Molecular Metabolism最新文献

{"title":"Incretin-responsive human pancreatic adipose tissue organoids: A functional model for fatty pancreas research","authors":"E. Lorza-Gil ,&nbsp;O.D. Strauss ,&nbsp;E. Ziegler ,&nbsp;K. Kansy ,&nbsp;M.-T. Katschke ,&nbsp;G. Rahimi ,&nbsp;D. Neuscheler ,&nbsp;L. Sandforth ,&nbsp;A. Sandforth ,&nbsp;G. Sancar ,&nbsp;B. Kaufmann ,&nbsp;D. Hartmann ,&nbsp;S. Singer ,&nbsp;A.L. Mihaljevic ,&nbsp;R. Jumpertz-von Schwartzenberg ,&nbsp;J. Sbierski-Kind ,&nbsp;T.D. Müller ,&nbsp;A.L. Birkenfeld ,&nbsp;F. Gerst","doi":"10.1016/j.molmet.2024.102067","DOIUrl":"10.1016/j.molmet.2024.102067","url":null,"abstract":"<div><h3>Objective</h3><div>Infiltration of adipocytes into the pancreatic parenchyma has been linked to impaired insulin secretion in individuals with increased genetic risk of T2D and prediabetic conditions. However, the study of this ectopic fat depot has been limited by the lack of suitable <em>in vitro</em> models.</div></div><div><h3>Methods</h3><div>Here, we developed a novel 3D model of functionally mature human pancreatic adipose tissue organoids by aggregating human pancreatic adipose tissue-derived stromal vascular fraction (SVF) cells into organoids and differentiating them over 19 days.</div></div><div><h3>Results</h3><div>These organoids carry biological properties of the <em>in situ</em> pancreatic fat, presenting levels of adipogenic markers comparable to native pancreatic adipocytes and improved lipolytic and anti-lipolytic response compared to conventional 2D cultures. The organoids harbour a small population of immune cells, mimicking <em>in vivo</em> adipose environment. Furthermore, they express GIPR, allowing investigation of incretin effects in pancreatic fat. In accordance, GIP and the dual GLP1R/GIPR agonist tirzepatide stimulate lipolysis but had distinct effects on the expression of proinflammatory cytokines.</div></div><div><h3>Conclusions</h3><div>This novel adipose organoid model is a valuable tool to study the metabolic impact of incretin signalling in pancreatic adipose tissue, revealing potential therapeutic targets of incretins beyond islets. The donor-specific metabolic memory of these organoids enables examination of the pancreatic fat-islet crosstalk in a donor-related metabolic context.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102067"},"PeriodicalIF":7.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Essential role of germ cell glycerol-3-phosphate phosphatase for sperm health, oxidative stress control and male fertility in mice","authors":"Abel Oppong ,&nbsp;Yat Hei Leung ,&nbsp;Anindya Ghosh ,&nbsp;Marie-Line Peyot ,&nbsp;Marilène Paquet ,&nbsp;Carlos Morales ,&nbsp;Hugh J. Clarke ,&nbsp;Fahd Al-Mulla ,&nbsp;Alexandre Boyer ,&nbsp;S. R. Murthy Madiraju ,&nbsp;Derek Boerboom ,&nbsp;Cristian O'Flaherty ,&nbsp;Marc Prentki","doi":"10.1016/j.molmet.2024.102063","DOIUrl":"10.1016/j.molmet.2024.102063","url":null,"abstract":"<div><h3>Objectives</h3><div>Obesity, diabetes and high-calorie diets are associated with defective sperm function and lowered male fertility. Mature spermatozoa primarily use fructose and glucose, and glucose and glycerol metabolism are important for sperm function. We recently discovered a novel mammalian enzyme, glycerol-3-phosphate (Gro3P) phosphatase (G3PP), and showed that it operates the glycerol shunt by hydrolyzing Gro3P to glycerol, and regulates glucose, lipid and energy metabolism in pancreatic β-cells and liver. We now observed that G3PP expression is the highest in the testis and spermatozoa, and investigated its role in male fertility.</div></div><div><h3>Methods</h3><div>We examined G3PP expression during spermatogenesis in mouse and assessed male fertility and spermatozoon function in conditional germ cell specific G3PP-KO (cG3PP-KO) mice and tamoxifen-inducible conditional germ cell G3PP-KO (icG3PP-KO) mice. We also determined the structural and metabolic parameters and oxidative stress in the spermatozoa from icG3PP-KO and control mice.