bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024–07–28
eight papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.
  2. Topical menthol, a pharmacological cold mimic, induces cold sensitivity, adaptive thermogenesis and brown adipose tissue activation in mice.
  3. Misaligned feeding uncouples daily rhythms within brown adipose tissue and between peripheral clocks.
  4. Non-invasive mapping of brown adipose tissue activity with magnetic resonance imaging.
  5. Inhibition of ethanol-induced eNAMPT secretion attenuates liver ferroptosis through BAT-Liver communication.
  6. Mitochondrial functions and fatty acid profiles in fish heart: an insight into physiological limitations linked with thermal tolerance and age.
  7. Assessing the mechanism of facilitated proton transport across GUVs trapped in a microfluidic device.
  8. LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance.
  1. J Lipid Res. 2024 Jul 20. pii: S0022-2275(24)00106-8. [Epub ahead of print] 100601
    Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.
    Kailash Venkatraman, Itay Budin.
      Cardiolipin (CL) is a unique, four-chain phospholipid synthesized in the inner mitochondrial membrane (IMM). The acyl chain composition of CL is regulated through a remodeling pathway, whose loss causes mitochondrial dysfunction in Barth syndrome (BTHS). Yeast has been used extensively as a model system to characterize CL metabolism, but mutants lacking its two remodeling enzymes, Cld1p and Taz1p, exhibit mild structural and respiratory phenotypes compared to mammalian cells. Here we show the essential role of CL remodeling in the structure and function of the IMM in yeast grown under reduced oxygenation. Microaerobic fermentation, which mimics natural yeast environments, caused the accumulation of saturated fatty acids and, under these conditions, remodeling mutants showed a loss of IMM ultrastructure. We extended this observation to HEK293 cells, where iPLA2 inhibition by Bromoenol lactone resulted in respiratory dysfunction and cristae loss upon mild treatment with exogenous saturated fatty acids. In microaerobic yeast, remodeling mutants accumulated unremodeled, saturated CL, but also displayed reduced total CL levels, highlighting the interplay between saturation and CL biosynthesis and breakdown. We identified the mitochondrial phospholipase A1 Ddl1p as a regulator of CL levels, and those of its precursors phosphatidylglycerol and phosphatidic acid, under these conditions. Loss of DDL1 partially rescued IMM structure in cells unable to initiate CL remodeling and had differing lipidomic effects depending on oxygenation. These results introduce a revised yeast model for investigating CL remodeling and suggest that its structural functions are dependent on the overall lipid environment in the mitochondrion.
    Keywords:  Barth Syndrome; Cardiolipin; Lipid saturation; Mitochondria; Phospholipids
    DOI:  https://doi.org/10.1016/j.jlr.2024.100601
  2. Diabetes Obes Metab. 2024 Jul 23.
    Topical menthol, a pharmacological cold mimic, induces cold sensitivity, adaptive thermogenesis and brown adipose tissue activation in mice.
    Polina Sankina, Roshan Lal, Pragyanshu Khare, Stephan von Hörsten, Lars Fester, Vaishali Aggarwal, Katharina Zimmermann, Mahendra Bishnoi.
       AIM: Brown adipose tissue (BAT) thermogenesis has profound energy-expanding potential, which makes it an attractive target tissue to combat ever-increasing obesity and its other associated metabolic complications. Although it is fairly accepted that cold is a potent inducer of BAT activation and function, there are limited studies on the mechanisms of pharmacological cold-mimicking agents, such as the TRPM8 agonist, menthol, on BAT thermogenesis and activation.
    METHODS: Herein, we sought to determine the effect of topical application of menthol (10% w/v [4 g/kg] cream formulation/day for 15 days) on temperature sensitivity behaviour (thermal gradient assay, nesting behaviour), adaptive thermogenesis (infrared thermography, core body temperature), BAT sympathetic innervation (tyrosine hydroxylase immunohistochemistry) and activation (18F-FDG PET-CT analysis, Uncoupling Protein 1 immunohistochemistry and BAT gene expression), whole-body energy expenditure (indirect calorimetry) and other metabolic variables in male C57BL/6N mice.
    RESULTS: We show that male C57BL/6N mice: (a) develop a warm-seeking and cold-avoiding thermal preference phenotype; (b) display increased locomotor activity and adaptive thermogenesis; (c) show augmented sympathetic innervation in BAT and its activation; (d) exhibit enhanced gluconeogenic capacity (increased glucose excursion in response to pyruvate) and insulin sensitivity; and (e) show enhanced whole-body energy expenditure and induced lipid-utilizing phenotype after topical menthol application.
    CONCLUSIONS: Taken together, our findings highlight that pharmacological cold mimicking using topical menthol application presents a potential therapeutic strategy to counter weight gain and related complications.
