Publications by authors named "Martin Klingenspor"

172 Publications

Revisiting energy expenditure: how to correct mouse metabolic rate for body mass.

Nat Metab 2021 Sep 6. Epub 2021 Sep 6.

German Center for Diabetes Research, Neuherberg, Germany.

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http://dx.doi.org/10.1038/s42255-021-00451-2DOI Listing
September 2021

Secretin activates brown fat and induces satiation.

Nat Metab 2021 06 21;3(6):798-809. Epub 2021 Jun 21.

Turku PET Centre, University of Turku, Turku, Finland.

Brown adipose tissue (BAT) thermogenesis is activated by feeding. Recently, we revealed a secretin-mediated gut-BAT-brain axis, which stimulates satiation in mice, but the purpose of meal-induced BAT activation in humans has been unclear. In this placebo-controlled, randomized crossover study, we investigated the effects of intravenous secretin on BAT metabolism (measured with [F]FDG and [O]HO positron emission tomography) and appetite (measured with functional magnetic resonance imaging) in healthy, normal weight men (GUTBAT trial no. NCT03290846). Participants were blinded to the intervention. Secretin increased BAT glucose uptake (primary endpoint) compared to placebo by 57% (median (interquartile range, IQR), 0.82 (0.77) versus 0.59 (0.53) μmol per 100 g per min, 95% confidence interval (CI) (0.09, 0.89), P = 0.002, effect size r = 0.570), while BAT perfusion remained unchanged (mean (s.d.) 4.73 (1.82) versus 6.14 (3.05) ml per 100 g per min, 95%CI (-2.91, 0.07), P = 0.063, effect size d = -0.549) (n = 15). Whole body energy expenditure increased by 2% (P = 0.011) (n = 15). Secretin attenuated blood-oxygen level-dependent activity (primary endpoint) in brain reward circuits during food cue tasks (significance level false discovery rate corrected at P = 0.05) (n = 14). Caloric intake did not significantly change, but motivation to refeed after a meal was delayed by 39 min (P = 0.039) (n = 14). No adverse effects were detected. Here we show in humans that secretin activates BAT, reduces central responses to appetizing food and delays the motivation to refeed after a meal. This suggests that meal-induced, secretin-mediated BAT activation is relevant in the control of food intake in humans. As obesity is increasing worldwide, this appetite regulating axis offers new possibilities for clinical research in treating obesity.
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http://dx.doi.org/10.1038/s42255-021-00409-4DOI Listing
June 2021

Secretin as a Satiation Whisperer With the Potential to Turn into an Obesity-curbing Knight.

Endocrinology 2021 Sep;162(9)

Chair for Molecular Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany.

The obesity pandemic requires effective preventative and therapeutic intervention strategies. Successful and sustained obesity treatment is currently limited to bariatric surgery. Modulating the release of gut hormones is considered promising to mimic bariatric surgery with its beneficial effects on food intake, body weight, and blood glucose levels. The gut peptide secretin was the first molecule to be termed a hormone; nevertheless, only recently has it been established as a legitimate anorexigenic peptide. In contrast to gut hormones that crosstalk with the brain either directly or by afferent neuronal projections, secretin mediates meal-associated brown fat thermogenesis to induce meal termination, thereby qualifying this physiological mechanism as an attractive, peripheral target for the treatment of obesity. In this perspective, it is of pivotal interest to deepen our as yet superficial knowledge on the physiological roles of secretin as well as meal-associated thermogenesis in energy balance and body weight regulation. Of note, the emerging differences between meal-associated thermogenesis and cold-induced thermogenesis must be taken into account. In fact, there is no correlation between these 2 entities. In addition, the investigation of potential effects of secretin in hedonic-driven food intake, bariatric surgery and chronic treatment using suitable application strategies to overcome pharmacokinetic limitations will provide further insight into its potential to influence energy balance. The aim of this article is to review the facts on secretin's metabolic effects, address prevailing gaps in our knowledge, and provide an overview on the opportunities and challenges of the therapeutic potential of secretin in body weight control.
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http://dx.doi.org/10.1210/endocr/bqab113DOI Listing
September 2021

LncRNA Ctcflos orchestrates transcription and alternative splicing in thermogenic adipogenesis.

EMBO Rep 2021 07 31;22(7):e51289. Epub 2021 May 31.

Chair for Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.

The recruitment of thermogenic brite adipocytes within white adipose tissue attenuates obesity and metabolic comorbidities, arousing interest in understanding the underlying regulatory mechanisms. The molecular network of brite adipogenesis, however, remains largely unresolved. In this light, long noncoding RNAs (lncRNAs) emerged as a versatile class of modulators that control many steps within the differentiation machinery. Leveraging the naturally varying propensities of different inbred mouse strains for white adipose tissue browning, we identify the nuclear lncRNA Ctcflos as a pivotal orchestrator of thermogenic gene expression during brite adipocyte differentiation. Mechanistically, Ctcflos acts as a pleiotropic regulator, being essential for the transcriptional recruitment of the early core thermogenic regulatory program and the modulation of alternative splicing to drive brite adipogenesis. This is showcased by Ctcflos-regulated gene transcription and splicing of the key browning factor Prdm16 toward the isoform that is specific for the thermogenic gene program. Conclusively, our findings emphasize the mechanistic versatility of lncRNAs acting at several independent levels of gene expression for effective regulation of key differentiation factors to direct cell fate and function.
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http://dx.doi.org/10.15252/embr.202051289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256291PMC
July 2021

Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity.

