bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023‒11‒05
eight papers selected by
José Carlos de Lima-Júnior, Washington University
  1. ATP-Bound State of the Uncoupling Protein 1 (UCP1) from Molecular Simulations.
  2. A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice.
  3. Adiponectin stimulates Sca1+CD34- adipocyte precursor cells associated with hyperplastic expansion and beiging of brown and white adipose tissue.
  4. Uncoupling protein 1-driven Cre ( Ucp1-Cre ) is expressed in the epithelial cells of mammary glands and various non-adipose tissues.
  5. DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress.
  6. LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.
  7. Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling.
  8. The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans.
  1. J Phys Chem B. 2023 Nov 03.
    ATP-Bound State of the Uncoupling Protein 1 (UCP1) from Molecular Simulations.
    Luise Jacobsen, Laura Lydersen, Himanshu Khandelia.
      The uncoupling protein 1 (UCP1) dissipates the transmembrane (TM) proton gradient in the inner mitochondrial membrane (IMM) by leaking protons across the membrane and producing heat in the process. Such a nonshivering production of heat in the brown adipose tissue can combat obesity-related diseases. UCP1-associated proton leak is activated by free fatty acids and inhibited by purine nucleotides. The mechanism of proton leak and the binding sites of the activators (fatty acids) remain unknown, while the binding site of the inhibitors (nucleotides) was described recently. Using molecular dynamics simulations, we generated a conformational ensemble of UCP1. Using metadynamics-based free energy calculations, we obtained the most likely ATP-bound conformation of UCP1. Our conformational ensemble provides a molecular basis for a breadth of prior biochemical data available for UCP1. Based on the simulations, we make the following testable predictions about the mechanisms of activation of proton leak and proton leak inhibition by ATP: (1) R277 plays the dual role of stabilizing ATP at the binding site for inhibition and acting as a proton surrogate for D28 in the absence of a proton during proton transport, (2) the binding of ATP to UCP1 is mediated by residues R84, R92, R183, and S88, (3) R92 shuttles ATP from the E191-R92 gate in the intermembrane space to the nucleotide binding site and serves to increase ATP affinity, (4) ATP can inhibit proton leak by controlling the ionization states of matrix facing lysine residues such as K269 and K56, and (5) fatty acids can bind to UCP1 from the IMM either via the cavity between TM1 and TM2 or between TM5 and TM6. Our simulations set the platform for future investigations into the proton transport and inhibition mechanisms of UCP1.
    DOI:  https://doi.org/10.1021/acs.jpcb.3c03473
  2. J Clin Invest. 2023 Nov 01. pii: e170072. [Epub ahead of print]133(21):
    A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice.
    Zhengyi Zhang, Ya Cui, Vivien Su, Dan Wang, Marcus J Tol, Lijing Cheng, Xiaohui Wu, Jason Kim, Prashant Rajbhandari, Sicheng Zhang, Wei Li, Peter Tontonoz, Claudio J Villanueva, Tamer Sallam.
      Interplay between energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of specialized niche, adipocytes require the activity of the nuclear receptor PPARγ for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ; however, the molecular mechanisms by which PPARγ licenses white adipose tissue to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ/long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity. Pharmacologic inhibition or genetic deletion of the lncRNA Lexis enhances uncoupling protein 1-dependent (UCP1-dependent) and -independent thermogenesis. Adipose-specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT that preserves white adipose tissue plasticity.
    Keywords:  Adipose tissue; Cardiology; Metabolism; Molecular genetics; Noncoding RNAs
    DOI:  https://doi.org/10.1172/JCI170072
  3. Metabolism. 2023 Oct 31. pii: S0026-0495(23)00320-7. [Epub ahead of print] 155716
    Adiponectin stimulates Sca1+CD34- adipocyte precursor cells associated with hyperplastic expansion and beiging of brown and white adipose tissue.
    Marco Bauzá-Thorbrügge, Milica Vujičić, Belén Chanclón, Vilborg Palsdottir, Nicolas J Pillon, Anna Benrick, Ingrid Wernstedt Asterholm.