</div></div><div><h3>Results</h3><div>G3PP expression in mouse spermatocytes and spermatids markedly increases during spermatogenesis. Male cG3PP-KO mice, in which germ cell G3PP is deleted from embryonic stage, are infertile due to dysfunctional sperm with reduced motility and capacitation, and elevated spontaneous acrosomal reaction and oxidative stress. However, icG3PP-KO male mice do not have altered fertility, due to the presence of ∼10% normal spermatozoa. icG3PP-KO spermatozoa display significantly reduced functionality and morphological and ultrastructural alterations. The icG3PP-KO spermatozoa show reduced glycerol production, elevated levels of Gro3P and reactive oxygen species (ROS), and oxidative stress that is associated with increased mitochondrial membrane potential.</div></div><div><h3>Conclusions</h3><div>Germ cell G3PP deletion leads to the generation of spermatozoa that are functionally and structurally abnormal, likely due to the build-up of Gro3P that increases mitochondrial membrane potential, ROS, and oxidative stress and alters spermatozoa function. Overall, the results indicate that G3PP and the glycerol shunt are essential for normal spermatozoa function and male fertility.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102063"},"PeriodicalIF":7.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased susceptibility to diet-induced obesity in female mice impairs ovarian steroidogenesis: The role of elevated leptin signalling on nodal activity inhibition in theca cells","authors":"Karolina Wołodko ,&nbsp;Tjaša Šentjurc ,&nbsp;Edyta Walewska ,&nbsp;Elżbieta Laniecka ,&nbsp;Magdalena Jura ,&nbsp;António Galvão","doi":"10.1016/j.molmet.2024.102062","DOIUrl":"10.1016/j.molmet.2024.102062","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;Susceptibility to obesity in humans is driven by the intricate interplay of genetic, environmental and behavioural factors. Moreover, the mechanisms linking maternal obesity to infertility remain largely understudied. In this study, we investigated how variable susceptibility to obesity in mice affects ovarian steroidogenesis, with a particular focus on the leptin-mediated dysregulation of Nodal signalling pathway in theca cells (TC).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;C56BL/6J (B6) and 129S1/SvlmJ (129) mice, models of maternal obesity (MO), were fed a chow diet (CD) and a high fat diet (HFD) for 16 weeks. To investigate the contrasting effects of leptin on ovarian steroidogenesis, B6 mice pharmacologically treated with leptin for 16 days on CD were used to model hyperleptinemia, while homozygous ob/ob (−/−) mice with genetic leptin deficiency, also on a CD, were used to examine the effects of obesity in the absence of leptin. Following the characterisation of the mouse phenotype, gonadal fat (GON), whole ovaries (WO), ovarian TC and granulosa cell (GC) fractions were collected for mRNA transcription and protein expression analysis. Finally, &lt;em&gt;in vitro&lt;/em&gt; treated ovarian explants obtained from B6 mice were used to further elucidate the effects of Nodal on steroidogenesis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The significant gain in body weight (BW) and fat mass (FM) in HFD-fed B6 mice (p &lt; 0.05), was associated with increased mRNA transcription of the adipose tissue expansion genes &lt;em&gt;Polymerase I and transcript release factor&lt;/em&gt; (&lt;em&gt;Cavin&lt;/em&gt;), &lt;em&gt;Secreted frizzled-related protein 5&lt;/em&gt; (&lt;em&gt;Sfrp5&lt;/em&gt;) and &lt;em&gt;Mesoderm specific transcript&lt;/em&gt; (&lt;em&gt;Mest&lt;/em&gt;) in GON (p &lt; 0.05). Furthermore, the HFD-fed B6 mice presented also impaired glucose metabolism