bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–08–25
seventeen papers selected by
Xiong Weng, University of Edinburgh
  1. Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH.
  2. PCPE-1, a brown adipose tissue-derived cytokine, promotes obesity-induced liver fibrosis.
  3. Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue.
  4. The microbiota-dependent tryptophan metabolite alleviates high-fat diet-induced insulin resistance through the hepatic AhR/TSC2/mTORC1 axis.
  5. FAM210A: An emerging regulator of mitochondrial homeostasis.
  6. Antagonism of β-arrestins in IL-4-driven microglia reactivity via the Samd4/mTOR/OXPHOS axis in Parkinson's disease.
  7. LEAP2 ameliorates high fat diet-impaired glucose tolerance and enhances glucose-stimulated insulin secretion from β cells through PPARγ signal pathway.
  8. Oxysterol Sensing Through GPR183 Triggers Endothelial Senescence in Hypertension.
  9. Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2.
  10. Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
  11. Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
  12. Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity.
  13. FOXO-regulated OSER1 reduces oxidative stress and extends lifespan in multiple species.
  14. Overexpression of METTL14 mediates steatohepatitis and insulin resistance in mice.
  15. IRX3 promotes adipose tissue browning and inhibits fibrosis in obesity-resistant mice.
  16. DNA damage-induced proteasome phosphorylation controls substrate recognition and facilitates DNA repair.
  17. Key Questions and Gaps in Understanding Adipose Tissue Macrophages and Early-Life Metabolic Programming.
  1. Nat Commun. 2024 Aug 21. 15(1): 7173
    Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH.
    Laurent L'homme, Benan Pelin Sermikli, Joel T Haas, Sébastien Fleury, Sandrine Quemener, Valentine Guinot, Emelie Barreby, Nathalie Esser, Robert Caiazzo, Hélène Verkindt, Benjamin Legendre, Violeta Raverdy, Lydie Cheval, Nicolas Paquot, Jacques Piette, Sylvie Legrand-Poels, Myriam Aouadi, François Pattou, Bart Staels, David Dombrowicz.
      Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.
    DOI:  https://doi.org/10.1038/s41467-024-51078-2
  2. EMBO J. 2024 Aug 19.
    PCPE-1, a brown adipose tissue-derived cytokine, promotes obesity-induced liver fibrosis.
    Yung Ting Hsiao, Yohko Yoshida, Shujiro Okuda, Manabu Abe, Seiya Mizuno, Satoru Takahashi, Hironori Nakagami, Ryuichi Morishita, Kenya Kamimura, Shuji Terai, Tin May Aung, Ji Li, Takaaki Furihata, Jing Yuan Tang, Kenneth Walsh, Akihito Ishigami, Tohru Minamino, Ippei Shimizu.
      Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly understood. Here, we identified the secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), as a brown adipose tissue (BAT)-derived adipokine that promotes liver fibrosis in a murine obesity-induced MASH model. BAT-specific or systemic PCPE-1 depletion in mice ameliorated liver fibrosis, whereas, PCPE-1 gain of function in BAT enhanced hepatic fibrosis. High-calorie diet-induced ER stress increased PCPE-1 production in BAT through the activation of IRE-1/JNK/c-Fos/c-Jun signaling. Circulating PCPE-1 levels are increased in the plasma of MASH patients, suggesting a therapeutic possibility. In sum, our results uncover PCPE-1 as a novel systemic control factor of liver fibrosis.
    Keywords:  BATokine; Fibrosis; MASH; Obesity; PCPE-1
    DOI:  https://doi.org/10.1038/s44318-024-00196-0
  3. Nat Commun. 2024 Aug 22. 15(1): 7215
    Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue.
    Chih-Hao Wang, Tadataka Tsuji, Li-Hong Wu, Cheng-Ying Yang, Tian Lian Huang, Mari Sato, Farnaz Shamsi, Yu-Hua Tseng.
      Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-024-51579-0
  4. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2400385121
    The microbiota-dependent tryptophan metabolite alleviates high-fat diet-induced insulin resistance through the hepatic AhR/TSC2/mTORC1 axis.
    Wei Du, Shanshan Jiang, Shengxiang Yin, Rongjiang Wang, Chunling Zhang, Bin-Cheng Yin, Jialin Li, Li Li, Nan Qi, Ying Zhou, Bang-Ce Ye.
