Publications by authors named "Miroslav Balaz"

34 Publications

Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation.

Cell Metab 2021 Mar 22;33(3):547-564.e7. Epub 2020 Dec 22.

Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid lipase (LAL)-mediated processing. Endothelial cell-specific LAL deficiency results in impaired thermogenic capacity as a consequence of reduced recruitment of brown and brite/beige adipocytes. Mechanistically, TRL processing by LAL induces proliferation of endothelial cells and adipocyte precursors via beta-oxidation-dependent production of reactive oxygen species, which in turn stimulates hypoxia-inducible factor-1α-dependent proliferative responses. In conclusion, this study demonstrates a physiological role for TRL particle uptake into BAT and WAT and establishes endothelial lipoprotein processing as an important determinant of adipose tissue remodeling during thermogenic adaptation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2020.12.001DOI Listing
March 2021

Relation of diet-induced thermogenesis to brown adipose tissue activity in healthy men.

Am J Physiol Endocrinol Metab 2021 01 23;320(1):E93-E101. Epub 2020 Nov 23.

Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel and University of Basel, Basel, Switzerland.

Human brown adipose tissue (BAT) is a thermogenic tissue activated by the sympathetic nervous system in response to cold exposure. It contributes to energy expenditure (EE) and takes up glucose and lipids from the circulation. Studies in rodents suggest that BAT contributes to the transient rise in EE after food intake, so-called diet-induced thermogenesis (DIT). We investigated the relationship between human BAT activity and DIT in response to glucose intake in 17 healthy volunteers. We assessed DIT, cold-induced thermogenesis (CIT), and maximum BAT activity at three separate study visits within 2 wk. DIT was measured by indirect calorimetry during an oral glucose tolerance test. CIT was assessed as the difference in EE after cold exposure of 2-h duration as compared with warm conditions. Maximal activity of BAT was assessed by 18-F-fluoro-deoxyglucose (F-FDG) F-FDG-PET/MRI after cold exposure and concomitant pharmacological stimulation with mirabegron. Seventeen healthy men (mean age = 23.4 yr, mean body mass index = 23.2 kg/m) participated in the study. EE increased from 1,908 (±181) kcal/24 h to 2,128 (±277) kcal/24 h ( < 0.0001, +11.5%) after mild cold exposure. An oral glucose load increased EE from 1,911 (±165) kcal/24 h to 2,096 (±167) kcal/24 h at 60 min ( < 0.0001, +9.7%). The increase in EE in response to cold was significantly associated with BAT activity ( = 0.43, = 0.004). However, DIT was not associated with BAT activity ( = 0.015, = 0.64). DIT after an oral glucose load was not associated with stimulated F-FDG uptake into BAT, suggesting that DIT is independent from BAT activity in humans (Clinicaltrials.gov Registration No. NCT03189511). Cold-induced thermogenesis (CIT) was related to BAT activity as determined by FDG-PET/MRI after stimulation of BAT. Diet-induced thermogenesis (DIT) was not related to stimulated BAT activity. Supraclavicular skin temperature was related to CIT but not to DIT. DIT in humans is probably not a function of BAT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpendo.00237.2020DOI Listing
January 2021

snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis.

Nature 2020 11 28;587(7832):98-102. Epub 2020 Oct 28.

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.

Adipose tissue is usually classified on the basis of its function as white, brown or beige (brite). It is an important regulator of systemic metabolism, as shown by the fact that dysfunctional adipose tissue in obesity leads to a variety of secondary metabolic complications. In addition, adipose tissue functions as a signalling hub that regulates systemic metabolism through paracrine and endocrine signals. Here we use single-nucleus RNA-sequencing (snRNA-seq) analysis in mice and humans to characterize adipocyte heterogeneity. We identify a rare subpopulation of adipocytes in mice that increases in abundance at higher temperatures, and we show that this subpopulation regulates the activity of neighbouring adipocytes through acetate-mediated modulation of their thermogenic capacity. Human adipose tissue contains higher numbers of cells of this subpopulation, which could explain the lower thermogenic activity of human compared to mouse adipose tissue and suggests that targeting this pathway could be used to restore thermogenic activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2856-xDOI Listing
November 2020

Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.

Nat Metab 2019 08 19;1(8):830-843. Epub 2019 Aug 19.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-019-0101-4DOI Listing
August 2019

ESRRG and PERM1 Govern Mitochondrial Conversion in Brite/Beige Adipocyte Formation.

