Publications by authors named "Christian Wolfrum"

121 Publications

GHS-R in brown fat potentiates differential thermogenic responses under metabolic and thermal stresses.

PLoS One 2021 1;16(4):e0249420. Epub 2021 Apr 1.

USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States of America.

In response to cold or diet, fatty acids are dissipated into heat through uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). This process is termed non-shivering thermogenesis, which is important for body temperature maintenance and contributes to obesity pathogenesis. Thermogenic enhancement has been considered a promising anti-obesity strategy. Ghrelin and its receptor Growth Hormone Secretagogue Receptor (GHS-R) have critical roles in energy intake, nutrient sensing, and lipid metabolism. We previously reported that global Ghsr-knockout mice have increased energy expenditure due to enhanced thermogenesis. To determine the site of action for GHS-R mediated thermogenesis, we generated brown adipocyte-specific Ghsr knockout mice (UCP1-CreER/Ghsrf/f) and assessed thermogenic responses under regular diet (RD) fed homeostatic metabolic state or high-fat diet (HFD) fed metabolically-impaired obese state, under normal or cold housing environment. Under a RD-feeding, UCP1-CreER/Ghsrf/f mice showed increased body fat and a slightly elevated core body temperature under cold but not under normal temperature. Consistently, the expression of thermogenic genes in BAT of RD-fed UCP1-CreER/Ghsrf/f mice was increased in reposes to cold. Under HFD feeding, HFD-fed UCP1-CreER/Ghsrf/f mice showed no difference in body fat or body temperature under either normal or cold exposure. Interestingly, the expression of thermogenic genes in BAT of HFD-fed UCP1-CreER/Ghsrf/f mice was upregulated under normal temperature but downregulated under cold exposure. Overall, our data show that GHS-R has cell-autonomous effect in brown adipocytes, and GHS-R regulates BAT thermogenic activity in a temperature- and metabolic state-dependent manner. The thermogenic effect of GHS-R in BAT is more pronounced in cold environment and differentially variable based on metabolic state; under cold exposure, GHS-R inhibition in BAT activates thermogenesis under homeostatic state but suppresses thermogenesis under obese state. Our finding collectively suggests that GHS-R in BAT, acting as a "metabolic thermostat", differentially regulates thermogenesis in response to different metabolic and thermal stimuli.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249420PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016305PMC
April 2021

The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling.

Cell Metab 2021 Apr 10;33(4):833-844.e5. Epub 2021 Feb 10.

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, 72076 Tübingen, Germany. Electronic address:

Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism. In DIO mice, acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, and this coincides with decreased body weight and food intake and improved glucose handling. Chronic central and peripheral administration of acyl-GIP lowers body weight and food intake in wild-type mice, but shows blunted/absent efficacy in CNS-Gipr KO mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 is extinguished in CNS-Gipr KO mice. Our data hence establish a key role of CNS Gipr for control of energy metabolism.
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http://dx.doi.org/10.1016/j.cmet.2021.01.015DOI Listing
April 2021

Creatine supplementation and thermogenesis in humans-a futile exercise?

Nat Metab 2021 Jan;3(1):9-10

ETH Zürich, Zürich, Switzerland.

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http://dx.doi.org/10.1038/s42255-020-00337-9DOI Listing
January 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.
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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.
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http://dx.doi.org/10.1038/s41586-020-2856-xDOI Listing
November 2020

Brown fat does not cause cachexia in cancer patients: A large retrospective longitudinal FDG-PET/CT cohort study.

PLoS One 2020 8;15(10):e0239990. Epub 2020 Oct 8.

Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland.

Background: Brown adipose tissue (BAT) is a specialized form of adipose tissue, able to increase energy expenditure by heat generation in response to various stimuli. Recently, its pathological activation has been implicated in the pathogenesis of cancer cachexia. To establish a causal relationship, we retrospectively investigated the longitudinal changes in BAT and cancer in a large FDG-PET/CT cohort.

Methods: We retrospectively analyzed 13 461 FDG-PET/CT examinations of n = 8 409 patients at our institution from the winter months of 2007-2015. We graded the activation strength of BAT based on the anatomical location of the most caudally activated BAT depot into three tiers, and the stage of the cancer into five general grades. We validated the cancer grading by an interreader analysis and correlation with histopathological stage. Ambient temperature data (seven-day average before the examination) was obtained from a meteorological station close to the hospital. Changes of BAT, cancer, body mass index (BMI) and temperature between the different examinations were examined with Spearman's test and a mixed linear model for correlation, and with a causal inference algorithm for causality.

