bims-obesme 2024-07-21 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024‒07‒21
nine papers selected by
Xiong Weng, University of Edinburgh

PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.
B3galt5 functions as a PXR target gene and regulates obesity and insulin resistance by maintaining intestinal integrity.
Multi-step regulation of microRNA expression and secretion into small extracellular vesicles by insulin.
The role of NAD-dependent deacetylase sirtuin-2 in liver metabolic stress through regulating pyruvate kinase M2 ubiquitination.
In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation.
Age-related increases in fibroblast-secreted IGFBP2 increase melanoma cell invasion and lipid synthesis.
Mfn2-dependent fusion pathway of PE-enriched micron-sized vesicles.
Regulation of and challenges in targeting NAD+ metabolism.
Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity.

Nat Commun. 2024 Jul 16. 15(1): 5956

PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.

Mahdi Moqri, Andrea Cipriano, Daniel J Simpson, Sajede Rasouli, Tara Murty, Tineke Anna de Jong, Daniel Nachun, Guilherme de Sena Brandine, Kejun Ying, Andrei Tarkhov, Karolina A Aberg, Edwin van den Oord, Wanding Zhou, Andrew Smith, Crystal Mackall, Vadim N Gladyshev, Steve Horvath, Michael P Snyder, Vittorio Sebastiano.

DNA methylation (DNAm) is one of the most reliable biomarkers of aging across mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, DNAm gain is less characterized. Studies have demonstrated that CpGs which gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, whole-genome examination of all PRC2 targets as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, we show that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the "PRC2-AgeIndex," defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells which can distinguish the effect of different anti-aging interventions.

DOI: https://doi.org/10.1038/s41467-024-50098-2
Nat Commun. 2024 Jul 14. 15(1): 5919

B3galt5 functions as a PXR target gene and regulates obesity and insulin resistance by maintaining intestinal integrity.

Jinhang Zhang, Ya Huang, Hong Li, Pengfei Xu, Qinhui Liu, Yang Sun, Zijing Zhang, Tong Wu, Qin Tang, Qingyi Jia, Yan Xia, Ying Xu, Xiandan Jing, Jiahui Li, Li Mo, Wen Xie, Aijuan Qu, Jinhan He, Yanping Li.

Pregnane X receptor (PXR) has been reported to regulate glycolipid metabolism. The dysfunction of intestinal barrier contributes to metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown. Here, we show that activation of PXR by tributyl citrate (TBC), an intestinal-selective PXR agonist, improves high fat diet (HFD)-induced obesity. The metabolic benefit of intestinal PXR activation is associated with upregulation of β-1,3 galactosyltransferase 5 (B3galt5). Our results reveal that B3galt5 mainly expresses in the intestine and is a direct PXR transcriptional target. B3galt5 knockout exacerbates HFD-induced obesity, insulin resistance and inflammation. Mechanistically, B3galt5 is essential to maintain the integrity of intestinal mucus barrier. B3galt5 ablation impairs the O-glycosylation of mucin2, destabilizes the mucus layer, and increases intestinal permeability. Furthermore, B3galt5 deficiency abolishes the beneficial effect of intestinal PXR activation on metabolic disorders. Our results suggest the intestinal-selective PXR activation regulates B3galt5 expression and maintains metabolic homeostasis, making it a potential therapeutic strategy in obesity.

DOI: https://doi.org/10.1038/s41467-024-50198-z
Cell Rep. 2024 Jul 11. pii: S2211-1247(24)00820-9. [Epub ahead of print]43(7): 114491

Multi-step regulation of microRNA expression and secretion into small extracellular vesicles by insulin.

Marsel Lino, Ruben Garcia-Martin, Vitor Rosetto Muñoz, Gabriel Palermo Ruiz, Allah Nawaz, Bruna Brasil Brandão, Jonathan Dreyfus, Hui Pan, C Ronald Kahn.

  Tissues release microRNAs (miRNAs) in small extracellular vesicles (sEVs) including exosomes, which can regulate gene expression in distal cells, thus acting as modulators of local and systemic metabolism. Here, we show that insulin regulates miRNA secretion into sEVs from 3T3-L1 adipocytes and that this process is differentially regulated from cellular expression. Thus, of the 53 miRNAs upregulated and 66 miRNAs downregulated by insulin in 3T3-L1 sEVs, only 12 were regulated in parallel in cells. Insulin regulated this process in part by phosphorylating hnRNPA1, causing it to bind to AU-rich motifs in miRNAs, mediating their secretion into sEVs. Importantly, 43% of insulin-regulated sEV-miRNAs are implicated in obesity and insulin resistance. These include let-7 and miR-103, which we show regulate insulin signaling in AML12 hepatocytes. Together, these findings demonstrate an important layer to insulin's regulation of adipose biology and provide a mechanism of tissue crosstalk in obesity and other hyperinsulinemic states.

