bims-obesme 2024-11-03 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024–11–03
twelve papers selected by
Xiong Weng, University of Edinburgh

Protein O-GlcNAcylation coupled to Hippo signaling drives vascular dysfunction in diabetic retinopathy.
RNA-binding protein YBX3 promotes PPARγ-SLC3A2 mediated BCAA metabolism fueling brown adipogenesis and thermogenesis.
Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase.
Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.
Leptin-activated hypothalamic BNC2 neurons acutely suppress food intake.
Rhythmic IL-17 production by γδ T cells maintains adipose de novo lipogenesis.
Amino acid is a major carbon source for hepatic lipogenesis.
Identification of lipid senolytics targeting senescent cells through ferroptosis induction.
Adipose Tissue-Resident Sphingomonas Paucimobilis Suppresses Adaptive Thermogenesis by Reducing 15-HETE Production and Inhibiting AMPK Pathway.
DNA methylation and non-coding RNAs in metabolic disorders: Epigenetic Roles of Nutrients, Dietary Patterns and Weight Loss Interventions for Precision Nutrition.
The post-translational modification O-GlcNAc is a sensor and regulator of metabolism.
The cGAS-STING pathway is an in vivo modifier of genomic instability syndromes.

Nat Commun. 2024 Oct 29. 15(1): 9334

Protein O-GlcNAcylation coupled to Hippo signaling drives vascular dysfunction in diabetic retinopathy.

Yi Lei, Qiangyun Liu, Binggui Chen, Fangfang Wu, Yiming Li, Xue Dong, Nina Ma, Ziru Wu, Yanfang Zhu, Lu Wang, Yuxin Fu, Yuming Liu, Yinting Song, Mei Du, Heng Zhang, Jidong Zhu, Timothy J Lyons, Ting Wang, Junhao Hu, Heping Xu, Mei Chen, Hua Yan, Xiaohong Wang.

Metabolic disorder significantly contributes to diabetic vascular complications, including diabetic retinopathy, the leading cause of blindness in the working-age population. However, the molecular mechanisms by which disturbed metabolic homeostasis causes vascular dysfunction in diabetic retinopathy remain unclear. O-GlcNAcylation modification acts as a nutrient sensor particularly sensitive to ambient glucose. Here, we observe pronounced O-GlcNAc elevation in retina endothelial cells of diabetic retinopathy patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase effectively mitigates vascular dysfunction. Mechanistically, we find that Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are O-GlcNAcylated in diabetic retinopathy. We identify threonine 383 as an O-GlcNAc site on YAP, which inhibits its phosphorylation at serine 397, leading to its stabilization and activation, thereby promoting vascular dysfunction by inducing a pro-angiogenic and glucose metabolic transcriptional program. This work emphasizes the critical role of the O-GlcNAc-Hippo axis in the pathogenesis of diabetic retinopathy and suggests its potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41467-024-53601-x
Mol Metab. 2024 Oct 29. pii: S2212-8778(24)00184-4. [Epub ahead of print] 102053

RNA-binding protein YBX3 promotes PPARγ-SLC3A2 mediated BCAA metabolism fueling brown adipogenesis and thermogenesis.

Lin-Yun Chen, Li-Wen Wang, Jie Wen, Jing-Dong Cao, Rui Zhou, Jin-Lin Yang, Ye Xiao, Tian Su, Yan Huang, Qi Guo, Hai-Yan Zhou, Xiang-Hang Luo, Xu Feng.