and insulin sensitivity (p &lt; 0.05). In contrast, the HFD-fed 129 mice exhibited no changes in BW and FM, maintaining glucose and insulin metabolism. At the ovarian level, decreased protein expression of Steroidogenic Acute Regulatory Protein (StAR) in WO obtained from HFD-fed B6 mice (p = 0.05), was followed by reduced transcription of key steroidogenic genes like &lt;em&gt;Star&lt;/em&gt; and &lt;em&gt;Cytochrome P450 17a1&lt;/em&gt; (&lt;em&gt;Cyp17a&lt;/em&gt;) in TC (p &lt; 0.05). Furthermore, the transcription of &lt;em&gt;Nodal&lt;/em&gt; and its receptors was downregulated (p &lt; 0.05), whereas mRNA levels of &lt;em&gt;Suppressor of cytokine signalling 3 (Socs3)&lt;/em&gt; and &lt;em&gt;SMAD family member 7 (Smad7)&lt;/em&gt; were upregulated in TC obtained from HFD-fed B6 mice (p &lt; 0.05). No changes were seen in the genes regulating steroidogenesis, Nodal signalling, or &lt;em&gt;Socs3&lt;/em&gt; and &lt;em&gt;Smad7&lt;/em&gt; activity in the ovaries of HFD-fed 129 mice. Importantly, the pharmacological treatment of lean mice with leptin, upregulated the ovarian transcription of &lt;em&gt;Socs3&lt;/em&gt; and &lt;em&gt;Smad7&lt;/em&gt;, while downregulating &lt;em&gt;Nodal&lt;/em&gt; and its receptors (p &lt; 0.05). Finally, &lt;em&gt;in vitro&lt;/em&gt; pharmacological inhi","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102062"},"PeriodicalIF":7.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variable glucagon metabolic actions in diverse mouse models of obesity and type 2 diabetes","authors":"Yuqin Wu ,&nbsp;Andrea Y. Chan ,&nbsp;Jana Hauke ,&nbsp;Okka Htin Aung ,&nbsp;Ashish Foollee ,&nbsp;Maria Almira S. Cleofe ,&nbsp;Helen Stölting ,&nbsp;Mei-Ling Han ,&nbsp;Katherine J. Jeppe ,&nbsp;Christopher K. Barlow ,&nbsp;Jürgen G. Okun ,&nbsp;Patricia M. Rusu ,&nbsp;Adam J. Rose","doi":"10.1016/j.molmet.2024.102064","DOIUrl":"10.1016/j.molmet.2024.102064","url":null,"abstract":"<div><h3>Objective</h3><div>The study aimed to investigate the effects of glucagon on metabolic pathways in mouse models of obesity, fatty liver disease, and type 2 diabetes (T2D) to determine the extent and variability of hepatic glucagon resistance in these conditions.</div></div><div><h3>Methods</h3><div>We investigated glucagon's effects in mouse models of fatty liver disease, obesity, and type 2 diabetes (T2D), including male BKS-db/db, high-fat diet-fed, and western diet-fed C57Bl/6 mice. Glucagon tolerance tests were performed using the selective glucagon receptor agonist acyl-glucagon (IUB288). Blood glucose, serum and liver metabolites include lipids and amino acids were measured. Additionally, liver protein expression related to glucagon signalling and a comprehensive liver metabolomics were performed.</div></div><div><h3>Results</h3><div>Western diet-fed mice displayed impaired glucagon response, with reduced blood glucose and PKA activation. In contrast, high-fat diet-fed and db/db mice maintained normal glucagon sensitivity, showing significant elevations in blood glucose and phospho-PKA motif protein expression. Acyl-glucagon treatment also lowered liver alanine and histidine levels in high-fat diet-fed mice, but not in western diet-fed mice. Additionally, some amino acids, such as methionine, were increased by acyl-glucagon only in chow diet control mice. Despite normal glucagon sensitivity in PKA signalling, db/db mice had a distinct metabolomic response, with acyl-glucagon significantly altering 90 metabolites in db/+ mice but only 42 in db/db mice, and classic glucagon-regulated metabolites, such as cyclic adenosine monophosphate (cAMP), being less responsive in db/db mice.</div></div><div><h3>Conclusions</h3><div>The study reveals that hepatic glucagon resistance in obesity and T2D is complex and not uniform across metabolic pathways, underscoring the complexity of glucagon action in these conditions.