bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022–09–04
seventeen papers selected by
José Carlos de Lima-Júnior, University of California San Francisco
  1. The role of somatosensory innervation of adipose tissues.
  2. Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism.
  3. Overexpression of Pregnancy Zone Protein in Fat Antagonizes Diet-Induced Obesity Under an Intermittent Fasting Regime.
  4. Association of shivering threshold time with body composition and brown adipose tissue in young adults.
  5. Selective adipocyte loss of Angiopoietin-2 prompts female-specific obesity and metabolic syndrome.
  6. TFAM expression in brown adipocytes confers obesity resistance by secreting extracellular vesicles that promote self-activation.
  7. Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing.
  8. Individual variation in heat substitution: is activity in the cold energetically cheaper for some individuals than others?
  9. Obesity-resistance of UCP1-deficient mice associates with sustained FGF21 sensitivity in inguinal adipose tissue.
  10. Piezo1 stimulates mitochondrial function via cAMP signaling.
  11. Adipocytes control food intake and weight regain via Vacuolar-type H+ ATPase.
  12. Proton-driven alternating access in a spinster lipid transporter.
  13. The human mitochondrial genome contains a second light strand promoter.
  14. Dexamethasone-associated metabolic effects in male mice are partially caused by depletion of endogenous corticosterone.
  15. Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.
  16. Blocking beige fat biogenesis.
  17. SLC41A1 knockout mice display normal magnesium homeostasis.
  1. Nature. 2022 Aug 31.
    The role of somatosensory innervation of adipose tissues.
    Yu Wang, Verina H Leung, Yunxiao Zhang, Victoria S Nudell, Meaghan Loud, M Rocio Servin-Vences, Dong Yang, Kristina Wang, Maria Dolores Moya-Garzon, Veronica L Li, Jonathan Z Long, Ardem Patapoutian, Li Ye.
      Adipose tissues communicate with the central nervous system to maintain whole-body energy homeostasis. The mainstream view is that circulating hormones secreted by the fat convey the metabolic state to the brain, which integrates peripheral information and regulates adipocyte function through noradrenergic sympathetic output1. Moreover, somatosensory neurons of the dorsal root ganglia innervate adipose tissue2. However, the lack of genetic tools to selectively target these neurons has limited understanding of their physiological importance. Here we developed viral, genetic and imaging strategies to manipulate sensory nerves in an organ-specific manner in mice. This enabled us to visualize the entire axonal projection of dorsal root ganglia from the soma to subcutaneous adipocytes, establishing the anatomical underpinnings of adipose sensory innervation. Functionally, selective sensory ablation in adipose tissue enhanced the lipogenic and thermogenetic transcriptional programs, resulting in an enlarged fat pad, enrichment of beige adipocytes and elevated body temperature under thermoneutral conditions. The sensory-ablation-induced phenotypes required intact sympathetic function. We postulate that beige-fat-innervating sensory neurons modulate adipocyte function by acting as a brake on the sympathetic system. These results reveal an important role of the innervation by dorsal root ganglia of adipose tissues, and could enable future studies to examine the role of sensory innervation of disparate interoceptive systems.
    DOI:  https://doi.org/10.1038/s41586-022-05137-7
  2. Sci Rep. 2022 Sep 01. 12(1): 14883
    Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism.
    Yohko Yoshida, Ippei Shimizu, Atsuhiro Shimada, Keita Nakahara, Sachiko Yanagisawa, Minoru Kubo, Shinji Fukuda, Chiharu Ishii, Hiromitsu Yamamoto, Takamasa Ishikawa, Kuniyuki Kano, Junken Aoki, Goro Katsuumi, Masayoshi Suda, Kazuyuki Ozaki, Yutaka Yoshida, Shujiro Okuda, Shigeo Ohta, Shiki Okamoto, Yasuhiko Minokoshi, Kanako Oda, Toshikuni Sasaoka, Manabu Abe, Kenji Sakimura, Yoshiaki Kubota, Norihiko Yoshimura, Shingo Kajimura, Maria Zuriaga, Kenneth Walsh, Tomoyoshi Soga, Tohru Minamino.
      Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.
    DOI:  https://doi.org/10.1038/s41598-022-19245-x
  3. Front Physiol. 2022 ;13 950619
    Overexpression of Pregnancy Zone Protein in Fat Antagonizes Diet-Induced Obesity Under an Intermittent Fasting Regime.
    Xiaoxiao Jiang, Jun Lin, Meng Dong, Xiaomeng Liu, Yuanyuan Huang, Hanlin Zhang, Rongcai Ye, Huiqiao Zhou, Chunlong Yan, Shouli Yuan, Li Chen, Rui Jiang, Kexin Zheng, Wanzhu Jin.
      The intermittent fasting regimen (IFR) has been certified as an effective strategy for improving metabolism. But the underlying mechanism is still obscure. Beige induction in white adipose tissue (WAT) by IFR may account for this. It has been demonstrated that the erupting of pregnancy zone protein (PZP) from the liver coincides with membrane translocation of grp78 in brown adipocytes during IFR to activate brown adipose tissue (BAT), which may partly explain the metabolic benefits of IFR. Liver-derived PZP appears to be responsible for all metabolic regulatory functions; the effect of boosting energy expenditure disappeared in liver-deficient mice. To verify whether any liver-specific modification was essential for functional PZP, we used the PZP adipose tissue-specific overexpression mice model (PZP TG). We found that the metabolic disorders induced by high-fat diet were improved in PZP TG mice under IFR. Additionally, in addition to the activation of BAT, UCP1 protein and angiogenesis were increased in WAT, as well as the expression of genes associated with glucose utilization. These results demonstrate that PZP fat-specific TG increased the energy conversion of WAT, indicating that WAT may be another direct target for PZP during IFR.
    Keywords:  beige; intermittent fasting regimen; pregnancy zone protein; vascularization; white adipose tissue
    DOI:  https://doi.org/10.3389/fphys.2022.950619
  4. J Therm Biol. 2022 Aug;pii: S0306-4565(22)00092-4. [Epub ahead of print]108 103277
    Association of shivering threshold time with body composition and brown adipose tissue in young adults.
    Aashley S D Sardjoe Mishre, Borja Martinez-Tellez, Francisco M Acosta, Guillermo Sanchez-Delgado, Maaike E Straat, Andrew G Webb, Hermien E Kan, Patrick C N Rensen, Jonatan R Ruiz.
       PURPOSE: Brown adipose tissue (BAT) increases metabolic heat production in response to cold exposure. Body size and composition are involved in the human cold response, yet the influence of BAT herein have not fully been explored. Here, we aimed to study the association of the cold-induced shivering threshold time with body composition, BAT, the perception of shivering and skin temperature in young adults.
    METHODS: 110 young healthy adults (81 females; age = 21.7 ± 2.1 years, BMI = 24.2 ± 4.3 kg/m2) underwent 2 h of individualized cooling, followed by the quantification of BAT using a18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography-computed tomography (PET-CT) scan. Body mass index (BMI), lean mass, fat mass and body surface area (BSA) were also measured. Shivering threshold time was defined as the time until shivering occurred using an individualized cooling protocol.
    RESULTS: The shivering threshold time was on average 116.1 min for males and 125.8 min for females, and was positively associated to BMI (β = 3.106; R2 = 0.141; p = 0.001), lean mass (β = 2.295; R2 = 0.128; p = 0.001) and fat mass (β = 1.492; R2 = 0.121; p = 0.001) in females, but not in males (all p ≥ 0.409). The shivering threshold time was positively associated with BSA in males (p = 0.047) and females (p = 0.001), but it was not associated with BAT volume or [18F]FDG uptake nor with the perception of shivering and skin temperature perception in both sexes.