   OBJECTIVE: Activating brown adipose tissue (BAT) thermogenesis is a promising approach to combat obesity and metabolic disorders. The post-transcriptional regulation of BAT thermogenesis mediated by RNA-binding proteins (RBPs) is still not fully understood. This study explores the physiological role of novel RBPs in BAT differentiation and thermogenesis.
METHODS: We used multiple public datasets to screen out novel RBPs responsible for BAT differentiation and thermogenesis. In vitro loss- and gain-of-function experiments were performed in both C3H10T1/2 preadipocytes and mature brown adipocytes to determine the role of Y-box binding protein 3 (YBX3) in brown adipocyte differentiation and thermogenesis. Adeno-associated virus (AAV)-mediated BAT-specific knockdown or overexpression of Ybx3 was applied to investigate the function of YBX3 in vivo.
RESULTS: YBX3 is a brown adipocyte-enriched RBP induced by cold stimulation and β-adrenergic signaling. Both in vitro loss- and gain-of-function experiments demonstrate that YBX3 is essential for brown adipocyte differentiation and thermogenesis. BAT-specific loss of Ybx3 dampens thermogenesis and exacerbates diet-induced obesity in mice, while overexpression of Ybx3 promotes thermogenesis and confers protection against diet-induced metabolic dysfunction. Transcriptome analysis and mitochondrial stress test indicate that Ybx3 deficiency compromises the mitochondrial oxidative phosphorylation, leading to thermogenic failure. Mechanistically, YBX3 stabilizes the mRNA of Slc3a2 and Pparg, which facilitates branched-chain amino acid (BCAA) influx and catabolism and fuels brown adipocyte differentiation and thermogenesis.
CONCLUSIONS: YBX3 facilitates BAT fueling BCAA to boost thermogenesis and energy expenditure, which protects against obesity and metabolic dysfunction. Thus, YBX3 could be a promising therapeutic target for obesity.

Keywords:  Branched-chain amino acid; Brown adipose tissue; Obesity; Thermogenesis; YBX3

DOI:  https://doi.org/10.1016/j.molmet.2024.102053
Cell Metab. 2024 Oct 26. pii: S1550-4131(24)00410-8. [Epub ahead of print]

Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase.

Joyce Y Liu, Ramya S Kuna, Laura V Pinheiro, Phuong T T Nguyen, Jaclyn E Welles, Jack M Drummond, Nivitha Murali, Prateek Sharma, Julianna G Supplee, Mia Shiue, Steven Zhao, Aimee T Farria, Avi Kumar, Mauren L Ruchhoeft, Christina Demetriadou, Daniel S Kantner, Adam Chatoff, Emily Megill, Paul M Titchenell, Nathaniel W Snyder, Christian M Metallo, Kathryn E Wellen.

  ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol-lowering drug bempedoic acid (BPA), which also improves steatosis in mice. While BPA potently suppresses hepatic DNL and increases fat catabolism, it is unclear if ACLY is its primary molecular target in reducing liver triglyceride. We show that on a Western diet, loss of hepatic ACLY alone or together with the acetyl-CoA synthetase ACSS2 unexpectedly exacerbates steatosis, linked to reduced PPARα target gene expression and fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triacylglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic steatosis are ACLY independent. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation and that BPA exerts substantial effects on hepatic lipid metabolism independently of ACLY.

Keywords:  ACLY; ACSS2; PPARα; bempedoic acid; lipid metabolism; metabolic dysfunction-associated steatotic liver disease

DOI:  https://doi.org/10.1016/j.cmet.2024.10.014
Nat Metab. 2024 Oct 31.

Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.

Jonas M Kristensen, Rasmus Kjøbsted, Trine J Larsen, Christian S Carl, Janne R Hingst, Johan Onslev, Jesper B Birk, Anette Thorup, Dorte E Steenberg, Jonas R Knudsen, Nicolai S Henriksen, Elise J Needham, Jens F Halling, Anders Gudiksen, Carsten F Rundsten, Kristian E Hanghøj, Sara E Stinson, Birgitte Hoier, Camilla C Hansen, Thomas E Jensen, Ylva Hellsten, Henriette Pilegaard, Niels Grarup, Jesper Olesen, Sean J Humphrey, David E James, Michael L Pedersen, Erik A Richter, Torben Hansen, Marit E Jørgensen, Jørgen F P Wojtaszewski.

In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes1. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies.

DOI: https://doi.org/10.1038/s42255-024-01153-1
Nature. 2024 Oct 30.

Leptin-activated hypothalamic BNC2 neurons acutely suppress food intake.

Han L Tan, Luping Yin, Yuqi Tan, Jessica Ivanov, Kaja Plucinska, Anoj Ilanges, Brian R Herb, Putianqi Wang, Christin Kosse, Paul Cohen, Dayu Lin, Jeffrey M Friedman.

Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism1. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons2. However, whereas AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect3-5. This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that rapidly suppresses appetite. Here we report the discovery of a new population of leptin-target neurons expressing basonuclin 2 (Bnc2) in the arcuate nucleus that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is modulated by leptin, sensory food cues and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action.

