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  • 1. Böhm, Anja
    et al.
    Keuper, Michaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Eberhard Karls University Tübingen, Germany.
    Meile, Tobias
    Zdichavsky, Marty
    Fritsche, Andreas
    Häring, Hans-Ulrich
    Hrabe de Angelis, Martin
    Staiger, Harald
    Franko, Andras
    Increased mitochondrial respiration of adipocytes from metabolically unhealthy obese compared to healthy obese individuals2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 12407Article in journal (Refereed)
    Abstract [en]

    Among obese subjects, metabolically healthy (MHO) and unhealthy obese (MUHO) subjects exist, the latter being characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Insulin resistance and obesity are known to associate with alterations in mitochondrial density, morphology, and function. Therefore, we assessed mitochondrial function in human subcutaneous preadipocytes as well as in differentiated adipocytes derived from well-matched donors. Primary subcutaneous preadipocytes from 4 insulin-resistant (MUHO) versus 4 insulin-sensitive (MHO), non-diabetic, morbidly obese Caucasians (BMI > 40 kg/m(2)), matched for sex, age, BMI, and percentage of body fat, were differentiated in vitro to adipocytes. Real-time cellular respiration was measured using an XF24 Extracellular Flux Analyzer (Seahorse). Lipolysis was stimulated by forskolin (FSK) treatment. Mitochondrial respiration was fourfold higher in adipocytes versus preadipocytes (p = 1.6*10(-9)). In adipocytes, a negative correlation of mitochondrial respiration with donors' insulin sensitivity was shown (p = 0.0008). Correspondingly, in adipocytes of MUHO subjects, an increased basal respiration (p = 0.002), higher proton leak (p = 0.04), elevated ATP production (p = 0.01), increased maximal respiration (p = 0.02), and higher spare respiratory capacity (p = 0.03) were found, compared to MHO. After stimulation with FSK, the differences in ATP production, maximal respiration and spare respiratory capacity were blunted. The differences in mitochondrial respiration between MUHO/MHO were not due to altered mitochondrial content, fuel switch, or lipid metabolism. Thus, despite the insulin resistance of MUHO, we could clearly show an elevated mitochondrial respiration of MUHO adipocytes. We suggest that the higher mitochondrial respiration reflects a compensatory mechanism to cope with insulin resistance and its consequences. Preserving this state of compensation might be an attractive goal for preventing or delaying the transition from insulin resistance to overt diabetes.

  • 2. Elhag, Sara
    et al.
    Stremmel, Christopher
    Zehrer, Annette
    Plocke, Josefine
    Hennel, Roman
    Keuper, Michaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Knabe, Clarissa
    Winterhalter, Julia
    Gölling, Vanessa
    Tomas, Lukas
    Weinberger, Tobias
    Fischer, Maximilian
    Liu, Lulu
    Wagner, Franziska
    Lorenz, Michael
    Stark, Konstantin
    Häcker, Hans
    Schmidt-Supprian, Marc
    Völker, Uwe
    Jastroch, Martin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lauber, Kirsten
    Straub, Tobias
    Walzog, Barbara
    Hammer, Elke
    Schulz, Christian
    Differences in Cell-Intrinsic Inflammatory Programs of Yolk Sac and Bone Marrow Macrophages2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 12, article id 3564Article in journal (Refereed)
    Abstract [en]

    Background: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood. Methods: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages. Results: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1 beta production in response to canonical and non-canonical inflammasome activation. Conclusions: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions.