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102064"},"PeriodicalIF":7.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time-restricted feeding prevents memory impairments induced by obesogenic diet consumption, via hippocampal thyroid hormone signaling","authors":"Jean-Christophe Helbling ,&nbsp;Rachel Ginieis ,&nbsp;Pierre Mortessagne ,&nbsp;Mariano Ruiz-Gayo ,&nbsp;Ioannis Bakoyiannis ,&nbsp;Eva-Gunnel Ducourneau ,&nbsp;Dominique Ciocca ,&nbsp;Illona-Marie Bouleté ,&nbsp;Alexandre Favereaux ,&nbsp;Aurélia Ces ,&nbsp;Enrica Montalban ,&nbsp;Lucile Capuron ,&nbsp;Freddy Jeanneteau ,&nbsp;Guillaume Ferreira ,&nbsp;Etienne Challet ,&nbsp;Marie-Pierre Moisan","doi":"10.1016/j.molmet.2024.102061","DOIUrl":"10.1016/j.molmet.2024.102061","url":null,"abstract":"<div><h3>Objective</h3><div>The early consumption of calorie-rich diet disrupts circadian rhythms and has adverse effects on memory, yet the effects of time-restricted feeding (TRF) and the underlying molecular mechanisms are unknown. Here, we set out to identify the behavioral and molecular circadian rhythms disruptions generated by juvenile obesogenic diet consumption and their restoration by TRF in male mice.</div></div><div><h3>Methods</h3><div>Metabolic rhythms were measured by indirect calorimetry and memory performances by behavioral tasks. Hippocampal translatome (pS6_TRAP), enrichment and co-regulated gene network analyses were conducted to identify the molecular pathways involved in memory impairments and their restoration by TRF. Differential exon usage analyses, mass spectrometry and pharmacological intervention were used to confirm thyroid hormone signaling involvement.</div></div><div><h3>Results</h3><div>We show that four weeks of TRF restore the rhythmicity of metabolic parameters and prevents memory impairments in mice fed a high fat-high sucrose (HFS) diet since weaning, independently of body fat levels. Hippocampal translatome and differential exon usage analyses indicate that impaired memory of mice under <em>ad libitum</em> HFS diet is accompanied by reduced thyroid hormone signaling and altered expression of astrocytic genes regulating glutamate neurotransmission. TRF restored the diurnal expression variation of part of these genes and intra-hippocampal infusion of T3, the active form of thyroid hormone, rescues memory performances and astrocytic gene expression of <em>ad libitum</em> HFS diet-fed mice.</div></div><div><h3>Conclusions</h3><div>Thus, thyroid hormones contribute to the TRF positive effects on both metabolism and memory in mice fed an obesogenic diet, highlighting this nutritional approach as a powerful tool in addressing obesity brain comorbidities and paving the way for further mechanistic studies on hippocampal thyroid signaling.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102061"},"PeriodicalIF":7.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLIS3: A novel transcriptional regulator of mitochondrial functions and metabolic reprogramming in postnatal kidney and polycystic kidney disease","authors":"Justin B. Collier ,&nbsp;Hong Soon Kang ,&nbsp;Yun-Gil Roh ,&nbsp;Chitrangda Srivastava ,&nbsp;Sara A. Grimm ,&nbsp;Alan K. Jarmusch ,&nbsp;Anton M. Jetten","doi":"10.1016/j.molmet.2024.102052","DOIUrl":"10.1016/j.molmet.2024.102052","url":null,"abstract":"<div><h3><strong>Objectives</strong></h3><div>Deficiency in the transcription factor (TF) GLI-Similar 3 (GLIS3) in humans and mice leads to the development of polycystic kidney disease (PKD). In this study, we investigate the role of GLIS3 in the regulation of energy metabolism and mitochondrial functions in relation to its role in normal kidney and metabolic reprogramming in PKD pathogenesis.</div></div><div><h3>Methods</h3><div>Transcriptomics, cistromics, and metabolomics were used to obtain insights into the role of GLIS3 in the regulation of energy homeostasis and mitochondrial metabolism in normal kidney and PKD pathogenesis using GLIS3-deficient mice.