bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–06–16
sixteen papers selected by
Xiong Weng, University of Edinburgh
  1. Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response.
  2. An adipoincretin effect links adipostasis with insulin secretion.
  3. Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes.
  4. Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma.
  5. Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.
  6. Gut microbial β-Glucuronidase: A key regulator of endobiotic homeostasis.
  7. The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.
  8. Alternative isoform expression of key thermogenic genes in human beige adipocytes.
  9. Coenzyme A biosynthesis: mechanisms of regulation, function and disease.
  10. FIT2 proteins and lipid droplet emergence, an interplay between phospholipid synthesis, surface tension, and membrane curvature.
  11. Acetylation of histones and non-histone proteins is not a mere consequence of ongoing transcription.
  12. Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy in mice.
  13. Targeting PKCa alleviates iron overload in diabetes and hemochromatosis through the inhibition of ferroportin.
  14. Lipid-encapsulated mRNA encoding an extended serum half-life interleukin-22 ameliorates metabolic disease in mice.
  15. Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH.
  16. Glycodeoxycholic acid inhibits primary bile acid synthesis with minor effects on glucose- and lipid homeostasis in humans.
  1. Nat Aging. 2024 Jun 10.
    Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response.
    Jooman Park, Ruoci Hu, Yanyu Qian, Shaolei Xiong, Asma Sana El-Sabbagh, Meram Ibrahim, Jaden Wang, Ziqiao Xu, Zhengjia Chen, Qing Song, Zhenyuan Song, Gege Yan, Abeer M Mahmoud, Yanlin He, Brian T Layden, Jiwang Chen, Sang-Ging Ong, Pingwen Xu, Yuwei Jiang.
      Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages that they offer are compromised with aging. Here we show that treating mice with estrogen (E2), a hormone that decreases with age, can counteract the age-related decline in beige adipogenesis when exposed to cold temperature while concurrently enhancing energy expenditure and improving glucose tolerance in mice. Mechanistically, we found that nicotinamide phosphoribosyl transferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related endoplasmic reticulum (ER) stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. Together, our findings shed light on the mechanisms regulating the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT-controlled ER stress pathway as a key regulator of this process.
    DOI:  https://doi.org/10.1038/s43587-024-00633-z
  2. Trends Endocrinol Metab. 2024 Jun;pii: S1043-2760(23)00222-9. [Epub ahead of print]35(6): 466-477
    An adipoincretin effect links adipostasis with insulin secretion.
    Giovanni Solinas, Barbara Becattini.
      The current paradigm for the insulin system focuses on the phenomenon of glucose-stimulated insulin secretion and insulin action on blood glucose control. This historical glucose-centric perspective may have introduced a conceptual bias in our understanding of insulin regulation. A body of evidence demonstrating that in vivo variations in blood glucose and insulin secretion can be largely dissociated motivated us to reconsider the fundamental design of the insulin system as a control system for metabolic homeostasis. Here, we propose that a minimal glucose-centric model does not accurately describe the physiological behavior of the insulin system and propose a new paradigm focusing on the effects of incretins, arguing that under fasting conditions, insulin is regulated by an adipoincretin effect.
    Keywords:  AKT; PI3K; cancer; diabetes; growth factors; mTOR
    DOI:  https://doi.org/10.1016/j.tem.2023.10.009
  3. Nat Metab. 2024 Jun 13.
    Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes.
    Hüsün S Kizilkaya, Kimmie V Sørensen, Jakob S Madsen, Peter Lindquist, Jonathan D Douros, Jette Bork-Jensen, Alessandro Berghella, Peter A Gerlach, Lærke S Gasbjerg, Jacek Mokrosiński, Stephanie A Mowery, Patrick J Knerr, Brian Finan, Jonathan E Campbell, David A D'Alessio, Diego Perez-Tilve, Felix Faas, Signe Mathiasen, Jørgen Rungby, Henrik T Sørensen, Allan Vaag, Jens S Nielsen, Jens-Christian Holm, Jeannet Lauenborg, Peter Damm, Oluf Pedersen, Allan Linneberg, Bolette Hartmann, Jens J Holst, Torben Hansen, Shane C Wright, Volker M Lauschke, Niels Grarup, Alexander S Hauser, Mette M Rosenkilde.
      Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.
    DOI:  https://doi.org/10.1038/s42255-024-01061-4
  4. bioRxiv. 2024 May 28. pii: 2024.05.27.596106. [Epub ahead of print]
    Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma.
    Nicole M Marsh, Melissa J S MacEwen, Jane Chea, Heidi L Kenerson, Albert A Kwong, Timothy M Locke, Francisco Javier Miralles, Tanmay Sapre, Natasha Gozali, G Ekin Atilla-Gokcumen, Shao-En Ong, John D Scott, Raymond S Yeung, Yasemin Sancak.
      Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter coordinates metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial metabolic pathways has remained unexplored. Here, we investigate the metabolic consequences of uniporter loss- and gain-of-function, and identify a key transcriptional regulator that mediates these effects. Using gene expression profiling and proteomic, we find that loss of uniporter function increases the expression of proteins in the branched-chain amino acid (BCAA) catabolism pathway. Activity is further augmented through phosphorylation of the enzyme that catalyzes this pathway's committed step. Conversely, in the liver cancer fibrolamellar carcinoma (FLC)-which we demonstrate to have high mitochondrial calcium levels- expression of BCAA catabolism enzymes is suppressed. We also observe uniporter-dependent suppression of the transcription factor KLF15, a master regulator of liver metabolic gene expression, including those involved in BCAA catabolism. Notably, loss of uniporter activity upregulates KLF15, along with its transcriptional target ornithine transcarbamylase (OTC), a component of the urea cycle, suggesting that uniporter hyperactivation may contribute to the hyperammonemia observed in FLC patients. Collectively, we establish that FLC has increased mitochondrial calcium levels, and identify an important role for mitochondrial calcium signaling in metabolic adaptation through the transcriptional regulation of metabolism.
    DOI:  https://doi.org/10.1101/2024.05.27.596106
  5. Nature. 2024 Jun 12.
    Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.
    Jackie E Bader, Melissa M Wolf, Gian Luca Lupica-Tondo, Matthew Z Madden, Bradley I Reinfeld, Emily N Arner, Emma S Hathaway, KayLee K Steiner, Gabriel A Needle, Zaid Hatem, Madelyn D Landis, Eden E Faneuff, Amondrea Blackman, Elysa M Wolf, Matthew A Cottam, Xiang Ye, Madison E Bates, Kyra Smart, Wenjun Wang, Laura V Pinheiro, Anthos Christofides, DuPreez Smith, Vassiliki A Boussiotis, Scott M Haake, Kathryn E Beckermann, Kathryn E Wellen, Cynthia A Reinhart-King, C Henrique Serezani, Cheng-Han Lee, Christa Aubrey, Heidi Chen, W Kimryn Rathmell, Alyssa H Hasty, Jeffrey C Rathmell.
      Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.
    DOI:  https://doi.org/10.1038/s41586-024-07529-3
  6. Cell Host Microbe. 2024 Jun 12. pii: S1931-3128(24)00179-3. [Epub ahead of print]32(6): 783-785
    Gut microbial β-Glucuronidase: A key regulator of endobiotic homeostasis.
    Lijun Ning, Jie Hong.
      Previous studies have explored the role of the gut microbiota in regulating endobiotic homeostasis, but the precise mechanisms remain unclear. In this issue of Cell Host & Microbe, Simpson et al. identified two predominant subtypes of gut microbial β-Glucuronidase (gmGUS) that can reactivate hormones and neurotransmitters to regulate endobiotic homeostasis.
    DOI:  https://doi.org/10.1016/j.chom.2024.05.007
  7. Nat Commun. 2024 Jun 08. 15(1): 4915
    The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.
    Joan Serrano, Jordan Boyd, Ian S Brown, Carter Mason, Kathleen R Smith, Katalin Karolyi, Santosh K Maurya, Nishita N Meshram, Vanida Serna, Grace M Link, Stephen J Gardell, George A Kyriazis.
      The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.