      Type 2 diabetes (T2D) is potentially linked to disordered tryptophan metabolism that attributes to the intricate interplay among diet, gut microbiota, and host physiology. However, underlying mechanisms are substantially unknown. Comparing the gut microbiome and metabolome differences in mice fed a normal diet (ND) and high-fat diet (HFD), we uncover that the gut microbiota-dependent tryptophan metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) is present at lower concentrations in mice with versus without insulin resistance. We further demonstrate that the microbial transformation of tryptophan into 5-HIAA is mediated by Burkholderia spp. Additionally, we show that the administration of 5-HIAA improves glucose intolerance and obesity in HFD-fed mice, while preserving hepatic insulin sensitivity. Mechanistically, 5-HIAA promotes hepatic insulin signaling by directly activating AhR, which stimulates TSC2 transcription and thus inhibits mTORC1 signaling. Moreover, T2D patients exhibit decreased fecal levels of 5-HIAA. Our findings identify a noncanonical pathway of microbially producing 5-HIAA from tryptophan and indicate that 5-HIAA might alleviate the pathogenesis of T2D.
    Keywords:  gut microbiota; insulin signaling; tryptophan metabolism; type 2 diabetes
    DOI:  https://doi.org/10.1073/pnas.2400385121
  5. Bioessays. 2024 Aug 19. e2400090
    FAM210A: An emerging regulator of mitochondrial homeostasis.
    Yubo Wang, Feng Yue.
      Mitochondrial homeostasis serves as a cornerstone of cellular function, orchestrating a delicate balance between energy production, redox status, and cellular signaling transduction. This equilibrium involves a myriad of interconnected processes, including mitochondrial dynamics, quality control mechanisms, and biogenesis and degradation. Perturbations in mitochondrial homeostasis have been implicated in a wide range of diseases, including neurodegenerative diseases, metabolic syndromes, and aging-related disorders. In the past decades, the discovery of numerous mitochondrial proteins and signaling has led to a more complete understanding of the intricate mechanisms underlying mitochondrial homeostasis. Recent studies have revealed that Family with sequence similarity 210 member A (FAM210A) is a novel nuclear-encoded mitochondrial protein involved in multiple aspects of mitochondrial homeostasis, including mitochondrial quality control, dynamics, cristae remodeling, metabolism, and proteostasis. Here, we review the function and physiological role of FAM210A in cellular and organismal health. This review discusses how FAM210A acts as a regulator on mitochondrial inner membrane to coordinate mitochondrial dynamics and metabolism.
    Keywords:  FAM210A; cristae remodeling; energy metabolism; mitochondrial dynamics; proteostasis; quality control
    DOI:  https://doi.org/10.1002/bies.202400090
  6. Sci Adv. 2024 Aug 23. 10(34): eadn4845
    Antagonism of β-arrestins in IL-4-driven microglia reactivity via the Samd4/mTOR/OXPHOS axis in Parkinson's disease.
    Jiaqi Liu, Yue Liang, Qinghao Meng, Jiayu Chen, Junwei Ma, Hong Zhu, Lei Cai, Nanshan Song, Jianhua Ding, Yi Fan, Ming Lu, Guangyu Wu, Yinquan Fang, Gang Hu.
      Interleukin-4 (IL-4)-exposed microglia acquire neuroprotective properties, but their functions and regulation in Parkinson's disease (PD) are poorly understood. In this study, we demonstrate that IL-4 enhances anti-inflammatory microglia reactivity, ameliorates the pathological features of PD, and reciprocally affects expression of β-arrestin 1 and β-arrestin 2 in microglia in PD mouse models. We also show that manipulation of two β-arrestins produces contrary effects on the anti-inflammatory states and neuroprotective action of microglia induced by IL-4 in vivo and in vitro. We further find that the functional antagonism of two β-arrestins is mediated through sequential activation of sterile alpha motif domain containing 4 (Samd4), mammalian target of rapamycin (mTOR), and mitochondrial oxidative phosphorylation (OXPHOS). Collectively, these data reveal opposing functions of two closely related β-arrestins in regulating the IL-4-induced microglia reactivity via the Samd4/mTOR/OXPHOS axis in PD mouse models and provide important insights into the pathogenesis and therapeutics of PD.
    DOI:  https://doi.org/10.1126/sciadv.adn4845
  7. Chin Med J (Engl). 2024 Aug 19.
    LEAP2 ameliorates high fat diet-impaired glucose tolerance and enhances glucose-stimulated insulin secretion from β cells through PPARγ signal pathway.