DOI: https://doi.org/10.1038/s41586-024-08108-2
Nature. 2024 Oct 30.

Rhythmic IL-17 production by γδ T cells maintains adipose de novo lipogenesis.

Aaron Douglas, Brenneth Stevens, Miguel Rendas, Harry Kane, Evan Lynch, Britta Kunkemoeller, Karl Wessendorf-Rodriguez, Emily A Day, Caroline Sutton, Martin Brennan, Katie O'Brien, Ayano C Kohlgruber, Hannah Prendeville, Amanda E Garza, Luke A J O'Neill, Kingston H G Mills, Christian M Metallo, Henrique Veiga-Fernandes, Lydia Lynch.

The circadian rhythm of the immune system helps to protect against pathogens1-3; however, the role of circadian rhythms in immune homeostasis is less well understood. Innate T cells are tissue-resident lymphocytes with key roles in tissue homeostasis4-7. Here we use single-cell RNA sequencing, a molecular-clock reporter and genetic manipulations to show that innate IL-17-producing T cells-including γδ T cells, invariant natural killer T cells and mucosal-associated invariant T cells-are enriched for molecular-clock genes compared with their IFNγ-producing counterparts. We reveal that IL-17-producing γδ (γδ17) T cells, in particular, rely on the molecular clock to maintain adipose tissue homeostasis, and exhibit a robust circadian rhythm for RORγt and IL-17A across adipose depots, which peaks at night. In mice, loss of the molecular clock in the CD45 compartment (Bmal1∆Vav1) affects the production of IL-17 by adipose γδ17 T cells, but not cytokine production by αβ or IFNγ-producing γδ (γδIFNγ) T cells. Circadian IL-17 is essential for de novo lipogenesis in adipose tissue, and mice with an adipocyte-specific deficiency in IL-17 receptor C (IL-17RC) have defects in de novo lipogenesis. Whole-body metabolic analysis in vivo shows that Il17a-/-Il17f-/- mice (which lack expression of IL-17A and IL-17F) have defects in their circadian rhythm for de novo lipogenesis, which results in disruptions to their whole-body metabolic rhythm and core-body-temperature rhythm. This study identifies a crucial role for IL-17 in whole-body metabolic homeostasis and shows that de novo lipogenesis is a major target of IL-17.

DOI: https://doi.org/10.1038/s41586-024-08131-3
Cell Metab. 2024 Oct 22. pii: S1550-4131(24)00397-8. [Epub ahead of print]

Amino acid is a major carbon source for hepatic lipogenesis.

Yilie Liao, Qishan Chen, Lei Liu, Haipeng Huang, Jingyun Sun, Xiaojie Bai, Chenchen Jin, Honghao Li, Fangfang Sun, Xia Xiao, Yahong Zhang, Jia Li, Weiping Han, Suneng Fu.

  Increased de novo lipogenesis is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity, but the macronutrient carbon source for over half of hepatic fatty acid synthesis remains undetermined. Here, we discover that dietary protein, rather than carbohydrates or fat, is the primary nutritional risk factor for MASLD in humans. Consistently, ex vivo tracing studies identify amino acids as a major carbon supplier for the tricarboxylic acid (TCA) cycle and lipogenesis in isolated mouse hepatocytes. In vivo, dietary amino acids are twice as efficient as glucose in fueling hepatic fatty acid synthesis. The onset of obesity further drives amino acids into fatty acid synthesis through reductive carboxylation, while genetic and chemical interventions that divert amino acid carbon away from lipogenesis alleviate hepatic steatosis. Finally, low-protein diets (LPDs) not only prevent body weight gain in obese mice but also reduce hepatic lipid accumulation and liver damage. Together, this study uncovers the significant role of amino acids in hepatic lipogenesis and suggests a previously unappreciated nutritional intervention target for MASLD.

Keywords:  DNL; MASH; MASLD; NAFLD; amino acids; dietary protein; glucose; glutamine; lipogenesis

DOI:  https://doi.org/10.1016/j.cmet.2024.10.001
bioRxiv. 2024 Oct 14. pii: 2024.10.14.618023. [Epub ahead of print]

Identification of lipid senolytics targeting senescent cells through ferroptosis induction.