    CONCLUSION: The shivering threshold time is positively associated with whole-body adiposity and lean mass in females, but not in males. The shivering threshold time was positively associated with BSA, but no association was observed with BAT nor with the perception of shivering or skin temperature. Future research should consider the influence of body composition when applying cooling protocols among individuals with different phenotypical features.
    Keywords:  Cold perception; Shivering time; Thermogenesis; brown fat
    DOI:  https://doi.org/10.1016/j.jtherbio.2022.103277
  5. Mol Metab. 2022 Aug 30. pii: S2212-8778(22)00157-0. [Epub ahead of print] 101588
    Selective adipocyte loss of Angiopoietin-2 prompts female-specific obesity and metabolic syndrome.
    Bin Ni, Shanshan Chen, Kathleen A Ryan, Michael L Maitland, Jared S Farrar, Martin Witzenrath, Birgitt Gubier, Cindy Serdjebi, Karine Bertotti, Rui Wang, Fadi N Salloum, Luigi Marino, Braxton D Mitchell, Francesco S Celi.
      Thermogenic fat differentiation and function can be promoted through multiple pathways, resulting in a common cell phenotype characterized by the expression of Uncoupling Protein-1 and the ability to dissipate energy, but local and systemic stimuli are necessary to promote adequate thermogenic fat vascularization, which is a precondition for the transport of substrate and the dissipation of heat. Angiopoietin-2 is an important driver of vascularization, and its transcription is in part promoted by estrogen signaling. In this study we demonstrate that adipose tissue-specific knock out of Angiopoietin-2 causes a female-specific reduced thermogenic fat differentiation and function, resulting in obesity and impaired glucose tolerance with end-organ features consistent with metabolic syndrome. In humans, angiopoietin-2 levels are higher in females than in males, and are inversely correlated with adiposity and age more strongly in pre-menopause when compared to post-menopause. Collectively, these data indicate a novel and important role for estrogen-mediated Angiopoietin-2 adipose tissue production in the protection against calorie overload in females, and potentially in the development of postmenopausal weight gain.
    Keywords:  ANGPT2; Ucp1; brown fat; estrogen; female; obesity
    DOI:  https://doi.org/10.1016/j.molmet.2022.101588
  6. iScience. 2022 Sep 16. 25(9): 104889
    TFAM expression in brown adipocytes confers obesity resistance by secreting extracellular vesicles that promote self-activation.
    Masakazu Fujii, Daiki Setoyama, Kazuhito Gotoh, Yushi Dozono, Mikako Yagi, Masataka Ikeda, Tomomi Ide, Takeshi Uchiumi, Dongchon Kang.
      The occurrence of diet-induced obesity has been increasing worldwide and has become a major health concern. Mitochondria are densely distributed in brown adipose tissue and are involved in lipid consumption. Therefore, increasing energy expenditure through the activation of brown adipocytes may be a potential therapy for obesity. Our findings showed that mitochondrial transcription factor A (TFAM) homozygous transgenic (TgTg) mice had highly activated brown adipocytes and increased expression of oxidative phosphorylation, leading to resistance to obesity. Transplantation models of TFAM-expressing brown adipocytes could mimic the phenotype of TFAM TgTg mice, and proving their anti-obesity effect. We found that brown adipocytes secrete exosomes which enable self-activation in an autocrine and paracrine manner. The secretion was enhanced in TFAM TgTg brown adipocytes, resulting in a higher activation. These findings may lead to a promising treatment strategy for obesity through selective stimulation of exosome secretion.
    Keywords:  Cell biology; Human metabolism; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.104889
  7. Commun Biol. 2022 Sep 02. 5(1): 900
    Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing.
    Christopher J Groten, Brian A MacVicar.