EMBO Mol Med 2021 May 5;13(5):e13548. Epub 2021 May 5.

Rudolf-Virchow-Zentrum, Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.

Lipids are the most energy-dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron-mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high-fat diet-induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity.
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http://dx.doi.org/10.15252/emmm.202013548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103097PMC
May 2021

Fibroblast growth factor induced Ucp1 expression in preadipocytes requires PGE2 biosynthesis and glycolytic flux.

FASEB J 2021 05;35(5):e21572

Department of Molecular Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany.

High uncoupling protein 1 (Ucp1) expression is a characteristic of differentiated brown adipocytes and is linked to adipogenic differentiation. Paracrine fibroblast growth factor 8b (FGF8b) strongly induces Ucp1 transcription in white adipocytes independent of adipogenesis. Here, we report that FGF8b and other paracrine FGFs act on brown and white preadipocytes to upregulate Ucp1 expression via a FGFR1-MEK1/2-ERK1/2 axis, independent of adipogenesis. Transcriptomic analysis revealed an upregulation of prostaglandin biosynthesis and glycolysis upon Fgf8b treatment of preadipocytes. Oxylipin measurement by LC-MS/MS in FGF8b conditioned media identified prostaglandin E as a putative mediator of FGF8b induced Ucp1 transcription. RNA interference and pharmacological inhibition of the prostaglandin E biosynthetic pathway confirmed that PGE2 is causally involved in the control over Ucp1 transcription. Importantly, impairment of or failure to induce glycolytic flux blunted the induction of Ucp1, even in the presence of PGE . Lastly, a screening of transcription factors identified Nrf1 and Hes1 as required regulators of FGF8b induced Ucp1 expression. Thus, we conclude that paracrine FGFs co-regulate prostaglandin and glucose metabolism to induce Ucp1 expression in a Nrf1/Hes1-dependent manner in preadipocytes, revealing a novel regulatory network in control of Ucp1 expression in a formerly unrecognized cell type.
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http://dx.doi.org/10.1096/fj.202002795RDOI Listing
May 2021

Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists.

Mol Metab 2021 Jul 6;49:101181. Epub 2021 Feb 6.

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:

Objective: We assessed the spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics of GIPR mono-agonists, GLP-1R mono-agonists including semaglutide, and GLP-1/GIP dual-agonists MAR709 and tirzepatide.

Methods: Receptor G protein recruitment and internalization/trafficking dynamics were assessed using bioluminescence resonance energy transfer (BRET)-based technology and live-cell HILO microscopy.

Results: Relative to native and acylated GLP-1 agonists, MAR709 and tirzepatide showed preserved maximal cAMP production despite partial Gα recruitment paralleled by diminished ligand-induced receptor internalization at both target receptors. Despite MAR709's lower internalization rate, GLP-1R co-localization with Rab11-associated recycling endosomes was not different between MAR709 and GLP-1R specific mono-agonists.

Conclusions: Our data indicated that MAR709 and tirzepatide induce unique spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics relative to native peptides, semaglutide, and matched mono-agonist controls. These findings support the hypothesis that the structure of GLP-1/GIP dual-agonists confer a biased agonism that, in addition to its influence on intracellular signaling, uniquely modulates receptor trafficking.
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http://dx.doi.org/10.1016/j.molmet.2021.101181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921015PMC
July 2021

Multicompartmental non-invasive sensing of postprandial lipemia in humans with multispectral optoacoustic tomography.

Mol Metab 2021 05 5;47:101184. Epub 2021 Feb 5.

Technical University of Munich, School of Medicine, Chair of Biological Imaging, Germany; Helmholtz Zentrum München, Neuherberg, Institute of Biological and Medical Imaging, Germany. Electronic address:

Objective: Postprandial lipid profiling (PLP), a risk indicator of cardiometabolic disease, is based on frequent blood sampling over several hours after a meal, an approach that is invasive and inconvenient. Non-invasive PLP may offer an alternative for disseminated human monitoring. Herein, we investigate the use of clinical multispectral optoacoustic tomography (MSOT) for non-invasive, label-free PLP via direct lipid-sensing in human vasculature and soft tissues.

Methods: Four (n = 4) subjects (3 females and 1 male, age: 28 ± 7 years) were enrolled in the current pilot study. We longitudinally measured the lipid signals in arteries, veins, skeletal muscles, and adipose tissues of all participants at 30-min intervals for 6 h after the oral consumption of a high-fat meal.

Results: Optoacoustic lipid-signal analysis showed on average a 63.4% intra-arterial increase at ~ 4 h postprandially, an 83.9% intra-venous increase at ~ 3 h, a 120.8% intra-muscular increase at ~ 3 h, and a 32.8% subcutaneous fat increase at ~ 4 h.

Conclusion: MSOT provides the potential to study lipid metabolism that could lead to novel diagnostics and prevention strategies by label-free, non-invasive detection of tissue biomarkers implicated in cardiometabolic diseases.
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http://dx.doi.org/10.1016/j.molmet.2021.101184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918675PMC
May 2021

Isolation, Culture, and Functional Analysis of Murine Thermogenic Adipocytes.

STAR Protoc 2020 Dec 22;1(3):100118. Epub 2020 Sep 22.

Chair for Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Gregor-Mendel-Str. 2, 85354 Freising, Germany.