Front Endocrinol (Lausanne) 2020 12;11:387. Epub 2020 Jun 12.

Institute of Food, Nutrition and Health, Department of Health Sciences and Technology (D-HEST), ETH Zürich, Zurich, Switzerland.

When exposed to cold temperatures, mice increase their thermogenic capacity by an expansion of brown adipose tissue mass and the formation of brite/beige adipocytes in white adipose tissue depots. However, the process of the transcriptional changes underlying the conversion of a phenotypic white to brite/beige adipocytes is only poorly understood. By analyzing transcriptome profiles of inguinal adipocytes during cold exposure and in mouse models with a different propensity to form brite/beige adipocytes, we identified ESRRG and PERM1 as modulators of this process. The production of heat by mitochondrial uncoupled respiration is a key feature of brite/beige compared to white adipocytes and we show here that both candidates are involved in PGC1α transcriptional network to positively regulate mitochondrial capacity. Moreover, we show that an increased expression of ESRRG or PERM1 supports the formation of brown or brite/beige adipocytes and . These results reveal that ESRRG and PERM1 are early induced in and important regulators of brite/beige adipocyte formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2020.00387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304443PMC
June 2020

Cold Exposure Distinctively Modulates Parathyroid and Thyroid Hormones in Cold-Acclimatized and Non-Acclimatized Humans.

Endocrinology 2020 07;161(7)

Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.

Cold-induced activation of thermogenesis modulates energy metabolism, but the role of humoral mediators is not completely understood. We aimed to investigate the role of parathyroid and thyroid hormones in acute and adaptive response to cold in humans. Examinations were performed before/after 15 minutes of ice-water swimming (n = 15) or 120 to 150 minutes of cold-induced nonshivering thermogenesis (NST) applied to cold-acclimatized (n = 6) or non-acclimatized (n = 11) individuals. Deep-neck brown adipose tissue (BAT) was collected from non-acclimatized patients undergoing elective neck surgery (n = 36). Seasonal variations in metabolic/hormonal parameters of ice-water swimmers were evaluated. We found that in ice-water swimmers, PTH and TSH increased and free T3, T4 decreased after a 15-minute winter swim, whereas NST-inducing cold exposure failed to regulate PTH and free T4 and lowered TSH and free T3. Ice-water swimming-induced increase in PTH correlated negatively with systemic calcium and positively with phosphorus. In non-acclimatized men, NST-inducing cold decreased PTH and TSH. Positive correlation between systemic levels of PTH and whole-body metabolic preference for lipids as well as BAT volume was found across the 2 populations. Moreover, NST-cooling protocol-induced changes in metabolic preference for lipids correlated positively with changes in PTH. Finally, variability in circulating PTH correlated positively with UCP1/UCP1, PPARGC1A, and DIO2 in BAT from neck surgery patients. Our data suggest that regulation of PTH and thyroid hormones during cold exposure in humans varies by cold acclimatization level and/or cold stimulus intensity. Possible role of PTH in NST is indicated by its positive relationships with whole-body metabolic preference for lipids, BAT volume, and UCP1 content.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/endocr/bqaa051DOI Listing
July 2020

Low-dose F-FDG TOF-PET/MR for accurate quantification of brown adipose tissue in healthy volunteers.

EJNMMI Res 2020 Jan 23;10(1). Epub 2020 Jan 23.

Department of Nuclear Medicine, University Hospital Zürich, Rämistrasse 100, 8091, Zürich, Switzerland.

Background: Positron emission tomography (PET) is increasingly applied for in vivo brown adipose tissue (BAT) research in healthy volunteers. To limit the radiation exposure, the injected F-FDG tracer dose should be as low as possible. With simultaneous PET/MR imaging, the radiation exposure due to computed tomography (CT) can be avoided, but more importantly, the PET acquisition time can often be increased to match the more extensive magnetic resonance (MR) imaging protocol. The potential gain in detected coincidence counts, due to the longer acquisition time, can then be applied to decrease the injected tracer dose. The aim of this study was to investigate the minimal F-FDG dose for a 10-min time-of-flight (TOF) PET/MR acquisition that would still allow accurate quantification of supraclavicular BAT volume and activity.