Results: We found n = 283 patients with at least two examinations and active BAT in at least one of them. There was no significant interaction between the changes in BAT activation, cancer burden or BMI. Temperature changes exhibited a strong negative correlation with BAT activity (ϱ = -0.57, p<0.00001). These results were confirmed with the mixed linear model. Causal inference revealed a link of Temperature ➜ BAT in all subjects and also of BMI ➜ BAT in subjects who had lost weight and increased cancer burden, but no role of cancer and no causal links of BAT ➜ BMI.

Conclusions: Our data did not confirm the hypothesis that BAT plays a major role in cancer-mediated weight loss. Temperature changes are the main driver of incidental BAT activity on FDG-PET scans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239990PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544086PMC
December 2020

[Bachelor of Human Medicine at the ETH Zurich. A Contribution to the Training of Tomorrow's Physicians].

Praxis (Bern 1994) 2020 Sep;109(11):853-858

Departement Gesundheitswissenschaften und Technologie, ETH Zürich.

Bachelor of Human Medicine at the ETH Zurich. A Contribution to the Training of Tomorrow's Physicians With ever-changing lifestyles and an increasingly older but also more dynamic society, the maintenance and health as well as the improvement of treatment play a central role. At the same time, developments in bioinformatics, molecular biosciences and imaging techniques are revolutionizing medicine. In order to fully exploit the new possibilities, for example in medical technology or personalised medicine, doctors with a sound knowledge in several disciplines will be needed in the future. In-depth knowledge in the medical, technical and biological sciences will become indispensable. This is where the new Bachelor of Human Medicine at the Swiss Federal Institute of Technology (ETH) Zurich has been in place since autumn 2017, combining medical with technical and scientific aspects of human health. In addition to traditional medical content, it also covers topics from the bioinformatics and medical technology sectors. The continuation of the studies takes place at one of the partner universities in Basel, Lugano or Zurich.
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http://dx.doi.org/10.1024/1661-8157/a003562DOI Listing
September 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.
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http://dx.doi.org/10.1038/s42255-019-0101-4DOI Listing
August 2019

Reply to 'Confounding issues in the 'humanized' brown fat of mice'.

Nat Metab 2020 04 13;2(4):305-306. Epub 2020 Apr 13.

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

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http://dx.doi.org/10.1038/s42255-020-0193-xDOI Listing
April 2020

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

Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization.

Cell Metab 2020 Jun;31(6):1136-1153.e7

Laboratory of Exercise and Health, Department Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, 8603 Zurich, Switzerland. Electronic address:

Endothelial cell (EC)-derived signals contribute to organ regeneration, but angiocrine metabolic communication is not described. We found that EC-specific loss of the glycolytic regulator pfkfb3 reduced ischemic hindlimb revascularization and impaired muscle regeneration. This was caused by the reduced ability of macrophages to adopt a proangiogenic and proregenerative M2-like phenotype. Mechanistically, loss of pfkfb3 reduced lactate secretion by ECs and lowered lactate levels in the ischemic muscle. Addition of lactate to pfkfb3-deficient ECs restored M2-like polarization in an MCT1-dependent fashion. Lactate shuttling by ECs enabled macrophages to promote proliferation and fusion of muscle progenitors. Moreover, VEGF production by lactate-polarized macrophages was increased, resulting in a positive feedback loop that further stimulated angiogenesis. Finally, increasing lactate levels during ischemia rescued macrophage polarization and improved muscle reperfusion and regeneration, whereas macrophage-specific mct1 deletion prevented M2-like polarization. In summary, ECs exploit glycolysis for angiocrine lactate shuttling to steer muscle regeneration from ischemia.
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http://dx.doi.org/10.1016/j.cmet.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267778PMC
June 2020

Feeding brown fat: dietary phytochemicals targeting non-shivering thermogenesis to control body weight.

Proc Nutr Soc 2020 08 15;79(3):338-356. Epub 2020 Apr 15.

