bims-obesme 2024-12-22 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024–12–22
ten papers selected by
Xiong Weng, University of Edinburgh

Unveiling adipose populations linked to metabolic health in obesity.
FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology.
Serpina3c Deficiency Promotes Obesity-related Hypertriglyceridemia and Inflammation through Activation of the Hif1α-glycolysis Axis in Adipose Tissue.
Targeting the GDF15 Signalling for Obesity Treatment: Recent Advances and Emerging Challenges.
Mapping mitochondrial aging.
Inter-organ communication is a critical machinery to regulate metabolism and aging.
ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice.
Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.
The role of CYP-sEH derived lipid mediators in regulating mitochondrial biology and cellular senescence: implications for the aging heart.
Dnmt3a-mediated de novo methylation balances memory Th1 and Tfh cell plasticity and functionality.

Cell Metab. 2024 Dec 11. pii: S1550-4131(24)00452-2. [Epub ahead of print]

Unveiling adipose populations linked to metabolic health in obesity.

Isabel Reinisch, Adhideb Ghosh, Falko Noé, Wenfei Sun, Hua Dong, Peter Leary, Arne Dietrich, Anne Hoffmann, Matthias Blüher, Christian Wolfrum.

  Precision medicine is still not considered as a standard of care in obesity treatment, despite a large heterogeneity in the metabolic phenotype of individuals with obesity. One of the strongest factors influencing the variability in metabolic disease risk is adipose tissue (AT) dysfunction; however, there is little understanding of the link between distinct cell populations, cell-type-specific transcriptional programs, and disease severity. Here, we generated a comprehensive cellular map of subcutaneous and visceral AT of individuals with metabolically healthy and unhealthy obesity. By combining single-nucleus RNA-sequencing data with bulk transcriptomics and clinical parameters, we identified that mesothelial cells, adipocytes, and adipocyte-progenitor cells exhibit the strongest correlation with metabolic disease. Furthermore, we uncovered cell-specific transcriptional programs, such as the transitioning of mesothelial cells to a mesenchymal phenotype, that are involved in uncoupling obesity from metabolic disease. Together, these findings provide valuable insights by revealing biological drivers of clinical endpoints.

Keywords:  adipocytes; adipose tissue; insulin resistance; insulin sensitivity; mesothelial cells; metabolically healthy obesity; obesity; precision medicine; snRNA-seq; visceral adipose tissue

DOI:  https://doi.org/10.1016/j.cmet.2024.11.006
Cell Metab. 2024 Dec 11. pii: S1550-4131(24)00447-9. [Epub ahead of print]

FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology.

Lexiang Yu, Yong Xiao Yang, Zhen Gong, Qianfen Wan, Yifei Du, Qiuzhong Zhou, Yang Xiao, Tarik Zahr, Zhaobin Wang, Zhewei Yu, Kangkang Yang, Jinyang Geng, Susan K Fried, Jing Li, Rebecca A Haeusler, Kam W Leong, Lin Bai, Yingjie Wu, Lei Sun, Pan Wang, Bao Ting Zhu, Liheng Wang, Li Qiang.

  Immunoglobulin G (IgG) is traditionally recognized as a plasma protein that neutralizes antigens for immune defense. However, our research demonstrates that IgG predominantly accumulates in adipose tissue during obesity development, triggering insulin resistance and macrophage infiltration. This accumulation is governed by neonatal Fc receptor (FcRn)-dependent recycling, orchestrated in adipose progenitor cells and macrophages during the early and late stages of diet-induced obesity (DIO), respectively. Targeting FcRn abolished IgG accumulation and rectified insulin resistance and metabolic degeneration in DIO. By integrating artificial intelligence (AI) modeling with in vivo and in vitro experimental models, we unexpectedly uncovered an interaction between IgG's Fc-CH3 domain and the insulin receptor's ectodomain. This interaction hinders insulin binding, consequently obstructing insulin signaling and adipocyte functions. These findings unveil adipose IgG accumulation as a driving force in obesity pathophysiology, providing a novel therapeutic strategy to tackle metabolic dysfunctions.