    Keywords:  TRPM8; brown adipose tissue; lipid utilizing; menthol; thermogenesis; topical
    DOI:  https://doi.org/10.1111/dom.15781
  3. Cell Rep. 2024 Jul 23. pii: S2211-1247(24)00852-0. [Epub ahead of print]43(8): 114523
    Misaligned feeding uncouples daily rhythms within brown adipose tissue and between peripheral clocks.
    Victoria A Acosta-Rodríguez, Filipa Rijo-Ferreira, Laura van Rosmalen, Mariko Izumo, Noheon Park, Chryshanthi Joseph, Chelsea Hepler, Anneke K Thorne, Jeremy Stubblefield, Joseph Bass, Carla B Green, Joseph S Takahashi.
      Extended food consumption during the rest period perturbs the phase relationship between circadian clocks in the periphery and the brain, leading to adverse health effects. Beyond the liver, how metabolic organs respond to a timed hypocaloric diet is largely unexplored. We investigated how feeding schedules impacted circadian gene expression in epididymal white and brown adipose tissue (eWAT and BAT) compared to the liver and hypothalamus. We restricted food to either daytime or nighttime in C57BL/6J male mice, with or without caloric restriction. Unlike the liver and eWAT, rhythmic clock genes in the BAT remained insensitive to feeding time, similar to the hypothalamus. We uncovered an internal split within the BAT in response to conflicting environmental cues, displaying inverted oscillations on a subset of metabolic genes without modifying its local core circadian machinery. Integrating tissue-specific responses on circadian transcriptional networks with metabolic outcomes may help elucidate the mechanism underlying the health burden of eating at unusual times.
    Keywords:  CP: Metabolism; brown adipose tissue; caloric restriction; circadian clocks; dietary interventions; liver; misaligned feeding; mouse behavior; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.celrep.2024.114523
  4. Nat Metab. 2024 Jul;6(7): 1367-1379
    Non-invasive mapping of brown adipose tissue activity with magnetic resonance imaging.
    Zimeng Cai, Qiaoling Zhong, Yanqiu Feng, Qian Wang, Zuoman Zhang, Cailv Wei, Zhinan Yin, Changhong Liang, Chong Wee Liew, Lawrence Kazak, Aaron M Cypess, Zaiyi Liu, Kejia Cai.
      Thermogenic brown adipose tissue (BAT) has a positive impact on whole-body metabolism. However, in vivo mapping of BAT activity typically relies on techniques involving ionizing radiation, such as [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) and computed tomography (CT). Here we report a noninvasive metabolic magnetic resonance imaging (MRI) approach based on creatine chemical exchange saturation transfer (Cr-CEST) contrast to assess in vivo BAT activity in rodents and humans. In male rats, a single dose of the β3-adrenoceptor agonist (CL 316,243) or norepinephrine, as well as cold exposure, triggered a robust elevation of the Cr-CEST MRI signal, which was consistent with the [18F]FDG PET and CT data and 1H nuclear magnetic resonance measurements of creatine concentration in BAT. We further show that Cr-CEST MRI detects cold-stimulated BAT activation in humans (both males and females) using a 3T clinical scanner, with data-matching results from [18F]FDG PET and CT measurements. This study establishes Cr-CEST MRI as a promising noninvasive and radiation-free approach for in vivo mapping of BAT activity.
    DOI:  https://doi.org/10.1038/s42255-024-01082-z
  5. Redox Biol. 2024 Jul 22. pii: S2213-2317(24)00252-0. [Epub ahead of print]75 103274
    Inhibition of ethanol-induced eNAMPT secretion attenuates liver ferroptosis through BAT-Liver communication.
    Yujia Zhou, Nengzhi Pang, Wenli Li, Qiuyan Li, Jing Luo, Yingying Gu, Qianrong Hu, Yi Jie Ding, Yan Sun, Jie Pan, Mengqi Gao, Ying Xiao, Sixi Ma, Yanxu Hao, Huichun Xing, Evendro Fei Fang, Wenhua Ling, Zhenfeng Zhang, Lili Yang.
       BACKGROUND & AIMS: Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) has long been recognized as an adipokine. However, the exact role of eNAMPT in alcoholic liver disease (ALD) and its relevance to brown adipose tissue (BAT) remain largely unknown. This study aimed to evaluate the impact of eNAMPT on liver function and the underlying mechanisms involved in BAT-Liver communication.
    METHODS: Serum eNAMPT levels were detected in the serum of both ALD patients and mice. Chronic and binge ethanol feeding was used to induce alcoholic liver injury in mice. An eNAMPT antibody, a coculture model of brown adipocytes and hepatocytes, and BAT-specific Nampt knockdown mice were used to investigate the role of eNAMPT in ALD.