Studying brown and brite adipose tissue requires precise and reliable quantification of cellular thermogenesis. This protocol describes the isolation of primary murine pre-adipocytes, differentiation into thermogenic brown and brite adipocytes, and subsequent oxygen consumption analysis. Commonly applied procedures only measure basal and maximal proton leak-linked oxygen consumption but not explicitly uncoupling protein 1 (UCP1)-dependent respiration. Meaningful oxygen consumption analyses require (1) the activation of UCP1, (2) control over intracellular free-fatty-acid levels, and (3) inhibition of ATP-consuming futile cycles. For complete details on the use and execution of this protocol, please refer to Li et al. (2014, 2017, 2018) and Schweizer et al. (2018).
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http://dx.doi.org/10.1016/j.xpro.2020.100118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757011PMC
December 2020

No Effect of Dietary Fish Oil Supplementation on the Recruitment of Brown and Brite Adipocytes in Mice or Humans under Thermoneutral Conditions.

Mol Nutr Food Res 2021 01 21;65(2):e2000681. Epub 2020 Dec 21.

Chair for Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences, Freising, 85354, Germany.

Scope: Brown and brite adipocytes within the mammalian adipose organ provide non-shivering thermogenesis and thus, have an exceptional capacity to dissipate chemical energy as heat. Polyunsaturated fatty acids (PUFA) of the n3-series, abundant in fish oil, have been repeatedly demonstrated to enhance the recruitment of thermogenic capacity in these cells, consequently affecting body adiposity and glucose tolerance. These effects are scrutinized in mice housed in a thermoneutral environment and in a human dietary intervention trial.

Methods And Results: Mice are housed in a thermoneutral environment eliminating the superimposing effect of mild cold-exposure on thermogenic adipocyte recruitment. Dietary fish oil supplementation in two different inbred mouse strains neither affects body mass trajectory nor enhances the recruitment of brown and brite adipocytes, both in the presence and absence of a β3-adrenoreceptor agonist imitating the effect of cold-exposure on adipocytes. In line with these findings, dietary fish oil supplementation of persons with overweight or obesity fails to recruit thermogenic adipocytes in subcutaneous adipose tissue.

Conclusion: Thus, the authors' data question the hypothesized potential of n3-PUFA as modulators of adipocyte-based thermogenesis and energy balance regulation.
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http://dx.doi.org/10.1002/mnfr.202000681DOI Listing
January 2021

Uncoupling protein 1 expression does not protect mice from diet-induced obesity.

Am J Physiol Endocrinol Metab 2020 Nov 30. Epub 2020 Nov 30.

Chair for Molecular Nutritional Medicine, Technical University of Munich, Germany.

We studied the metabolic phenotype of a novel Ucp1-LUC-iRFP713 knock-in reporter gene mouse model originally generated to monitor endogenous Ucp1 gene expression. Both reporter mice and reporter cells reliably reflected Ucp1 gene expression in vivo and in vitro. We here report an unexpected reduction in UCP1 content in homozygous knock-in (KI) reporter mice. As a result, the thermogenic capacity of KI mice stimulated by norepinephrine was largely blunted, making them more sensitive to an acute cold exposure. In return, these reporter mice with reduced UCP1 expression enabled us to investigate the physiological role of UCP1 in the prevention of weight gain. We observed no substantial differences in body mass across the three genotypes, irrespective of the type of diet or the ambient temperature, possibly due to the insufficient UCP1 activation. Indeed, activation of UCP1 by daily injection of the selective β-adrenergic receptor agonist CL316,243 resulted in significantly greater reduction of body weight in WT mice than in KI mice. Taken together, we conclude that the intact expression of UCP1 is essential for cold-induced thermogenesis but the presence of UCP1 per se does not protect mice from diet-induced obesity.
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http://dx.doi.org/10.1152/ajpendo.00285.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260371PMC
November 2020

A Phenotyping Platform to Characterize Healthy Individuals Across Four Stages of Life - The Study.

Front Nutr 2020 28;7:582387. Epub 2020 Oct 28.

ZIEL - Institute for Food & Health, Technical University of Munich, Freising, Germany.

Nutritional habits and requirements are changing over the lifespan, but the dynamics of nutritional issues and the diet-health relationship in the major stages of the human life cycle are not sufficiently understood. A human phenotyping research platform for nutrition studies was established to recruit and phenotype selected population groups across different stages of life. The project is the backbone of the highly interdisciplinary competence cluster of nutrition research aiming to identify dietary determinants of a healthy life throughout the lifespan and to develop healthier and tasty convenience foods with high consumer acceptance. The phenotyping program included anthropometry, body composition analysis, assessment of energy metabolism, health and functional status, multisensory perception, metabolic phenotyping, lifestyle, sociodemography, chronobiology, and assessment of dietary intake including food preferences and aversions. In total, 503 healthy volunteers at four defined phases of life including 3-5-year old children ( = 44), young adults aged 18-25 years ( = 94), adults aged 40-65 years ("middle agers," = 205), and older adults aged 75-85 years ( = 160) were recruited and comprehensively phenotyped. Plasma, serum, buffy coat, urine, feces and saliva samples were collected and stored at -80°C. Significant differences in anthropometric and metabolic parameters between the four groups were found. A major finding was the decrease in fat-free mass and the concomitant increase in % body fat in both sexes across the adult lifespan. The dataset will provide novel information on differences in diet-related parameters over the lifespan and is available for targeted analyses. We expect that this novel platform approach will have implications for the development of innovative food products tailored to promote healthy eating throughout life. DRKS, DRKS00009797. Registered on 20 January 2016, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&_ID=DRKS00009797.
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http://dx.doi.org/10.3389/fnut.2020.582387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657309PMC
October 2020

Disturbed gut microbiota and bile homeostasis in -infected mice contributes to metabolic dysregulation and growth impairment.