</div></div><div><h3>Results</h3><div>Transcriptome analysis showed that many genes critical for mitochondrial biogenesis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and the tricarboxylic acid (TCA) cycle, including <em>Tfam</em>, <em>Tfb1m</em>, <em>Tfb2m</em>, <em>Ppargc1a</em>, <em>Ppargc1b, Atp5j2</em>, <em>Hadha</em>, and <em>Sdha,</em> are significantly suppressed in kidneys from both ubiquitous and tissue-specific <em>Glis3-</em>deficient mice. ChIP-Seq analysis demonstrated that GLIS3 is associated with the regulatory region of many of these genes, indicating that their transcription is directly regulated by GLIS3. Cistrome analyses revealed that GLIS3 binding loci frequently located near those of hepatocyte nuclear factor 1-Beta (HNF1B) and nuclear respiratory factor 1 (NRF1) suggesting GLIS3 regulates transcription of many metabolic and mitochondrial function-related genes in coordination with these TFs. Seahorse analysis and untargeted metabolomics corroborated that mitochondrial OXPHOS utilization is suppressed in GLIS3-deficient kidneys and showed that key metabolites in glycolysis, TCA cycle, and glutamine pathways were altered indicating increased reliance on aerobic glycolysis and glutamine anaplerosis. These features of metabolic reprogramming may contribute to a bioenergetic environment that supports renal cyst formation and progression in <em>Glis3</em>-deficient mice kidneys.</div></div><div><h3>Conclusions</h3><div>We identify GLIS3 as a novel positive regulator of the transition from aerobic glycolysis to OXPHOS in normal early postnatal kidney development by directly regulating the transcription of mitochondrial metabolic genes. Loss of GLIS3 induces several features of renal cell metabolic reprogramming. Our study identifies GLIS3 as a new participant in an interconnected transcription regulatory network, that includes HNF1B and NRF1, critical in the regulation of mitochondrial-related gene expression and energy metabolism in normal postnatal kidneys and PKD pathogenesis in <em>Glis3</em>-deficient mice.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102052"},"PeriodicalIF":7.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TOMM40 regulates hepatocellular and plasma lipid metabolism via an LXR-dependent pathway","authors":"Neil V. Yang ,&nbsp;Justin Y. Chao ,&nbsp;Kelly A. Garton ,&nbsp;Tommy Tran ,&nbsp;Sarah M. King ,&nbsp;Joseph Orr ,&nbsp;Jacob H. Oei ,&nbsp;Alexandra Crawford ,&nbsp;Misun Kang ,&nbsp;Reena Zalpuri ,&nbsp;Danielle M. Jorgens ,&nbsp;Pranav Konchadi ,&nbsp;John S. Chorba ,&nbsp;Elizabeth Theusch ,&nbsp;Ronald M. Krauss","doi":"10.1016/j.molmet.2024.102056","DOIUrl":"10.1016/j.molmet.2024.102056","url":null,"abstract":"<div><h3>Objective</h3><div>The gene encoding TOMM40 (Transporter of Outer Mitochondrial Membrane 40) is adjacent to that encoding APOE, which has a central role in lipid and lipoprotein metabolism. While human genetic variants near <em>APOE</em> and <em>TOMM40</em> have been shown to be strongly associated with plasma lipid levels, a specific role for TOMM40 in lipid metabolism has not been established, and the present study was aimed at assessing this possibility.</div></div><div><h3>Methods</h3><div><em>TOMM40</em> was knocked down by siRNA in human hepatoma HepG2 cells, and effects on mitochondrial function, lipid phenotypes, and crosstalk between mitochondria, ER, and lipid droplets were examined. Additionally, hepatic and plasma lipid levels were measured in mice following shRNA-induced knockdown of <em>Tomm40</em> shRNA.