Methods: Twenty datasets from 13 volunteers were retrospectively included from a prospective clinical study. PET emission datasets were modified to simulate step-wise reductions of the original 75 MBq injected dose. The resulting PET images were visually and quantitatively assessed and compared to a 4-min reference scan. For the visual assessment, the image quality and artifacts were scored using a 5-point and a 3-point Likert scale. For the quantitative analysis, image noise and artifacts, BAT metabolic activity, BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were investigated.

Results: The visual assessment showed still good image quality for the 35%, 30%, and 25% activity reconstructions with no artifacts. Quantitatively, the background noise was similar to the reference for the 35% and 30% activity reconstructions and the artifacts started to increase significantly in the 25% and lower activity reconstructions. There was no significant difference in supraclavicular BAT metabolic activity, BMV, and TBG between the reference and the 35% to 20% activity reconstructions.

Conclusions: This study indicates that when the PET acquisition time is matched to the 10-min MRI protocol, the injected F-FDG tracer dose can be reduced to approximately 19 MBq (25%) while maintaining image quality and accurate supraclavicular BAT quantification. This could decrease the effective dose from 1.4 mSv to 0.36 mSv.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13550-020-0592-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977803PMC
January 2020

Structure-function relationships of HDL in diabetes and coronary heart disease.

JCI Insight 2020 01 16;5(1). Epub 2020 Jan 16.

Institute of Clinical Chemistry, University of Zurich and University Hospital of Zurich, Zurich, Switzerland.

High-density lipoproteins (HDL) contain hundreds of lipid species and proteins and exert many potentially vasoprotective and antidiabetogenic activities on cells. To resolve structure-function-disease relationships of HDL, we characterized HDL of 51 healthy subjects and 98 patients with diabetes (T2DM), coronary heart disease (CHD), or both for protein and lipid composition, as well as functionality in 5 cell types. The integration of 40 clinical characteristics, 34 nuclear magnetic resonance (NMR) features, 182 proteins, 227 lipid species, and 12 functional read-outs by high-dimensional statistical modeling revealed, first, that CHD and T2DM are associated with different changes of HDL in size distribution, protein and lipid composition, and function. Second, different cellular functions of HDL are weakly correlated with each other and determined by different structural components. Cholesterol efflux capacity (CEC) was no proxy of other functions. Third, 3 potentially novel determinants of HDL function were identified and validated by the use of artificially reconstituted HDL, namely the sphingadienine-based sphingomyelin SM 42:3 and glycosylphosphatidylinositol-phospholipase D1 for the ability of HDL to inhibit starvation-induced apoptosis of human aortic endothelial cells and apolipoprotein F for the ability of HDL to promote maximal respiration of brown adipocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.131491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030825PMC
January 2020

Antioxidants protect against diabetes by improving glucose homeostasis in mouse models of inducible insulin resistance and obesity.

Diabetologia 2019 11 15;62(11):2094-2105. Epub 2019 Jul 15.

Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Swiss Federal Institute of Technology, ETH Zürich, CH-8603, Schwerzenbach, Switzerland.

Aims/hypothesis: In the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy.

Methods: We studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant's effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism.

Results: Acute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia.

Conclusions/interpretation: We conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-019-4937-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805816PMC
November 2019

Statins: benefits and risks revisited.

Aging (Albany NY) 2019 07;11(13):4300-4302

Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach 8603, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.102056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660028PMC
July 2019

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation.

Cell Metab 2019 04 20;29(4):901-916.e8. Epub 2018 Dec 20.

Institute of Food, Nutrition, and Health, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland. Electronic address:

Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2018.11.017DOI Listing
April 2019

BATLAS: Deconvoluting Brown Adipose Tissue.

Cell Rep 2018 10;25(3):784-797.e4

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland. Electronic address:

Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.09.044DOI Listing
October 2018

Outdoor Temperature Influences Cold Induced Thermogenesis in Humans.

Front Physiol 2018 23;9:1184. Epub 2018 Aug 23.

Department of Endocrinology, Diabetes & Metabolism, University Hospital of Basel, Basel, Switzerland.

