bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–03–16
ten papers selected by
Xiong Weng, University of Edinburgh
  1. Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD.
  2. Central FGF19 signaling enhances energy homeostasis and adipose tissue thermogenesis through sympathetic activation in obese mice.
  3. Myeloid sirtuin 6 deficiency causes obesity in mice by inducing norepinephrine degradation to limit thermogenic tissue function.
  4. Genetic variation modulates susceptibility to aberrant DNA hypomethylation and imprint deregulation in naive pluripotent stem cells.
  5. A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation.
  6. An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells.
  7. ATF4 drives regulatory T cell functional specification in homeostasis and obesity.
  8. Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis.
  9. Engineering mtDNA deletions by reconstituting end joining in human mitochondria.
  10. Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbA1c levels but not with type 2 diabetes.
  1. Cell Rep. 2025 Mar 11. pii: S2211-1247(25)00236-0. [Epub ahead of print]44(3): 115465
    Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD.
    Jinyang Li, Xiancheng Chen, Shiyu Song, Wangjie Jiang, Tianjiao Geng, Tiantian Wang, Yan Xu, Yongqiang Zhu, Jun Lu, Yongxiang Xia, Rong Wang.
      
    DOI:  https://doi.org/10.1016/j.celrep.2025.115465
  2. Am J Physiol Endocrinol Metab. 2025 Mar 10.
    Central FGF19 signaling enhances energy homeostasis and adipose tissue thermogenesis through sympathetic activation in obese mice.
    Lucas Zangerolamo, Marina Carvalho, Carina Solon, Davi Sidarta-Oliveira, Gabriela M Soares, Carine Marmentini, Antonio C Boschero, Yu-Hua Tseng, Licio A Velloso, Helena C L Barbosa.
      Fibroblast growth factor 19 (FGF19) signaling in the brain is associated with body weight loss, reduced food intake, and improved glycemic control in obese mice through unclear mechanisms. Here, we investigated the effects of central FGF19 administration on peripheral tissues, focusing on adipose tissue, and its contributions to body weight loss. Using single-cell RNA sequencing of the adult murine hypothalamus, we found that FGF19 has the potential to target multiple cell populations, including astrocytes-tanycytes, microglia, neurons, and oligodendrocytes. Central delivery of FGF19 decreased body weight gain and ameliorated glucose-insulin homeostasis in diet-induced obese (DIO) mice. These results were accompanied by increased energy expenditure and reduced peripheric inflammation. Notably, these effects were attributable to the increased activity of thermogenic adipocytes, as up-regulated thermogenic markers in brown and inguinal adipose tissue and improved cold tolerance were induced by central FGF19. However, under blunted sympathetic activity, the described effects were abolished. Moreover, cold exposure induced upregulation of FGF19 receptors and coreceptors specifically in the hypothalamus, suggesting a critical metabolic adaptation for thermoregulation and energy homeostasis. Our findings indicate that central FGF19 signaling improves energy homeostasis in DIO mice, at least in part, by stimulating sympathetic activity and adipose tissue thermogenesis. These findings highlight FGF19's potential as a therapeutic target for obesity and metabolic disorders.
    Keywords:  Brown Adipose Tissue; Energy Homeostasis; FGF19; Glucose metabolism; Hypothalamus; Obesity
    DOI:  https://doi.org/10.1152/ajpendo.00488.2024
  3. Sci Signal. 2025 Mar 11. 18(877): eadl6441
    Myeloid sirtuin 6 deficiency causes obesity in mice by inducing norepinephrine degradation to limit thermogenic tissue function.
    Wei Wang, Jichao Liang, Yinliang Zhang, Junjun Wang, Xiaolei Miao, Yongsheng Chang, Yong Chen.
      Brown and beige adipocytes dissipate energy to generate heat through uncoupled respiration, and the hormone norepinephrine plays an important role in stimulating brown fat thermogenesis and beige adipocyte development in white adipose depots. Increasing energy expenditure by promoting the function and development of brown and beige fat is a potential approach to treat obesity and diabetes. Here, we investigated the effects of macrophage sirtuin 6 (SIRT6) on the regulation of the norepinephrine content of brown adipose tissue (BAT) and on obesity in mice. Myeloid SIRT6 deficiency impaired the thermogenic function of BAT, thereby decreasing core body temperatures because of reduced norepinephrine concentrations in BAT and subsequently leading to cold sensitivity. In addition, the oxygen consumption rate was reduced, resulting in severe insulin resistance and obesity. Furthermore, macrophage SIRT6 deficiency inhibited BAT thermogenesis after cold exposure or norepinephrine treatment and cold exposure-induced increases in markers of lipid metabolism and thermogenesis in white adipose tissue. Myeloid-specific SIRT6 deficiency promoted H3K9 acetylation in the promoter regions and the expression of genes encoding the norepinephrine-degrading enzyme MAOA and the norepinephrine transporter SLC6A2 in macrophages in BAT, leading to norepinephrine degradation and obesity. Our findings indicate that SIRT6 in macrophages is essential for maintaining norepinephrine concentrations in BAT in mice.
