bims-obesme 2024-09-08 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024‒09‒08
eleven papers selected by
Xiong Weng, University of Edinburgh

Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice.
Spatial Transcriptomic Study Reveals Heterogeneous Metabolic Adaptation and a Role of Pericentral PPARα/CAR/Ces2a Axis During Fasting in Mouse Liver.
Adipose stem cells are sexually dimorphic cells with dual roles as preadipocytes and resident fibroblasts.
ImAge quantitates aging and rejuvenation.
Keep calm and carry H3K27me1 off.
Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome.
Dysglycemia and liver lipid content determine the relationship of insulin resistance with hepatic OXPHOS capacity in obesity.
A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.
Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis.
Global 13C tracing and metabolic flux analysis of intact human liver tissue ex vivo.
Polyribonucleotide nucleotidyltransferase 1 participates in metabolic-associated fatty liver disease pathogenesis by affecting lipid metabolism and mitochondrial homeostasis.

Nat Commun. 2024 Sep 05. 15(1): 7746

Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice.

Min Yang, Jing Ge, Yu-Lian Liu, Huan-Yu Wang, Zhi-Han Wang, Dan-Pei Li, Rui He, Yu-Yu Xie, Hong-Yan Deng, Xue-Min Peng, Wen-She Wang, Jia-Dai Liu, Zeng-Zhe Zhu, Xue-Feng Yu, Pema Maretich, Shingo Kajimura, Ru-Ping Pan, Yong Chen.

Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Mitochondrial acyl-CoA synthetase long-chain family member 1 (ACSL1) localizes in the mitochondria and plays a key role in fatty acid oxidation; however, the regulatory mechanism of the subcellular localization remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that shows dynamic expression during beige fat activation and facilitates the translocation of ACSL1 from the mitochondria to the endolysosomal pathway for degradation. Depletion of sortilin in adipocytes results in an increase of mitochondrial ACSL1 and the activation of AMPK/PGC1α signaling, thereby activating beige fat and preventing high-fat diet (HFD)-induced obesity and insulin resistance. Collectively, our findings indicate that sortilin controls adipose tissue fatty acid oxidation by substrate fuel selection during beige fat activation and provides a potential targeted approach for the treatment of metabolic diseases.

DOI: https://doi.org/10.1038/s41467-024-52218-4
Adv Sci (Weinh). 2024 Sep 05. e2405240

Spatial Transcriptomic Study Reveals Heterogeneous Metabolic Adaptation and a Role of Pericentral PPARα/CAR/Ces2a Axis During Fasting in Mouse Liver.

Shiguan Wang, Bowen Xu, Jinyuan Liang, Yawei Feng, Penghu Han, Jing Shen, Xinying Li, Mengqi Zheng, Tingguo Zhang, Cuijuan Zhang, Ping Mi, Yi Zhang, Zhiping Liu, Shiyang Li, Detian Yuan.

  Spatial heterogeneity and plasticity of the mammalian liver are critical for systemic metabolic homeostasis in response to fluctuating nutritional conditions. Here, a spatially resolved transcriptomic landscape of mouse livers across fed, fasted and refed states using spatial transcriptomics is generated. This approach elucidated dynamic temporal-spatial gene cascades and how liver zonation-both expression levels and patterns-adapts to shifts in nutritional status. Importantly, the pericentral nuclear receptor Nr1i3 (CAR) as a pivotal regulator of triglyceride metabolism is pinpointed. It is showed that the activation of CAR in the pericentral region is transcriptionally governed by Pparα. During fasting, CAR activation enhances lipolysis by upregulating carboxylesterase 2a, playing a crucial role in maintaining triglyceride homeostasis. These findings lay the foundation for future mechanistic studies of liver metabolic heterogeneity and plasticity in response to nutritional status changes, offering insights into the zonated pathology that emerge during liver disease progression linked to nutritional imbalances.

Keywords:  constitutive androstane receptor (CAR); fasting response; liver zonation; metabolic heterogeneity; peroxisome proliferator‐activated receptor alpha (Pparα); spatial transcriptomics

DOI:  https://doi.org/10.1002/advs.202405240
Nat Commun. 2024 Sep 02. 15(1): 7643

Adipose stem cells are sexually dimorphic cells with dual roles as preadipocytes and resident fibroblasts.