  • 3.
    Gaudry, Michael J.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Keuper, Michaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jastroch, Martin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Molecular evolution of thermogenic uncoupling protein 1 and implications for medical intervention of human disease2019In: Molecular Aspects of Medicine, ISSN 0098-2997, E-ISSN 1872-9452, Vol. 68, p. 6-17Article, review/survey (Refereed)
    Abstract [en]

    In eutherian mammals, brown adipose tissue (BAT) permits non-shivering thermogenesis (NST) through high metabolic rates catalyzed by the unique mitochondrial uncoupling protein 1 (UCP1). The tissue has recently gained remarkable attention due to its discovery in adult humans. Approaching BAT and UCP1 as therapeutic targets to combust surplus energy bares high potential to combat the epidemic of the metabolic syndrome that has precipitated in our society as a result of our modern lifestyles. Our understanding of the physiological and molecular control of BAT may benefit tremendously from consideration of its evolution that basically outlines the blueprint of how to construct a fat burning tissue. Here, we discuss the evolutionary history of UCP1 and BAT, from its origins and emergence to its downfall in several mammalian lineages. Additionally, we delineate the annotation of UCPs in vertebrates by analyzing genomic organization and summarize the phylogeny of UCP1 within the closest relatives of humans, the great apes. Outlining whether the molecular networks controlling thermogenesis in adipose tissue (commonly known as the browning potential) pre-dated the classical thermogenic function of BAT and UCP1, and whether the evolutionary inactivation of UCP1 enhanced compensatory thermogenic mechanisms, should be of major interest to those who aim to access adipose tissue thermogenesis in a biomedical context.

  • 4.
    Herrnhold, Marie
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hamp, Isabel
    Plettenburg, Oliver
    Jastroch, Martin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Keuper, Michaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Adverse bioenergetic effects of N-acyl amino acids in human adipocytes overshadow beneficial mitochondrial uncoupling2023In: Redox Biology, E-ISSN 2213-2317, Vol. 66, article id 102874Article in journal (Refereed)
    Abstract [en]

    Objective: Enhancing energy turnover via uncoupled mitochondrial respiration in adipose tissue has great potential to improve human obesity and other metabolic complications. However, the amount of human brown adipose tissue and its uncoupling protein 1 (UCP1) is low in obese patients. Recently, a class of endogenous molecules, N-acyl amino acids (NAAs), was identified as mitochondrial uncouplers in murine adipocytes, presumably acting via the adenine nucleotide translocator (ANT). Given the translational potential, we investigated the bioenergetic effects of NAAs in human adipocytes, characterizing beneficial and adverse effects, dose ranges, amino acid derivatives and underlying mechanisms.

    Method: NAAs with neutral (phenylalanine, leucine, isoleucine) and polar (lysine) residues were synthetized and assessed in intact and permeabilized human adipocytes using plate-based respirometry. The Seahorse technology was applied to measure bioenergetic parameters, dose-dependency, interference with UCP1 and adenine nucleotide translocase (ANT) activity, as well as differences to the established chemical uncouplers niclosamide ethanolamine (NEN) and 2,4-dinitrophenol (DNP).

    Result: NAAs with neutral amino acid residues potently induce uncoupled respiration in human adipocytes in a dose-dependent manner, even in the presence of the UCP1-inhibitor guanosine diphosphate (GDP) and the ANT-inhibitor carboxyatractylate (CAT). However, neutral NAAs significantly reduce maximal oxidation rates, mitochondrial ATP-production, coupling efficiency and reduce adipocyte viability at concentrations above 25 μM. The in vitro therapeutic index (using induced proton leak and viability as determinants) of NAAs is lower than that of NEN and DNP.

    Conclusion: NAAs are potent mitochondrial uncouplers in human adipocytes, independent of UCP1 and ANT. However, previously unnoticed adverse effects harm adipocyte functionality, reduce the therapeutic index of NAAs in vitro and therefore question their suitability as anti-obesity agents without further chemical modifications.