Keywords:  CP: Metabolism; CP: Molecular biology; RNA binding proteins; adipocyte; exosomes; extracellular miRNAs; insulin; insulin signaling; miRNA; small extracellular vesicles

DOI:  https://doi.org/10.1016/j.celrep.2024.114491
J Transl Med. 2024 Jul 14. 22(1): 656

The role of NAD-dependent deacetylase sirtuin-2 in liver metabolic stress through regulating pyruvate kinase M2 ubiquitination.

Jingru Guo, Junshu Nie, Dongni Li, Huaixiu Zhang, Tianrui Zhao, Shoufeng Zhang, Li Ma, Jingjing Lu, Hong Ji, Shize Li, Sha Tao, Bin Xu.

  NAD-dependent deacetylase Sirt2 is involved in mammalian metabolic activities, matching energy demand with energy production and expenditure, and is relevant to a variety of metabolic diseases. Here, we constructed Sirt2 knockout and adeno-associated virus overexpression mice and found that deletion of hepatic Sirt2 accelerated primary obesity and insulin resistance in mice with concomitant hepatic metabolic dysfunction. However, the key targets of Sirt2 are unknown. We identified the M2 isoform of pyruvate kinase (PKM2) as a key Sirt2 target involved in glycolysis in metabolic stress. Through yeast two-hybrid and mass spectrometry combined with multi-omics analysis, we identified candidate acetylation modification targets of Sirt2 on PKM2 lysine 135 (K135). The Sirt2-mediated deacetylation-ubiquitination switch of PKM2 regulated the development of glycolysis. Here, we found that Sirt2 deficiency led to impaired glucose tolerance and insulin resistance and induced primary obesity. Sirt2 severely disrupted liver function in mice under metabolic stress, exacerbated the metabolic burden on the liver, and affected glucose metabolism. Sirt2 underwent acetylation modification of lysine 135 of PKM2 through a histidine 187 enzyme active site-dependent effect and reduced ubiquitination of the K48 ubiquitin chain of PKM2. Our findings reveal that the hepatic glucose metabolism links nutrient state to whole-body energetics through the rhythmic regulation of Sirt2.

Keywords:  Acetylation; Glycolysis; Metabolism; PKM2; Sirt2

DOI:  https://doi.org/10.1186/s12967-024-05435-w
Cardiovasc Diabetol. 2024 Jul 18. 23(1): 258

In-depth phosphoproteomic profiling of the insulin signaling response in heart tissue and cardiomyocytes unveils canonical and specialized regulation.

Jonathan Samuel Achter, Estefania Torres Vega, Andrea Sorrentino, Konstantin Kahnert, Katrine Douglas Galsgaard, Pablo Hernandez-Varas, Michael Wierer, Jens Juul Holst, Jørgen Frank Pind Wojtaszewski, Robert William Mills, Rasmus Kjøbsted, Alicia Lundby.

  BACKGROUND: Insulin signaling regulates cardiac substrate utilization and is implicated in physiological adaptations of the heart. Alterations in the signaling response within the heart are believed to contribute to pathological conditions such as type-2 diabetes and heart failure. While extensively investigated in several metabolic organs using phosphoproteomic strategies, the signaling response elicited in cardiac tissue in general, and specifically in the specialized cardiomyocytes, has not yet been investigated to the same extent.METHODS: Insulin or vehicle was administered to male C57BL6/JRj mice via intravenous injection into the vena cava. Ventricular tissue was extracted and subjected to quantitative phosphoproteomics analysis to evaluate the insulin signaling response. To delineate the cardiomyocyte-specific response and investigate the role of Tbc1d4 in insulin signal transduction, cardiomyocytes from the hearts of cardiac and skeletal muscle-specific Tbc1d4 knockout mice, as well as from wildtype littermates, were studied. The phosphoproteomic studies involved isobaric peptide labeling with Tandem Mass Tags (TMT), enrichment for phosphorylated peptides, fractionation via micro-flow reversed-phase liquid chromatography, and high-resolution mass spectrometry measurements.
RESULTS: We quantified 10,399 phosphorylated peptides from ventricular tissue and 12,739 from isolated cardiomyocytes, localizing to 3,232 and 3,128 unique proteins, respectively. In cardiac tissue, we identified 84 insulin-regulated phosphorylation events, including sites on the Insulin Receptor (InsrY1351, Y1175, Y1179, Y1180) itself as well as the Insulin receptor substrate protein 1 (Irs1S522, S526). Predicted kinases with increased activity in response to insulin stimulation included Rps6kb1, Akt1 and Mtor. Tbc1d4 emerged as a major phosphorylation target in cardiomyocytes. Despite limited impact on the global phosphorylation landscape, Tbc1d4 deficiency in cardiomyocytes attenuated insulin-induced Glut4 translocation and induced protein remodeling. We observed 15 proteins significantly regulated upon knockout of Tbc1d4. While Glut4 exhibited decreased protein abundance consequent to Tbc1d4-deficiency, Txnip levels were notably increased. Stimulation of wildtype cardiomyocytes with insulin led to the regulation of 262 significant phosphorylation events, predicted to be regulated by kinases such as Akt1, Mtor, Akt2, and Insr. In cardiomyocytes, the canonical insulin signaling response is elicited in addition to regulation on specialized cardiomyocyte proteins, such as Kcnj11Y12 and DspS2597. Details of all phosphorylation sites are provided.
CONCLUSION: We present a first global outline of the insulin-induced phosphorylation signaling response in heart tissue and in isolated adult cardiomyocytes, detailing the specific residues with changed phosphorylation abundances. Our study marks an important step towards understanding the role of insulin signaling in cardiac diseases linked to insulin resistance.