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

Excessive adipose accumulation, which is the main driver for the development of secondary metabolic complications, has reached epidemic proportions and combined pharmaceutical, educational and nutritional approaches are required to reverse the current rise in global obesity prevalence rates. Brown adipose tissue (BAT) is a unique organ able to dissipate energy and thus a promising target to enhance BMR to counteract a positive energy balance. In addition, active BAT might support body weight maintenance after weight loss to prevent/reduce relapse. Natural products deliver valuable bioactive compounds that have historically helped to alleviate disease symptoms. Interest in recent years has focused on identifying nutritional constituents that are able to induce BAT activity and thereby enhance energy expenditure. This review provides a summary of selected dietary phytochemicals, including isoflavones, catechins, stilbenes, the flavonoids quercetin, luteolin and resveratrol as well as the alkaloids berberine and capsaicin. Most of the discussed phytochemicals act through distinct molecular pathways e.g. sympathetic nerve activation, AMP-kinase signalling, SIRT1 activity or stimulation of oestrogen receptors. Thus, it might be possible to utilise this multitude of pathways to co-activate BAT using a fine-tuned combination of foods or combined nutritional supplements.
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http://dx.doi.org/10.1017/S0029665120006928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663322PMC
August 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.
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http://dx.doi.org/10.1210/endocr/bqaa051DOI Listing
July 2020

ASK1 inhibits browning of white adipose tissue in obesity.

Nat Commun 2020 04 2;11(1):1642. Epub 2020 Apr 2.

Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, CH-8032, Zurich, Switzerland.

Increasing energy expenditure via induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Herein, we identify adipocyte-expressed apoptosis signal-regulating kinase 1 (ASK1) as regulator of adipose tissue browning. High fat diet-fed adipocyte-specific ASK1 knockout mice reveal increased UCP1 protein levels in inguinal adipose tissue concomitant with elevated energy expenditure, reduced obesity and ameliorated glucose tolerance compared to control littermates. In addition, ASK1-depletion blunts LPS-mediated downregulation of isoproterenol-induced UCP1 in subcutaneous fat both in vitro and in vivo. Conversely, adipocyte-specific ASK1 overexpression in chow-fed mice attenuates cold-induced UCP1 protein levels in inguinal fat. Mechanistically, ASK1 phosphorylates interferon regulatory factor 3 (IRF3) resulting in reduced Ucp1 expression. Taken together, our studies unravel a role of ASK1 in mediating the inhibitory effect of caloric surplus or LPS-treatment on adipose tissue browning. Adipocyte ASK1 might be a pharmacological target to combat obesity and associated morbidities.
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http://dx.doi.org/10.1038/s41467-020-15483-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118089PMC
April 2020

A Genetic Model to Study the Contribution of Brown and Brite Adipocytes to Metabolism.

Cell Rep 2020 03;30(10):3424-3433.e4

Institute of Food Nutrition and Health and Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich (ETH), 8603 Schwerzenbach, Switzerland. Electronic address:

UCP1-dependent thermogenesis is studied to define new strategies to ameliorate obesity and type 2 diabetes; however, animal models are mostly limited to germline mutations of UCP1, which can effect adaptive changes in UCP1-independent pathways. We develop an inducible mouse model for the sequential ablation of UCP1 brown and brite/beige adipocytes in adult mice. We demonstrate that activated brown adipocytes can increase systemic energy expenditure (EE) by 30%, while the contribution of brite/beige UCP1 cells is <5%. Notably, UCP1 adipocytes do not contribute to circulating FGF21 levels, either at room temperature or after cold exposure. We demonstrate that the FGF21-mediated effects on EE and glucose homeostasis are partially dependent on the presence of UCP1 cells, while the effect on weight loss is not. In conclusion, acute UCP1 cell deletion may be a useful model to study the impact of brown and brite/beige adipocytes on metabolism.
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http://dx.doi.org/10.1016/j.celrep.2020.02.055DOI Listing
March 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.
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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.
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http://dx.doi.org/10.1172/jci.insight.131491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030825PMC
January 2020

Brown Adipose Crosstalk in Tissue Plasticity and Human Metabolism.