  • 5.
    Keipert, Susanne
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Gaudry, Michael J.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kutschke, Maria
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Keuper, Michaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dela Rosa, Margeoux A. S.
    Cheng, Yiming
    Monroy Kuhn, José M.
    Laterveer, Rutger
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cotrim, Camila A.
    Giere, Peter
    Perocchi, Fabiana
    Feederle, Regina
    Crichton, Paul G.
    Lutter, Dominik
    Jastroch, Martin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Two-stage evolution of mammalian adipose tissue thermogenesis2024In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 384, no 6700, p. 1111-1117Article in journal (Refereed)
    Abstract [en]

    Brown adipose tissue (BAT) is a heater organ that expresses thermogenic uncoupling protein 1 (UCP1) to maintain high body temperatures during cold stress. BAT thermogenesis is considered an overarching mammalian trait, but its evolutionary origin is unknown. We show that adipose tissue of marsupials, which diverged from eutherian mammals ~150 million years ago, expresses a nonthermogenic UCP1 variant governed by a partial transcriptomic BAT signature similar to that found in eutherian beige adipose tissue. We found that the reconstructed UCP1 sequence of the common eutherian ancestor displayed typical thermogenic activity, whereas therian ancestor UCP1 is nonthermogenic. Thus, mammalian adipose tissue thermogenesis may have evolved in two distinct stages, with a prethermogenic stage in the common therian ancestor linking UCP1 expression to adipose tissue and thermal stress. We propose that in a second stage, UCP1 acquired its thermogenic function specifically in eutherians, such that the onset of mammalian BAT thermogenesis occurred only after the divergence from marsupials. 

  • 6.
    Keuper, Michaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    On the role of macrophages in the control of adipocyte energy metabolism2019In: Endocrine Connections, E-ISSN 2049-3614, Vol. 8, no 6, p. r105-R121Article, review/survey (Refereed)
    Abstract [en]

    The crosstalk between macrophages (MF) and adipocytes within white adipose tissue (WAT) influences obesity-associated insulin resistance and other associated metabolic disorders, such as atherosclerosis, hypertension and type 2 diabetes. MF infiltration is increased in WAT during obesity, which is linked to decreased mitochondrial content and activity. The mechanistic interplay between MF and mitochondrial function of adipocytes is under intense investigation, as MF and inflammatory pathways exhibit a pivotal role in the reprogramming of WAT metabolism in physiological responses during cold, fasting and exercise. Thus, the underlying immunometabolic pathways may offer therapeutic targets to correct obesity and metabolic disease. Here, I review the current knowledge on the quantity and the quality of human adipose tissue macrophages (ATM phi) and their impact on the bioenergetics of human adipocytes. The effects of ATM phi and their secreted factors on mitochondrial function of white adipocytes are discussed, including recent research on MF as part of an immune signaling cascade involved in the 'browning' of WAT, which is defined as the conversion from white, energy-storing adipocytes into brown, energy-dissipating adipocytes.

  • 7.
    Keuper, Michaela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Eberhard Karls University Tübingen, Germany; German Center for Diabetes Research (DZD), Germany.
    Häring, Hans-Ulrich
    Staiger, Harald
    Circulating FGF21 Levels in Human Health and Metabolic Disease2020In: Experimental and clinical endocrinology & diabetes, ISSN 0947-7349, E-ISSN 1439-3646, Vol. 128, no 11, p. 752-770Article, review/survey (Refereed)
    Abstract [en]

    Human fibroblast growth factor 21 (FGF21) is primarily produced and secreted by the liver as a hepatokine. This hormone circulates to its target tissues (e. g., brain, adipose tissue), which requires two components, one of the preferred FGF receptor isoforms (FGFR1c and FGFR3c) and the co-factor betaKlotho (KLB) to trigger downstream signaling pathways. Although targeting FGF21 signaling in humans by analogues and receptor agonists results in beneficial effects, e. g., improvements in plasma lipids and decreased body weight, it failed to recapitulate the improvements in glucose handling shown for many mouse models. FGF21's role and metabolic effects in mice and its therapeutic potential have extensively been reviewed elsewhere. In this review we focus on circulating FGF21 levels in humans and their associations with disease and clinical parameters, focusing primarily on obesity and obesity-associated diseases such as type-2 diabetes. We provide a comprehensive overview on human circulating FGF21 levels under normal physiology and metabolic disease. We discuss the emerging field of inactivating FGF21 in human blood by fibroblast activation protein (FAP) and its potential clinical implications.

