bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2024–03–24
three papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Lac-Phe mediates the effects of metformin on food intake and body weight.
  2. Activation of GPR81 by lactate drives tumour-induced cachexia.
  3. Stem cell factor and cKIT modulate endothelial glycolysis in hypoxia.
  1. Nat Metab. 2024 Mar 18.
    Lac-Phe mediates the effects of metformin on food intake and body weight.
    Shuke Xiao, Veronica L Li, Xuchao Lyu, Xudong Chen, Wei Wei, Fahim Abbasi, Joshua W Knowles, Alan Sheng-Hwa Tung, Shuliang Deng, Gaurav Tiwari, Xu Shi, Shuning Zheng, Laurie Farrell, Zsu-Zsu Chen, Kent D Taylor, Xiuqing Guo, Mark O Goodarzi, Alexis C Wood, Yii-Der Ida Chen, Leslie A Lange, Stephen S Rich, Jerome I Rotter, Clary B Clish, Usman A Tahir, Robert E Gerszten, Mark D Benson, Jonathan Z Long.
      Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2+ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin's effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin.
    DOI:  https://doi.org/10.1038/s42255-024-00999-9
  2. Nat Metab. 2024 Mar 18.
    Activation of GPR81 by lactate drives tumour-induced cachexia.
    Xidan Liu, Shijin Li, Qionghua Cui, Bujing Guo, Wanqiu Ding, Jie Liu, Li Quan, Xiaochuan Li, Peng Xie, Li Jin, Ye Sheng, Wenxin Chen, Kai Wang, Fanxin Zeng, Yifu Qiu, Changlu Liu, Yan Zhang, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao.
      Cachexia affects 50-80% of patients with cancer and accounts for 20% of cancer-related death, but the underlying mechanism driving cachexia remains elusive. Here we show that circulating lactate levels positively correlate with the degree of body weight loss in male and female patients suffering from cancer cachexia, as well as in clinically relevant mouse models. Lactate infusion per se is sufficient to trigger a cachectic phenotype in tumour-free mice in a dose-dependent manner. Furthermore, we demonstrate that adipose-specific G-protein-coupled receptor (GPR)81 ablation, similarly to global GPR81 deficiency, ameliorates lactate-induced or tumour-induced adipose and muscle wasting in male mice, revealing adipose GPR81 as the major mediator of the catabolic effects of lactate. Mechanistically, lactate/GPR81-induced cachexia occurs independently of the well-established protein kinase A catabolic pathway, but it is mediated by a signalling cascade sequentially activating Gi-Gβγ-RhoA/ROCK1-p38. These findings highlight the therapeutic potential of targeting GPR81 for the treatment of this life-threatening complication of cancer.
    DOI:  https://doi.org/10.1038/s42255-024-01011-0
  3. Cardiovasc Res. 2024 Mar 20. pii: cvae058. [Epub ahead of print]
    Stem cell factor and cKIT modulate endothelial glycolysis in hypoxia.
    Hayoung Jeong, Ryul-I Kim, Hyunwoo Koo, Yang Hee Choi, Minju Kim, Hyejin Roh, Sang Gyu Park, Jong-Hyuk Sung, Koung Li Kim, Wonhee Suh.
       AIMS: In hypoxia, endothelial cells proliferate, migrate, and form new vasculature in a process called angiogenesis. Recent studies have suggested that endothelial cells rely on glycolysis to meet metabolic needs for angiogenesis in ischemic tissues and several studies have investigated the molecular mechanisms integrating angiogenesis and endothelial metabolism. Here, we investigated the role of stem cell factor (SCF) and its receptor, cKIT, in regulating endothelial glycolysis during hypoxia-driven angiogenesis.
    METHODS AND RESULTS: SCF and cKIT signaling increased the glucose uptake, lactate production, and glycolysis in human endothelial cells under hypoxia. Mechanistically, SCF and cKIT signaling enhanced the expression of genes encoding glucose transporter 1 (GLUT1) and glycolytic enzymes via Akt- and ERK1/2-dependent increased translation of hypoxia inducible factor 1A (HIF1A). In hypoxic conditions, reduction of glycolysis and HIF-1α expression using chemical inhibitors significantly reduced the SCF-induced in vitro angiogenesis in human endothelial cells. Compared with normal mice, mice with oxygen-induced retinopathy (OIR), characterized by ischemia-driven pathological retinal neovascularization, displayed increased levels of SCF, cKIT, HIF-1α, GLUT1, and glycolytic enzymes in the retina. Moreover, cKIT-positive neovessels in the retina of mice with OIR showed elevated expression of GLUT1 and glycolytic enzymes. Further, blocking SCF and cKIT signaling using anti-SCF neutralizing IgG and cKIT mutant mice significantly reduced the expression of HIF-1α, GLUT1, and glycolytic enzymes and decreased the pathological neovascularization in the retina of mice with OIR.
    CONCLUSION: We demonstrated that SCF and cKIT signaling regulates angiogenesis by controlling endothelial glycolysis in hypoxia and elucidated the SCF/cKIT/HIF-1α axis as a novel metabolic regulation pathway during hypoxia-driven pathological angiogenesis.
    Keywords:  angiogenesis; cKIT; endothelial cell; glycolysis; hypoxia inducible factor; stem cell factor
    DOI:  https://doi.org/10.1093/cvr/cvae058
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