Endocr Rev 2020 01;41(1)

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

Infants rely on brown adipose tissue (BAT) as a primary source of thermogenesis. In some adult humans, residuals of brown adipose tissue are adjacent to the central nervous system and acute activation increases metabolic rate. Brown adipose tissue (BAT) recruitment occurs during cold acclimation and includes secretion of factors, known as batokines, which target several different cell types within BAT, and promote adipogenesis, angiogenesis, immune cell interactions, and neurite outgrowth. All these processes seem to act in concert to promote an adapted BAT. Recent studies have also provided exciting data on whole body metabolic regulation with a broad spectrum of mechanisms involving BAT crosstalk with liver, skeletal muscle, and gut as well as the central nervous system. These widespread interactions might reflect the property of BAT of switching between an active thermogenic state where energy is highly consumed and drained from the circulation, and the passive thermoneutral state, where energy consumption is turned off. (Endocrine Reviews 41: XXX - XXX, 2020).
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http://dx.doi.org/10.1210/endrev/bnz007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006230PMC
January 2020

Liver ASK1 protects from non-alcoholic fatty liver disease and fibrosis.

EMBO Mol Med 2019 10 6;11(10):e10124. Epub 2019 Jun 6.

Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland.

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and may progress to non-alcoholic steatohepatitis (NASH) and liver fibrosis. The deficit of pharmacological therapies for the latter mainly results from an incomplete understanding of involved pathological mechanisms. Herein, we identify apoptosis signal-regulating kinase 1 (ASK1) as a suppressor of NASH and fibrosis formation. High-fat diet-fed and aged chow-fed liver-specific ASK1-knockout mice develop a higher degree of hepatic steatosis, inflammation, and fibrosis compared to controls. In addition, pharmacological inhibition of ASK1 increased hepatic lipid accumulation in wild-type mice. In line, liver-specific ASK1 overexpression protected mice from the development of high-fat diet-induced hepatic steatosis and carbon tetrachloride-induced fibrosis. Mechanistically, ASK1 depletion blunts autophagy, thereby enhancing lipid droplet accumulation and liver fibrosis. In human livers of lean and obese subjects, ASK1 expression correlated negatively with liver fat content and NASH scores, but positively with markers for autophagy. Taken together, ASK1 may be a novel therapeutic target to tackle NAFLD and liver fibrosis.
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http://dx.doi.org/10.15252/emmm.201810124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783644PMC
October 2019

Puerariae lobatae root extracts and the regulation of brown fat activity.

Phytomedicine 2019 Nov 23;64:153075. Epub 2019 Aug 23.

HanseMerkur Center for Traditional Chinese Medicine at the University Medical Center Hamburg-Eppendorf, Breitenfelder Straße 15, D-20251 Hamburg, Germany. Electronic address:

Background: Obesity is one of the major health problems worldwide. The induction of brown adipocyte formation and activity represents a promising therapeutic option by increasing energy expenditure. Asian herbs have the potential to treat obesity, however, pharmacological effects should be well documented at the molecular level first.

Hypothesis: A novel hypothesis-driven screening approach identified the root of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep (PLR) to have potential effects on obesity by stimulating brown adipocytes.

Study Design: This study explored the metabolic effects of PLR water extract (PLRE) in a high-fat diet-induced obesity mouse model and characterized its secondary metabolite composition.

Methods: Animals were orally treated daily for two weeks and the bioactivity of PLRE evaluated by measuring various parameters including body weight, circulating metabolites, energy expenditure and insulin sensitivity. The chemical composition of the mains components was obtained by HPLC-MS-ELSD-PDA. Based on the dereplication results and semi-quantitative estimation, pure molecules were selected for tests on adipocytes in vitro.

Results: PLRE induces brown adipocyte activity and triggers the formation of brown-like cells in inguinal fat tissue, weight loss, and improved glucose metabolism. These effects are primarily caused by cell-autonomous activation of brown adipocytes and not by autonomic nervous system regulation. Even though the analysis of PLRE revealed puerarin as the most abundant secondary metabolite, it showed no effect on brown adipocyte formation and function. Brown adipocyte activity was induced dose-dependently by two other isoflavones, daidzein, and genistein. Daidzein is present in a very small amount in PLRE, but various glycosidic isoflavones, including puerarin, may release daidzein after metabolism.

