Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity.,Cell Metabolism

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Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity.
Cell Metabolism ( IF 27.7 ) Pub Date : 2019-08-15 , DOI: 10.1016/j.cmet.2019.07.010
José M Bravo-San Pedro ₁ , Valentina Sica ₁ , Isabelle Martins ₁ , Jonathan Pol ₁ , Friedemann Loos ₁ , Maria Chiara Maiuri ₁ , Sylvère Durand ₁ , Noélie Bossut ₁ , Fanny Aprahamian ₁ , Gerasimos Anagnostopoulos ₂ , Mireia Niso-Santano ₃ , Fernando Aranda ₄ , Ignacio Ramírez-Pardo ₅ , Justine Lallement ₆ , Jessica Denom ₆ , Erwan Boedec ₇ , Philip Gorwood ₈ , Nicolas Ramoz ₉ , Karine Clément ₁₀ , Veronique Pelloux ₁₀ , Alili Rohia ₁₀ , François Pattou ₁₁ , Violeta Raverdy ₁₁ , Robert Caiazzo ₁₁ , Raphaël G P Denis ₆ , Patricia Boya ₅ , Lorenzo Galluzzi ₁₂ , Frank Madeo ₁₃ , Stéphanie Migrenne-Li ₆ , Céline Cruciani-Guglielmacci ₆ , Nektarios Tavernarakis ₁₄ , Carlos López-Otín ₁₅ , Christophe Magnan ₆ , Guido Kroemer ₁₆

Affiliation

INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France; Team "Metabolism, Cancer & Immunity", Équipe 11 labellisée par la Ligue contre le Cancer, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France; Team "Metabolism, Cancer & Immunity", Équipe 11 labellisée par la Ligue contre le Cancer, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Faculté de Médecine, Université de Paris Saclay, Kremlin Bicêtre, France.
Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), Department of Biochemistry and Molecular Biology and Genetics, University of Extremadura, Faculty of Nursing and Occupational Therapy, Cáceres, Spain.
Group of Immune receptors of the Innate and Adaptive System, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
Université of Paris, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France.
INSERM U1149, Center of Research on Inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS), ERL 8252, Paris, France.
Clinique des Maladies Mentales et de l'Encéphale (CMME), Hôpital Sainte-Anne, Université of Paris, Paris, France; INSERM U894, Centre de Psychiatrie et Neurosciences (CPN), Université of Paris, Paris, France.
INSERM U894, Centre de Psychiatrie et Neurosciences (CPN), Université of Paris, Paris, France.
Sorbonne Université, Inserm, NutriOMics team, Pitié-Salpêtrière Hospital, Paris, France.
University of Lille, CHU Lille, Inserm UMR 1190, European Genomic Institute for Diabetes, Lille, France.
Team "Metabolism, Cancer & Immunity", Équipe 11 labellisée par la Ligue contre le Cancer, Paris, France; Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
BioTechMed, Graz, Austria; Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstrasse, Graz, Austria.
Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Nikolaou Plastira 100, Heraklion, Crete, Greece.
INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France; Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France; Team "Metabolism, Cancer & Immunity", Équipe 11 labellisée par la Ligue contre le Cancer, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, China; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.

Autophagy facilitates the adaptation to nutritional stress. Here, we show that short-term starvation of cultured cells or mice caused the autophagy-dependent cellular release of acyl-CoA-binding protein (ACBP, also known as diazepam-binding inhibitor, DBI) and consequent ACBP-mediated feedback inhibition of autophagy. Importantly, ACBP levels were elevated in obese patients and reduced in anorexia nervosa. In mice, systemic injection of ACBP protein inhibited autophagy, induced lipogenesis, reduced glycemia, and stimulated appetite as well as weight gain. We designed three approaches to neutralize ACBP, namely, inducible whole-body knockout, systemic administration of neutralizing antibodies, and induction of antiACBP autoantibodies in mice. ACBP neutralization enhanced autophagy, stimulated fatty acid oxidation, inhibited appetite, reduced weight gain in the context of a high-fat diet or leptin deficiency, and accelerated weight loss in response to dietary changes. In conclusion, neutralization of ACBP might constitute a strategy for treating obesity and its co-morbidities.

中文翻译：

酰基辅酶A结合蛋白是触发食物摄入和肥胖的致脂因子。

自噬促进了对营养压力的适应。在这里，我们显示培养的细胞或小鼠的短期饥饿导致酰基辅酶A结合蛋白（ACBP，也称为地西epa结合抑制剂，DBI）的自噬依赖性细胞释放以及随之而来的ACBP介导的自噬反馈抑制。重要的是，肥胖患者的ACBP水平升高，神经性厌食症降低。在小鼠中，全身注射ACBP蛋白可抑制自噬，诱导脂肪生成，降低血糖，刺激食欲以及体重增加。我们设计了三种中和ACBP的方法，即可诱导的全身敲除，中和抗体的全身给药以及在小鼠中诱导抗ACBP自身抗体。ACBP中和可增强自噬，刺激脂肪酸氧化，抑制食欲，在高脂饮食或瘦素缺乏的情况下减少体重增加，并因饮食变化而加速体重减轻。总之，中和ACBP可能构成治疗肥胖症及其合并症的策略。

更新日期：2019-09-30

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