Keywords:  FcRn; IgG; adipose tissue remodeling; insulin receptor; insulin resistance; obesity

DOI:  https://doi.org/10.1016/j.cmet.2024.11.001
Clin Sci (Lond). 2024 Dec 18. pii: CS20242610. [Epub ahead of print]

Serpina3c Deficiency Promotes Obesity-related Hypertriglyceridemia and Inflammation through Activation of the Hif1α-glycolysis Axis in Adipose Tissue.

Jiaqi Guo, Zhenjun Ji, Yu Jiang, Ya Wu, Shaofan Wang, Peng Zheng, Mengchen Yang, Yongjun Li, Genshan Ma, Yuyu Yao.

  Adipose tissue dysfunction leads to abnormal lipid metabolism and high inflammation levels. This research aims to explore the role of Serpina3c, which is highly expressed in adipocytes, in obesity-related hypertriglyceridemia and metaflammation. Serpina3c global knockout (KO) mice, adipocyte-specific Serpina3c overexpressing mice, Serpina3c knockdown (KD) mice, and hypoxia-inducible factor 1 alpha (Hif1α) KD mice were fed a high-fat diet (HFD) for 16 weeks to generate obesity-related hypertriglyceridemia mice models. In the present study, Serpina3c KO mice and adipocyte-specific Serpina3c KD mice exhibited more severe obesity-related hypertriglyceridemia and metaflammation under HFD conditions. Serpina3c KO epididymal white adipose tissue (eWAT) primary stromal vascular fraction (SVF)-derived adipocytes exhibited higher lipid (triglyceride and non-esterified fatty acid) levels and higher fatty acid synthase expression after palmitic acid stimulation. Adipocyte-specific Serpina3c overexpression in KO mice prevented the KO group phenotype. The RNA-seq and in vitro validation revealed that Hif1α and the glycolysis pathways were upregulated in Serpina3c KD adipocytes, which were all validated by in vitro and in vivo reverse experiments. Co-immunoprecipitation (co-IP) provided evidence that Serpina3c bound nuclear factor erythroid 2-related factor 2 (Nrf2) to regulate Hif1α. Nrf2 KD reduced Hif1α and Fasn expression, decreased lipid content, and reduced the extracellular acidification rate in Serpina3c KO adipocytes. Metabolomics revealed that lactic acid (LD) levels in eWAT were responsible for adipose-associated macrophage inflammation. In summary, Serpina3c inhibits the Hif1α-glycolysis pathway and reduces de novo lipogenesis and LD secretion in adipocytes by binding to Nrf2, thereby improving HFD-induced lipid metabolism disorders and alleviating adipose tissue macrophage inflammation.

Keywords:  Adipose Tissue; De novo lipogenesis; Glycolysis; Hif1α; Hypertriglyceridemia; Serpina3c

DOI:  https://doi.org/10.1042/CS20242610
J Cell Mol Med. 2024 Dec;28(24): e70251

Targeting the GDF15 Signalling for Obesity Treatment: Recent Advances and Emerging Challenges.

Jincheng Zhang, Jingquan Sun, Jielang Li, Hongwei Xia.

  The growth differentiation factor 15 (GDF15)-glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) pathway plays a crucial role in the regulation of metabolism, appetite and body weight control. Obesity is an increasingly prevalent chronic disease worldwide, necessitating effective treatment strategies. Recent preclinical and clinical studies have highlighted that targeting the GDF15-GFRAL signalling pathway is a promising approach for treating obesity, particularly because it has minimal impact on skeletal muscle mass, which is essential to preserve during weight loss. Given its distinctive mechanisms, the GDF15-GFRAL axis represents an attractive target for addressing various metabolic disorders, especially obesity. In this review, we will explore how the GDF15-GFRAL axis is regulated, its distribution in the body and its role in the regulation of metabolism, appetite and obesity. Additionally, we will discuss recent advances and potential challenges in targeting the GDF15-GFRAL axis for obesity treatment.