Sci Transl Med 2020 10;12(565)

Institute of Medical Microbiology, RWTH University Hospital, 52074 Aachen, Germany.

Although infection with the human enteropathogen causes self-limited diarrhea in adults, infant populations in endemic areas experience persistent pathogen carriage in the absence of diarrhea. The persistence of this protozoan parasite in infants has been associated with reduced weight gain and linear growth (height-for-age). The mechanisms that support persistent infection and determine the different disease outcomes in the infant host are incompletely understood. Using a neonatal mouse model of persistent infection, we demonstrate that induced bile secretion and used the bile constituent phosphatidylcholine as a substrate for parasite growth. In addition, we show that infection altered the enteric microbiota composition, leading to enhanced bile acid deconjugation and increased expression of fibroblast growth factor 15. This resulted in elevated energy expenditure and dysregulated lipid metabolism with reduced adipose tissue, body weight gain, and growth in the infected mice. Our results indicate that this enteropathogen's modulation of bile acid metabolism and lipid metabolism in the neonatal mouse host led to an altered body composition, suggesting how infection could contribute to growth restriction in infants in endemic areas.
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http://dx.doi.org/10.1126/scitranslmed.aay7019DOI Listing
October 2020

Submucosal enteric neurons of the cavine distal colon are sensitive to hypoosmolar stimuli.

J Physiol 2020 12 16;598(23):5317-5332. Epub 2020 Sep 16.

Institute for Physiology and Cell Biology, University of Veterinary Medicine, Foundation, Hannover, Germany.

Key Points: Neurons of the enteric submucous plexus are challenged by osmolar fluctuations during digestion and absorption of nutrients. Central neurons are very sensitive to changes in osmolality but knowledge on that issue related to enteric neurons is sparse. The present study focuses on investigation of osmosensitivity of submucosal neurons including potential molecular mediating mechanisms. Results show that submucosal neurons respond to hypoosmolar stimuli with increased activity which is partially mediated by the transient receptor potential vanilloid 4 channel. We provided important information on osmosensitive properties of enteric neurons. These data are fundamental to better explain the nerve-mediated control of the gastrointestinal functions during physiological and pathophysiological (diarrhoea) conditions.

Abstract: Enteric neurons are located inside the gut wall, where they are confronted with changes in osmolality during (inter-) digestive periods. In particular, neurons of the submucous plexus (SMP), located between epithelial cells and blood vessels may sense and respond to osmotic shifts. The present study was conducted to investigate osmosensitivity of enteric submucosal neurons and the potential role of the transient receptor potential vanilloid 4 channel (TRPV4) as a mediator of enteric neuronal osmosensitivity. Therefore, freshly dissected submucosal preparations from guinea pig colon were investigated for osmosensitivity using voltage-sensitive dye and Ca imaging. Acute hypoosmolar stimuli (final osmolality reached at ganglia of 94, 144 and 194 mOsm kg ) were applied to single ganglia using a local perfusion system. Expression of TRPV4 in the SMP was quantified using qRT-PCR, and GSK1016790A and HC-067047 were used to activate or block the receptor, respectively, revealing its relevance in enteric osmosensitivity. On average, 11.0 [7.0/17.0] % of submucosal neurons per ganglion responded to the hypoosmolar stimulus. The Ca imaging experiments showed that glia responded to the hypoosmolar stimulus, but with a delay in comparison with neurons. mRNA expression of TRPV4 could be shown in the SMP and blockade of the receptor by HC-067047 significantly decreased the number of responding neurons (0.0 [0.0/6.3] %) while the TRPV4 agonist GSK1016790A caused action potential discharge in a subpopulation of osmosensitive enteric neurons. The results of the present study provide insight into the osmosensitivity of submucosal enteric neurons and strongly indicate the involvement of TRPV4 as an osmotransducer.
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http://dx.doi.org/10.1113/JP280309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722197PMC
December 2020

Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes.

J Hepatol 2020 12 26;73(6):1347-1359. Epub 2020 Jun 26.

Institute of Pathology, Technical University of Munich, Munich, Germany.

Background & Aims: Selective elimination of virus-infected hepatocytes occurs through virus-specific CD8 T cells recognizing peptide-loaded MHC molecules. Herein, we report that virus-infected hepatocytes are also selectively eliminated through a cell-autonomous mechanism.

Methods: We generated recombinant adenoviruses and genetically modified mouse models to identify the molecular mechanisms determining TNF-induced hepatocyte apoptosis in vivo and used in vivo bioluminescence imaging, immunohistochemistry, immunoblot analysis, RNAseq/proteome/phosphoproteome analyses, bioinformatic analyses, mitochondrial function tests.