Martin Uhrbom, Lars Muhl, Guillem Genové, Jianping Liu, Henrik Palmgren, Ida Alexandersson, Fredrik Karlsson, Alex-Xianghua Zhou, Sandra Lunnerdal, Sonja Gustafsson, Byambajav Buyandelger, Kasparas Petkevicius, Ingela Ahlstedt, Daniel Karlsson, Leif Aasehaug, Liqun He, Marie Jeansson, Christer Betsholtz, Xiao-Rong Peng.

Cell identities are defined by intrinsic transcriptional networks and spatio-temporal environmental factors. Here, we explored multiple factors that contribute to the identity of adipose stem cells, including anatomic location, microvascular neighborhood, and sex. Our data suggest that adipose stem cells serve a dual role as adipocyte precursors and fibroblast-like cells that shape the adipose tissue's extracellular matrix in an organotypic manner. We further find that adipose stem cells display sexual dimorphism regarding genes involved in estrogen signaling, homeobox transcription factor expression and the renin-angiotensin-aldosterone system. These differences could be attributed to sex hormone effects, developmental origin, or both. Finally, our data demonstrate that adipose stem cells are distinct from mural cells, and that the state of commitment to adipogenic differentiation is linked to their anatomic position in the microvascular niche. Our work supports the importance of sex and microvascular function in adipose tissue physiology.

DOI: https://doi.org/10.1038/s41467-024-51867-9
Nat Aging. 2024 Aug 29.

ImAge quantitates aging and rejuvenation.

Martin Alvarez-Kuglen, Kenta Ninomiya, Haodong Qin, Delany Rodriguez, Lorenzo Fiengo, Chen Farhy, Wei-Mien Hsu, Brian Kirk, Aaron Havas, Gen-Sheng Feng, Amanda J Roberts, Rozalyn M Anderson, Manuel Serrano, Peter D Adams, Tatyana O Sharpee, Alexey V Terskikh.

For efficient, cost-effective and personalized healthcare, biomarkers that capture aspects of functional, biological aging, thus predicting disease risk and lifespan more accurately and reliably than chronological age, are essential. We developed an imaging-based chromatin and epigenetic age (ImAge) that captures intrinsic age-related trajectories of the spatial organization of chromatin and epigenetic marks in single nuclei, in mice. We show that such trajectories readily emerge as principal changes in each individual dataset without regression on chronological age, and that ImAge can be computed using several epigenetic marks and DNA labeling. We find that interventions known to affect biological aging induce corresponding effects on ImAge, including increased ImAge upon chemotherapy treatment and decreased ImAge upon caloric restriction and partial reprogramming by transient OSKM expression in liver and skeletal muscle. Further, ImAge readouts from chronologically identical mice inversely correlated with their locomotor activity, suggesting that ImAge may capture elements of biological and functional age. In sum, we developed ImAge, an imaging-based biomarker of aging with single-cell resolution rooted in the analysis of spatial organization of epigenetic marks.

DOI: https://doi.org/10.1038/s43587-024-00685-1
Neuron. 2024 Sep 04. pii: S0896-6273(24)00536-1. [Epub ahead of print]112(17): 2829-2832

Keep calm and carry H3K27me1 off.

Rafael Alcalá-Vida, Angel Barco.

In this issue of Neuron, Torres-Berrío et al.1 show that stress-susceptible mice exhibit elevated H3K27me1 levels in nucleus accumbens neurons due to the action of the SUZ12 VEFS domain, strengthening the link between specific epigenetic changes and long-lasting stress-induced social, emotional, and cognitive alterations.

DOI: https://doi.org/10.1016/j.neuron.2024.07.014
Nat Aging. 2024 Aug 29.

Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome.

Suchira Gallage, Elaine E Irvine, Jose Efren Barragan Avila, Virinder Reen, Silvia M A Pedroni, Imanol Duran, Vikas Ranvir, Sanjay Khadayate, Joaquim Pombo, Sharon Brookes, Danijela Heide, Gopuraja Dharmalingham, Agharul I Choudhury, Indrabahadur Singh, Nicolás Herranz, Santiago Vernia, Mathias Heikenwalder, Jesús Gil, Dominic J Withers.

Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan.

DOI: https://doi.org/10.1038/s43587-024-00695-z
J Hepatol. 2024 Aug 30. pii: S0168-8278(24)02490-5. [Epub ahead of print]

Dysglycemia and liver lipid content determine the relationship of insulin resistance with hepatic OXPHOS capacity in obesity.