    DOI:  https://doi.org/10.1038/s41467-024-49100-8
  8. Front Endocrinol (Lausanne). 2024 ;15 1395750
    Alternative isoform expression of key thermogenic genes in human beige adipocytes.
    Sarah Hazell Pickering, Mohamed Abdelhalim, Philippe Collas, Nolwenn Briand.
       Background: The beneficial effect of thermogenic adipocytes in maintaining body weight and protecting against metabolic disorders has raised interest in understanding the regulatory mechanisms defining white and beige adipocyte identity. Although alternative splicing has been shown to propagate adipose browning signals in mice, this has yet to be thoroughly investigated in human adipocytes.
    Methods: We performed parallel white and beige adipogenic differentiation using primary adipose stem cells from 6 unrelated healthy subjects and assessed differential gene and isoform expression in mature adipocytes by RNA sequencing.
    Results: We find 777 exon junctions with robust differential usage between white and beige adipocytes in all 6 subjects, mapping to 562 genes. Importantly, only 10% of these differentially spliced genes are also differentially expressed, indicating that alternative splicing constitutes an additional layer of gene expression regulation during beige adipocyte differentiation. Functional classification of alternative isoforms points to a gain of function for key thermogenic transcription factors such as PPARG and CITED1, and enzymes such as PEMT, or LPIN1. We find that a large majority of the splice variants arise from differential TSS usage, with beige-specific TSSs being enriched for PPARγ and MED1 binding compared to white-specific TSSs. Finally, we validate beige specific isoform expression at the protein level for two thermogenic regulators, PPARγ and PEMT.
    Discussion: These results suggest that differential isoform expression through alternative TSS usage is an important regulatory mechanism for human adipocyte thermogenic specification.
    Keywords:  adipose differentiation; alternative splicing; alternative transcript isoforms; beige adipocyte; human adipose stem cells (hASCs); human thermogenic adipocytes; transcriptomics
    DOI:  https://doi.org/10.3389/fendo.2024.1395750
  9. Nat Metab. 2024 Jun 13.
    Coenzyme A biosynthesis: mechanisms of regulation, function and disease.
    Samuel A Barritt, Sarah E DuBois-Coyne, Christian C Dibble.
      The tricarboxylic acid cycle, nutrient oxidation, histone acetylation and synthesis of lipids, glycans and haem all require the cofactor coenzyme A (CoA). Although the sources and regulation of the acyl groups carried by CoA for these processes are heavily studied, a key underlying question is less often considered: how is production of CoA itself controlled? Here, we discuss the many cellular roles of CoA and the regulatory mechanisms that govern its biosynthesis from cysteine, ATP and the essential nutrient pantothenate (vitamin B5), or from salvaged precursors in mammals. Metabolite feedback and signalling mechanisms involving acetyl-CoA, other acyl-CoAs, acyl-carnitines, MYC, p53, PPARα, PINK1 and insulin- and growth factor-stimulated PI3K-AKT signalling regulate the vitamin B5 transporter SLC5A6/SMVT and CoA biosynthesis enzymes PANK1, PANK2, PANK3, PANK4 and COASY. We also discuss methods for measuring CoA-related metabolites, compounds that target CoA biosynthesis and diseases caused by mutations in pathway enzymes including types of cataracts, cardiomyopathy and neurodegeneration (PKAN and COPAN).
    DOI:  https://doi.org/10.1038/s42255-024-01059-y
  10. Front Cell Dev Biol. 2024 ;12 1422032
    FIT2 proteins and lipid droplet emergence, an interplay between phospholipid synthesis, surface tension, and membrane curvature.
    Juliette Graff, Roger Schneiter.
