blood leukocyte (+ 100%; P < 0.01) and peritoneal leukocyte (+ 50%; P < 0.05) lipid loading and an increased atherosclerosis susceptibility (+ 31%; P < 0.05). These effects could be attributed to aggravated hyperlipidemia, i.e. higher plasma free cholesterol (+ 33%; P < 0.001) and cholesteryl esters (+ 39%; P < 0.001), and the development of hepatosteatosis. In conclusion, we have shown that hematopoietic USF1 deficiency is associated with an increased atherosclerosis susceptibility in LDL receptor knockout mice. These findings argue against a contribution of macrophage-specific USF1 deficiency to the previously described beneficial effect of total body USF1 deficiency on atherosclerosis susceptibility in mice.Peer reviewe

Colesevelam enhances the beneficial effects of brown fat activation on hyperlipidemia and atherosclerosis development

Aims Brown fat activation accelerates the uptake of cholesterol-enriched remnants by the liver and thereby lowers plasma cholesterol, consequently protecting against atherosclerosis development. Hepatic cholesterol is then converted into bile acids (BAs) that are secreted into the intestine and largely maintained within the enterohepatic circulation. We now aimed to evaluate the effects of prolonged brown fat activation combined with inhibition of intestinal BA reabsorption on plasma cholesterol metabolism and atherosclerosis development and results APOE∗3-Leiden.CETP mice with humanized lipoprotein metabolism were treated for 9 weeks with the selective b3-adrenergic receptor (AR) agonist CL316,243 to substantially activate brown fat. Prolonged b3-AR agonism reduced faecal BA excretion (-31%), while markedly increasing plasma levels of total BAs (258%), cholic acid-derived BAs (295%), and chenodeoxycholic acid-derived BAs (217%), and decreasing the expression of hepatic genes involved in BA production. In subsequent experiments, mice were additionally treated with the BA sequestrant Colesevelam to inhibit BA reabsorption. Concomitant intestinal BA sequestration increased faecal BA excretion, normalized plasma BA levels, and reduced hepatic cholesterol. Moreover, concomitant BA sequestration further reduced plasma total cholesterol (-49%) and non-high-density lipoprotein cholesterol (-56%), tended to further attenuate atherosclerotic lesion area (-54%). Concomitant BA sequestration further increased the proportion of lesion-free valves (34%) and decreased the relative macrophage area within the lesion (-26%), thereby further increasing the plaque stability index (44%). Conclusion BA sequestration prevents the marked accumulation of plasma BAs as induced by prolonged brown fat activation, thereby further improving cholesterol metabolism and reducing atherosclerosis development. These data suggest that combining brown fat activation with BA sequestration is a promising new therapeutic strategy to reduce hyperlipidaemia and cardiovascular diseases

Supraclavicular skin temperature measured by iButtons and 18Ffluorodeoxyglucose uptake by brown adipose tissue in adults

This study is part of a Ph.D. thesis conducted in the Biomedicine Doctoral Studies of the University of Granada, Spain.Currently, 18 [F]-Fluorodeoxyglucose (18F-FDG) in combination with a positron emission tomography/computed tomography (PET/CT) scan analysis is the most commonly used method to quantify human BAT volume and activity. However, this technique presents several drawbacks which negatively affect participant's health. The aim of the present work is to determine whether supraclavicular skin temperature can be used as an indirect marker of cold-induced BAT and skeletal muscle 18F-FDG uptake in adults, while taking into account body composition. We performed a personalized cooling protocol just before an 18F-FDG-PET/CT scan, and we measured supraclavicular skin temperature before (in warm conditions) and after the cooling protocol in 88 adults (n = 57 women, mean age: 21.9 ± 2.1 years old, body mass index: 24.5 ± 4.3 km/m2). We found that supraclavicular skin temperature at the warm and cold periods was weakly and positively associated with BAT activity (SUVmean and SUVpeak: β = 3.000; R2 = 0.072; P = 0.022 and β = 2.448; R2 = 0.060; P = 0.021), but not with skeletal muscle 18F-FDG uptake, after controlling for body composition. We performed further analyses and the positive associations persisted only in the group of women. In conclusion, supraclavicular skin temperature in warm and cold conditions seems to be related with cold-induced 18F-FDG uptake by BAT only in women, although the low explained variance of these associations means that there are other factors involved in the supraclavicular skin temperature.This study was supported by the Spanish Ministry of Economy and Competitiveness, Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI13/01393) and Retos de la Sociedad (DEP2016-79512-R), Fondos Estructurales de la Unión Europea (FEDER), by the Spanish Ministry of Education (FPU 13/04365, 14/04172, and 16/05159), by the Fundación Iberoamericana de Nutrición (FINUT), by the Redes temáticas de investigación cooperativa RETIC (Red SAMID RD16/0022), by AstraZeneca HealthCare Foundation and by the University of Granada Plan Propio de Investigación 2016 -Excellence actions: Unit of Excellence on Exercise and Health (UCEES) - and Plan Propio de Investigación 2018 - Programa Contratos-Puente, and the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades (FEDER: ref. SOMM17/6107/UGR)

The impact of using BARCIST 1.0 criteria on quantification of BAT volume and activity in three independent cohorts of adults

Human brown adipose tissue (BAT) is commonly assessed by cold-induced 18F-fluorodeoxyglucose (FDG) PET-CT using several quantification criteria. Uniform criteria for data analysis became available recently (BARCIST 1.0). We compared BAT volume and activity following BARCIST 1.0 criteria against the most commonly used criteria [Hounsfield Units (HU):-250, -50, standardized uptake value (SUV):2.0; HU: Not applied, SUV:2.0 and HU:-180, -10, SUV:1.5] in a prospective study using three independent cohorts of men including young lean adults, young overweight/obese adults and middle-aged overweight/obese adults. BAT volume was the most variable outcome between criteria. While BAT volume calculated using the HU: NA; SUV: 2.0 criteria was up to 207% higher than the BAT volume calculated based on BARCIST 1.0 criteria, it was up to 57% lower using the HU: -250, -50; SUV: 2.0 criteria compared to the BARCIST 1.0. Similarly, BAT activity (expressed as SUVmean) also differed between different thresholds mainly because SUVmean depends on BAT volume. SUVpeak was the most consistent BAT outcome across the four study criteria. Of note, we replicated these findings in three independent cohorts. In conclusion, BAT volume and activity as determined by 18F-FDG-PET/CT highly depend on the quantification criteria used. Future human BAT studies should conduct sensitivity analysis with different thresholds in order to understand whether results are driven by the selected HU and/or SUV thresholds. The design of the present study precludes providing any conclusive threshold, but before more definitive thresholds for HU and SUV are available, we support the use of BARCIST 1.0 criteria to facilitate interpretation of BAT characteristics between research groups