Lei Justan Zhang, Rahagir Salekeen, Carolina Soto-Palma, Osama Elsallabi, Hongping Ye, Brian Hughes, Borui Zhang, Allancer Nunes, Kyooa Lee, Wandi Xu, Abdalla Mohamed, Ellie Piepgras, Sara J McGowan, Luise Angelini, Ryan O'Kelly, Xianlin Han, Laura J Niedernhofer, Paul D Robbins.

  Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent cell-based phenotypic drug screen, we identified a class of conjugated polyunsaturated fatty acids, specifically α-eleostearic acid and its methyl ester derivative, as novel senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice. Importantly, these novel lipids induced senolysis through ferroptosis, rather than apoptosis or necrosis, by exploiting elevated iron, cytosolic PUFAs and ROS levels in senescent cells. Mechanistic studies and computational analyses further revealed their key targets in the ferroptosis pathway, ACSL4, LPCAT3, and ALOX15, important for lipid-induced senolysis. This new class of ferroptosis-inducing lipid senolytics provides a novel approach to slow aging and treat age-related disease, targeting senescent cells that are primed for ferroptosis.

Keywords:  PUFA; aging; eleostearic acid; fatty acid; ferroptosis; healthspan; lipid; senescence; senolysis; senolytic; senotherapeutic

DOI:  https://doi.org/10.1101/2024.10.14.618023
Adv Sci (Weinh). 2024 Oct 30. e2310236

Adipose Tissue-Resident Sphingomonas Paucimobilis Suppresses Adaptive Thermogenesis by Reducing 15-HETE Production and Inhibiting AMPK Pathway.

Yucheng Zhu, Ruiqi Yang, Zhangchao Deng, Bohua Deng, Kun Zhao, Chen Dai, Gang Wei, YanJiang Wang, Jinshui Zheng, Zhuqing Ren, Wentao Lv, Yingping Xiao, Zhinan Mei, Tongxing Song.

  Obesity represents a low-grade chronic inflammation status, which is associated with compromised adaptive thermogenesis. However, the mechanisms underlying the defective activation of thermogenesis in chronic inflammation remain unclear. Here, a chronic inflammatory model is first estabolished by injecting mice with low-dose lipopolysaccharide (LPS) before cold exposure, and then it is verified that LPS treatment can decrease the core body temperature of mice and alter the microbial distribution in epididymal white adipose tissue (eWAT). An adipose tissue-resident bacterium Sphingomonas paucimobilis is identified as a potential inhibitor on the activation of brown fat and browning of inguinal WAT, resulting in defective adaptive thermogenesis. Mechanically, LPS and S. paucimobilis inhibit the production and release of 15-HETE by suppressing its main metabolic enzyme 12 lipoxygenase (12-LOX) and 15- Hydroxyeicosatetraenoic acid (15-HETE) rescues the impaired thermogenesis. Interestingly, 15-HETE directly binds to AMP-activated protein kinase α (AMPKα) and elevates the phosphorylation of AMPK, leading to the activation of uncoupling protein 1 (UCP1) and mitochondrial oxidative phosphorylation (OXPHOS) complexes. Further analysis with human obesity subjects reveals that individuals with high body mass index displayed lower 15-HETE levels. Taken together, this work improves the understanding of how chronic inflammation impairs adaptive thermogenesis and provides novel targets for alleviating obesity.

Keywords:  15‐HETE; AMPK; adaptive thermogenesis; adipose tissues; chronic inflammation; microbes

DOI:  https://doi.org/10.1002/advs.202310236
Lifestyle Genom. 2024 Oct 31. 1-27

DNA methylation and non-coding RNAs in metabolic disorders: Epigenetic Roles of Nutrients, Dietary Patterns and Weight Loss Interventions for Precision Nutrition.

Carolina F Nicoletti, Taís S Assmann, Leticia L Souza, José Alfredo Martinez.