</div></div><div><h3>Results</h3><div>In HepG2 cells, <em>TOMM40</em> knockdown upregulated expression of <em>APOE</em> and <em>LDLR</em> in part via activation of LXRB (NR1H2) by oxysterols, with consequent increased uptake of VLDL and LDL. This is in part due to disruption of mitochondria-endoplasmic reticulum contact sites, with resulting accrual of reactive oxygen species and non-enzymatically derived oxysterols. With <em>TOMM40</em> knockdown, cellular triglyceride and lipid droplet content were increased, effects attributable in part to receptor-mediated VLDL uptake, since lipid staining was significantly reduced by concomitant suppression of either <em>LDLR</em> or <em>APOE</em>. In contrast, cellular cholesterol content was reduced due to LXRB-mediated upregulation of the ABCA1 transporter as well as increased production and secretion of oxysterol-derived cholic acid. Consistent with the findings in hepatoma cells, <em>in vivo</em> knockdown of <em>TOMM40</em> in mice resulted in significant reductions of plasma triglyceride and cholesterol concentrations, reduced hepatic cholesterol and increased triglyceride content, and accumulation of lipid droplets leading to development of steatosis.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate a role for TOMM40 in regulating hepatic lipid and plasma lipoprotein levels and identify mechanisms linking mitochondrial function with lipid metabolism.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102056"},"PeriodicalIF":7.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-dose valine attenuates diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) in mice by enhancing leptin sensitivity and modulating the gut microbiome","authors":"Felicianna ,&nbsp;Emily K.K. Lo ,&nbsp;Congjia Chen ,&nbsp;Marsena J. Ismaiah ,&nbsp;Fangfei Zhang ,&nbsp;Hoi Kit Matthew Leung ,&nbsp;Hani El-Nezami","doi":"10.1016/j.molmet.2024.102059","DOIUrl":"10.1016/j.molmet.2024.102059","url":null,"abstract":"<div><h3>Objectives</h3><div>Elevated circulating branched-chain amino acids (BCAAs) have been associated with obesity, insulin resistance, and MASLD. Nonetheless, BCAA supplementation has been shown to provide protective outcomes towards the intervention of MASLD. Currently, there is a lack of study towards the contribution of the BCAA: valine on MASLD. Herein, the effect of low-dose valine supplementation was investigated for its role in the progression of MASLD.</div></div><div><h3>Methods</h3><div>C57BL/6J mice were fed a high-fat/high-cholesterol diet (HFD) to induce MASLD. Upon the establishment of MASLD, valine was supplemented via voluntary oral administration. Clinical and biochemical parameters associated with MASLD were measured, and molecular mechanism and gut microbiota modulation from the effect of valine were investigated.</div></div><div><h3>Results</h3><div>Low-dose valine was found to attenuate the progression of MASLD, significantly reducing the gain in body weight, liver weight, and epididymal white adipose tissue (eWAT) weight, while also attenuating hyperglycemia and hyperleptinemia, and improving serum lipid profiles. Mechanistically, in the liver, genes related to hepatic lipogenesis and cholesterol biosynthesis were downregulated, while those associated with fatty acid oxidation, autophagy, and antioxidant capacity were upregulated, and AMPK pathway activity was enhanced. Liver and hypothalamic leptin resistance and inflammation were also attenuated, allowing better appetite control in mice fed a HFD and leading to reduced food intake. Additionally, metabolic flexibility in the eWAT was improved, and the gut microbiome was modulated by low-dose valine supplementation.</div></div><div><h3>Conclusion</h3><div>Low-dose valine supplementation attenuates MASLD by enhancing systemic leptin sensitivity and modulating the gut microbiome.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102059"},"PeriodicalIF":7.