      Lipid droplets (LDs) serve as intracellular compartments primarily dedicated to the storage of metabolic energy in the form of neutral lipids. The processes that regulate and control LD biogenesis are being studied extensively and are gaining significance due to their implications in major metabolic disorders, including type 2 diabetes and obesity. A protein of particular interest is Fat storage-Inducing Transmembrane 2 (FIT2), which affects the emergence step of LD biogenesis. Instead of properly emerging towards the cytosol, LDs in FIT2-deficient cells remain embedded within the membrane of the endoplasmic reticulum (ER). In vitro studies revealed the ability of FIT2 to bind both di- and triacylglycerol (DAG/TAG), key players in lipid storage, and its activity to cleave acyl-CoA. However, the translation of these in vitro functions to the observed embedding of LDs in FIT2 deficient cells remains to be established. To understand the role of FIT2 in vivo, we discuss the parameters that affect LD emergence. Our focus centers on the role that membrane curvature and surface tension play in LD emergence, as well as the impact that the lipid composition exerts on these key parameters. In addition, we discuss hypotheses on how FIT2 could function locally to modulate lipids at sites of LD emergence.
    Keywords:  Kennedy pathway; inositol auxotroph; lipid droplet morphology; lipid metabolism; membrane dynamics; metabolic disorders
    DOI:  https://doi.org/10.3389/fcell.2024.1422032
  11. Nat Commun. 2024 Jun 11. 15(1): 4962
    Acetylation of histones and non-histone proteins is not a mere consequence of ongoing transcription.
    Tim Liebner, Sinan Kilic, Jonas Walter, Hitoshi Aibara, Takeo Narita, Chunaram Choudhary.
      In all eukaryotes, acetylation of histone lysine residues correlates with transcription activation. Whether histone acetylation is a cause or consequence of transcription is debated. One model suggests that transcription promotes the recruitment and/or activation of acetyltransferases, and histone acetylation occurs as a consequence of ongoing transcription. However, the extent to which transcription shapes the global protein acetylation landscapes is not known. Here, we show that global protein acetylation remains virtually unaltered after acute transcription inhibition. Transcription inhibition ablates the co-transcriptionally occurring ubiquitylation of H2BK120 but does not reduce histone acetylation. The combined inhibition of transcription and CBP/p300 further demonstrates that acetyltransferases remain active and continue to acetylate histones independently of transcription. Together, these results show that histone acetylation is not a mere consequence of transcription; acetyltransferase recruitment and activation are uncoupled from the act of transcription, and histone and non-histone protein acetylation are sustained in the absence of ongoing transcription.
    DOI:  https://doi.org/10.1038/s41467-024-49370-2
  12. Nat Commun. 2024 Jun 12. 15(1): 5010
    Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy in mice.
    Anna R Smith, Fatima Rizvi, Elissa Everton, Anisah Adeagbo, Susan Wu, Ying Tam, Hiromi Muramatsu, Norbert Pardi, Drew Weissman, Valerie Gouon-Evans.
      Primary human hepatocyte (PHH) transplantation is a promising alternative to liver transplantation, whereby liver function could be restored by partial repopulation of the diseased organ with healthy cells. However, currently PHH engraftment efficiency is low and benefits are not maintained long-term. Here we refine two male mouse models of human chronic and acute liver diseases to recapitulate compromised hepatocyte proliferation observed in nearly all human liver diseases by overexpression of p21 in hepatocytes. In these clinically relevant contexts, we demonstrate that transient, yet robust expression of human hepatocyte growth factor and epidermal growth factor in the liver via nucleoside-modified mRNA in lipid nanoparticles, whose safety was validated with mRNA-based COVID-19 vaccines, drastically improves PHH engraftment, reduces disease burden, and improves overall liver function. This strategy may overcome the critical barriers to clinical translation of cell therapies with primary or stem cell-derived hepatocytes for the treatment of liver diseases.
    DOI:  https://doi.org/10.1038/s41467-024-49332-8
  13. Blood. 2024 Jun 11. pii: blood.2024023829. [Epub ahead of print]
    Targeting PKCa alleviates iron overload in diabetes and hemochromatosis through the inhibition of ferroportin.
    Somesh Banerjee, Shaolei Lu, Anand Jain, Irene Wang, Hui Tao, Shanthi Srinivasan, Elizabeta Nemeth, Peijian He.