Energy expenditure (EE) increases in response to cold exposure, which is called cold induced thermogenesis (CIT). Brown adipose tissue (BAT) has been shown to contribute significantly to CIT in human adults. BAT activity and CIT are acutely influenced by ambient temperature. In the present study, we investigated the long-term effect of seasonal temperature variation on human CIT. We measured CIT in 56 healthy volunteers by indirect calorimetry. CIT was determined as difference between EE during warm conditions (EE) and after a defined cold stimulus (EE). We recorded skin temperatures at eleven anatomically predefined locations, including the supraclavicular region, which is adjacent to the main human BAT depot. We analyzed the relation of EE, CIT and skin temperatures to the daily minimum, maximum and mean outdoor temperature averaged over 7 or 30 days, respectively, prior to the corresponding study visit by linear regression. We observed a significant inverse correlation between outdoor temperatures and EE and CIT, respectively, while EE was not influenced. The daily maximum temperature averaged over 7 days correlated best with EE (R = 0.123, p = 0.008) and CIT (R = 0.200, p = 0.0005). The mean skin temperatures before and after cold exposure were not related to outdoor temperatures. However, the difference between supraclavicular and parasternal skin temperature after cold exposure was inversely related to the average maximum temperature during the preceding 7 days (R = 0.07575, p = 0.0221). CIT is significantly related to outdoor temperatures indicating dynamic adaption of thermogenesis and BAT activity to environmental stimuli in adult humans. www.ClinicalTrials.gov, Identifier NCT02682706.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2018.01184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115528PMC
August 2018

Publisher Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.

Nat Med 2018 Nov;24(11):1777

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.

In the version of this article originally published, the bars in the mean temperature graph in Fig. 1a were incorrectly aligned. The left-most bar should have been aligned with the Apr label on the projected month of conception axis. The error has been corrected in the print, PDF and HTML versions of this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-018-0163-yDOI Listing
November 2018

Author Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.

Nat Med 2018 Nov;24(11):1776

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.

In the version of this article originally published, the months on the axis labeled projected month of conception in Fig. 1a were out of order. April and March should have been the first and last months listed, respectively. The error has been corrected in the print, PDF and HTML versions of this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-018-0162-zDOI Listing
November 2018

Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.

Nat Med 2018 09 9;24(9):1372-1383. Epub 2018 Jul 9.

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.

Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-018-0102-yDOI Listing
September 2018

Muscular Power during a Lifting Task Increases after Three Months of Resistance Training in Overweight and Obese Individuals.

Sports (Basel) 2017 Jun 8;5(2). Epub 2017 Jun 8.

Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava 83306, Slovakia.

Background: This study evaluates the effect on power produced during a modified lifting task in the overweight and obese after three months of either resistance or aerobic training.

Methods: Seventeen male subjects divided randomly into two groups performed deadlift and deadlift high pull, both with increasing weights up to maximal power, prior to and after the training programs (three sessions per week).

Results: Their mean power increased significantly during the deadlift at 20 kg (14.3%, p = 0.026), 30 kg (17.7%, p = 0.008), 40 kg (16.5%, p = 0.011), 50 kg (14.5%, p = 0.020), and 60 kg (14.3%, p = 0.021) and during the deadlift high pull at 30 kg (9.9%, p = 0.037), 40 kg (10.1%, p = 0.035), and 50 kg (8.2%, p = 0.044) after the resistance training. However, the group that participated in the aerobic training failed to show any significant changes in power performance during either the deadlift or deadlift high pull.

Conclusion: Three months of resistance training enhances power outputs during a lifting task with weights from 30 to 50 kg (~40%⁻60% of 1-repetition maximum) in the overweight and obese. Because this test was sensitive in revealing pre-post training changes in lifting performance, it should be implemented in the functional diagnostics for overweight and obese individuals and also complement existing testing methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/sports5020035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968996PMC
June 2017

Weight Loss and Adipose Tissue Browning in Humans: The Chicken or the Egg?

Trends Endocrinol Metab 2018 07 13;29(7):450-452. Epub 2018 Mar 13.

Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Swiss Federal Institute of Technology, ETH Zürich, CH-8603 Schwerzenbach, Switzerland. Electronic address:

Recruitment of thermogenic adipocytes within white fat depots represents a promising strategy to increase energy expenditure. Negative energy balance has been reported to promote adipose tissue browning in rodents. In a recent issue of Cell Reports, Barquissau et al. show that caloric restriction-associated weight loss does not induce browning of subcutaneous abdominal white fat in obese humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tem.2018.03.004DOI Listing
July 2018

Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase.