Results: We found that TNF precisely eliminated only virus-infected hepatocytes independently of local inflammation and activation of immune sensory receptors. TNF receptor I was equally relevant for NF-kB activation in healthy and infected hepatocytes, but selectively mediated apoptosis in infected hepatocytes. Caspase 8 activation downstream of TNF receptor signaling was dispensable for apoptosis in virus-infected hepatocytes, indicating an unknown non-canonical cell-intrinsic pathway promoting apoptosis in hepatocytes. We identified a unique state of mitochondrial vulnerability in virus-infected hepatocytes as the cause for this non-canonical induction of apoptosis through TNF. Mitochondria from virus-infected hepatocytes showed normal biophysical and bioenergetic functions but were characterized by reduced resilience to calcium challenge. In the presence of unchanged TNF-induced signaling, reactive oxygen species-mediated calcium release from the endoplasmic reticulum caused mitochondrial permeability transition and apoptosis, which identified a link between extrinsic death receptor signaling and cell-intrinsic mitochondrial-mediated caspase activation.

Conclusion: Our findings reveal a novel concept in immune surveillance by identifying a cell-autonomous defense mechanism that selectively eliminates virus-infected hepatocytes through mitochondrial permeability transition.

Lay Summary: The liver is known for its unique immune functions. Herein, we identify a novel mechanism by which virus-infected hepatocytes can selectively eliminate themselves through reduced mitochondrial resilience to calcium challenge.
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http://dx.doi.org/10.1016/j.jhep.2020.06.026DOI Listing
December 2020

The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation.

Nat Commun 2020 05 8;11(1):2306. Epub 2020 May 8.

Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.

During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62 mice, global p62 and Ucp1-Cre p62 mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.
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http://dx.doi.org/10.1038/s41467-020-16230-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211001PMC
May 2020

Meltome atlas-thermal proteome stability across the tree of life.

Nat Methods 2020 05 13;17(5):495-503. Epub 2020 Apr 13.

Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.

We have used a mass spectrometry-based proteomic approach to compile an atlas of the thermal stability of 48,000 proteins across 13 species ranging from archaea to humans and covering melting temperatures of 30-90 °C. Protein sequence, composition and size affect thermal stability in prokaryotes and eukaryotic proteins show a nonlinear relationship between the degree of disordered protein structure and thermal stability. The data indicate that evolutionary conservation of protein complexes is reflected by similar thermal stability of their proteins, and we show examples in which genomic alterations can affect thermal stability. Proteins of the respiratory chain were found to be very stable in many organisms, and human mitochondria showed close to normal respiration at 46 °C. We also noted cell-type-specific effects that can affect protein stability or the efficacy of drugs. This meltome atlas broadly defines the proteome amenable to thermal profiling in biology and drug discovery and can be explored online at http://meltomeatlas.proteomics.wzw.tum.de:5003/ and http://www.proteomicsdb.org.
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http://dx.doi.org/10.1038/s41592-020-0801-4DOI Listing
May 2020

The gut hormone secretin triggers a gut-brown fat-brain axis in the control of food intake.

Exp Physiol 2020 08 6;105(8):1206-1213. Epub 2020 May 6.

TUM School of Life Sciences, Technical University of Munich, Freising, Germany.

New Findings: What is the topic of this review? Brown fat's role in meal-associated thermogenesis and the related consequences for energy balance regulation with a focus on the gut hormone secretin, which has been identified as the endocrine molecular mediator of meal-associated brown fat thermogenesis. What advances does it highlight? The finding of the secretin-induced gut-brown fat-brain axis creates new opportunities to manipulate brown fat and thereby energy balance in a natural way while living in a thermoneutral environment. The role of brown fat as a mere catabolic heater organ needs to be revised and more attention should be directed towards the regulatory role of brown fat beyond energy expenditure.

Abstract: Brown fat research concentrates on the energy expenditure function of this heating organ, whereas previous evidence for a role of brown fat in regulating energy intake has been mostly neglected. Ingestion of a single mixed meal activates human brown fat thermogenesis to the same degree as cold. In mice, activation of brown fat thermogenesis with a β -adrenergic receptor agonist inhibits food intake. Pharmacological β-blockade, however, inhibits neither meal-associated thermogenesis nor food intake. We recently identified the gut hormone secretin as a non-adrenergic activator of brown fat. In vivo, secretin treatment acutely increases energy expenditure and inhibits food intake in wild-type, but not in uncoupling protein 1 (UCP1)-knockout (KO) mice, which lack thermogenic brown fat function. Concurrently, secretin alters gene expression of melanocortinergic peptides of hypothalamic neurons in wild-type mice, but not UCP1-KO. Blocking endogenous secretin with a neutralizing antibody attenuates brown fat thermogenesis during refeeding, increases food intake of mice, and alters ad libitum feeding behaviour. Taken together, these findings demonstrate that secretin triggers an endocrine gut-brown adipose tissue-brain axis in the control of satiation. We hypothesize that meal-associated activation of brown adipose tissue thermogenesis induced by secretin results in a rise in brain temperature and increased melanocortinergic signalling. Taken together, brown fat is not a mere heating organ dissipating excess calories but also involved in gut-brain communication in the control of food intake.
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http://dx.doi.org/10.1113/EP087878DOI Listing
August 2020

Fatty Acid Metabolite Profiling Reveals Oxylipins as Markers of Brown but Not Brite Adipose Tissue.

Front Endocrinol (Lausanne) 2020 21;11:73. Epub 2020 Feb 21.

Chair for Molecular Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany.