      Ferroportin (Fpn) is the only iron exporter, playing a crucial role in systemic iron homeostasis. Fpn is negatively regulated by its ligand hepcidin, but other potential regulators in physiological and disease conditions remain poorly understood. Diabetes is a metabolic disorder that develops body iron loading with unknown mechanisms. By utilizing diabetic mouse models and human duodenal specimens, we demonstrated that intestinal Fpn expression was increased in diabetes in a hepcidin-independent manner. Protein kinase C (PKC) is hyperactivated in diabetes. We showed that PKC was required to sustain baseline Fpn expression and diabetes induced Fpn upregulation in the enterocytes and macrophages. Knockout of PKC abolished diabetes associated iron overload. Mechanistically, activation of PKC increased the exocytotic while decreased the endocytic trafficking of Fpn in the resting state. Hyperactive PKC also suppressed hepcidin-induced ubiquitination, internalization, and degradation of Fpn. We further observed that iron loading in the enterocytes and macrophages activated PKC, acting as a novel mechanism to enhance Fpn-dependent iron efflux. Finally, we demonstrated that the loss-of-function of PKC and pharmacological inhibition of PKC significantly alleviated hereditary hemochromatosis associated iron overload. Our study has highlighted, for the first time, that PKC is an important positive regulator of Fpn and a new target in the control of iron homeostasis.
    DOI:  https://doi.org/10.1182/blood.2024023829
  14. Mol Metab. 2024 Jun 11. pii: S2212-8778(24)00096-6. [Epub ahead of print] 101965
    Lipid-encapsulated mRNA encoding an extended serum half-life interleukin-22 ameliorates metabolic disease in mice.
    Susanna Canali, Alexander W Fischer, Mychael Nguyen, Karl Anderson, Lorna Wu, Anne-Renee Graham, Chiaowen Joyce Hsiao, Chinmayi Bankar, Nancy Dussault, Veronica Ritchie, Meagan Goodridge, Todd Sparrow, Allison Pannoni, Sze-Wah Tse, Vivienne Woo, Kaitlin Klovdahl, Jared Iacovelli, Eric Huang.
       OBJECTIVE: Interleukin (IL)-22 is a potential therapeutic protein for the treatment of metabolic diseases such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease due to its involvement in multiple cellular pathways and observed hepatoprotective effects. The short serum half-life of IL-22 has previously limited its use in clinical applications; however, the development of mRNA-lipid nanoparticle (LNP) technology offers a novel therapeutic approach that uses a host-generated IL-22 fusion protein. In the present study, the effects of administration of an mRNA-LNP encoding IL-22 on metabolic disease parameters was investigated in various mouse models.
    METHODS: C57BL/6NCrl mice were used to confirm mouse serum albumin (MSA)-IL-22 protein expression prior to assessments in C57BL/6NTac and CETP/ApoB transgenic mouse models of metabolic disease. Mice were fed either regular chow or a modified amylin liver nonalcoholic steatohepatitis-inducing diet prior to receiving either LNP-encapsulated MSA-IL-22 or MSA mRNA via intravenous or intramuscular injection. Metabolic markers were monitored for the duration of the experiments, and postmortem histology assessment and analysis of metabolic gene expression pathways were performed.
    RESULTS: MSA-IL-22 was detectable for ≥8 days following administration. Improvements in body weight, lipid metabolism, glucose metabolism, and lipogenic and fibrotic marker gene expression in the liver were observed in the MSA-IL-22-treated mice, and these effects were shown to be durable.
    CONCLUSIONS: These results support the application of mRNA-encoded IL-22 as a promising treatment strategy for metabolic syndrome and associated comorbidities in human populations.
    Keywords:  (≤6 words): interleukin-22; lipid nanoparticle therapeutic; messenger RNA; metabolic disorders; metabolic dysfunction-associated steatotic liver disease; serum lipid parameters
    DOI:  https://doi.org/10.1016/j.molmet.2024.101965
  15. Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00184-0. [Epub ahead of print]
    Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH.
    Jing Zhang, Yu Wang, Meiyang Fan, Yanglong Guan, Wentao Zhang, Fumeng Huang, Zhengqiang Zhang, Xiaomeng Li, Bingyu Yuan, Wenbin Liu, Manman Geng, Xiaowei Li, Jing Xu, Congshan Jiang, Wenjuan Zhao, Feng Ye, Wenhua Zhu, Liesu Meng, Shemin Lu, Rikard Holmdahl.