Conclusion: This approach demonstrated the positive effects of PLRE on a diet-induced obesity mouse model and provided clues on the mode of action of PLRE at the molecular level.
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http://dx.doi.org/10.1016/j.phymed.2019.153075DOI Listing
November 2019

Identification of chemotypes in bitter melon by metabolomics: a plant with potential benefit for management of diabetes in traditional Chinese medicine.

Metabolomics 2019 07 18;15(8):104. Epub 2019 Jul 18.

School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, CMU - Rue Michel-Servet 1, CH-1206, Geneva 4, Switzerland.

Introduction: Bitter melon (Momordica charantia, Cucurbitaceae) is a popular edible medicinal plant, which has been used as a botanical dietary supplement for the treatment of diabetes and obesity in Chinese folk medicine. Previously, our team has proved that cucurbitanes triterpenoid were involved in bitter melon's anti-diabetic effects as well as on increasing energy expenditure. The triterpenoids composition can however be influenced by changes of varieties or habitats.

Objectives: To clarify the significance of bioactive metabolites diversity among different bitter melons and to provide a guideline for selection of bitter melon varieties, an exploratory study was carried out using a UHPLC-HRMS based metabolomic study to identify chemotypes.

Methods: Metabolites of 55 seed samples of bitter melon collected in different parts of China were profiled by UHPLC-HRMS. The profiling data were analysed with multivariate (MVA) statistical methods. Principle component analysis (PCA) and hierarchical cluster analysis (HCA) were applied for sample differentiation. Marker compounds were identified by comparing spectroscopic data with isolated compounds, and additional triterpenes were putatively identified by propagating annotations through a molecular network (MN) generated from UHPLC-HRMS & MS/MS metabolite profiling.

Results: PCA and HCA provided a good discrimination between bitter melon samples from various origins in China. This study revealed for the first time the existence of two chemotypes of bitter melon. Marker compounds of those two chemotypes were identified at different MSI levels. The combined results of MN and MVA demonstrated that the two chemotypes mainly differ in their richness in cucurbitane versus oleanane triterpenoid glycosides (CTGs vs. OTGs).

Conclusion: Our finding revealed a clear chemotype distribution of bioactive components across bitter melon varieties. While bioactivities of individual CTGs and OTGs still need to be investigated in more depth, our results could help in future the selection of bitter melon varieties with optimised metabolites profile for an improved management of diabetes with this popular edible Chinese folk medicine.
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http://dx.doi.org/10.1007/s11306-019-1565-7DOI Listing
July 2019

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.
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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.

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

Overexpression of cyclooxygenase-2 in adipocytes reduces fat accumulation in inguinal white adipose tissue and hepatic steatosis in high-fat fed mice.

Sci Rep 2019 06 20;9(1):8979. Epub 2019 Jun 20.

Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark.

Cyclooxygenases are known as important regulators of metabolism and immune processes via conversion of C20 fatty acids into various regulatory lipid mediators, and cyclooxygenase activity has been implicated in browning of white adipose tissues. We generated transgenic (TG) C57BL/6 mice expressing the Ptgs2 gene encoding cyclooxygenase-2 (COX-2) in mature adipocytes. TG mice fed a high-fat diet displayed marginally lower weight gain with less hepatic steatosis and a slight improvement in insulin sensitivity, but no difference in glucose tolerance. Compared to littermate wildtype mice, TG mice selectively reduced inguinal white adipose tissue (iWAT) mass and fat cell size, whereas the epididymal (eWAT) fat depot remained unchanged. The changes in iWAT were accompanied by increased levels of specific COX-derived lipid mediators and increased mRNA levels of interleukin-33, interleukin-4 and arginase-1, but not increased expression of uncoupling protein 1 or increased energy expenditure. Epididymal WAT (eWAT) in TG mice exhibited few changes except from increased infiltration with eosinophils. Our findings suggest a role for COX-2-derived lipid mediators from adipocytes in mediating type 2 immunity cues in subcutaneous WAT associated with decreased hepatic steatosis, but with no accompanying induction of browning and increased energy expenditure.
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http://dx.doi.org/10.1038/s41598-019-45062-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586826PMC
June 2019

Environmental and Nutritional Effects Regulating Adipose Tissue Function and Metabolism Across Generations.

Adv Sci (Weinh) 2019 Jun 16;6(11):1900275. Epub 2019 Apr 16.

