bims-obesme 2024-08-11 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024–08–11
twelve papers selected by
Xiong Weng, University of Edinburgh

Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner.
PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity.
Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
An in vitro model of adipose tissue-associated macrophages.
Metaboepigenetic regulation of gene expression in obesity and insulin resistance.
Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms.
p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells.
PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis.
A novel peptide encoded by circ-SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac-mediated CD36 transcription in NAFLD.
Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion.
Digitising the ageing process with epigenetic clocks.
AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism.

Nat Commun. 2024 Aug 05. 15(1): 6622

Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner.

Benjamin M Steiner, Abigail M Benvie, Derek Lee, Yuwei Jiang, Daniel C Berry.

Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ-expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4-deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity.

DOI: https://doi.org/10.1038/s41467-024-50985-8
Nature. 2024 Aug 07.

PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity.

Wei Wei, Xuchao Lyu, Andrew L Markhard, Sipei Fu, Rachel E Mardjuki, Peter E Cavanagh, Xianfeng Zeng, Jakub Rajniak, Nannan Lu, Shuke Xiao, Meng Zhao, Maria Dolores Moya-Garzon, Steven D Truong, Jonathan Chiu-Chun Chou, Lianna W Wat, Saranya Chidambaranathan-Reghupaty, Laetitia Coassolo, Duo Xu, Fangfang Shen, Wentao Huang, Cuauhtemoc B Ramirez, Cholsoon Jang, Lingyin Li, Katrin J Svensson, Michael A Fischbach, Jonathan Z Long.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance.

DOI: https://doi.org/10.1038/s41586-024-07801-6
Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00278-X. [Epub ahead of print]

Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.

Yiming Zhang, Cassandra B Higgins, Stefani Tica, Joshua A Adams, Jiameng Sun, Shannon C Kelly, Xiaoyu Zong, Dennis J Dietzen, Terri Pietka, Samuel J Ballentine, Leah Shriver, Gary Patti, Yin Cao, Brian J DeBosch.

  Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.

Keywords:  arginase; diabetes; fasting; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; nicotinamide adenine dinucleotide; nicotinamide riboside; obesity; tricarboxylic acid cycle; urea cycle

DOI:  https://doi.org/10.1016/j.cmet.2024.07.007
J Biosci. 2024 ;pii: 79. [Epub ahead of print]49

An in vitro model of adipose tissue-associated macrophages.

Karishma Bhatia, Sandhya Tiwari, Vikas Kumar Gupta, Neerav M Sapariya, Sanjeev K Upadhyay.

Obesity-related chronic low-grade inflammation plays a central role in the development of insulin resistance. Macrophages are key players in adipose tissue homeostasis, and their phenotypic shift from the anti-inflammatory or alternatively activated (M2) form to the pro-inflammatory, classically activated (M1) form is a hallmark of insulin resistance. However, adipose tissue macrophages (ATMs) have been identified as a distinct subpopulation of macrophages in several recent studies. These ATMs, described as metabolically activated macrophages (MMe), differ from M1 and are primarily found in the adipose tissue of obese individuals. In our study, we developed an in vitro model of MMe macrophages to establish a simple and reproducible system to understand their characteristics and role in the pathophysiology of insulin resistance. We examined their characteristics such as inflammatory patterns, surface markers, and metabolic features, and compared them with M1 and M2 macrophages. We found that a cell line-based in vitro model effectively mirrors the characteristics of ATMs, highlighting distinct inflammatory phenotypes, metabolism, surface markers, altered lysosomal activity, and ER stress akin to macrophages in vivo. This model captures the subtle distinctions between MMe and M1, and can be effectively used to study several features of macrophage-adipose interactions of therapeutic importance.
Metabolomics. 2024 Aug 03. 20(5): 91

Metaboepigenetic regulation of gene expression in obesity and insulin resistance.

Swapan K Das, Mary E Comeau, Carl D Langefeld.