      Impaired self-renewal of Kupffer cells (KCs) leads to inflammation in metabolic dysfunction-associated steatohepatitis (MASH). Here, we identify neutrophil cytosolic factor 1 (NCF1) as a critical regulator of iron homeostasis in KCs. NCF1 is upregulated in liver macrophages and dendritic cells in humans with metabolic dysfunction-associated steatotic liver disease and in MASH mice. Macrophage NCF1, but not dendritic cell NCF1, triggers KC iron overload, ferroptosis, and monocyte-derived macrophage infiltration, thus aggravating MASH progression. Mechanistically, elevated oxidized phospholipids induced by macrophage NCF1 promote Toll-like receptor (TLR4)-dependent hepatocyte hepcidin production, leading to increased KC iron deposition and subsequent KC ferroptosis. Importantly, the human low-functional polymorphic variant NCF190H alleviates KC ferroptosis and MASH in mice. In conclusion, macrophage NCF1 impairs iron homeostasis in KCs by oxidizing phospholipids, triggering hepatocyte hepcidin release and KC ferroptosis in MASH, highlighting NCF1 as a therapeutic target for improving KC fate and limiting MASH progression.
    Keywords:  Kupffer cells; NCF1; ferroptosis; hepatocytes; iron deposition; lipid peroxidation; macrophages; metabolic dysfunction-associated steatohepatitis; oxidized phospholipids; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.008
  16. J Clin Endocrinol Metab. 2024 Jun 12. pii: dgae399. [Epub ahead of print]
    Glycodeoxycholic acid inhibits primary bile acid synthesis with minor effects on glucose- and lipid homeostasis in humans.
    Emma C E Meessen, Soumia Majait, Ümran Ay, Steven W Olde Damink, Johannes A Romijn, Jens J Holst, Bolette Hartmann, Folkert Kuipers, Max Nieuwdorp, Frank G Schaap, Albert K Groen, E Marleen Kemper, Maarten R Soeters.
       BACKGROUND: Bile acids play vital roles in control of lipid-, glucose-, and energy metabolism by activating Takeda G protein-coupled receptor 5 (TGR5) and Farnesoid X receptor (FXR), the latter promoting production of the endocrine-acting fibroblast growth factor 19 (FGF19). Short-term administration of single bile acids has been reported to enhance plasma levels of GLP-1 and to enhance energy expenditure. However, prolonged bile acid supplementation, e.g. of chenodeoxycholic acid (CDCA) for gallstone dissolution, has been reported to have adverse effects.
    STUDY DESIGN: In this proof-of-concept study, we assessed the safety and metabolic effects of oral glycine-conjugated deoxycholic acid (GDCA) administration at 10 mg/kg/day using regular and slow-release capsules (mimicking physiological bile acid release) over 30 days in two groups of each 10 healthy lean men respectively.
    MAIN FINDINGS: GDCA increased postprandial total bile acid and FGF19 concentrations while suppressing those of the primary bile acids CDCA and cholic acid. Plasma levels of 7α-hydroxy-4-cholesten-3-one were reduced, indicating repressed hepatic bile acid synthesis. There were minimal effects on indices of lipid-, glucose-, and energy metabolism. No serious adverse events were reported during GDCA administration in either capsule types, although 50% of participants showed mild increases in plasma levels of liver transaminases and 80% (regular capsules) and 50% (slow-release capsules) of participants experienced gastrointestinal adverse events.
    CONCLUSION: GDCA administration leads to elevated FGF19 levels and effectively inhibits primary bile acid synthesis, supporting therapy compliance and its effectiveness. However, effects on lipid, glucose- and energy metabolism were minimal, indicating that expanding the pool of this relatively hydrophobic bile acid does not impact energy metabolism in healthy subjects.
    Keywords:  Bile acids; Farnesoid X receptor; Glucagon-like peptide 1; Takeda G protein-coupled receptor 5; glycodeoxycholic acid; humans; metabolic diseases
    DOI:  https://doi.org/10.1210/clinem/dgae399
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