      Neuronal activation is fundamental to information processing by the brain and requires mitochondrial energy metabolism. Mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) has long been implicated in the control of energy metabolism and intracellular Ca2+ signalling, but its importance to neuronal function in the brain remains unclear. Here, we used in situ electrophysiology and two-photon imaging of mitochondrial Ca2+, cytosolic Ca2+, and NAD(P)H to test the relevance of MCU activation to pyramidal neuron Ca2+ signalling and energy metabolism during action potential firing. We demonstrate that mitochondrial Ca2+ uptake by the MCU is tuned to enhanced firing rate and the strength of this relationship varied between neurons of discrete brain regions. MCU activation promoted electron transport chain activity and chemical reduction of NAD+ to NADH. Moreover, Ca2+ buffering by mitochondria attenuated cytosolic Ca2+ signals and thereby reduced the coupling between activity and the slow afterhyperpolarization, a ubiquitous regulator of excitability. Collectively, we demonstrate that the MCU is engaged by accelerated spike frequency to facilitate neuronal activity through simultaneous control of energy metabolism and excitability. As such, the MCU is situated to promote brain functions associated with high frequency signalling and may represent a target for controlling excessive neuronal activity.
    DOI:  https://doi.org/10.1038/s42003-022-03848-1
  8. J Exp Biol. 2022 Aug 29. pii: jeb.244186. [Epub ahead of print]
    Individual variation in heat substitution: is activity in the cold energetically cheaper for some individuals than others?
    Caroline M Maloney, Vincent Careau.
      In many endotherms, a potentially important yet often overlooked mechanism to save energy is the use of the heat generated by active skeletal muscles to replace heat that would have been generated by thermogenesis (i.e., "activity-thermoregulatory heat substitution"). While substitution has been documented numerous times, the extent of individual variation in substitution has never been quantified. Here, we used a home-cage respirometry system to repeatedly measure substitution through the concomitant monitoring of metabolic rate (MR) and locomotor activity in 46 female white-footed mice (Peromyscus leucopus). A total of 117 measures of substitution were taken by quantifying the difference in the slope of the relationship between MR and locomotor activity speed at two different ambient temperatures. Consistency repeatability (±se) of substitution was 0.313±0.131 - hence, about a third of the variation in substitution occurs at the among-individual level. Body length and heart mass were positively correlated with substitution whereas surface area was negatively correlated with substitution. These two sub-organismal traits accounted for the majority of the among-individual variation (i.e., individual differences in substitution were not significant after accounting for these traits). Overall, our results imply that the energetic cost of activity below the thermoneutral zone is consistently cheaper from some individuals than others, and that the energy saved from substitution might be available to invest in fitness-enhancing activities.
    Keywords:  Activity-thermoregulatory heat substitution; Energy compensation; Repeatability; Thermoregulation
    DOI:  https://doi.org/10.1242/jeb.244186
  9. Front Endocrinol (Lausanne). 2022 ;13 909621
    Obesity-resistance of UCP1-deficient mice associates with sustained FGF21 sensitivity in inguinal adipose tissue.
    Marlou Klein Hazebroek, Susanne Keipert.
      Metabolic diseases represent the major health burden of our modern society. With the need of novel therapeutic approaches, fibroblast growth factor 21 (FGF21) is a promising target, based on metabolic improvements upon FGF21 administration in mice and humans. Endogenous FGF21 serum levels, however, are increased during obesity-related diseases, suggesting the development of FGF21 resistance during obesity and thereby lowering FGF21 efficacy. In uncoupling protein 1 knockout (UCP1 KO) mice, however, elevated endogenous FGF21 levels mediate resistance against diet-induced obesity. Here, we show that after long-term high fat diet feeding (HFD), circulating FGF21 levels become similarly high in obese wildtype and obesity-resistant UCP1 KO mice, suggesting improved FGF21 sensitivity in UCP1 KO mice. To test this hypothesis, we injected FGF21 after long-term HFD and assessed the metabolic and molecular effects. The UCP1 KO mice lost weight directly upon FGF21 administration, whereas body weights of WT mice resisted weight loss in the initial phase of the treatment. The FGF21 treatment induced expression of liver Pck1, a typical FGF21-responsive gene, in both genotypes. In iWAT, FGF21-responsive genes were selectively induced in UCP1 KO mice, strongly associating FGF21-sensitivity in iWAT with healthy body weights. Thus, these data support the concept that FGF21-sensitivity in adipose tissue is key for metabolic improvements during obesogenic diets.