   INTRODUCTION: Variation in DNA methylation (DNAm) in adipose tissue is associated with the pathogenesis of obesity and insulin resistance. The activity of enzymes involved in altering DNAm levels is dependent on several metabolite cofactors.
OBJECTIVES: To understand the role of metabolites as mechanistic regulators of epigenetic marks, we tested the association between selected plasma metabolites and DNAm levels in the adipose tissue of African Americans.
METHODS: In the AAGMEx cohort (N = 256), plasma levels of metabolites were measured by untargeted liquid chromatography-mass spectrometry; adipose tissue DNAm and transcript levels were measured by reduced representation bisulfite sequencing, and expression microarray, respectively.
RESULTS: Among the 21 one-carbon metabolism pathway metabolites evaluated, six were associated with gluco-metabolic traits (PFDR < 0.05, for BMI, SI, or Matsuda index) in AAGMEx. Methylation levels of 196, 116, and 180 CpG-sites were associated (P < 0.0001) with S-adenosylhomocysteine (SAH), cystine, and hypotaurine, respectively. Cis-expression quantitative trait methylation (cis eQTM) analyses suggested the role of metabolite-level-associated CpG sites in regulating the expression of adipose tissue transcripts, including genes in G-protein coupled receptor signaling pathway. Plasma SAH level-associated CpG sites chr19:3403712 and chr19:3403735 were also associated with the expression of G-protein subunit alpha 15 (GNA15) in adipose. The expression of GNA15 was significantly correlated with BMI (β = 1.87, P = 1.9 × 10-16) and SI (β = -1.61, P = 2.49 × 10-5).
CONCLUSION: Our study suggests that a subset of metabolites modulates the methylation levels of CpG sites in specific loci and, in turn, regulates the expression of transcripts involved in obesity and insulin resistance.

Keywords:   Cis-eQTM; African American; DNA methylation; Insulin resistance; Metabolite; Obesity

DOI:  https://doi.org/10.1007/s11306-024-02159-2
Nat Commun. 2024 Aug 08. 15(1): 6777

Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms.

Soeun Kang, Maciek R Antoniewicz, Nissim Hay.

Metabolic rewiring during the proliferation-to-quiescence transition is poorly understood. Here, using a model of contact inhibition-induced quiescence, we conducted 13C-metabolic flux analysis in proliferating (P) and quiescent (Q) mouse embryonic fibroblasts (MEFs) to investigate this process. Q cells exhibit reduced glycolysis but increased TCA cycle flux and mitochondrial respiration. Reduced glycolytic flux in Q cells correlates with reduced glycolytic enzyme expression mediated by yes-associated protein (YAP) inhibition. The increased TCA cycle activity and respiration in Q cells is mediated by induced mitochondrial pyruvate carrier (MPC) expression, rendering them vulnerable to MPC inhibition. The malate-to-pyruvate flux, which generates NADPH, is markedly reduced by modulating malic enzyme 1 (ME1) dimerization in Q cells. Conversely, the malate dehydrogenase 1 (MDH1)-mediated oxaloacetate-to-malate flux is reversed and elevated in Q cells, driven by high mitochondrial-derived malate levels, reduced cytosolic oxaloacetate, elevated MDH1 levels, and a high cytoplasmic NAD+/NADH ratio. Transcriptomic analysis revealed large number of genes are induced in Q cells, many of which are associated with the extracellular matrix (ECM), while YAP-dependent and cell cycle-related genes are repressed. The results suggest that high TCA cycle flux and respiration in Q cells are required to generate ATP and amino acids to maintain de-novo ECM protein synthesis and secretion.

DOI: https://doi.org/10.1038/s41467-024-51117-y
Nat Cell Biol. 2024 Aug 05.

p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells.

Julia Majewska, Amit Agrawal, Avi Mayo, Lior Roitman, Rishita Chatterjee, Jarmila Sekeresova Kralova, Tomer Landsberger, Yonatan Katzenelenbogen, Tomer Meir-Salame, Efrat Hagai, Ilanit Sopher, Juan-Felipe Perez-Correa, Wolfgang Wagner, Avi Maimon, Ido Amit, Uri Alon, Valery Krizhanovsky.

The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.

DOI: https://doi.org/10.1038/s41556-024-01465-0
Adv Sci (Weinh). 2024 Aug 09. e2403177

PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis.

Wenxiang Chu, Weilin Peng, Yingying Lu, Yishan Liu, Qisheng Li, Haibin Wang, Liang Wang, Bangke Zhang, Zhixiao Liu, Lin Han, Hongdao Ma, Haisong Yang, Chaofeng Han, Xuhua Lu.

  Epigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By transcriptional sequence and ATAC analysis, this study identifies that activation of RANK signaling upregulates PRMT6 by epigenetic modification, triggering a metabolic switching from fatty acids oxidation toward glycolysis. Conversely, Prmt6 deficiency reverses this shift, markedly reducing HIF-1α-mediated glycolysis and enhancing fatty acid oxidation. Consequently, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss in ovariectomized (OVX) mice. At the molecular level, Prmt6 deficiency reduces asymmetric dimethylation of H3R2 at the promoters of genes including Ppard, Acox3, and Cpt1a, enhancing genomic accessibility for fatty acid oxidation. PRMT6 thus emerges as a metabolic checkpoint, mediating metabolic switch from fatty acid oxidation to glycolysis, thereby supporting osteoclastogenesis. Unveiling PRMT6's critical role in epigenetically orchestrating metabolic shifts in osteoclastogenesis offers a promising target for anti-resorptive therapy.