Cell Rep 2018 01;22(3):760-773

Institute of Food, Nutrition and Health, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland. Electronic address:

Peroxisome proliferator-activated receptors (PPARs) have been suggested as the master regulators of adipose tissue formation. However, their role in regulating brown fat functionality has not been resolved. To address this question, we generated mice with inducible brown fat-specific deletions of PPARα, β/δ, and γ, respectively. We found that both PPARα and β/δδ are dispensable for brown fat function. In contrast, we could show that ablation of PPARγ in vitro and in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARγ function and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARγ-mediated regulation of brown fat function and activation by β-adrenergic signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2017.12.067DOI Listing
January 2018

Three months of resistance training in overweight and obese individuals improves reactive balance control under unstable conditions.

J Back Musculoskelet Rehabil 2017 ;30(2):353-362

Slovak Academy of Sciences, Institute of Experimental Endocrinology, Bratislava, Slovakia.

Background: Contrary to static and dynamic balance, there is a lack of scientific evidence on the training induced changes in reactive balance control in response to unexpected perturbations in overweight and obese individuals.

Objective: This study evaluates the effect of 3 months of resistance and aerobic training programs on postural responses to unexpected perturbations under stable and unstable conditions in the overweight and obese.

Methods: A group of 17 overweight and obese subjects, divided into two groups, underwent either resistance or aerobic training for a period of 3 months (3 sessions per week). Prior to and after completing the training, they performed the load release balance test while standing on either a stable or unstable surface, with eyes open and closed.

Results: Peak posterior center of pressure (CoP) displacement, and the time to peak posterior CoP displacement during a bipedal stance on a foam surface with eyes open (17.3%, p = 0.019 and 15.4%, p = 0.029) and eyes closed (15.0%, p = 0.027 and 13.2%, p = 0.034), decreased significantly. In addition, the total anterior to posterior CoP displacement, and the time from peak anterior to peak posterior CoP displacement, both with eyes open (18.1%, p = 0.017 and 12.2%, p = 0.040) and eyes closed (16.3%, p = 0.023 and 11.7%, p = 0.044), also significantly decreased. However, after completing the resistance training, the parameters registered while standing on a stable platform, both with eyes open and closed, did not change significantly. The group that underwent an aerobic training also failed to show any significant changes in parameters of the load release balance test.

Conclusion: Three months of resistance training in overweight and obese subjects improves reactive balance control in response to unexpected perturbations under unstable conditions, both with and without visual cues. Due to the fact that this unstable load release balance test was found to be sensitive in revealing post-training changes, it would be suitable for implementing in the functional diagnostic for this group, in addition to complementing existing testing methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/BMR-160585DOI Listing
May 2017

Unilateral Stability and Visual Feedback Body Control Improves After Three-Month Resistance Training in Overweight Individuals.

J Mot Behav 2017 Jul-Aug;49(4):398-406. Epub 2016 Oct 11.

b Institute of Experimental Endocrinology, Slovak Academy of Sciences , Bratislava , Slovakia.

The authors evaluated the effect of 3 months of resistance and aerobic training (3 sessions/week) on body balance in a group of 25 overweight and obese individuals. Prior to and after the training, they performed static and task-oriented balance tests under various conditions. Mean center of pressure (CoP) velocity and mean trace length of the CoP in the y-axis registered during a one-legged stance significantly decreased after the resistance training (19.1%, p = .024; 29.3%, p = .009). Mean trace length of the CoP in the y-axis decreased significantly also during a bipedal stance on a foam surface with eyes open and closed (10.9%, p = .040; 18.2%, p = .027). In addition, mean CoP distance and mean squared CoP distance in the anteroposterior direction during a visually guided center of mass (CoM) tracking task significantly improved (14.7%, p = .033; 28.2%, p = .016). However, only mean trace length of the CoP in the y-axis during a bipedal stance on a foam surface with eyes open and closed significantly decreased after the aerobic training (10.3%, p = .047; 16.5%, p = .029). It may be concluded that resistance training is more efficient for the improvement of the anteroposterior unilateral stability and the accuracy of the regulation of the CoM anteroposterior position than aerobic training in overweight and obese individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00222895.2016.1219307DOI Listing
September 2018

Upper and Lower Body Muscle Power Increases After 3-Month Resistance Training in Overweight and Obese Men.