    Jiaxi Li, Mei Li, Hao Ke, Yang Han, Yanhong Huang, Yan Zhou, Ziqiang Luo, Chen Chen, Dandan Feng.
      
    DOI:  https://doi.org/10.1097/CM9.0000000000003215
  8. Circ Res. 2024 Aug 23.
    Oxysterol Sensing Through GPR183 Triggers Endothelial Senescence in Hypertension.
    Qingqing Chu, Yujia Li, Jichao Wu, Yanjiao Gao, Xiangyun Guo, Jing Li, Hang Lv, Min Liu, Wei Tang, Peng Zhan, Tao Zhang, Huili Hu, Hong Liu, Jinpeng Sun, Xiaojie Wang, Fan Yi.
       BACKGROUND: Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown.
    METHODS: Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study.
    RESULTS: Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice.
    CONCLUSIONS: This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.
    Keywords:  cellular senescence; hypertension; lipid metabolism; oxysterols; receptors, G-protein-coupled
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324722
  9. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2405746121
    Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2.
    Souradipta Ganguly, Sara Brin Rosenthal, Kei Ishizuka, Ty D Troutman, Theresa V Rohm, Naser Khader, German Aleman-Muench, Yasuyo Sano, Sebastiano Archilei, Pejman Soroosh, Jerrold M Olefsky, Ariel E Feldstein, Tatiana Kisseleva, Rohit Loomba, Christopher K Glass, David A Brenner, Debanjan Dhar.
      While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2+ macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2+ macrophages are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation.
    Keywords:  Trem2; fibrosis; lipid associated macrophages (LAM); macrophage; steatohepatitis
    DOI:  https://doi.org/10.1073/pnas.2405746121
  10. Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00287-0. [Epub ahead of print]
    Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
    Traci E LaMoia, Brandon T Hubbard, Mateus T Guerra, Ali Nasiri, Ikki Sakuma, Mario Kahn, Dongyan Zhang, Russell P Goodman, Michael H Nathanson, Yasemin Sancak, Mark Perelis, Vamsi K Mootha, Gerald I Shulman.
      To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.
    Keywords:  CAMKII; Q-Flux; calcium; fat oxidation; glucose oxidation; isocitrate dehydrogenase flux; metabolic dysfunction-associated steatotic liver disease; mitochondria; mitochondrial calcium uniporter; succinate dehydrogenase flux; tricarboxylic acid cycle; type 2 diabetes; α-ketoglutarate dehydrogenase flux
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.016
  11. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2322755121
    Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
    Max L Valenstein, Pranav V Lalgudi, Xin Gu, Jibril F Kedir, Martin S Taylor, Raghu R Chivukula, David M Sabatini.
      The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth and metabolism in response to many environmental cues, including nutrients. Amino acids signal to mTORC1 by modulating the guanine nucleotide loading states of the heterodimeric Rag GTPases, which bind and recruit mTORC1 to the lysosomal surface, its site of activation. The Rag GTPases are tethered to the lysosome by the Ragulator complex and regulated by the GATOR1, GATOR2, and KICSTOR multiprotein complexes that localize to the lysosomal surface through an unknown mechanism(s). Here, we show that mTORC1 is completely insensitive to amino acids in cells lacking the Rag GTPases or the Ragulator component p18. Moreover, not only are the Rag GTPases and Ragulator required for amino acids to regulate mTORC1, they are also essential for the lysosomal recruitment of the GATOR1, GATOR2, and KICSTOR complexes, which stably associate and traffic to the lysosome as the "GATOR" supercomplex. The nucleotide state of RagA/B controls the lysosomal association of GATOR, in a fashion competitively antagonized by the N terminus of the amino acid transporter SLC38A9. Targeting of Ragulator to the surface of mitochondria is sufficient to relocalize the Rags and GATOR to this organelle, but not to enable the nutrient-regulated recruitment of mTORC1 to mitochondria. Thus, our results reveal that the Rag-Ragulator complex is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway and underscore that mTORC1 activation requires signal transduction on the lysosomal surface.
    Keywords:  biochemistry; mTOR signaling; nutrient sensing
    DOI:  https://doi.org/10.1073/pnas.2322755121
  12. Signal Transduct Target Ther. 2024 Aug 23. 9(1): 218
    Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity.