    Keywords:  FGF21 resistance; FGF21 sensitivity; beige fat; beta klotho; browning; diet induced obesity
    DOI:  https://doi.org/10.3389/fendo.2022.909621
  10. FASEB J. 2022 Oct;36(10): e22519
    Piezo1 stimulates mitochondrial function via cAMP signaling.
    Xuehua Li, Jacob Kordsmeier, Intawat Nookaew, Ha-Neui Kim, Jinhu Xiong.
      Mechanical signals stimulate mitochondrial function but the molecular mechanisms are not clear. Here, we show that the mechanically sensitive ion channel Piezo1 plays a critical role in mitochondrial adaptation to mechanical stimulation. The activation of Piezo1 induced mitochondrial calcium uptake and oxidative phosphorylation (OXPHOS). In contrast, loss of Piezo1 reduced the mitochondrial oxygen consumption rate (OCR) and adenosine triphosphate (ATP) production in calvarial cells and these changes were associated with increased expression of the phosphodiesterases Pde4a and lower cyclic AMP (cAMP) levels. In addition, Piezo1 increased cAMP production and the activation of a cAMP-responsive transcriptional reporter. Consistent with this, cAMP was sufficient to increase mitochondrial OCR and the inhibition of phosphodiesterases augmented the increase in OCR induced by Piezo1. Moreover, the inhibition of cAMP production or activity of protein kinase A, a kinase activated by cAMP, prevented the increase in OCR induced by Piezo1. These results demonstrate that cAMP signaling contributes to the increase in mitochondrial OXPHOS induced by activation of Piezo1.
    DOI:  https://doi.org/10.1096/fj.202200300R
  11. Nat Commun. 2022 Aug 30. 13(1): 5092
    Adipocytes control food intake and weight regain via Vacuolar-type H+ ATPase.
    Rizaldy C Zapata, Maria Carretero, Felipe Castellani Gomes Reis, Besma S Chaudry, Jachelle Ofrecio, Dinghong Zhang, Roman Sasik, Theodore Ciaraldi, Michael Petrascheck, Olivia Osborn.
      Energy metabolism becomes dysregulated in individuals with obesity and many of these changes persist after weight loss and likely play a role in weight regain. In these studies, we use a mouse model of diet-induced obesity and weight loss to study the transcriptional memory of obesity. We found that the 'metabolic memory' of obesity is predominantly localized in adipocytes. Utilizing a C. elegans-based food intake assay, we identify 'metabolic memory' genes that play a role in food intake regulation. We show that expression of ATP6v0a1, a subunit of V-ATPase, is significantly induced in both obese mouse and human adipocytes that persists after weight loss. C. elegans mutants deficient in Atp6v0A1/unc32 eat less than WT controls. Adipocyte-specific Atp6v0a1 knockout mice have reduced food intake and gain less weight in response to HFD. Pharmacological disruption of V-ATPase assembly leads to decreased food intake and less weight re-gain. In summary, using a series of genetic tools from invertebrates to vertebrates, we identify ATP6v0a1 as a regulator of peripheral metabolic memory, providing a potential target for regulation of food intake, weight loss maintenance and the treatment of obesity.
    DOI:  https://doi.org/10.1038/s41467-022-32764-5
  12. Nat Commun. 2022 Sep 02. 13(1): 5161
    Proton-driven alternating access in a spinster lipid transporter.
    Reza Dastvan, Ali Rasouli, Sepehr Dehghani-Ghahnaviyeh, Samantha Gies, Emad Tajkhorshid.