      BACKGROUND: The adipocyte hormone adiponectin improves insulin sensitivity and there is an inverse correlation between adiponectin levels and type-2 diabetes risk. Previous research shows that adiponectin remodels the adipose tissue into a more efficient metabolic sink. For instance, mice that overexpress adiponectin show increased capacity for hyperplastic adipose tissue expansion as evident from smaller and metabolically more active white adipocytes. In contrast, the brown adipose tissue (BAT) of these mice looks "whiter" possibly indicating reduced metabolic activity. Here, we aimed to further establish the effect of adiponectin on adipose tissue expansion and adipocyte mitochondrial function as well as to unravel mechanistic aspects in this area.METHODS: Brown and white adipose tissues from adiponectin overexpressing (APN tg) mice and littermate wildtype controls, housed at room and cold temperature, were studied by histological, gene/protein expression and flow cytometry analyses. Metabolic and mitochondrial functions were studied by radiotracers and Seahorse-based technology. In addition, mitochondrial function was assessed in cultured adiponectin deficient adipocytes from APN knockout and heterozygote mice.
    RESULTS: APN tg BAT displayed increased proliferation prenatally leading to enlarged BAT. Postnatally, APN tg BAT turned whiter than control BAT, confirming previous reports. Furthermore, elevated adiponectin augmented the sympathetic innervation/activation within adipose tissue. APN tg BAT displayed reduced metabolic activity and reduced mitochondrial oxygen consumption rate (OCR). In contrast, APN tg inguinal white adipose tissue (IWAT) displayed enhanced metabolic activity. These metabolic differences between genotypes were apparent also in cultured adipocytes differentiated from BAT and IWAT stroma vascular fraction, and the OCR was reduced in both brown and white APN heterozygote adipocytes. In both APN tg BAT and IWAT, the mesenchymal stem cell-related genes were upregulated along with an increased abundance of Lineage-Sca1+CD34- "beige-like" adipocyte precursor cells. In vitro, the adiponectin receptor agonist Adiporon increased the expression of the proliferation marker Pcna and decreased the expression of Cd34 in Sca1+ mesenchymal stem cells.
    CONCLUSIONS: We propose that the seemingly opposite effect of adiponectin on BAT and IWAT is mediated by a common mechanism; while reduced adiponectin levels are linked to lower adipocyte OCR, elevated adiponectin levels stimulate expansion of adipocyte precursor cells that produce adipocytes with intrinsically higher metabolic rate than classical white but lower metabolic rate than classical brown adipocytes. Moreover, adiponectin can modify the adipocytes' metabolic activity directly and by enhancing the sympathetic innervation within a fat depot.
    Keywords:  Adipocyte; Adipocyte precursor cell; Adiponectin; Brown adipose tissue; Mitochondria; White adipose tissue
    DOI:  https://doi.org/10.1016/j.metabol.2023.155716
  4. bioRxiv. 2023 Oct 22. pii: 2023.10.19.563175. [Epub ahead of print]
    Uncoupling protein 1-driven Cre ( Ucp1-Cre ) is expressed in the epithelial cells of mammary glands and various non-adipose tissues.
    Kyungchan Kim, Jamie Wann, Hyeong-Geug Kim, Jisun So, Evan D Rosen, Hyun Cheol Roh.
      Objective: Uncoupling protein 1 (UCP1), a mitochondrial protein responsible for nonshivering thermogenesis in adipose tissue, serves as a distinct marker for thermogenic brown and beige adipocytes. Ucp1-Cre mice are thus widely used to genetically manipulate these thermogenic adipocytes. However, evidence suggests that UCP1 may also be expressed in non-adipocyte cell types. In this study, we investigated the presence of UCP1 expression in different mouse tissues that have not been previously reported.Methods: We employed Ucp1-Cre mice crossed with Cre-inducible transgenic reporter Nuclear tagging and Translating Ribosome Affinity Purification (NuTRAP) mice, to investigate Ucp1 - Cre expression in various tissues of adult female mice and developing embryos. Tamoxifen-inducible Ucp1-CreERT2 mice crossed with NuTRAP mice were used to assess active UCP1 expression. Immunostaining, RNA analysis, and single-cell/nucleus RNA-seq (sc/snRNA-seq) data analysis were performed to determine the expression of endogenous UCP1 and Ucp1-Cre -driven reporter expression. We also investigated the impact of UCP1 deficiency on mammary gland development and function using Ucp1 -knockout (KO) mice.