    Lu Fang, Changjie Liu, Zong-Zhe Jiang, Mengxiao Wang, Kang Geng, Yangkai Xu, Yujie Zhu, Yiwen Fu, Jing Xue, Wenxin Shan, Qi Zhang, Jie Chen, Jiahong Chen, Mingming Zhao, Yuxuan Guo, K W Michael Siu, Y Eugene Chen, Yong Xu, Donghui Liu, Lemin Zheng.
      Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.
    DOI:  https://doi.org/10.1038/s41392-024-01930-0
  13. Nat Commun. 2024 Aug 21. 15(1): 7144
    FOXO-regulated OSER1 reduces oxidative stress and extends lifespan in multiple species.
    Jiangbo Song, Zhiquan Li, Lei Zhou, Xin Chen, Wei Qi Guinevere Sew, Héctor Herranz, Zilu Ye, Jesper Velgaard Olsen, Yuan Li, Marianne Nygaard, Kaare Christensen, Xiaoling Tong, Vilhelm A Bohr, Lene Juel Rasmussen, Fangyin Dai.
      FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 (OSER1), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased ATP production, and altered transcription of mitochondrial genes. Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging.
    DOI:  https://doi.org/10.1038/s41467-024-51542-z
  14. Heliyon. 2024 Aug 15. 10(15): e35467
    Overexpression of METTL14 mediates steatohepatitis and insulin resistance in mice.
    Ji-Xiang Zhou, Man-Yi Yang, Deng-Gao Zhai, Qin Jiang, Qi Zhang.
       Background: Lipid accumulation and redox imbalance, resulting from dysregulation of hepatic fatty acids oxidation, contribute to the development of steatohepatitis and insulin resistance. Recently, dysregulated RNA N6-methyladenosine (m6A) methylation modification has been found involving fatty liver. However, the role of methyltransferase-like 14 (METTL14), the core component of m6A methylation, in the development of steatohepatitis is unknown. Herein, we aimed to explore the role of METTL14 on steatohepatitis and insulin resistance in mice with metabolic dysfunction-associated steatotic liver disease (MASLD).
    Methods: The liver tissues of mice and patients with MASLD were collected to detect the expression of METTL14. METTL14 overexpression and METTL14 silence were used to investigate the effect of METTL14 on lipid metabolism disorder in vivo and in vitro. Knockout of METTL14 in primary hepatocytes was used to investigate the role of Sirtuin 1 (SIRT1) on lipid accumulation induced by METTL14.
    Results: METTL14 was dramatically up-regulated in the livers of db/db mice, high-fat diet (HFD)-fed mice, and patients with MASLD. METTL14 overexpression exacerbated MASLD and promoted lipid metabolism disorder and insulin resistance in mice. Conversely, METTL14 knockout ameliorated lipid deposition and insulin resistance in HFD-fed mice. Furthermore, METTL14 overexpression facilitated lipid accumulation, while METTL14 knockout reduced lipid accumulation in HepG2 cells and primary hepatocytes. In addition, METTL14 lost up-regulated SIRT1 expression in hepatocytes. SIRT1 deficiency abrogated the ameliorating effects of METTL14 downregulation in MASLD mice.
    Conclusions: These findings suggest that dysfunction of the METTL14-SIRT1 pathway might promote hepatic steatosis and insulin resistance.
    Keywords:  Fatty acid β-oxidation; METTL14; Metabolic dysfunction-associated steatotic liver disease; Sirtuin 1
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e35467
  15. Int J Biochem Cell Biol. 2024 Aug 20. pii: S1357-2725(24)00130-4. [Epub ahead of print] 106638
    IRX3 promotes adipose tissue browning and inhibits fibrosis in obesity-resistant mice.
    Xi-Yue Yan, Yuan-Yuan Luo, Hui-Jian Chen, Xiao-Qin Hu, Peng Zheng, Hong-Ting Fang, Fei Ding, Li Zhang, Zhen Li, You-E Yan.
      Obesity is one of the threats to human health and survival. High fat diet (HFD)-induced obesity leads to adipose tissue fibrosis and a series of metabolic diseases. There are some people still thin under HFD, a phenomenon known as the "obesity resistance (OR) phenotype". It was found that Iroquois homeobox 3 (IRX3) is considered as a regulator in obesity, but the regulatory mechanism between OR and IRX3 is still unclear. In this study, we investigated obesity resistance (OR) on a high-fat diet (HFD) and the role of the Iroquois homeobox 3 (IRX3) gene. Using mice, we observed that OR mice had lower body weights, reduced liver lipid synthesis, and increased white adipose tissue (WAT) lipolysis compared to obesity-prone (OP) mice. Additionally, OR mice exhibited spontaneous WAT browning and less fibrosis, correlating with higher Irx3 expression. Utilizing 3T3-L1 differentiated adipocytes, our study demonstrated that overexpression of Irx3 promoted thermogenesis-related gene expression and reduced adipocyte fibrosis. Therefore, Irx3 promotes WAT browning and inhibits fibrosis in OR mice. These results provide insight into the differences between obesity and OR, new perspectives on obesity treatment, and guidance for lessening adipose tissue fibrosis.