    RESULTS: Serum eNAMPT levels are elevated in ALD patients and are significantly positively correlated with the liver injury index. In ALD mice, neutralizing eNAMPT reduced the elevated levels of circulating eNAMPT induced by ethanol and attenuated liver injury. In vitro experiments revealed that eNAMPT induced hepatocyte ferroptosis through the TLR4-dependent mitochondrial ROS-induced ferritinophagy pathway. Furthermore, ethanol stimulated eNAMPT secretion from brown adipocytes but not from other adipocytes. In the coculture model, ethanol-induced release of eNAMPT from brown adipocytes promoted hepatocyte ferroptosis. In BAT-specific Nampt-knockdown mice, ethanol-induced eNAMPT secretion was significantly reduced, and alcoholic liver injury were attenuated. These effects can be reversed by intraperitoneal injection of eNAMPT.
    CONCLUSION: Inhibition of ethanol-induced eNAMPT secretion from BAT attenuates liver injury and ferroptosis. Our study reveals a previously uncharacterized critical role of eNAMPT-mediated BAT-Liver communication in ALD and highlights its potential as a therapeutic target.
    Keywords:  Alcoholic liver injury; Brown adipose tissue; Ferroptosis; Mitochondrial dysfunction; eNAMPT
    DOI:  https://doi.org/10.1016/j.redox.2024.103274
  6. J Exp Biol. 2024 Jul 22. pii: jeb.247502. [Epub ahead of print]
    Mitochondrial functions and fatty acid profiles in fish heart: an insight into physiological limitations linked with thermal tolerance and age.
    Simon Chouinard-Boisvert, Léopold Ghinter, Amélie St-Pierre, Mathieu Mortz, Véronique Desrosiers, France Dufresne, Jean-Claude Tardif, Johnny Huard, Pascal Sirois, Samuel Fortin, Pierre U Blier.
      Heart failure is among the first major consequences of heat stress in aquatic ectotherms. Mitochondria produce most of the ATP used by the heart and represent almost half of the volume in cardiac cells. It has therefore been hypothesized that mitochondrial dysfunctions may be highly involved in heart failure associated with heat stress. The present study aims to investigate if CTmax is linked to the thermal sensitivity of three-spined sticklebacks' (G. aculeatus) cardiac mitochondria, and if it is influenced by heart fatty acid composition and age. To do so, we measured the CTmax of 30 fish. The cardiac mitochondrial oxygen consumption was measured by high resolution respirometry at three temperatures and heart lipid profiles were obtained by Gas chromatography (GC) coupled with a Flame Ionization Detector (FID). Fish age was estimated via otolith readings. Fatty acid profiles showed no correlation with CTmax, but EPA levels were higher in older individuals. Mitochondrial respiration was measured in 35 fish using high resolution respirometry. It was strongly affected by temperature and showed a drastic drop in OXPHOS respiration fed by Complex I and Complex I+II, while uncoupled respiration plateaued at CTmax temperature. Our results suggest that Complex I is an important modulator of the impact of temperature on mitochondrial respiration at high temperatures but is not the main limiting factor in physiological conditions (maximal OXPHOS). Mitochondrial respiration was also affected by fish age, showing a general decrease in older individuals.
    Keywords:  Age; CTmax; Ectotherms; Membrane lipids; Mitochondrial respiration
    DOI:  https://doi.org/10.1242/jeb.247502
  7. Biophys J. 2024 Jul 25. pii: S0006-3495(24)00489-2. [Epub ahead of print]
    Assessing the mechanism of facilitated proton transport across GUVs trapped in a microfluidic device.
    Dominik Ruppelt, Elena L M Ackermann, Tom Robinson, Claudia Steinem.
      Proton transport across lipid membranes is one of the most fundamental reactions that make up living organisms. In vitro, however, the study of proton transport reactions can be very challenging due to limitations imposed by proton concentrations, compartment size, and unstirred layers as well as buffer exchange and buffer capacity. In this study, we have developed a proton permeation assay based on the microfluidic trapping of giant vesicles enclosing the pH-sensitive dye pyranine to address some of these challenges. Time-resolved fluorescence imaging upon a rapid pH shift enabled us to investigate the facilitated H+-permeation mediated by either a channel or a carrier. Specifically, we compared the proton transport rates as a function of different proton gradients of the channel gramicidin D and the proton carrier carbonyl cyanide-m-chlorophenyl hydrazone (CCCP). Our results demonstrate the efficacy of the assay in monitoring proton transport reactions and distinguishing between a channel-like and a carrier-like mechanism. This groundbreaking result enabled us to elucidate the enigmatic mode of the proton permeation mechanism of the recently discovered natural fibupeptide lugdunin.
    DOI:  https://doi.org/10.1016/j.bpj.2024.07.030
  8. Nat Commun. 2024 Jul 20. 15(1): 6126
    LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance.
    Olga Kubrak, Anne F Jørgensen, Takashi Koyama, Mette Lassen, Stanislav Nagy, Jacob Hald, Gianluca Mazzoni, Dennis Madsen, Jacob B Hansen, Martin Røssel Larsen, Michael J Texada, Jakob L Hansen, Kenneth V Halberg, Kim Rewitz.
      Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network.
    DOI:  https://doi.org/10.1038/s41467-024-50468-w
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:22.