Metabolites of omega-6 and omega-3 polyunsaturated fatty acids are important signaling molecules implicated in the control of adipogenesis and energy balance regulation. Some of these metabolites belonging to the group of oxylipins have been associated with non-shivering thermogenesis in mice mediated by brown or brite adipose tissue. We aimed to identify novel molecules with thermogenic potential and to clarify the relevance of these findings in a translational context. Therefore, we characterized and compared the oxylipin profiles of murine and human adipose tissues with different abundance of brown or brite adipocytes. A broad panel of 36 fatty acid metabolites was quantified in brown and white adipose tissues of C57BL/6J mice acclimatized to different ambient temperatures and in biopsies of human supraclavicular brown and white adipose tissue. The oxylipin profile of murine brite adipose tissue was not distinguishable from white adipose tissue, suggesting that adipose tissue browning is not associated with major changes in the oxylipin metabolism. Human brown and white adipose tissue also exhibited similar metabolite profiles. This is in line with previous studies proposing human brown adipose tissue to resemble the nature of murine brite adipose tissue representing a heterogeneous mixture of brite and white adipocytes. Although the global oxylipin profile served as a marker for the abundance of thermogenic adipocytes in bona fide brown but not white adipose tissue, we identified 5-HETE and 5,6-EET as individual compounds consistently associated with the abundance of brown or brite adipocytes in human BAT and murine brite fat. Further studies need to establish whether these candidates are mere markers or functional effectors of thermogenic capacity.
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http://dx.doi.org/10.3389/fendo.2020.00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046592PMC
March 2021

Proteomic and Metabolite Profiling Reveals Profound Structural and Metabolic Reorganization of Adipocyte Mitochondria in Obesity.

Obesity (Silver Spring) 2020 03 7;28(3):590-600. Epub 2020 Feb 7.

Chair of Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.

Objective: Previous studies have revealed decreased mitochondrial respiration in adipocytes of obese mice. This study aimed to identify the molecular underpinnings of altered mitochondrial metabolism in adipocytes.

Methods: Untargeted proteomics of mitochondria isolated from adipocytes and metabolite profiling of adipose tissues were conducted in diet-induced obese (DIO) and lean mice. Subcutaneous and intra-abdominal adipose tissues were studied to depict depot-specific alterations.

Results: In subcutaneous adipocytes of DIO mice, changes in proteins related to mitochondrial structure and function were observed. Mitochondrial proteins of the inner and outer membrane were strongly reduced, whereas proteins of key matrix metabolic pathways were increased in the obese versus lean state, as further substantiated by metabolite profiling. A pronounced decrease in the oxidative phosphorylation (OXPHOS) enzymatic equipment and cristae density of the inner membrane was identified. In intra-abdominal adipocytes, similar systematic downregulation of the OXPHOS machinery in obesity occurred, but there was no regulation of outer membrane or matrix proteins.

Conclusions: Protein components of the OXPHOS machinery are systematically downregulated in adipose tissues of DIO mice compared with lean mice. Loss of the mitochondrial OXPHOS capacity in adipocytes may aggravate the development of metabolic disease.
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http://dx.doi.org/10.1002/oby.22737DOI Listing
March 2020

Systems-Genetics-Based Inference of a Core Regulatory Network Underlying White Fat Browning.

Cell Rep 2019 12;29(12):4099-4113.e5

Chair for Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Gregor-Mendel-Str. 2, 85354 Freising, Germany; EKFZ-Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Gregor-Mendel-Str. 2, 85354 Freising, Germany. Electronic address:

Recruitment of brite/beige cells, known as browning of white adipose tissue (WAT), is an efficient way to turn an energy-storing organ into an energy-dissipating one and may therefore be of therapeutic value in combating obesity. However, a comprehensive understanding of the regulatory mechanisms mediating WAT browning is still lacking. Here, we exploit the large natural variation in WAT browning propensity between inbred mouse strains to gain an inclusive view of the core regulatory network coordinating this cellular process. Combining comparative transcriptomics, perturbation-based validations, and gene network analyses, we present a comprehensive gene regulatory network of inguinal WAT browning, revealing up to four distinct regulatory modules with key roles for uncovered transcriptional factors, while also providing deep insights into the genetic architecture of brite adipogenesis. The presented findings therefore greatly increase our understanding of the molecular drivers mediating the intriguing cellular heterogeneity and plasticity of adipose tissue.
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http://dx.doi.org/10.1016/j.celrep.2019.11.053DOI Listing
December 2019

Uncoupling protein 1 and the capacity for nonshivering thermogenesis are components of the glucose homeostatic system.

Am J Physiol Endocrinol Metab 2020 02 12;318(2):E198-E215. Epub 2019 Nov 12.

Chair for Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences, Freising, Germany.

Uncoupling protein 1 (Ucp1) provides nonshivering thermogenesis (NST) fueled by the dissipation of energy from macronutrients in brown and brite adipocytes. The availability of thermogenic fuels is facilitated by the uptake of extracellular glucose. This conjunction renders thermogenic adipocytes in brown and white adipose tissue (WAT) a potential target against obesity and glucose intolerance. We employed wild-type (WT) and Ucp1-ablated mice to elucidate this relationship. In three experiments of similar setup, Ucp1-ablated mice fed a high-fat diet (HFD) had either reduced or similar body mass gain, food intake, and metabolic efficiency compared with WT mice, challenging the hypothesized role of this protein in the development of diet-induced obesity. Despite the absence of increased body mass, oral glucose tolerance was robustly impaired in Ucp1-ablated mice in response to HFD. Postprandial glucose uptake was attenuated in brown adipose tissue but enhanced in subcutaneous WAT of Ucp1-ablated mice. These differences were explainable by expression of the insulin-responsive member 4 of the facilitated glucose transporter family and fully in line with the capacity for NST in these very tissues. Thus, the postprandial glucose uptake of adipose tissues serves as a surrogate measure for Ucp1-dependent and independent capacity for NST. Collectively, our findings corroborate Ucp1 as a modulator of adipose tissue glucose uptake and systemic glucose homeostasis but challenge its hypothesized causal effect on the development of obesity.
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http://dx.doi.org/10.1152/ajpendo.00121.2019DOI Listing
February 2020

The lipidome of primary murine white, brite, and brown adipocytes-Impact of beta-adrenergic stimulation.