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics after O-GlcNAc alteration identified cellular processes promoting aneuploidy after loss of O-GlcNAc transferase","authors":"Samuel S. Boyd ,&nbsp;Dakota R. Robarts ,&nbsp;Khue Nguyen ,&nbsp;Maite Villar ,&nbsp;Ibtihal M. Alghusen ,&nbsp;Manasi Kotulkar ,&nbsp;Aspin Denson ,&nbsp;Halyna Fedosyuk ,&nbsp;Stephen A. Whelan ,&nbsp;Norman C.Y. Lee ,&nbsp;John Hanover ,&nbsp;Wagner B. Dias ,&nbsp;Ee Phie Tan ,&nbsp;Steven R. McGreal ,&nbsp;Antonio Artigues ,&nbsp;Russell H. Swerdlow ,&nbsp;Jeffrey A. Thompson ,&nbsp;Udayan Apte ,&nbsp;Chad Slawson","doi":"10.1016/j.molmet.2024.102060","DOIUrl":"10.1016/j.molmet.2024.102060","url":null,"abstract":"<div><h3>Objective</h3><div>Pharmacologic or genetic manipulation of O-GlcNAcylation, an intracellular, single sugar post-translational modification, are difficult to interpret due to the pleotropic nature of O-GlcNAc and the vast signaling pathways it regulates.</div></div><div><h3>Method</h3><div>To address the pleotropic nature of O-GlcNAc, we employed either OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) liver knockouts, or pharmacological inhibition of OGA coupled with multi-Omics analysis and bioinformatics.</div></div><div><h3>Results</h3><div>We identified numerous genes, proteins, phospho-proteins, or metabolites that were either inversely or equivalently changed between conditions. Moreover, we identified pathways in OGT knockout samples associated with increased aneuploidy. To test and validate these pathways, we induced liver growth in OGT knockouts by partial hepatectomy. OGT knockout livers showed a robust aneuploidy phenotype with disruptions in mitosis, nutrient sensing, protein metabolism/amino acid metabolism, stress response, and HIPPO signaling demonstrating how OGT is essential in controlling aneuploidy pathways.</div></div><div><h3>Conclusion</h3><div>These data show how a multi-Omics platform can disentangle the pleotropic nature of O-GlcNAc to discern how OGT fine-tunes multiple cellular pathways involved in aneuploidy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102060"},"PeriodicalIF":7.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes","authors":"Lorraine Soares De Oliveira ,&nbsp;Joseph E. Kaserman ,&nbsp;Anne H. Van Der Spek ,&nbsp;Nora J. Lee ,&nbsp;Hendrik J. Undeutsch ,&nbsp;Rhiannon B. Werder ,&nbsp;Andrew A. Wilson ,&nbsp;Anthony N. Hollenberg","doi":"10.1016/j.molmet.2024.102057","DOIUrl":"10.1016/j.molmet.2024.102057","url":null,"abstract":"<div><h3>Objective</h3><div>Thyroid hormone (TH) action is mediated by thyroid hormone receptor (THR) isoforms. While THRβ1 is likely the main isoform expressed in liver, its role in human hepatocytes is not fully understood.</div></div><div><h3>Methods</h3><div>To elucidate the role of THRβ1 action in human hepatocytes we used CRISPR/Cas9 editing to knock out THRβ1 in induced pluripotent stem cells (iPSC). Following directed differentiation to the hepatic lineage, iPSC-derived hepatocytes were then interrogated to determine the role of THRβ1 in ligand-independent and -dependent functions.</div></div><div><h3>Results</h3><div>We found that the loss of THRβ1 promoted alterations in proliferation rate and metabolic pathways regulated by T3, including gluconeogenesis, lipid oxidation, fatty acid synthesis, and fatty acid uptake. We observed that key genes involved in liver metabolism are regulated through both T3 ligand-dependent and -independent THRβ1 signaling mechanisms. Finally, we demonstrate that following THRβ1 knockout, several key metabolic genes remain T3 responsive suggesting they are THRα targets.</div></div><div><h3>Conclusions</h3><div>These results highlight that iPSC-derived hepatocytes are an effective platform to study mechanisms regulating TH signaling in human hepatocytes.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102057"},"PeriodicalIF":7.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}