Keywords:  PRMT6; fatty acids oxidation; glycolysis; metabolic reprogramming; osteoclastogenesis

DOI:  https://doi.org/10.1002/advs.202403177
Clin Transl Med. 2024 Aug;14(8): e1801

A novel peptide encoded by circ-SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac-mediated CD36 transcription in NAFLD.

Yue Wang, Xinyao Tian, Zhecheng Wang, Deshun Liu, Xuzi Zhao, Xin Sun, Zuoyu Tu, Zekuan Li, Yan Zhao, Shusen Zheng, Jihong Yao.

   BACKGROUND: As the leading cause of end-stage liver disease, nonalcoholic fatty liver disease (NAFLD) is mainly induced by lipid dyshomeostasis. The translation of endogenous circular RNAs (circRNAs) is closely related to the progression of various diseases, but the involvement of circRNAs in NAFLD has not been determined.
METHODS: Combined high-throughput circRNA profiles were used to identify circRNAs with translational potential. The underlying molecular mechanisms were investigated by RNA sequencing, pull-down/MS and site-specific mutagenesis.
RESULTS: In this study, we focused on circ-SLC9A6, an abnormally highly expressed circRNA in human and mouse liver tissue during NAFLD development that exacerbates metabolic dyshomeostasis in hepatocytes by encoding a novel peptide called SLC9A6-126aa in vivo and in vitro. YTHDF2-mediated degradation of m6A-modified circ-SLC9A6 was found to be essential for the regulation of SLC9A6-126aa expression. We further found that the phosphorylation of SLC9A6-126aa by AKT was crucial for its cytoplasmic localization and the maintenance of physiological homeostasis, whereas high-fat stress induced substantial translocation of unphosphorylated SLC9A6-126aa to the nucleus, resulting in a vicious cycle of lipid metabolic dysfunction. Nuclear SLC9A6-126aa promotes transcriptional activation of the target gene CD36 and enhances its occupancy of the CD36 promoter locus by regulating MOF-mediated histone H4K16 acetylation. Hepatic CD36 depletion significantly ameliorated hyperactivated MAPK signalling and lipid disturbance in SLC9A6-126aa transgenic mice. Clinically, increasing levels of SLC9A6-126aa were observed during NAFLD progression and were found to be positively correlated with the CD36 and MAPK cascades.
CONCLUSION: This study revealed the role of circ-SLC9A6-derived SLC9A6-126aa in the epigenetic modification-mediated regulation of lipid metabolism. Our findings may provide promising therapeutic targets for NAFLD and new insights into the pathological mechanisms of metabolic diseases.
HIGHLIGHTS: Under normal circumstances, driven by m6A modification, YTHDF2 directly recognizes and degrades circ-SLC9A6, thereby inhibiting the translation of SLC9A6-126aa. Additionally, AKT1 phosphorylates and inhibits the nuclear translocation of SLC9A6-126aa. In NAFLD, lipid overload leads to YTHDF2 and AKT1 deficiency, ultimately increasing the expression and nuclear import of SLC9A6-126aa. Nuclear SLC9A6-126aa binds directly to the CD36 promoter and initiates CD36 transcription, which induces lipid dyshomeostasis.

Keywords:  circ‐RNA translation; h4k16ac; lipid dyshomeostasis; nuclear transport; transcription

DOI:  https://doi.org/10.1002/ctm2.1801
Nat Commun. 2024 Aug 06. 15(1): 6697

Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion.

Zan Li, Baohong Shi, Na Li, Jun Sun, Xiangchen Zeng, Rui Huang, Seoyeon Bok, Xiaohui Chen, Jie Han, Alisha R Yallowitz, Shawon Debnath, Michelle Cung, Zheng Ling, Chuan-Qi Zhong, Yixang Hong, Gang Li, Mascha Koenen, Paul Cohen, Xinhui Su, Hongbin Lu, Matthew B Greenblatt, Ren Xu.

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.

DOI: https://doi.org/10.1038/s41467-024-51155-6
Lancet. 2024 Aug 03. pii: S0140-6736(24)01554-X. [Epub ahead of print]404(10451): 423

Digitising the ageing process with epigenetic clocks.

Steve Horvath, Eric J Topol.

DOI: https://doi.org/10.1016/S0140-6736(24)01554-X
J Cell Biol. 2024 Oct 07. pii: e202401024. [Epub ahead of print]223(10):

AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism.

Eline C Brombacher, Thiago A Patente, Alwin J van der Ham, Tijmen J A Moll, Frank Otto, Fenne W M Verheijen, Esther A Zaal, Arnoud H de Ru, Rayman T N Tjokrodirijo, Celia R Berkers, Peter A van Veelen, Bruno Guigas, Bart Everts.

Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity and suggest AMPK as a target to direct DC-driven tolerogenic responses in therapeutic settings.

DOI: https://doi.org/10.1083/jcb.202401024