Keywords:  Cardiac signaling; Cardiometabolic; Insulin resistance; Insulin signaling; Kinase; Metabolism; Phosphoproteomics; Phosphorylation; Proteomics; Tbc1d4

DOI:  https://doi.org/10.1186/s12933-024-02338-4
Cancer Res Commun. 2024 Jul 15.

Age-related increases in fibroblast-secreted IGFBP2 increase melanoma cell invasion and lipid synthesis.

Gretchen M Alicea, Payal Patel, Marie E Portuallo, Mitchell E Fane, Meihan Wei, Yash Chhabra, Agrani Dixit, Alexis E Carey, Vania Wang, Murilo Ramos Rocha, Reeti Behera, David W Speicher, Hsin-Yao Tang, Andrew V Kossenkov, Vito W Rebecca, Denis Wirtz, Ashani T Weeraratna.

Aged melanoma patients (>65 years old) have more aggressive disease relative to young patients (<55 years old) for reasons that are not completely understood. Analysis of the young and aged secretome from human dermal fibroblasts identified >5-fold levels of insulin-like growth factor binding protein 2 (IGFBP2) in the aged fibroblast secretome. IGFBP2 functionally triggers upregulation of the PI3K-dependent fatty acid biosynthesis program in melanoma cells. Melanoma cells co-cultured with aged dermal fibroblasts have higher levels of lipids relative to co-cultured with young dermal fibroblasts, which can be lowered by silencing IGFBP2 expression in fibroblasts, prior to treating with conditioned media. Conversely, ectopically treating melanoma cells with recombinant IGFBP2 in the presence of conditioned media from young fibroblasts, or overexpressing IGFBP2 in melanoma cells promoted lipid synthesis and accumulation in the melanoma cells. Treatment of young mice with rIGFBP2 increases tumor growth. Neutralizing IGFBP2 in vitro reduces migration and invasion in melanoma cells, and in vivo studies demonstrate that neutralizing IGFBP2 in syngeneic aged mice reduces tumor growth amd metastasis. Our results suggest that aged dermal fibroblasts increase melanoma cell aggressiveness through increased secretion of IGFBP2, stressing the importance of considering age when designing studies and treatment.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0176
Proc Natl Acad Sci U S A. 2024 Jul 23. 121(30): e2313609121

Mfn2-dependent fusion pathway of PE-enriched micron-sized vesicles.

Daniel A Peñalva, Ajay K Monnappa, Paolo Natale, Iván López-Montero.

  Mitofusins (Mfn1 and Mfn2) are the mitochondrial outer-membrane fusion proteins in mammals and belong to the dynamin superfamily of multidomain GTPases. Recent structural studies of truncated variants lacking alpha helical transmembrane domains suggested that Mfns dimerize to promote the approximation and the fusion of the mitochondrial outer membranes upon the hydrolysis of guanine 5'-triphosphate disodium salt (GTP). However, next to the presence of GTP, the fusion activity seems to require multiple regulatory factors that control the dynamics and kinetics of mitochondrial fusion through the formation of Mfn1-Mfn2 heterodimers. Here, we purified and reconstituted the full-length murine Mfn2 protein into giant unilamellar vesicles (GUVs) with different lipid compositions. The incubation with GTP resulted in the fusion of Mfn2-GUVs. High-speed video-microscopy showed that the Mfn2-dependent membrane fusion pathway progressed through a zipper mechanism where the formation and growth of an adhesion patch eventually led to the formation of a membrane opening at the rim of the septum. The presence of physiological concentration (up to 30 mol%) of dioleoyl-phosphatidylethanolamine (DOPE) was shown to be a requisite to observe GTP-induced Mfn2-dependent fusion. Our observations show that Mfn2 alone can promote the fusion of micron-sized DOPE-enriched vesicles without the requirement of regulatory cofactors, such as membrane curvature, or the assistance of other proteins.