    DOI:  https://doi.org/10.1126/scisignal.adl6441
  4. Stem Cell Reports. 2025 Mar 07. pii: S2213-6711(25)00054-2. [Epub ahead of print] 102450
    Genetic variation modulates susceptibility to aberrant DNA hypomethylation and imprint deregulation in naive pluripotent stem cells.
    C Parikh, R A Glenn, Y Shi, K Chatterjee, K Kasliwal, E E Swanzey, S Singer, S C Do, Y Zhan, Y Furuta, M Tahiliani, E Apostolou, A Polyzos, R Koche, J G Mezey, T Vierbuchen, M Stadtfeld.
      Naive pluripotent stem cells (nPSCs) frequently undergo pathological loss of DNA methylation at imprinted gene loci, posing a hurdle for biomedical applications and underscoring the need to identify underlying causes. We show that nPSCs from inbred mouse strains exhibit strain-specific susceptibility to locus-specific deregulation of imprinting marks during reprogramming and upon exposure to a mitogen-activated protein kinase (MAPK) inhibitor, a common approach to maintain naive pluripotency. Analysis of genetically diverse nPSCs from the Diversity Outbred (DO) stock confirms the impact of genetic variation on epigenome stability, which we leverage to identify trans-acting quantitative trait loci (QTLs) that modulate DNA methylation levels at specific targets or genome-wide. Analysis of multi-target QTLs on chromosomes 4 and 17 suggests candidate transcriptional regulators contributing to DNA methylation maintenance in nPSCs. We propose that genetic variants represent biomarkers to identify pluripotent cell lines with desirable properties and may allow the targeted engineering of nPSCs with stable epigenomes.
    Keywords:  DNA methylation; QTL mapping; diversity outbred mice; epigenetic instability; genomic imprinting; naive pluripotency
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102450
  5. Cell Metab. 2025 Feb 28. pii: S1550-4131(25)00062-2. [Epub ahead of print]
    A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation.
    Yu Wang, Yunxiao Zhang, Verina H Leung, Saba Heydari Seradj, Utku Sonmez, M Rocio Servin-Vences, Shuke Xiao, Xiangyu Ren, Leon Wang, Sassan A Mishkanian, Sejal A Kini, Jonathan Z Long, Darren J Lipomi, Li Ye, Ardem Patapoutian.
      Compared with the well-established functions of sympathetic innervation, the role of sensory afferents in adipose tissues remains less understood. Recent work has revealed the anatomical and physiological significance of adipose sensory innervation; however, its molecular underpinning remains unclear. Here, using organ-targeted single-cell RNA sequencing, we identified the mechanoreceptor PIEZO2 as one of the most prevalent receptors in fat-innervating dorsal root ganglia (DRG) neurons. PIEZO2 deletion in fat-innervating neurons induced transcriptional programs in adipose tissue resembling sympathetic activation, mirroring DRG ablation. Conversely, a gain-of-function PIEZO2 mutant shifted the adipose phenotypes in the opposite direction. These results indicate that PIEZO2 plays a major role in the sensory regulation of adipose tissues. This discovery opens new avenues for exploring mechanosensation in organs not traditionally considered mechanically active, such as adipose tissues, and therefore sheds light on the broader significance of mechanosensation in regulating organ function and homeostasis.
    Keywords:  adipose; mechanosensation
    DOI:  https://doi.org/10.1016/j.cmet.2025.02.004
  6. Nat Commun. 2025 Mar 07. 16(1): 1645
    An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells.
    Lu Guang, Shilin Ma, Ziyue Yao, Dan Song, Yu Chen, Shuqing Liu, Peng Wang, Jiali Su, Yuefan Wang, Lanfang Luo, Ng Shyh-Chang.