Am J Mens Health 2017 Nov 15;11(6):1728-1738. Epub 2016 Aug 15.

2 Institue of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.

This study evaluates the effect of 3 months resistance and aerobic training on muscle strength and power in 17 male overweight and obese men. Subjects underwent either a resistance or aerobic training for a period of 3 months (three sessions per week). Peak isometric force, rate of force development, peak power and height of countermovement and squat jumps, reactive strength index, and mean power in the concentric phase of bench presses were all assessed prior to and after completing the training program. Results identified a significant increase of mean power during both countermovement bench presses at 30 kg (18.6%, p = .021), 40 kg (14.6%, p = .033), and 50 kg (13.1%, p = .042) and concentric-only bench presses at 30 kg (19.6%, p = .017) and 40 kg (13.9%, p = .037) after the resistance training. There was also a significant increase in the height of the jump (12.8%, p = .013), peak power (10.1%, p = .026), and peak velocity (9.7%, p = .037) during the countermovement jump and height of the jump (11.8%, p = .019), peak power (9.6%, p = .032), and peak velocity (9.5%, p = .040) during the squat jump. There were no significant changes in the reactive strength index, peak force, and the rate of force development after the resistance training. The aerobic group failed to show any significant improvements in these parameters. It may be concluded that 3 months of resistance training without caloric restriction enhances upper and lower body muscle power in overweight and obese men.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1557988316662878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675262PMC
November 2017

Bmp4 Promotes a Brown to White-like Adipocyte Shift.

Cell Rep 2016 08 11;16(8):2243-2258. Epub 2016 Aug 11.

Swiss Federal Institute of Technology, Department of Health Science, Institute of Food Nutrition and Health, Laboratory of Translational Nutrition Biology, Schwerzenbach 8603, Switzerland. Electronic address:

While Bmp4 has a well-established role in the commitment of mesenchymal stem cells into the adipogenic lineage, its role in brown adipocyte formation and activity is not well defined. Here, we show that Bmp4 has a dual function in adipogenesis by inducing adipocyte commitment while inhibiting the acquisition of a brown phenotype during terminal differentiation. Selective brown adipose tissue overexpression of Bmp4 in mice induces a shift from a brown to a white-like adipocyte phenotype. This effect is mediated by Smad signaling and might be in part due to suppression of lipolysis, via regulation of hormone sensitive lipase expression linked to reduced Ppar activity. Given that we observed a strong correlation between BMP4 levels and adipocyte size, as well as insulin sensitivity in humans, we propose that Bmp4 is an important factor in the context of obesity and type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2016.07.048DOI Listing
August 2016

Proteomic Analysis of Human Brown Adipose Tissue Reveals Utilization of Coupled and Uncoupled Energy Expenditure Pathways.

Sci Rep 2016 07 15;6:30030. Epub 2016 Jul 15.

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.

Human brown adipose tissue (BAT) has become an attractive target to combat the current epidemical spread of obesity and its associated co-morbidities. Currently, information on its functional role is primarily derived from rodent studies. Here, we present the first comparative proteotype analysis of primary human brown adipose tissue versus adjacent white adipose tissue, which reveals significant quantitative differences in protein abundances and in turn differential functional capabilities. The majority of the 318 proteins with increased abundance in BAT are associated with mitochondrial metabolism and confirm the increased oxidative capacity. In addition to uncoupling protein 1 (UCP1), the main functional effector for uncoupled respiration, we also detected the mitochondrial creatine kinases (CKMT1A/B, CKMT2), as effective modulators of ATP synthase coupled respiration, to be exclusively expressed in BAT. The abundant expression and utilization of both energy expenditure pathways in parallel highlights the complex functional involvement of BAT in human physiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep30030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945940PMC
July 2016

Chronic liquid nutrition intake induces obesity and considerable but reversible metabolic alterations in Wistar rats.

J Physiol Biochem 2016 Jun 3;72(2):225-43. Epub 2016 Mar 3.

Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia.