Keywords:  GDF15; GFRAL; appetite suppression; energy metabolism; obesity; weight loss

DOI:  https://doi.org/10.1111/jcmm.70251
Elife. 2024 Dec 20. pii: e105191. [Epub ahead of print]13

Mapping mitochondrial aging.

Alessandro Bitto.

  Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.

Keywords:  aging; cellular respiration; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology

DOI:  https://doi.org/10.7554/eLife.105191
Trends Endocrinol Metab. 2024 Dec 17. pii: S1043-2760(24)00320-5. [Epub ahead of print]

Inter-organ communication is a critical machinery to regulate metabolism and aging.

Kyohei Tokizane, Shin-Ichiro Imai.

  Inter-organ communication (IOC) is a complex mechanism involved in maintaining metabolic homeostasis and healthy aging. Dysregulation of distinct forms of IOC is linked to metabolic derangements and age-related pathologies, implicating these processes as a potential target for therapeutic intervention to promote healthy aging. In this review, we delve into IOC mediated by hormonal signaling, circulating factors, organelle signaling, and neuronal networks and examine their roles in regulating metabolism and aging. Given the role of the hypothalamus as a high-order control center for aging and longevity, we particularly emphasize the importance of its communication with peripheral organs and pave the way for a better understanding of this critical machinery in metabolism and aging.

Keywords:  aging; hypothalamus; inter-organ communication; metabolism

DOI:  https://doi.org/10.1016/j.tem.2024.11.013
Nat Commun. 2024 Dec 16. 15(1): 10652

ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice.

David Lau, Stephanie Tobin, Horia Pribiag, Shingo Nakajima, Alexandre Fisette, Dominique Matthys, Anna Kristyna Franco Flores, Marie-Line Peyot, S R Murthy Madiraju, Marc Prentki, David Stellwagen, Thierry Alquier, Stephanie Fulton.

α/β-hydrolase domain 6 (ABHD6) is a lipase linked to physiological functions affecting energy metabolism. Brain ABHD6 degrades 2-arachidonoylglycerol and thereby modifies cannabinoid receptor signalling. However, its functional role within mesoaccumbens circuitry critical for motivated behaviour and considerably modulated by endocannabinoids was unknown. Using three viral approaches, we show that control of the nucleus accumbens by neuronal ABHD6 is a key determinant of body weight and reward-directed behaviour in male mice. Contrary to expected outcomes associated with increasing endocannabinoid tone, loss of ABHD6 in nucleus accumbens, but not ventral tegmental area, neurons completely prevents diet-induced obesity, reduces food- and drug-seeking and enhances physical activity without affecting anxiodepressive behaviour. These effects are explained by attenuated inhibitory synaptic transmission onto medium spiny neurons. ABHD6 deletion in nucleus accumbens neurons and dopamine ventral tegmental area neurons produces contrasting effects on effortful responding for food. Intraventricular infusions of an ABHD6 inhibitor also restrain appetite and promote weight loss. Together, these results reveal functional specificity of pre- and post-synaptic mesoaccumbens neuronal ABHD6 to differentially control energy balance and propose ABHD6 inhibition as a potential anti-obesity tool.

DOI: https://doi.org/10.1038/s41467-024-54819-5
Aging Cell. 2024 Dec 16. e14402

Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.

Amy R Vandiver, Alejandro Torres, Amberly Sanden, Thang L Nguyen, Jasmine Gasilla, Mary T Doan, Vahan Martirosian, Austin Hoang, Jonathan Wanagat, Michael A Teitell.

  The mitochondrial genome (mtDNA) is an important source of inherited extranuclear variation. Clonal increases in mtDNA mutation heteroplasmy have been implicated in aging and disease, although the impact of this shift on cell function is challenging to assess. Reprogramming to pluripotency affects mtDNA mutation heteroplasmy. We reprogrammed three human fibroblast lines with known heteroplasmy for deleterious mtDNA point or deletion mutations. Quantification of mutation heteroplasmy in the resulting 76 induced pluripotent stem cell (iPSC) clones yielded a bimodal distribution, creating three sets of clones with high levels or absent mutation heteroplasmy with matched nuclear genomes. iPSC clones with elevated deletion mutation heteroplasmy show altered growth dynamics, which persist in iPSC-derived progenitor cells. We identify transcriptomic and metabolic shifts consistent with increased investment in neutral lipid synthesis as well as increased epigenetic age in high mtDNA deletion mutation iPSC, consistent with changes occurring in cellular aging. Together, these data demonstrate that high mtDNA mutation heteroplasmy induces changes occurring in cellular aging.