BACKGROUND: Dysregulation of epigenetic processes and abnormal epigenetic profiles are associated with various metabolic disorders. Nutrition, as an environmental factor, can induce epigenetic changes through both direct exposure and transgenerational inheritance, continuously altering gene expression and shaping the phenotype. Nutrients consumed through food or supplementation, such as vitamin B12, folate, vitamin B6, and choline, play a pivotal role in DNA methylation, a critical process for gene regulation. Additionally, there is mounting evidence that the expression of non-coding RNAs (ncRNAs) can be modulated by the intake of specific nutrients and natural compounds, thereby influencing processes involved in the onset and progression of metabolic diseases.
SUMMARY: Evidence suggests that dietary patterns, weight-loss interventions, nutrients and nutritional bioactive compounds can modulate the expression of various miRNAs and DNA methylation levels, contributing to development of metabolic disorders such as obesity and type 2 diabetes. Furthermore, several studies have proposed that DNA methylation and microRNA (miRNA) expression could serve as biomarkers for the effects of weight-loss programs.
KEY MESSAGE: Despite ongoing debate regarding the effects of nutrient supplementation on DNA methylation levels and the expression of ncRNAs, certain DNA methylation marks and ncRNA expressions might predict the risk of metabolic disorders and act as biomarkers for forecasting the success of therapies within the framework of precision medicine and nutrition. The role of DNA methylation and miRNA expression as potential mediators of the effects of weight loss underscores their potential as biomarkers for the outcomes of weight loss programs. This highlights the influence of dietary patterns and weight-loss interventions on the regulation of miRNA expression and DNA methylation levels, suggesting an interaction between these epigenetic factors and the body's response to weight loss.

DOI: https://doi.org/10.1159/000541000
Open Biol. 2024 Oct;14(10): 240209

The post-translational modification O-GlcNAc is a sensor and regulator of metabolism.

Murielle M Morales, Matthew R Pratt.

  Cells must rapidly adapt to changes in nutrient conditions through responsive signalling cascades to maintain homeostasis. One of these adaptive pathways results in the post-translational modification of proteins by O-GlcNAc. O-GlcNAc modifies thousands of nuclear and cytoplasmic proteins in response to nutrient availability through the hexosamine biosynthetic pathway. O-GlcNAc is highly dynamic and can be added and removed from proteins multiple times throughout their life cycle, setting it up to be an ideal regulator of cellular processes in response to metabolic changes. Here, we describe the link between cellular metabolism and O-GlcNAc, and we explore O-GlcNAc's role in regulating cellular processes in response to nutrient levels. Specifically, we discuss the mechanisms of elevated O-GlcNAc levels in contributing to diabetes and cancer, as well as the role of decreased O-GlcNAc levels in neurodegeneration. These studies form a foundational understanding of aberrant O-GlcNAc in human disease and provide an opportunity to further improve disease identification and treatment.

Keywords:  O-GlcNAc; metabolism; modifications; post-translational; regulators; sensor

DOI:  https://doi.org/10.1098/rsob.240209
bioRxiv. 2024 Oct 18. pii: 2024.10.16.618655. [Epub ahead of print]

The cGAS-STING pathway is an in vivo modifier of genomic instability syndromes.

Marva Bergman, Uri Goshtchevsky, Tehila Atlan, Gwendoline Astre, Ryan Halabi, Hosniyah El, Eitan Moses, Aaron J J Lemus, Bérénice A Benayoun, Yehuda Tzfati, Ido Ben-Ami, Itamar Harel.

Mutations in genes involved in DNA damage repair (DDR) often lead to premature aging syndromes. While recent evidence suggests that inflammation, alongside mutation accumulation and cell death, may drive disease phenotypes, its precise contribution to in vivo pathophysiology remains unclear. Here, by modeling Ataxia Telangiectasia (A-T) and Bloom Syndrome in the African turquoise killifish ( N. furzeri ), we replicate key phenotypes of DDR syndromes, including infertility, cytoplasmic DNA fragments, and reduced lifespan. The link between DDR defects and inflammation is attributed to the activation of the cGAS-STING pathway and interferon signaling by cytoplasmic DNA. Accordingly, mutating cGAS partially rescues germline defects and senescence in A-T fish. Double mutants also display reversal of telomere abnormalities and suppression of transposable elements, underscoring cGAS's non-canonical role as a DDR inhibitor. Our findings emphasize the role of interferon signaling in A-T pathology and identify the cGAS-STING pathway as a potential therapeutic target for genomic instability syndromes.

DOI: https://doi.org/10.1101/2024.10.16.618655