PLoS Biol 2019 08 1;17(8):e3000412. Epub 2019 Aug 1.

ZIEL-Institute for Food & Health, Technical University of Munich, Freising, Germany.

Lipid species patterns are conserved within cells to maintain physicochemical properties of membranes and cellular functions. We present the lipidome, including sterols, glycerolipids (GLs), glycerophospholipids (GPLs), and sphingolipids (SLs), of primary ex vivo differentiated (I) white, (II) brite, and (III) brown adipocytes derived from primary preadipocytes isolated from (I) epididymal white, (II) inguinal white, and (III) intrascapular brown adipose tissue. Quantitative lipidomics revealed significantly decreased fractions of phosphatidylcholine (PC) and phosphatidylethanolamine (PE), with longer (C > 36) and more polyunsaturated species, as well as lower levels of cardiolipin (CL) in white than in brite and brown adipocytes. Together, the brite and brown lipidome was comparable and indicates differences in membrane lipid packing density compared with white adipocytes. Changes in ceramide species profile could be related to the degree of browning. Beta-adrenergic stimulation of brown adipocytes led to generation of saturated lyso-PC (LPC) increasing uncoupling protein (UCP) 1-mediated leak respiration. Application of stable isotope labeling showed that LPC formation was balanced by an increased de novo synthesis of PC.
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http://dx.doi.org/10.1371/journal.pbio.3000412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692052PMC
August 2019

Fibroblast growth factor 8b induces uncoupling protein 1 expression in epididymal white preadipocytes.

Sci Rep 2019 06 11;9(1):8470. Epub 2019 Jun 11.

Chair of Molecular Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany.

The number of brown adipocytes residing within murine white fat depots (brite adipocytes) varies a lot by depot, strain and physiological condition. Several endocrine fibroblast growth factors are implicated in the regulation of brite adipocyte abundance. The family of fibroblast growth factors can be categorized by their site of action into endocrine, paracrine and intracellular peptides. We here screened paracrine fibroblast growth factors for their potential to drive brite adipogenesis in differentiating epididymal white adipocytes and identified fibroblast growth factor 8b to induce uncoupling protein 1 expression, but at the same time to interfere in adipogenesis. In an in vivo trial, fibroblast growth factor 8b released into the epididymal fat depot failed to robustly increase the number of brite adipocytes. The specific action of fibroblast growth factor 8b on the uncoupling protein 1 promoter in cultured epididymal adipocytes provides a model system to dissect specific gene regulatory networks.
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http://dx.doi.org/10.1038/s41598-019-44878-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560125PMC
June 2019

Secretin Links Brown Fat to Food Intake: New Perspectives for Targeting Energy Balance in Humans.

Obesity (Silver Spring) 2019 06;27(6):875-877

Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.

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http://dx.doi.org/10.1002/oby.22477DOI Listing
June 2019

Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.

J Inherit Metab Dis 2019 09 11;42(5):839-849. Epub 2019 Jun 11.

Max Planck Institute for Molecular Genetics, Berlin, Germany.

Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by hemolytic anemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other observations indicate it could be a protein misfolding disease with tissue-specific differences in TPI activity. We generated a mouse model in which exchange of a conserved catalytic amino acid residue (isoleucine to valine, Ile170Val) reduces TPI specific activity without affecting the stability of the protein dimer. TPI mice exhibit an approximately 85% reduction in TPI activity consistently across all examined tissues, which is a stronger average, but more consistent, activity decline than observed in patients or symptomatic mouse models that carry structural defect mutant alleles. While monitoring protein expression levels revealed no evidence for protein instability, metabolite quantification indicated that glycolysis is affected by the active site mutation. TPI mice develop normally and show none of the disease symptoms associated with TPI deficiency. Therefore, without the stability defect that affects TPI activity in a tissue-specific manner, a strong decline in TPI catalytic activity is not sufficient to explain the pathological onset of TPI deficiency.
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http://dx.doi.org/10.1002/jimd.12105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887927PMC
September 2019

High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via Interleukin 8 and Alterations to the Gut Microbiome.

Gastroenterology 2019 08 15;157(2):492-506.e2. Epub 2019 Apr 15.

Irvine Cancer Research Center, Columbia University, New York, New York.

Background & Aims: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice.

Methods: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions.

Results: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development.

Conclusions: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
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http://dx.doi.org/10.1053/j.gastro.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662596PMC
August 2019

Adipose Mitochondrial Respiratory Capacity in Obesity is Impaired Independently of Glycemic Status of Tissue Donors.

Obesity (Silver Spring) 2019 05 26;27(5):756-766. Epub 2019 Mar 26.