    Keywords:  IRX3; browning; fibrosis; obesity resistance
    DOI:  https://doi.org/10.1016/j.biocel.2024.106638
  16. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2321204121
    DNA damage-induced proteasome phosphorylation controls substrate recognition and facilitates DNA repair.
    Xiaomei Zhang, Tianyi Zhu, Xuemei Li, Hongxia Zhao, Shixian Lin, Jun Huang, Bing Yang, Xing Guo.
      Upon DNA damage, numerous proteins are targeted for ubiquitin-dependent proteasomal degradation, which is an integral part of the DNA repair program. Although details of the ubiquitination processes have been intensively studied, little is known about whether and how the 26S proteasome is regulated in the DNA damage response (DDR). Here, we show that human Rpn10/PSMD4, one of the three ubiquitin receptors of the 26S proteasome, is rapidly phosphorylated in response to different types of DNA damage. The phosphorylation occurs at Rpn10-Ser266 within a conserved SQ motif recognized by ATM/ATR/DNA-PK. Blockade of S266 phosphorylation attenuates homologous recombination-mediated DNA repair and sensitizes cells to genotoxic insults. In vitro and in cellulo experiments indicate that phosphorylation of S266, located in the flexible linker between the two ubiquitin-interacting motifs (UIMs) of Rpn10, alters the configuration of UIMs, and actually reduces ubiquitin chain (substrate) binding. As a result, essential DDR proteins such as BRCA1 are spared from premature degradation and allowed sufficient time to engage in DNA repair, a scenario supported by proximity labeling and quantitative proteomic studies. These findings reveal an inherent self-limiting mechanism of the proteasome that, by controlling substrate recognition through Rpn10 phosphorylation, fine-tunes protein degradation for optimal responses under stress.
    Keywords:  DNA damage; Rpn10; phosphorylation; proteasome; ubiquitination
    DOI:  https://doi.org/10.1073/pnas.2321204121
  17. Am J Physiol Endocrinol Metab. 2024 Aug 22.
    Key Questions and Gaps in Understanding Adipose Tissue Macrophages and Early-Life Metabolic Programming.
    Kaitlyn Hill, Gregory P Mullen, Prabha Nagareddy, Kurt Zimmerman, Michael C Rudolph.
      The global obesity epidemic, with its associated comorbidities and increased risk of early mortality, underscores the urgent need for enhancing our understanding of the origins of this complex disease. It is increasingly clear that metabolism is programmed early in life and that metabolic programming can have life-long health consequences. As a critical metabolic organ sensitive to early-life stimuli, proper development of adipose tissue (AT) is crucial for life-long energy homeostasis. Early-life nutrients, especially fatty acids (FA), significantly influence the programming of AT and shape its function and metabolism. Of growing interest are the dynamic responses during pre- and postnatal development to proinflammatory omega-6 (n6) and anti-inflammatory omega-3 (n3) FA exposures in AT. In the US maternal diet, the ratio of 'pro-inflammatory' n6- to 'anti-inflammatory' n3-FA has grown dramatically due to the greater prevalence of n6-FA. Notably, AT macrophages (ATM) form a significant population within adipose stromal cells, playing not only an instrumental role in AT formation and maintenance, but also acting as key mediators of cell-to-cell lipid and cytokine signaling. Despite rapid advances in ATM and immunometabolism fields, research has focused on responses to obesogenic diets and during adulthood. Consequently, there is a significant gap in identifying the mechanisms contributing metabolic health, especially regarding lipid exposures during the establishment of ATM physiology. Our review highlights the current understanding of ATM diversity, their critical role in AT, and their potential role in early-life metabolic programming, as well as the broader implications for metabolism and health.
    Keywords:  Adipose Tissue Macrophage; Early-Life Metabolic Programming; Immunometabolism; Obesity; Omega-6 Fatty Acid
    DOI:  https://doi.org/10.1152/ajpendo.00140.2024
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:26.