bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–01–05
nine papers selected by
Xiong Weng, University of Edinburgh
  1. E3 ligase FBXW7 suppresses brown fat expansion and browning of white fat.
  2. SF1-specific deletion of the energy sensor AMPKγ2 induces obesity.
  3. Loss of Mfn1 but not Mfn2 enhances adipogenesis.
  4. The direct and indirect inhibition of proinflammatory adipose tissue macrophages by acarbose in diet-induced obesity.
  5. TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver.
  6. AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
  7. Vascular-Adipose Crosstalk: Angiogenesis and Adipose Tissue Remodeling.
  8. Genetic insights into global heterogeneity of type 2 diabetes.
  9. Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance.
  1. EMBO Rep. 2025 Jan 02.
    E3 ligase FBXW7 suppresses brown fat expansion and browning of white fat.
    Jian Yu, Xuejiang Gu, Yingying Guo, Mingyuan Gao, Shimiao Cheng, Meiyao Meng, Xiangdi Cui, Zhe Zhang, Wenxiu Guo, Dandan Yan, Maozheng Sheng, Linhui Zhai, Jing Ji, Xinhui Ma, Yu Li, Yuxiang Cao, Xia Wu, Jiejie Zhao, Yepeng Hu, Minjia Tan, Yan Lu, Lingyan Xu, Bin Liu, Cheng Hu, Xinran Ma.
      Thermogenic fat, including brown and beige fat, dissipates heat via thermogenesis and enhances energy expenditure. Thus, its activation represents a therapeutic strategy to combat obesity. Here, we demonstrate that levels of F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, negatively correlate with thermogenic fat functionality. FBXW7 overexpression in fat suppresses energy expenditure and thermogenesis, thus aggravates obesity and metabolic dysfunctions in mice. Conversely, FBXW7 depletion in fat leads to brown fat expansion and browning of white fat, and protects mice from diet induced obesity, hepatic steatosis, and hyperlipidemia. Mechanistically, FBXW7 binds to S6K1 and promotes its ubiquitination and proteasomal degradation, which in turn impacts glycolysis and brown preadipocyte proliferation via lactate. Besides, the beneficial metabolic effects of FBXW7 depletion in fat are attenuated by fat-specific knockdown of S6K1 in vivo. In summary, we provide evidence that adipose FBXW7 acts as a major regulator for thermogenic fat biology and energy homeostasis and serves as potential therapeutic target for obesity and metabolic diseases.
    Keywords:  Brown Fat Expansion; Browning of White Fat; Obesity; Thermogenic Fat; Ubiquitination
    DOI:  https://doi.org/10.1038/s44319-024-00337-w
  2. Mol Metab. 2024 Dec 31. pii: S2212-8778(24)00222-9. [Epub ahead of print] 102091
    SF1-specific deletion of the energy sensor AMPKγ2 induces obesity.
    Óscar Freire-Agulleiro, Ánxela Estévez-Salguero, Vitor Ferreira, Cassie Lynn Holleman, Julia García-Currás, Ismael González-García, Rubén Nogueiras, Manuel Tena-Sempere, Cristina García-Cáceres, Carlos Diéguez, Miguel López.
       OBJECTIVE: AMP-activated protein kinase (AMPK) is a heterotrimer complex consisting of a catalytic α subunit (α1, α2) with a serine/threonine kinase domain, and two regulatory subunits, β (β1, β2) and γ (γ1, γ2, γ3), encoded by different genes. In the hypothalamus, AMPK plays a crucial role in regulating energy balance, including feeding, energy expenditure, peripheral glucose and lipid metabolism. However, most research on hypothalamic AMPK has concentrated on the catalytic subunits AMPKα1 and AMPKα2, with little focus on the regulatory subunits.
    METHODS: To fill this gap of knowledge, we investigated the effects of selectively deleting the regulatory isoform AMPKγ2, which is a primary "energy sensor", in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH). Complete metabolic phenotyping and molecular analyses in brown adipose tissue (BAT), white adipose tissue (WAT) and liver were carried out.
    RESULTS: Our findings reveal that, in contrast to the obesity-protective effect of the genetic deletion of AMPKα subunits, the loss of AMPKγ2 leads to a sex-independent and feeding-independent obesity-prone phenotype due to decreased thermogenesis in brown adipose tissue (BAT) and reduced browning of WAT, resulting in lower energy expenditure. Additionally, SF1-Cre AMPKγ2 mice exhibit hepatic lipid accumulation, but surprisingly maintain normal glucose homeostasis.