Department of Nutritional Medicine, Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising-Weihenstephan, Germany.

Objective: The study aimed to investigate how obesity and glycemic state affect mitochondrial respiration and ATP-generating pathways in mature human adipocytes.

Methods: Subcutaneous (sc) and visceral (vc) adipocytes were isolated from patients undergoing abdominal surgery. Respiratory chain function was analyzed by high-resolution respirometry. Adipocyte ATP levels and lactate release were measured separately in the presence of either glycolysis (2-deoxy-D-glucose) or ATP synthase (oligomycin) inhibitors.

Results: A significant negative correlation between oxidative phosphorylation capacity and the BMI of tissue donors found in sc adipocytes (P < 0.05). Furthermore, respirometry revealed an inverse relationship between BMI and the electron transfer system capacity of sc (P < 0.05) but not vc adipocytes. In both depots, the respiratory capacity was not affected by the glycemic state. A positive correlation between BMI and adipocyte lactate release was measured independently of the tissue origin (sc: P = 0.01; vc: P < 0.05). Direct ATP measurements indicated that energy demands of adipocytes were predominantly fulfilled by glycolytic activity.

Conclusions: The study's data suggest that obesity is the primary driver of impaired adipocyte mitochondrial respiration because the glycemic state did not further deteriorate this situation. The adipocytes' energy needs are covered primarily by the glycolytic pathway.
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http://dx.doi.org/10.1002/oby.22435DOI Listing
May 2019

Opposing Actions of Adrenocorticotropic Hormone and Glucocorticoids on UCP1-Mediated Respiration in Brown Adipocytes.

Front Physiol 2018 17;9:1931. Epub 2019 Jan 17.

Chair for Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.

Brown fat is a potential target in the treatment of metabolic disorders as recruitment and activation of this thermogenic organ increases energy expenditure and promotes satiation. A large variety of G-protein coupled receptors, known as classical drug targets in pharmacotherapy, is expressed in brown adipocytes. In the present study, we analyzed transcriptome data for the expression of these receptors to identify potential pathways for the recruitment and activation of thermogenic capacity in brown fat. Our analysis revealed 12 G-coupled receptors abundantly expressed in murine brown fat. We screened ligands for these receptors in brown adipocytes for their ability to stimulate UCP1-mediated respiration and gene expression. Adrenocorticotropic hormone (ACTH), a ligand for the melanocortin 2 receptor (MC2R), turned out to be the most potent activator of UCP1 whereas its capability to stimulate gene expression was comparably low. Adrenocorticotropic hormone is the glandotropic hormone of the endocrine hypothalamus-pituitary-adrenal-axis stimulating the release of glucocorticoids in response to stress. In primary brown adipocytes ACTH acutely increased the cellular respiration rate similar to isoproterenol, a β-adrenergic receptor agonist. The effect of ACTH on brown adipocyte respiration was mediated via the MC2R as confirmed by using an antagonist. Inhibitor-based studies revealed that ACTH-induced respiration was dependent on protein kinase A and lipolysis, compatible with a rise of intracellular cAMP in response to ACTH. Furthermore, it is dependent on UCP1, as cells from UCP1-knockout mice did not respond. Taken together, ACTH is a non-adrenergic activator of murine brown adipocytes, initiating the canonical adenylyl cyclase-cAMP-protein kinase A-lipolysis-UCP1 pathway, and thus a potential target for the recruitment and activation of thermogenic capacity. Based on these findings in primary cell culture, the physiological significance might be that cold-induced ACTH in concert with norepinephrine released from sympathetic nerves contributes to BAT thermogenesis. Notably, dexamethasone attenuated isoproterenol-induced respiration. This effect increased gradually with the duration of pretreatment. , glucocorticoid release triggered by ACTH might oppose beta-adrenergic stimulation of metabolic fuel combustion in BAT and limit stress-induced hyperthermia.
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http://dx.doi.org/10.3389/fphys.2018.01931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344423PMC
January 2019

Bile acid supplementation decreases body mass gain in C57BL/6J but not 129S6/SvEvTac mice without increasing energy expenditure.

Sci Rep 2019 01 15;9(1):131. Epub 2019 Jan 15.

Chair of Molecular Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany.

Supplementation of cholate to a high fat diet can protect mice from diet-induced, increased body mass gain. It has been hypothesized that uncoupling protein 1 dependent, non-shivering thermogenesis in brown adipocytes provides the mechanism of increased energy expenditure to counteract excessive energy intake. We scrutinized this conjecture in wildtype mice and mice genetically devoid of a functional uncoupling protein 1 gene (C57BL/6J) as well as mice of the 129S6/SvEvTac strain that, in comparison, display an extraordinary capacity to recruit ectopic brown adipocytes. Protection from diet-induced, increased body mass gain by cholate supplementation was absent in 129S6/SvEvTac mice, a consequence of much lower bile acid absorption and spillover in this strain. Conversely, Ucp1-KO mice did not differ from C57BL/6J wildtype controls in any parameter assessed. Daily energy expenditure and resting metabolic rate of C57BL/6J mice remained unaffected by cholate supplementation. We conclude that protection of mice from diet-induced, increased body mass gain by cholate supplementation depends on the specific genetic background of C57BL/6J mice, does not involve increased energy expenditure and is independent of uncoupling protein 1 dependent non-shivering thermogenesis.
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http://dx.doi.org/10.1038/s41598-018-37464-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333827PMC
January 2019
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