  • 8.
    Keuper, Michaela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jastroch, Martin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The good and the BAT of metabolic sex differences in thermogenic human adipose tissue2021In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 533, article id 111337Article in journal (Refereed)
    Abstract [en]

    Thermogenic adipose tissue, which comprises classical brown and beige adipose tissue, has the ability to improve systemic metabolism. Its identification in adult humans has fostered extensive investigations on the therapeutic value to counteract obesity and metabolic disorders. Sex and gender differences of human thermogenic adipose tissue, however, are still understudied despite their importance for personalized treatment options. Here, we review studies reporting human sex differences of thermogenic adipose tissue and related potential improvements of systemic energy metabolism. An increasing body of evidence suggests higher prevalence, mass and activity of thermogenic adipose tissue in women, but the consequences for metabolic disease progression and mechanisms are largely unknown. Therefore, we also discuss observations on sex-specific adipose metabolism in experimental mouse and rat studies that may assist to establish molecular mechanisms and instruct future investigations in humans.

  • 9.
    Pfab, Alexander
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Belikov, Sergey
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Keuper, Michaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jastroch, Martin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mannervik, Mattias
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Inhibition of mitochondrial transcription by the neurotoxin MPP+2023In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 425, no 1, article id 113536Article in journal (Refereed)
    Abstract [en]

    The neurotoxin MPP+ triggers cell death of dopamine neurons and induces Parkinson's disease symptoms in mice and men, but the immediate transcriptional response to this neurotoxin has not been studied. We therefore treated human SH-SY5Y cells with a low dose (0.1 mM) of MPP+ and measured the effect on nascent transcription by precision run-on sequencing (PRO-seq). We found that transcription of the mitochondrial genome was significantly reduced already after 30 min, whereas nuclear gene transcription was unaffected. Inhibition of respiratory complex I by MPP+ led to reduced ATP production, that may explain the diminished activity of mitochondrial RNA polymerase. Our results show that MPP+ has a direct effect on mitochondrial function and transcription, and that other gene expression or epigenetic changes induced by this neurotoxin are secondary effects that reflect a cellular adaptation program.

  • 10. Tews, D.
    et al.
    Pula, T.
    Funcke, J. B.
    Jastroch, Martin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Keuper, Michaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Debatin, K. M.
    Wabitsch, M.
    Fischer-Posovszky, P.
    Elevated UCP1 levels are sufficient to improve glucose uptake in human white adipocytes2019In: Redox Biology, E-ISSN 2213-2317, Vol. 26, article id UNSP 101286Article in journal (Refereed)
    Abstract [en]

    Brown adipose tissue (BAT) has been considered beneficial for metabolic health by participating in the regulation of glucose homoeostasis. The browning factors that improve glucose uptake beyond normal levels are still unknown but glucose uptake is not affected in UCP1 knockout mice. Here, we demonstrate in human white adipocytes that basal/resting glucose uptake is improved by solely elevating UCP1 protein levels. Generating human white Simpson-Golabi-Behmel syndrome (SGBS) adipocytes with a stable knockout and overexpression of UCP1, we discovered that UCP1 overexpressing adipocytes significantly improve glucose uptake by 40%. Mechanistically, this is caused by higher glycolytic flux, seen as increased oxygen consumption, extracellular acidification and lactate secretion rates. The improvements in glucose handling are comparable to white-to-brown transitions, as judged by, for the first time, directly comparing in vitro differentiated mouse brown vs white adipocytes. Although no adipogenic, metabolic and mitochondrial gene expressions were significantly altered in SGBS cells, pharmacological inhibition of GLUT1 completely abrogated differences between UCP1 + and control cells, thereby uncovering GLUT1-mediated uptake as permissive gatekeeper. Collectively, our data demonstrate that elevating UCP1 levels is sufficient to improve human white adipocytes as a glucose sink without adverse cellular effects, thus not requiring the adrenergic controlled, complex network of browning which usually hampers translational efforts.

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