    CONCLUSIONS: Overall, these results highlight the distinct roles of AMPK subunits within the hypothalamus.
    Keywords:  AMPK; BAT; SF1; hypothalamus; obesity; thermogenesis
    DOI:  https://doi.org/10.1016/j.molmet.2024.102091
  3. PLoS One. 2024 ;19(12): e0306243
    Loss of Mfn1 but not Mfn2 enhances adipogenesis.
    Jake P Mann, Luis Carlos Tábara, Satish Patel, Pushpa Pushpa, Anna Alvarez-Guaita, Liang Dong, Afreen Haider, Koini Lim, Panna Tandon, Fabio Scurria, James E N Minchin, Stephen O'Rahilly S, Daniel J Fazakerley, Julien Prudent, Robert K Semple, David B Savage.
       OBJECTIVE: A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2) on adipogenesis in cultured cells.
    METHODS: We characterised adipocyte differentiation of wildtype (WT), Mfn1-/- and Mfn2-/- mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA.
    RESULTS: Mfn1-/- MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile including Pparg upregulation. Mfn2-/- MEFs also had a disrupted mitochondrial morphology, but in contrast to Mfn1-/- MEFs they showed reduced expression of adipocyte markers. Mfn1 and Mfn2 siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings.
    CONCLUSIONS: Loss of Mfn1 but not Mfn2 in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.
    DOI:  https://doi.org/10.1371/journal.pone.0306243
  4. Cell Rep Med. 2024 Dec 24. pii: S2666-3791(24)00654-2. [Epub ahead of print] 101883
    The direct and indirect inhibition of proinflammatory adipose tissue macrophages by acarbose in diet-induced obesity.
    Xiaohui Li, Shimeng Zheng, Haozhe Xu, Zihan Zhang, Xiaotong Han, Yunxiong Wei, Hua Jin, Xiaonan Du, Hufeng Xu, Mengyi Li, Zhongtao Zhang, Songlin Wang, Guangyong Sun, Dong Zhang.
      Inflammation is critical for obesity and obesity-induced insulin resistance (IR). In this study, we reveal the function and mechanism of acarbose on adipose tissue macrophage (ATM)-mediated inflammation in obesity and obesity-induced IR. First, acarbose enhances the abundance of propionic acid-producing Parasutterella, therefore indirectly inhibiting the survival and proinflammatory function of M1-like ATMs via GPR43. Most interestingly, acarbose can directly inhibit M1-like ATM-mediated inflammation through GPR120. Diet-induced obese mice exhibit nitrobenzoxadiazoles (NBD) fluorescence-labeled ATMs, but lean mice that also orally received NBD fluorescence-labeled acarbose do not exhibit NBD fluorescence-labeled ATMs. This direct inhibition of macrophages by acarbose is validated in mouse and human macrophages in vitro. In conclusion, our study reveals that acarbose directly and indirectly inhibits proinflammatory macrophage phenotype, which contributes to the improvement of obesity and obesity-induced IR. The understanding of the immune regulatory effects of acarbose may extend its potential for further therapeutic applications.
    Keywords:  Parasutterella excrementihominis; acarbose; adipose tissue macrophages; obesity; propionic acid
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101883
  5. EMBO Rep. 2025 Jan 02.
    TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver.
    Shilpa Thakur, Priya Rawat, Budheswar Dehury, Prosenjit Mondal.
      Impaired insulin receptor signaling is strongly linked to obesity-related metabolic conditions like non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes (T2DM). However, the exact mechanisms behind impaired insulin receptor (INSR) signaling in obesity induced by a high-fat diet remain elusive. In this study, we identify an E3 ubiquitin ligase, tripartite motif-containing protein 32 (TRIM32), as a key regulator of hepatic insulin signaling that targets the insulin receptor (INSR) for ubiquitination and proteasomal degradation in high-fat diet (HFD) mice. HFD induces the nuclear translocation of SREBP-1c (Sterol Regulatory Element-Binding Protein 1c), resulting in increased expression of TRIM32 in hepatocytes. TRIM32 ubiquitylates INSR and facilitates its proteasomal degradation, leading to severe insulin resistance and fat accumulation within the liver of high-fat diet induced obese (DIO) mice. Conversely, liver-specific knockdown of TRIM32 enhances INSR expression and hepatic insulin sensitivity. Reduced AMPK signaling and phosphorylation of SREBP-1c at S372 in high-fat DIO mice promotes the nuclear translocation of SREBP-1c, leading to increased TRIM32 expression. In conclusion, our results demonstrate that TRIM32 promotes diet-induced hepatic insulin resistance by targeting the INSR to degradation.