Sabine Kahl, Klaus Straßburger, Giovanni Pacini, Nina Trinks, Kalliopi Pafili, Lucia Mastrototaro, Bedair Dewidar, Theresia Sarabhai, Sandra Trenkamp, Irene Esposito, Matthias Schlensak, Frank A Granderath, Michael Roden.

  BACKGROUND & AIMS: Hepatic mitochondrial respiration is higher in steatosis, but lower in overt type 2 diabetes. We hypothesized that hepatic OXPHOS capacity increases with a greater degree of insulin resistance in obesity, independent of other metabolic diseases.METHODS: We analysed 65 humans without diabetes (BMI 50±7 kg/m2, HbA1c 5.5±0.4%) undergoing bariatric surgery. MASLD stages were assessed by histology, whole-body insulin sensitivity (PREDIcted-M index) by oral glucose tolerance tests, and maximal ADP-stimulated mitochondrial OXPHOS capacity by high-resolution respirometry of liver samples.
RESULTS: Prediabetes was present in 30 participants, and MASLD in 46 participants. Thereof, 25 had metabolic dysfunction-associated steatohepatitis (MASH), and seven had F2-F3 fibrosis. While simple regression did not detect an association of insulin sensitivity with hepatic OXPHOS capacity, interaction analyses revealed that the regression coefficient of OXPHOS capacity depended on fasting plasma glucose (FPG) and liver lipid content. Interestingly, the respective slopes were negative for FPG ≤100 mg/dl, but positive for FPG >100 mg/dl. Liver lipid content displayed similar behavior, with a threshold value of 24%. Post-challenge glycemia affected the association between insulin sensitivity and OXPHOS capacity normalized for citrate synthase activity. Presence of prediabetes affected hepatic insulin signaling, mitochondrial dynamics and fibrosis prevalence, while the presence of MASLD related to higher biomarkers of hepatic inflammation, cell damage and lipid peroxidation in people with normal glucose tolerance.
CONCLUSIONS: Rising liver lipid contents and plasma glucose concentrations, even in the non-diabetic range, are associated with a progressive decline of hepatic mitochondrial adaptation in people with obesity and insulin resistance. CLINTRIALS.
GOV IDENTIFIER: NCT01477957.

Keywords:  Energy metabolism; grade 3 obesity; impaired fasting glucose; impaired glucose tolerance; steatosis

DOI:  https://doi.org/10.1016/j.jhep.2024.08.012
Autophagy. 2024 Aug 30.

A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.

Sebastian J Hofer, Ioanna Daskalaki, Mahmoud Abdellatif, Ulrich Stelzl, Simon Sedej, Nektarios Tavernarakis, Guido Kroemer, Frank Madeo.

  Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice. Moreover, knockout or knockdown of the enzymes required for EIF5A hypusination abolish fasting-mediated autophagy enhancement and longevity extension in these organisms. Of note, autophagy and longevity induced by rapamycin obey the same rule, meaning that they are tied to an increase in spermidine synthesis. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin.

Keywords:  Aging; MTOR; autophagy; lifespan; rapamycin; spermidine

DOI:  https://doi.org/10.1080/15548627.2024.2396793
Nature. 2024 Sep 04.

Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis.

Minoru Takaoka, Xiaohui Zhao, Hwee Ying Lim, Costan G Magnussen, Owen Ang, Nadine Suffee, Patricia R Schrank, Wei Siong Ong, Dimitrios Tsiantoulas, Felix Sommer, Sarajo K Mohanta, James Harrison, Yaxing Meng, Ludivine Laurans, Feitong Wu, Yuning Lu, Leanne Masters, Stephen A Newland, Laura Denti, Mingyang Hong, Mouna Chajadine, Markus Juonala, Juhani S Koskinen, Mika Kähönen, Katja Pahkala, Suvi P Rovio, Juha Mykkänen, Russell Thomson, Tsuneyasu Kaisho, Andreas J R Habenicht, Marc Clement, Alain Tedgui, Hafid Ait-Oufella, Tian X Zhao, Meritxell Nus, Christiana Ruhrberg, Soraya Taleb, Jesse W Williams, Olli T Raitakari, Véronique Angeli, Ziad Mallat.

Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk1. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes2-4. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here, we make the unexpected observation that early intermittent feeding of mice with a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1+ resident macrophages are atheroprotective, and identify new biological pathways, related to actin filament organisation, whose alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insight into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat atherosclerotic cardiovascular disease.