We have previously described the development of substantial, but reversible obesity in Wistar rats fed with palatable liquid nutrition (Fresubin). In this study, we investigated changes in serum hormone levels, glycemia, fat mass, adipocyte size, and gene expression of adipokines and inflammatory markers in adipose tissue of Wistar rats fed by Fresubin (i) for 5 months, (ii) up to 90 days of age, or (iii) after 90 days of age to characterize metabolic alterations and their reversibility in rats fed with Fresubin. An intra-peritoneal glucose tolerance test was also performed to determine levels of serum leptin, adiponectin, insulin, and C-peptide in 2- and 4-month-old animals. In addition, mesenteric and epididymal adipose tissue weight, adipocyte diameter, and gene expression of pro- and anti-inflammatory adipokines and other markers were determined at the end of the study. Chronic Fresubin intake significantly increased adipocyte diameter, reduced glucose tolerance, and increased serum leptin, adiponectin, insulin, and C-peptide levels. Moreover, gene expression of leptin, adiponectin, CD68, and nuclear factor kappa B was significantly increased in mesenteric adipose tissue of Fresubin fed rats. Monocyte chemotactic protein 1 messenger RNA (mRNA) levels increased in mesenteric adipose tissue only in the group fed Fresubin during the entire experiment. In epididymal adipose tissue, fatty acid binding protein 4 mRNA levels were significantly increased in rats fed by Fresubin during adulthood. In conclusion, chronic Fresubin intake induced complex metabolic alterations in Wistar rats characteristic of metabolic syndrome. However, transition of rats from Fresubin to standard diet reversed these alterations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13105-016-0472-xDOI Listing
June 2016

Regulation of De Novo Adipocyte Differentiation Through Cross Talk Between Adipocytes and Preadipocytes.

Diabetes 2015 Dec 4;64(12):4075-87. Epub 2015 Sep 4.

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland

There are many known adipokines differentially secreted from the different adipose depots; however, their paracrine and autocrine effects on de novo adipocyte formation are not fully understood. By developing a coculture method of preadipocytes with primary subcutaneous and visceral adipocytes or tissue explants, we could show that the total secretome inhibited preadipocyte differentiation. Using a proteomics approach with fractionated secretome samples, we were able to identify a spectrum of factors that either positively or negatively affected adipocyte formation. Among the secreted factors, Slc27a1, Vim, Cp, and Ecm1 promoted adipocyte differentiation, whereas Got2, Cpq, interleukin-1 receptor-like 1/ST2-IL-33, Sparc, and Lgals3bp decreased adipocyte differentiation. In human subcutaneous adipocytes of lean subjects, obese subjects, and obese subjects with type 2 diabetes, Vim and Slc27a1 expression was negatively correlated with adipocyte size and BMI and positively correlated with insulin sensitivity, while Sparc and Got2 showed the opposite trend. Furthermore, we demonstrate that Slc27a1 was increased upon weight loss in morbidly obese patients, while Sparc expression was reduced. Taken together, our findings identify adipokines that regulate adipocyte differentiation through positive or negative paracrine and autocrine feedback loop mechanisms, which could potentially affect whole-body energy metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db14-1932DOI Listing
December 2015

Improved adipose tissue metabolism after 5-year growth hormone replacement therapy in growth hormone deficient adults: The role of zinc-α2-glycoprotein.

Adipocyte 2015 Apr-Jun;4(2):113-22. Epub 2014 Dec 17.

Institute of Experimental Endocrinology; Slovak Academy of Sciences ; Bratislava, Slovakia.

Growth hormone (GH) supplementation therapy to adults with GH deficiency has beneficial effects on adipose tissue lipid metabolism, improving thus adipocyte functional morphology and insulin sensitivity. However, molecular nature of these effects remains unclear. We therefore tested the hypothesis that lipid-mobilizing adipokine zinc-α2-glycoprotein is causally linked to GH effects on adipose tissue lipid metabolism. Seventeen patients with severe GH deficiency examined before and after the 5-year GH replacement therapy were compared with age-, gender- and BMI-matched healthy controls. Euglycemic hyperinsulinemic clamp was used to assess whole-body and adipose tissue-specific insulin sensitivity. Glucose tolerance was determined by oGTT, visceral and subcutaneous abdominal adiposity by MRI, adipocyte size morphometrically after collagenase digestion, lipid accumulation and release was studied in differentiated human primary adipocytes in association with GH treatment and zinc-α2-glycoprotein gene silencing. Five-year GH replacement therapy improved glucose tolerance, adipose tissue insulin sensitivity and reduced adipocyte size without affecting adiposity and whole-body insulin sensitivity. Adipose tissue zinc-α2-glycoprotein expression was positively associated with whole-body and adipose tissue insulin sensitivity and negatively with adipocyte size. GH treatment to adipocytes in vitro increased zinc-α2-glycoprotein expression (>50%) and was paralleled by enhanced lipolysis and decreased triglyceride accumulation (>35%). Moreover, GH treatment improved antilipolytic action of insulin in cultured adipocytes. Most importantly, silencing zinc-α2-glycoprotein eliminated all of the GH effects on adipocyte lipid metabolism. Effects of 5-year GH supplementation therapy on adipose tissue lipid metabolism and insulin sensitivity are associated with zinc-α2-glycoprotein. Presence of this adipokine is required for the GH action on adipocyte lipid metabolism in vitro.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4161/21623945.2014.973772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496981PMC
July 2015