Keywords:  giant unilamellar vesicles; membrane fusion; mitochondrial dynamics; mitofusin 2

DOI:  https://doi.org/10.1073/pnas.2313609121
Nat Rev Mol Cell Biol. 2024 Jul 18.

Regulation of and challenges in targeting NAD+ metabolism.

Marie E Migaud, Mathias Ziegler, Joseph A Baur.

Nicotinamide adenine dinucleotide, in its oxidized (NAD+) and reduced (NADH) forms, is a reduction-oxidation (redox) co-factor and substrate for signalling enzymes that have essential roles in metabolism. The recognition that NAD+ levels fall in response to stress and can be readily replenished through supplementation has fostered great interest in the potential benefits of increasing or restoring NAD+ levels in humans to prevent or delay diseases and degenerative processes. However, much about the biology of NAD+ and related molecules remains poorly understood. In this Review, we discuss the current knowledge of NAD+ metabolism, including limitations of, assumptions about and unappreciated factors that might influence the success or contribute to risks of NAD+ supplementation. We highlight several ongoing controversies in the field, and discuss the role of the microbiome in modulating the availability of NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), the presence of multiple cellular compartments that have distinct pools of NAD+ and NADH, and non-canonical NAD+ and NADH degradation pathways. We conclude that a substantial investment in understanding the fundamental biology of NAD+, its detection and its metabolites in specific cells and cellular compartments is needed to support current translational efforts to safely boost NAD+ levels in humans.

DOI: https://doi.org/10.1038/s41580-024-00752-w
J Adv Res. 2024 Jul 15. pii: S2090-1232(24)00299-6. [Epub ahead of print]

Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity.

Jiahao Li, Yufeng Tang, Guangping Lu, Qingbo Liu, Yuanfang Guo, Jie Wang, Mengjie Xiao, Ting Gao, Xiaohui Zhang, Junlian Gu.

  INTRODUCTION: Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders are related to kidney injury caused by ADR aggravated by obesity, and the specific molecular mechanism needs to be further clarified.OBJECTIVES: This study was designed to examine the role of p53-fibroblast growth factor 21 (FGF21) axis in ADR-induced renal injury aggravated by high fat diet (HFD).
METHODS: We engineered Fgf21 KO mice and used long-term (4 months) and short-term (0.5 months) HFD feeding, and ADR-injected mice, as well as STZ-induced type 1 diabetic mice and type 2 (db/db) diabetic mice to produce a in vivo model of nephrotoxicity. The specific effects of p53/FGF21 on regulation of lipid metabolism disorders and its downstream mediators in kidney were subsequently elucidated using a combination of functional and pathological analysis, RNA-sequencing, molecular biology and in vitro approaches.
RESULTS: Long-term HFD feeding mice exhibited compromised effects of FGF21 on alleviation of renal dysfunction and lipid accumulation following ADR administration. However, these impairments were reversed by p53 inhibitor (pifithrin-α, PFT-α). PFT-α sensitized FGF21 actions in kidney tissues, while knockout of Fgf21 impaired the protective effects of PFT-α on lipid metabolism. Mechanistically, p53 impaired the renal expression of FGF recepter-1 (FGFR1) and thereby developed gradually into FGF21 resistance via inhibiting hepatocyte nuclear factor alpha (HNF4α)-mediated transcriptional activation of Fgfr1. More importantly, exogenous supplementation of FGF21 or PFT-α could not only alleviate ADR-induced lipid metabolism disorder aggravated by HFD, but also reduce lipid accumulation caused by diabetic nephropathy.
CONCLUSION: Given the difficulties in developing the long-acting recombinant FGF21 analogs for therapeutic applications, sensitizing obesity-impaired FGF21 actions by suppression of p53 might be a therapeutic strategy for maintaining renal metabolic homeostasis during chemotherapy.

Keywords:  Adriamycin; FGF21 resistance; Lipid metabolism; Obesity; P53

DOI:  https://doi.org/10.1016/j.jare.2024.07.014