Department of Health Science and Technologies ETH Zürich Schorenstrasse 16 Schwerzenbach CH-8603 Switzerland.

The unabated rise in obesity prevalence during the last 40 years has spurred substantial interest in understanding the reasons for this epidemic. Studies in mice and humans have demonstrated that obesity is a highly heritable disease; however genetic variations within specific populations have so far not been able to explain this phenomenon to its full extent. Recent work has demonstrated that environmental cues can be sensed by an organism to elicit lasting changes, which in turn can affect systemic energy metabolism by different epigenetic mechanisms such as changes in small noncoding RNA expression, DNA methylation patterns, as well as histone modifications. These changes can directly modulate cellular function in response to environmental cues, however research during the last decade has demonstrated that some of these modifications might be transmitted to subsequent generations, thus modulating energy metabolism of the progeny in an inter- as well as transgenerational manner. In this context, adipose tissue has become a focus of research due to its plasticity, which allows the formation of energy storing (white) as well as energy wasting (brown/brite/beige) cells within the same depot. In this Review, the effects of environmental induced obesity with a particular focus on adipose tissue are discussed.
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http://dx.doi.org/10.1002/advs.201900275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548959PMC
June 2019

Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs.

Proc Natl Acad Sci U S A 2019 05 6;116(21):10547-10556. Epub 2019 May 6.

Laboratory of Translational Nutrition Biology, Department of Health Sciences and Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland;

There is a growing body of evidence linking maternal overnutrition to obesity and psychopathology that can be conserved across multiple generations. Recently, we demonstrated in a maternal high-fat diet (HFD; MHFD) mouse model that MHFD induced enhanced hedonic behaviors and obesogenic phenotypes that were conserved across three generations via the paternal lineage, which was independent of sperm methylome changes. Here, we show that sperm tRNA-derived small RNAs (tsRNAs) partly contribute to the transmission of such phenotypes. We observe increased expression of sperm tsRNAs in the F1 male offspring born to HFD-exposed dams. Microinjection of sperm tsRNAs from the F1-HFD male into normal zygotes reproduces obesogenic phenotypes and addictive-like behaviors, such as increased preference of palatable foods and enhanced sensitivity to drugs of abuse in the resultant offspring. The expression of several of the differentially expressed sperm tsRNAs predicted targets such as and GRIN3A, which have been implicated in addiction pathology, are altered in the mesolimbic reward brain regions of the F1-HFD father and the resultant HFD-tsRNA offspring. Together, our findings demonstrate that sperm tsRNA is a potential vector that contributes to the transmission of MHFD-induced addictive-like behaviors and obesogenic phenotypes across generations, thereby emphasizing its role in diverse pathological outcomes.
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http://dx.doi.org/10.1073/pnas.1820810116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534971PMC
May 2019

ZFP30 promotes adipogenesis through the KAP1-mediated activation of a retrotransposon-derived Pparg2 enhancer.

Nat Commun 2019 04 18;10(1):1809. Epub 2019 Apr 18.

Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland.

Krüppel-associated box zinc finger proteins (KZFPs) constitute the largest family of mammalian transcription factors, but most remain completely uncharacterized. While initially proposed to primarily repress transposable elements, recent reports have revealed that KFZPs contribute to a wide variety of other biological processes. Using murine and human in vitro and in vivo models, we demonstrate here that one poorly studied KZFP, ZFP30, promotes adipogenesis by directly targeting and activating a retrotransposon-derived Pparg2 enhancer. Through mechanistic studies, we further show that ZFP30 recruits the co-regulator KRAB-associated protein 1 (KAP1), which, surprisingly, acts as a ZFP30 co-activator in this adipogenic context. Our findings provide an understanding of both adipogenic and KZFP-KAP1 complex-mediated gene regulation, showing that the KZFP-KAP1 axis can also function in a non-repressive manner.
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http://dx.doi.org/10.1038/s41467-019-09803-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472429PMC
April 2019

Fat cells with a sweet tooth.

Nature 2019 01;565(7738):167-168

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http://dx.doi.org/10.1038/d41586-018-07739-6DOI Listing
January 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.
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http://dx.doi.org/10.1016/j.cmet.2018.11.017DOI Listing
April 2019