Adipokine zinc-α2-glycoprotein regulated by growth hormone and linked to insulin sensitivity.

Obesity (Silver Spring) 2015 Feb 7;23(2):322-8. Epub 2014 Aug 7.

Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.

Objective: Hypertrophic obesity is associated with impaired insulin sensitivity and lipid-mobilizing activity of zinc-α2-glycoprotein. Adipose tissue (AT) of growth hormone (GH) -deficient patients is characterized by extreme adipocyte hypertrophy due to defects in AT lipid metabolism. It was hypothesized that zinc-α2-glycoprotein is regulated by GH and mediates some of its beneficial effects in AT.

Methods: AT from patients with GH deficiency and individuals with obesity-related GH deficit was obtained before and after 5-year and 24-month GH supplementation therapy. GH action was tested in primary human adipocytes. Relationships of GH and zinc-α2-glycoprotein with adipocyte size and insulin sensitivity were evaluated in nondiabetic patients with noncancerous cachexia and hypertrophic obesity.

Results: AT in GH-deficient adults displayed a substantial reduction of zinc-α2-glycoprotein. GH therapy normalized AT zinc-α2-glycoprotein. Obesity-related relative GH deficit was associated with almost 80% reduction of zinc-α2-glycoprotein mRNA in AT. GH increased zinc-α2-glycoprotein mRNA in both AT of obese men and primary human adipocytes. Interdependence of GH and zinc-α2-glycoprotein in regulating AT morphology and metabolic phenotype was evident from their relationship with adipocyte size and AT-specific and whole-body insulin sensitivity.

Conclusions: The results demonstrate that GH is involved in regulation of AT zinc-α2-glycoprotein; however, the molecular mechanism linking GH and zinc-α2-glycoprotein in AT is yet unknown.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/oby.20856DOI Listing
February 2015

Subcutaneous adipose tissue zinc-α2-glycoprotein is associated with adipose tissue and whole-body insulin sensitivity.

Obesity (Silver Spring) 2014 Aug 22;22(8):1821-9. Epub 2014 Apr 22.

Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.

Objective: To examine the regulatory aspects of zinc-α2-glycoprotein (ZAG) association with obesity-related insulin resistance.

Methods: ZAG mRNA and protein were analyzed in subcutaneous adipose tissue (AT) and circulation of lean, obese, prediabetic, and type 2 diabetic men; both subcutaneous and visceral AT were explored in lean and extremely obese. Clinical and ex vivo findings were corroborated by results of in vitro ZAG silencing experiment.

Results: Subcutaneous AT ZAG was reduced in obesity, with a trend to further decrease with prediabetes and type 2 diabetes. ZAG was 3.3-fold higher in subcutaneous than in visceral AT of lean individuals. All differences were lost in extreme obesity. Obesity-associated changes in AT were not paralleled by alterations of circulating ZAG. Subcutaneous AT ZAG correlated with adiposity, adipocyte hypertrophy, whole-body and AT insulin sensitivity, mitochondrial content, expression of GLUT4, PGC1α, and adiponectin. Subcutaneous AT ZAG and adipocyte size were the only predictors of insulin sensitivity, independent on age and BMI. Silencing ZAG resulted in reduced adiponectin, IRS1, GLUT4, and PGC1α gene expression in primary human adipocytes.

Conclusions: ZAG in subcutaneous, but not in visceral AT, was markedly reduced in obesity. Clinical, cellular, and molecular evidence indicate that ZAG plays an important role in modulating whole-body and AT insulin sensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/oby.20764DOI Listing
August 2014