    Results: Ucp1-Cre expression was observed in the mammary glands within the inguinal white adipose tissue of female Ucp1-Cre ; NuTRAP mice. However, endogenous Ucp1 was not actively expressed as Ucp1-CreERT2 failed to induce the reporter expression in the mammary glands. Ucp1-Cre was activated during embryonic development in various tissues, including mammary glands, as well as in the brain, kidneys, eyes, and ears, specifically in epithelial cells in these organs. While sc/snRNA-seq data suggest potential expression of UCP1 in mammary epithelial cells in adult mice and humans, Ucp1 -KO female mice displayed normal mammary gland development and function.
    Conclusions: Our findings reveal widespread Ucp1-Cre expression in various non-adipose tissue types, starting during early development. These results highlight the importance of exercising caution when interpreting data and devising experiments involving Ucp1-Cre mice.
    DOI:  https://doi.org/10.1101/2023.10.19.563175
  5. Nat Commun. 2023 Oct 30. 14(1): 6900
    DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress.
    Gautham Yepuri, Lisa M Ramirez, Gregory G Theophall, Sergei V Reverdatto, Nosirudeen Quadri, Syed Nurul Hasan, Lei Bu, Devi Thiagarajan, Robin Wilson, Raquel López Díez, Paul F Gugger, Kaamashri Mangar, Navneet Narula, Stuart D Katz, Boyan Zhou, Huilin Li, Aleksandr B Stotland, Roberta A Gottlieb, Ann Marie Schmidt, Alexander Shekhtman, Ravichandran Ramasamy.
      Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
    DOI:  https://doi.org/10.1038/s41467-023-42521-x
  6. Cell Rep. 2023 Nov 01. pii: S2211-1247(23)01226-3. [Epub ahead of print]42(11): 113214
    LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.
    Haoran Sun, Jun Zhang, Qianqian Ye, Ting Jiang, Xueling Liu, Xiaoyang Zhang, Fanyu Zeng, Jie Li, Yue Zheng, Xianlin Han, Chuan Su, Yuguang Shi.
      Phosphatidylglycerol (PG) is a mitochondrial phospholipid required for mitochondrial cristae structure and cardiolipin synthesis. PG must be remodeled to its mature form at the endoplasmic reticulum (ER) after mitochondrial biosynthesis to achieve its biological functions. Defective PG remodeling causes MEGDEL (non-alcohol fatty liver disease and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like) syndrome through poorly defined mechanisms. Here, we identify LPGAT1, an acyltransferase that catalyzes PG remodeling, as a candidate gene for MEGDEL syndrome. We show that PG remodeling by LPGAT1 at the ER is closely coordinated with mitochondrial transport through interaction with the prohibitin/TIMM14 mitochondrial import motor. Accordingly, ablation of LPGAT1 or TIMM14 not only causes aberrant fatty acyl compositions but also ER retention of newly remodeled PG, leading to profound loss in mitochondrial crista structure and respiration. Consequently, genetic deletion of the LPGAT1 in mice leads to cardinal features of MEGDEL syndrome, including 3-methylglutaconic aciduria, deafness, dilated cardiomyopathy, and premature death, which are highly reminiscent of those caused by TIMM14 mutations in humans.
    Keywords:  CP: Cell biology; LPGAT1; MEGDEL syndrome; mitochondrial dysfunction; phosphatidylglycerol; prohibitin/TIM complex
    DOI:  https://doi.org/10.1016/j.celrep.2023.113214
  7. Nat Genet. 2023 Nov 02.
    Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling.
    Program for Undiagnosed Diseases (UD-PrOZA)
      Phospholipase A/acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3-/- and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation. Accordingly, CRISPR-Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function.
    DOI:  https://doi.org/10.1038/s41588-023-01535-3
  8. Cell Metab. 2023 Oct 20. pii: S1550-4131(23)00377-7. [Epub ahead of print]
    The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans.
    Panu K Luukkonen, Kimmo Porthan, Noora Ahlholm, Fredrik Rosqvist, Sylvie Dufour, Xian-Man Zhang, Tiina E Lehtimäki, Wenla Seppänen, Marju Orho-Melander, Leanne Hodson, Kitt Falk Petersen, Gerald I Shulman, Hannele Yki-Järvinen.
      The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.
    Keywords:  GDF-15; NAD+; NADH; NAFLD; NASH; ketogenic diet; mitochondrial dysfunction; patatin-like phospholipase domain containing protein 3; redox; reductive stress
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.008
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