      Spinster (Spns) lipid transporters are critical for transporting sphingosine-1-phosphate (S1P) across cellular membranes. In humans, Spns2 functions as the main S1P transporter in endothelial cells, making it a potential drug target for modulating S1P signaling. Here, we employed an integrated approach in lipid membranes to identify unknown conformational states of a bacterial Spns from Hyphomonas neptunium (HnSpns) and to define its proton- and substrate-coupled conformational dynamics. Our systematic study reveals conserved residues critical for protonation steps and their regulation, and how sequential protonation of these proton switches coordinates the conformational transitions in the context of a noncanonical ligand-dependent alternating access. A conserved periplasmic salt bridge (Asp60TM2:Arg289TM7) keeps the transporter in a closed conformation, while proton-dependent conformational dynamics are significantly enhanced on the periplasmic side, providing a pathway for ligand exchange.
    DOI:  https://doi.org/10.1038/s41467-022-32759-2
  13. Mol Cell. 2022 Aug 23. pii: S1097-2765(22)00764-X. [Epub ahead of print]
    The human mitochondrial genome contains a second light strand promoter.
    Benedict G Tan, Christian D Mutti, Yonghong Shi, Xie Xie, Xuefeng Zhu, Pedro Silva-Pinheiro, Katja E Menger, Héctor Díaz-Maldonado, Wei Wei, Thomas J Nicholls, Patrick F Chinnery, Michal Minczuk, Maria Falkenberg, Claes M Gustafsson.
      The human mitochondrial genome must be replicated and expressed in a timely manner to maintain energy metabolism and supply cells with adequate levels of adenosine triphosphate. Central to this process is the idea that replication primers and gene products both arise via transcription from a single light strand promoter (LSP) such that primer formation can influence gene expression, with no consensus as to how this is regulated. Here, we report the discovery of a second light strand promoter (LSP2) in humans, with features characteristic of a bona fide mitochondrial promoter. We propose that the position of LSP2 on the mitochondrial genome allows replication and gene expression to be orchestrated from two distinct sites, which expands our long-held understanding of mitochondrial gene expression in humans.
    Keywords:  DdCBE; LSP2; POLRMT; light strand promoter; mitochondria; mitochondrial DNA; mitochondrial gene expression; mitochondrial promoter; mtDNA; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.011
  14. Front Endocrinol (Lausanne). 2022 ;13 960279
    Dexamethasone-associated metabolic effects in male mice are partially caused by depletion of endogenous corticosterone.
    Lisa L Koorneef, Merel van der Meulen, Sander Kooijman, Elena Sánchez-López, Jari F Scheerstra, Maaike C Voorhoeve, Ajith N Nadamuni Ramesh, Patrick C N Rensen, Martin Giera, Jan Kroon, Onno C Meijer.
      Synthetic glucocorticoids are clinically used to treat auto-immune and inflammatory disease. Despite the high efficacy, glucocorticoid treatments causes side effects such as obesity and insulin resistance in many patients. Via their pharmacological target, the glucocorticoid receptor (GR), glucocorticoids suppress endogenous glucocorticoid secretion. Endogenous, but not synthetic, glucocorticoids activate the mineralocorticoid receptor (MR) and side effects of synthetic glucocorticoids may thus not only result from GR hyperactivation but also from MR hypoactivation. Here, we tested the hypothesis that reactivation of MR with corticosterone add-on treatment can attenuate the metabolic effects of the synthetic glucocorticoid dexamethasone. Male 8-week-old C57Bl/6J mice received a high-fat diet supplemented with dexamethasone or vehicle, and were subcutaneously implanted with low-dose corticosterone- or vehicle-containing pellets. Dexamethasone strongly reduced body weight and fat mass gain, while corticosterone add-on partially normalized this. Dexamethasone-induced hyperglycemia and hyperinsulinemia were exacerbated by corticosterone add-on, which was prevented by MR antagonism. In subcutaneous white adipose tissue, corticosterone add-on prevented the dexamethasone-induced expression of intracellular lipolysis genes. In brown adipose tissue, dexamethasone also upregulated gene expression of brown adipose tissue identity markers, lipid transporters and lipolysis enzymes, which was prevented by corticosterone add-on. In conclusion, corticosterone add-on treatment prevents several, while exacerbating other metabolic effects of dexamethasone. While the exact role of MR remains elusive, this study suggests that corticosterone suppression by dexamethasone contributes to its effects in mice.