      Human GWAS have shown that obesogenic FTO polymorphisms correlate with lean mass, but the mechanisms have remained unclear. It is counterintuitive because lean mass is inversely correlated with obesity and metabolic diseases. Here, we use CRISPR to knock-in FTOrs9939609-A into hESC-derived tissue models, to elucidate potentially hidden roles of FTO during development. We find that among human tissues, FTOrs9939609-A most robustly affect human muscle progenitors' proliferation, differentiation, senescence, thereby accelerating muscle developmental and metabolic aging. An edited FTOrs9939609-A allele over-stimulates insulin/IGF signaling via increased muscle-specific enhancer H3K27ac, FTO expression and m6A demethylation of H19 lncRNA and IGF2 mRNA, with excessive insulin/IGF signaling leading to insulin resistance upon replicative aging or exposure to high fat diet. This FTO-m6A-H19/IGF2 circuit may explain paradoxical GWAS findings linking FTOrs9939609-A to both leanness and obesity. Our results provide a proof-of-principle that CRISPR-hESC-tissue platforms can be harnessed to resolve puzzles in human metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-53820-2
  7. Sci Immunol. 2025 Mar 14. 10(105): eadp7193
    ATF4 drives regulatory T cell functional specification in homeostasis and obesity.
    Ke Wang, Andrea Farrell, Enchen Zhou, Houji Qin, Zixuan Zeng, Kailun Zhou, Karina Cunha E Rocha, Dinghong Zhang, Gaowei Wang, Amha Atakilit, Dean Sheppard, Li-Fan Lu, Chunyu Jin, Wei Ying.
      Regulatory T cells (Tregs) have diverse functional specification in homeostasis and disease. However, how liver Tregs function and are transcriptionally regulated in obesity is not well understood. Here, we identified that effector Tregs expressing activating transcription factor 4 (ATF4) were enriched in the livers of obese mice. ATF4 was critical for driving an effector Treg transcriptional program, and ATF4-expressing Tregs promoted the development of obesity-induced liver fibrosis by enhancing transforming growth factor-β activation via integrin αvβ8. Treg-specific deletion of Atf4 resulted in reduced liver Tregs and attenuation of obesity-induced liver abnormalities. Furthermore, ATF4 was required to promote the differentiation of nonlymphoid tissue Treg precursors under steady state. These findings demonstrate that ATF4 is important for regulating Treg functional specification in homeostasis and obesity.
    DOI:  https://doi.org/10.1126/sciimmunol.adp7193
  8. Science. 2025 Mar 13. eado4188
    Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis.
    Hui Lin, Chuanshun Ma, Kui Cai, Lulu Guo, Xuemei Wang, Lin Lv, Chao Zhang, Jun Lin, Daolai Zhang, Chuan Ye, Tengwei Wang, Shenming Huang, Jifei Han, Zihao Zhang, Junyan Gao, Mingxiang Zhang, Zhao Pu, Fengyang Li, Yongyuan Guo, Xiaojun Zhou, Chengxue Qin, Fan Yi, Xiao Yu, Wei Kong, Changtao Jiang, Jin-Peng Sun.
      Ceramides play a central role in human health and disease, yet their role as systemic signaling molecules remain poorly understood. In this work, we identify FPR2 as a membrane receptor that specifically binds long-chain ceramides (C14-C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis via Gi-cyclic AMP signaling pathways, an effect that is reversed in the absence of FPR2. We present three cryo-electron microscopy structures of FPR2 in complex with Gi trimers bound to C16:0, C18:0 and C20:0 ceramides. The hydrophobic tails are deeply embedded in the orthosteric ligand pocket, which has a limited amount of plasticity. Modification of the ceramide binding motif in closely related receptors, such as FPR1 or FPR3, converts them from inactive to active ceramide receptors. Our findings provide a structural basis for adipocyte thermogenesis mediated by FPR2.
    DOI:  https://doi.org/10.1126/science.ado4188
  9. Cell. 2025 Mar 05. pii: S0092-8674(25)00194-1. [Epub ahead of print]
    Engineering mtDNA deletions by reconstituting end joining in human mitochondria.
    Yi Fu, Max Land, Tamar Kavlashvili, Ruobing Cui, Minsoo Kim, Emily DeBitetto, Toby Lieber, Keun Woo Ryu, Elim Choi, Ignas Masilionis, Rahul Saha, Meril Takizawa, Daphne Baker, Marco Tigano, Caleb A Lareau, Ed Reznik, Roshan Sharma, Ronan Chaligne, Craig B Thompson, Dana Pe'er, Agnel Sfeir.
      Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled precise base substitutions and the efficient elimination of genomes carrying pathogenic mutations. However, reconstituting mtDNA deletions linked to mitochondrial myopathies remains challenging. Here, we engineered mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. Using mitochondrial EJ (mito-EJ) and mito-ScaI, we generated a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion across the full spectrum of heteroplasmy. Investigating these cells revealed a critical threshold of ∼75% deleted genomes, beyond which oxidative phosphorylation (OXPHOS) protein depletion, metabolic disruption, and impaired growth in galactose-containing media were observed. Single-cell multiomic profiling identified two distinct nuclear gene deregulation responses: one triggered at the deletion threshold and another progressively responding to heteroplasmy. Ultimately, we show that our method enables the modeling of disease-associated mtDNA deletions across cell types and could inform the development of targeted therapies.
    Keywords:  DOGMA-seq; end joining; mitochondrial pathologies; mtDNA; mtDNA deletion
    DOI:  https://doi.org/10.1016/j.cell.2025.02.009
  10. Diabetologia. 2025 Mar 10.
    Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbA1c levels but not with type 2 diabetes.
    Kimmie V Sørensen, Johanne M Justesen, Lars Ängquist, Jette Bork-Jensen, Bolette Hartmann, Niklas R Jørgensen, Jørgen Rungby, Henrik T Sørensen, Allan Vaag, Jens S Nielsen, Jens J Holst, Oluf Pedersen, Allan Linneberg, Torben Hansen, Niels Grarup.
       AIMS/HYPOTHESIS: An intronic variant (rs10830963) in MTNR1B (encoding the melatonin receptor type 2 [MT2]) has been shown to strongly associate with impaired glucose regulation and elevated type 2 diabetes prevalence. However, MTNR1B missense variants have shown conflicting results on type 2 diabetes. Thus, we aimed to gain further insights into the impact of MTNR1B coding variants on type 2 diabetes prevalence and related phenotypes.
    METHODS: We conducted a cross-sectional study, performing MTNR1B variant burden testing of glycaemic phenotypes (N=248,454, without diabetes), other cardiometabolic phenotypes (N=330,453) and type 2 diabetes prevalence (case-control study; N=263,739) in the UK Biobank. Similar burden testing with glycaemic phenotypes was performed in Danish Inter99 participants without diabetes (N=5711), and type 2 diabetes prevalence (DD2 cohort serving as cases [N=2930] and Inter99 serving as controls [N=4243]). Finally, we evaluated the effects of MTNR1B variants on the melatonin-induced glucose regulation response in a recall-by-genotype study of individuals without diabetes.
    RESULTS: In the UK Biobank, MTNR1B variants were not associated with cardiometabolic phenotypes, including type 2 diabetes prevalence, except that carriers of missense MTNR1B variants causing impaired MT2 signalling exhibited higher HbA1c levels compared with non-carriers (effect size, β, 0.087 SD [95% CI 0.039, 0.135]). Similarly, no significant associations were observed with phenotypes associated with glycaemic phenotypes in the Inter99 population. However, carriers of variants impairing MT2 signalling demonstrated a nominally significant lower glucose-stimulated insulin response (β -0.47 SD [95% CI -0.82, -0.11]). A reduced insulin response was also observed in carriers of variants impairing MT2 signalling (β -476.0 [95% CI -928.6, -24.4]) or the rs10830963 variant (β -390.8 [95% CI -740.1, -41.6]) compared with non-carriers after melatonin treatment.
    CONCLUSIONS/INTERPRETATION: The higher type 2 diabetes prevalence previously observed in carriers of missense MTNR1B variants causing impairment in MT2 signalling was not replicated in the UK Biobank, yet carriers had elevated HbA1c levels.
    DATA AVAILABILITY: Data (Inter99 cohort and recall-by-genotype study) are available on reasonable request from the corresponding author. Requests for DD2 data are through the application form at https://dd2.dk/forskning/ansoeg-om-data . Access to UK Biobank data can be requested through the UK Biobank website ( https://www.ukbiobank.ac.uk/enable-your-research ).
    Keywords:   MTNR1B ; Genetic association study; HbA1c ; MT2; Melatonin; Melatonin receptor type 2; Recall-by-genotype investigation; Type 2 diabetes; Variants impairing receptor function; rs10830963
    DOI:  https://doi.org/10.1007/s00125-025-06381-y
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