    Keywords:  Insulin Receptor; Insulin Resistance; SREBP-1c; TRIM32; Ubiquitination
    DOI:  https://doi.org/10.1038/s44319-024-00348-7
  6. Nat Cell Biol. 2025 Jan 02.
    AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
    Xuewei Zhai, Ronghui Yang, Qiaoyun Chu, Zihao Guo, Pengjiao Hou, Xuexue Li, Changsen Bai, Ziwen Lu, Luxin Qiao, Yanxia Fu, Jing Niu, Binghui Li.
      Glucose metabolism has been studied extensively, but the role of glucose-derived excretory glycerol remains unclear. Here we show that hypoxia induces NADH accumulation to promote glycerol excretion and this pathway consumes NADH continuously, thus attenuating its accumulation and reductive stress. Aldolase B accounts for glycerol biosynthesis by forming a complex with glycerol 3-phosphate dehydrogenases GPD1 and GPD1L. Blocking GPD1, GPD1L or glycerol 3-phosphate phosphatase exacerbates reductive stress and suppresses cell proliferation under hypoxia and tumour growth in vivo. Overexpression of these enzymes increases glycerol excretion but still reduces cell viability under hypoxia and tumour proliferation due to energy stress. AMPK inactivates aldolase B to mitigate glycerol synthesis that dissipates ATP, alleviating NADH accumulation-induced energy crisis. Therefore, glycerol biosynthesis/excretion regulates the trade-off between reductive stress and energy stress. Moreover, this mode of regulation seems to be prevalent in reductive stress-driven transformations, enhancing our understanding of the metabolic complexity and guiding tumour treatment.
    DOI:  https://doi.org/10.1038/s41556-024-01549-x
  7. Circ Res. 2025 Jan 03. 136(1): 112-114
    Vascular-Adipose Crosstalk: Angiogenesis and Adipose Tissue Remodeling.
    Timothy P Fitzgibbons, Sophia Kogan, Khanh-Van Tran.
      
    Keywords:  Editorials; adipocytes; adipogenesis; adipose tissue; angiogenesis
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325899
  8. Nat Med. 2025 Jan 02.
    Genetic insights into global heterogeneity of type 2 diabetes.
    Miriam S Udler.
      
    DOI:  https://doi.org/10.1038/s41591-024-03413-9
  9. Nature. 2025 Jan 01.
    Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance.
    Kazuhiro Furuhashi, Miwako Kakiuchi, Ryosuke Ueda, Hiroko Oda, Simone Ummarino, Alexander K Ebralidze, Mahmoud A Bassal, Chen Meng, Tatsuyuki Sato, Jing Lyu, Min-Guk Han, Shoichi Maruyama, Yu Watanabe, Yuriko Sawa, Daisuke Kato, Hiroaki Wake, Boris Reizis, John A Frangos, David M Owens, Daniel G Tenen, Ionita C Ghiran, Simon C Robson, Joji Fujisaki.
      Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues1-3. The differential functions of heterogeneous stem cells and niches are important given the increasing clinical applications of stem-cell transplantation and immunotherapy. Whether hierarchical structures among stem cells at distinct niches exist and further control aspects of immune tolerance is unknown. Here we describe previously unknown new hierarchical arrangements in haematopoietic stem cells (HSCs) and bone marrow niches that dictate both regenerative potential and immune privilege. High-level nitric oxide-generating (NOhi) HSCs are refractory to immune attack and exhibit delayed albeit robust long-term reconstitution. Such highly immune-privileged, primitive NOhi HSCs co-localize with distinctive capillaries characterized by primary ciliated endothelium and high levels of the immune-checkpoint molecule CD200. These capillaries regulate the regenerative functions of NOhi HSCs through the ciliary protein IFT20 together with CD200, endothelial nitric oxide synthase and autophagy signals, which further mediate immunoprotection. Notably, previously described niche constituents, sinusoidal cells and type-H vessels2-10 co-localize with less immune-privileged and less potent NOlow HSCs. Together, we identify highly immune-privileged, late-rising primitive HSCs and characterize their immunoprotective niches comprising specialized vascular domains. Our results indicate that the niche orchestrates hierarchy in stem cells and immune tolerance, and highlight future immunotherapeutic targets.
    DOI:  https://doi.org/10.1038/s41586-024-08352-6
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