DOI: https://doi.org/10.1038/s41586-024-07993-x
Nat Metab. 2024 Aug 29.

Global 13C tracing and metabolic flux analysis of intact human liver tissue ex vivo.

Nina Grankvist, Cecilia Jönsson, Karin Hedin, Nicolas Sundqvist, Per Sandström, Bergthor Björnsson, Arjana Begzati, Evgeniya Mickols, Per Artursson, Mohit Jain, Gunnar Cedersund, Roland Nilsson.

Liver metabolism is central to human physiology and influences the pathogenesis of common metabolic diseases. Yet, our understanding of human liver metabolism remains incomplete, with much of current knowledge based on animal or cell culture models that do not fully recapitulate human physiology. Here, we perform in-depth measurement of metabolism in intact human liver tissue ex vivo using global 13C tracing, non-targeted mass spectrometry and model-based metabolic flux analysis. Isotope tracing allowed qualitative assessment of a wide range of metabolic pathways within a single experiment, confirming well-known features of liver metabolism but also revealing unexpected metabolic activities such as de novo creatine synthesis and branched-chain amino acid transamination, where human liver appears to differ from rodent models. Glucose production ex vivo correlated with donor plasma glucose, suggesting that cultured liver tissue retains individual metabolic phenotypes, and could be suppressed by postprandial levels of nutrients and insulin, and also by pharmacological inhibition of glycogen utilization. Isotope tracing ex vivo allows measuring human liver metabolism with great depth and resolution in an experimentally tractable system.

DOI: https://doi.org/10.1038/s42255-024-01119-3
Mol Metab. 2024 Aug 30. pii: S2212-8778(24)00153-4. [Epub ahead of print] 102022

Polyribonucleotide nucleotidyltransferase 1 participates in metabolic-associated fatty liver disease pathogenesis by affecting lipid metabolism and mitochondrial homeostasis.

Canghai Guan, Xinlei Zou, Chengru Yang, Wujiang Shi, Jianjun Gao, Yifei Ge, Zhaoqiang Xu, Shaowu Bi, Xiangyu Zhong.

  OBJECTIVE: Metabolic-associated fatty liver disease (MAFLD) represents one of the most prevalent chronic liver conditions worldwide, but its precise pathogenesis remains unclear. This research endeavors to elucidate the involvement and molecular mechanisms of polyribonucleotide nucleotidyltransferase 1 (PNPT1) in the progression of MAFLD.METHODS: The study employed western blot and qRT-PCR to evaluate PNPT1 levels in liver specimens from individuals diagnosed with MAFLD and in mouse models subjected to a high-fat diet. Cellular studies investigated the effects of PNPT1 on lipid metabolism, apoptosis, and mitochondrial stability in hepatocytes. Immunofluorescence was utilized to track the subcellular movement of PNPT1 under high lipid conditions. RNA immunoprecipitation and functional assays were conducted to identify interactions between PNPT1 and Mcl-1 mRNA. The role of PPARα as an upstream transcriptional regulator of PNPT1 was investigated. Recombinant adenoviral vectors were utilized to modulate PNPT1 expression in vivo.
RESULTS: PNPT1 was found to be markedly reduced in liver tissues from MAFLD patients and HFD mice. In vitro, PNPT1 directly regulated hepatic lipid metabolism, apoptosis, and mitochondrial stability. Under conditions of elevated lipids, PNPT1 relocated from mitochondria to cytoplasm, modifying its physiological functions. RNA immunoprecipitation revealed that the KH and S1 domains of PNPT1 bind to and degrade Mcl-1 mRNA, which in turn affects mitochondrial permeability. The transcriptional regulator PPARα was identified as a significant influencer of PNPT1, impacting both its expression and subsequent cellular functions. Alterations in PNPT1 expression were directly correlated with the progression of MAFLD in mice.
CONCLUSIONS: The study confirms the pivotal function of PNPT1 in the development of MAFLD through its interactions with Mcl-1 and its regulatory effects on lipid metabolism and mitochondrial stability. These insights highlight the intricate association between PNPT1 and MAFLD, shedding light on its molecular pathways and presenting a potential new therapeutic avenue for MAFLD management.

Keywords:  Mcl-1; PNPT1; PPARα; lipid metabolism; metabolic-associated fatty liver disease; mitochondrial membrane permeability

DOI:  https://doi.org/10.1016/j.molmet.2024.102022