    Keywords:  Aldosterone; GR-MR crosstalk; corticosterone; dexamethasone; eplerenone; glucocorticoid receptor; hypothalamus-pituitary-adrenal axis; mineralocorticoid receptor
    DOI:  https://doi.org/10.3389/fendo.2022.960279
  15. Nat Commun. 2022 Sep 02. 13(1): 5164
    Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.
    Jonas Benjamin Michaelis, Melinda Elaine Brunstein, Süleyman Bozkurt, Ludovico Alves, Martin Wegner, Manuel Kaulich, Christian Pohl, Christian Münch.
      Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the mitochondrial outer membrane. Strikingly, a number of conditions, including mitochondrial protein misfolding, can induce mitophagy without a loss in membrane potential. The underlying molecular details remain unclear. Here, we report that a loss of mitochondrial protein import, mediated by the pre-sequence translocase-associated motor complex PAM, is sufficient to induce mitophagy in polarized mitochondria. A genome-wide CRISPR/Cas9 screen for mitophagy inducers identifies components of the PAM complex. Protein import defects are able to induce mitophagy without a need for depolarization. Upon mitochondrial protein misfolding, PAM dissociates from the import machinery resulting in decreased protein import and mitophagy induction. Our findings extend the current mitophagy model to explain mitophagy induction upon conditions that do not affect membrane polarization, such as mitochondrial protein misfolding.
    DOI:  https://doi.org/10.1038/s41467-022-32564-x
  16. Sci Signal. 2022 Aug 30. 15(749): eade6057
    Blocking beige fat biogenesis.
    Amy E Baek.
      A ubiquitin E3 ligase complex limits the generation of beige fat.
    DOI:  https://doi.org/10.1126/scisignal.ade6057
  17. Am J Physiol Renal Physiol. 2022 Sep 01.
    SLC41A1 knockout mice display normal magnesium homeostasis.
    Barnabas P Ilenwabor, Gijs A C Franken, Gerhard Sponder, Caro Bos, Peter Racay, Martin Kolisek, Joost G J Hoenderop, Jeroen H F de Baaij.
      Transcellular magnesium (Mg2+) reabsorption in the distal convoluted tubule (DCT) of the kidneys plays an important role in maintaining systemic Mg2+ homeostasis. SLC41A1 is a sodium (Na+)-Mg2+ exchanger that mediates Mg2+ efflux from the cells and is hypothesized to facilitate basolateral extrusion of Mg2+ in the DCT. In this study, we generated a SLC41A1 knockout mouse model to examine the role of SLC41A1 in Mg2+ homeostasis. Slc41a1-/- mice exhibited similar serum and urine Mg2+ levels as their wildtype littermates. Dietary restriction of Mg2+ resulted in a reduced serum Mg2+ concentration and urinary Mg2+ excretion, which was similar in the wildtype and the knockout groups. Expression of genes encoding Mg2+ channels and transporters Trpm6, Trpm7, Cnnm2 and Slc41a3 were unchanged based on genotype. We investigated potential redundancy of SLC41A1 and its homologue SLC41A3 by generating a double knockout mouse. While Slc41a3-/- knockout mice showed significantly reduced serum Mg2+ compared to wildtype and Slc41a1-/- knockout groups, double knockout mice displayed similar serum Mg2+ levels as the single Slc41a3-/- knockout mice. In conclusion, our data shows that SLC41A1 is not involved in the regulation of systemic Mg2+ homeostasis in mice. Our data also demonstrate that SLC41A1 does not compensate for the loss of SLC41A3, suggesting different functions of these SLC41 proteins in vivo.
    Keywords:  Knockout mice; Magnesium; SLC41A1
    DOI:  https://doi.org/10.1152/ajprenal.00101.2022
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