Keywords:  aging; iPSC; mitochondria; mtDNA mutation

DOI:  https://doi.org/10.1111/acel.14402
Front Pharmacol. 2024 ;15 1486717

The role of CYP-sEH derived lipid mediators in regulating mitochondrial biology and cellular senescence: implications for the aging heart.

Ala Yousef, Liye Fang, Mobina Heidari, Joshua Kranrod, John M Seubert.

  Cellular senescence is a condition characterized by stable, irreversible cell cycle arrest linked to the aging process. The accumulation of senescent cells in the cardiac muscle can contribute to various cardiovascular diseases (CVD). Telomere shortening, epigenetic modifications, DNA damage, mitochondrial dysfunction, and oxidative stress are known contributors to the onset of cellular senescence in the heart. The link between mitochondrial processes and cellular senescence contributed to the age-related decline in cardiac function. These include changes in mitochondrial functions and behaviours that arise from various factors, including impaired dynamics, dysregulated biogenesis, mitophagy, mitochondrial DNA (mtDNA), reduced respiratory capacity, and mitochondrial structural changes. Thus, regulation of mitochondrial biology has a role in cellular senescence and cardiac function in aging hearts. Targeting senescent cells may provide a novel therapeutic approach for treating and preventing CVD associated with aging. CYP epoxygenases metabolize N-3 and N-6 polyunsaturated fatty acids (PUFA) into epoxylipids that are readily hydrolyzed to diol products by soluble epoxide hydrolase (sEH). Increasing epoxylipids levels or inhibition of sEH has demonstrated protective effects in the aging heart. Evidence suggests they may play a role in cellular senescence by regulating mitochondria, thus reducing adverse effects of aging in the heart. In this review, we discuss how mitochondria induce cellular senescence and how epoxylipids affect the senescence process in the aged heart.

Keywords:  CYP; PUFA; aging; epoxylipids; mitochondria; soluble epoxide hydrolase (sEH)

DOI:  https://doi.org/10.3389/fphar.2024.1486717
bioRxiv. 2024 Dec 06. pii: 2024.12.03.623450. [Epub ahead of print]

Dnmt3a-mediated de novo methylation balances memory Th1 and Tfh cell plasticity and functionality.

Bryant Perkins, Camille Novis, Andrew Baessler, Linda M Sircy, Monyca M Thomas, Malia Harrison-Chau, Andrew W Richens, Bryce Fuchs, Nguyen X Nguyen, Kaitlyn Flint, Katherine E Varley, J Scott Hale.

Following acute viral infection, naïve CD4+ T cells differentiate into T follicular helper (Tfh) and T helper 1 (Th1) cells that generate long-lived memory cells. However, it is unclear how memory Tfh and Th1 cells maintain their lineage commitment. Here we demonstrate that Tfh and Th1 lineages acquire distinct de novo DNA methylation programs that are preserved into memory. Using whole genome methylation analyses and deletion of DNA methyltransferase 3a, we found that de novo DNA methylation is required for generating epigenetic programing to enforce lineage commitment and preserve lineage-specific functions during a recall response to infection. Importantly, partial inhibition of de novo methylation using the methyltransferase inhibitor decitabine during priming enhances Tfh cell functionality in primary and secondary responses to viral infection. Together, these findings demonstrate that de novo DNA methylation is critical to balance lineage commitment and functionality of memory CD4+ T cell subsets and reveal novel potential strategies to modulate immune responses to infectious diseases.

DOI: https://doi.org/10.1101/2024.12.03.623450