title: Dual mode action of mangiferin in mouse liver under high fat diet.
abstract: Chronic over-nutrition is a major contributor to the spread of obesity and its related metabolic disorders. Development of therapeutics has been slow compared to the speedy increase in occurrence of these metabolic disorders. We have identified a natural compound, mangiferin (MGF) (a predominant component of the plants of Anemarrhena asphodeloides and Mangifera indica), that can protect against high fat diet (HFD) induced obesity, hyperglycemia, insulin resistance and hyperlipidemia in mice. However, the molecular mechanisms whereby MGF exerts these beneficial effects are unknown. To understand MGF mechanisms of action, we performed unbiased quantitative proteomic analysis of protein profiles in liver of mice fed with HFD utilizing 15N metabolically labeled liver proteins as internal standards. We found that out of 865 quantified proteins 87 of them were significantly differentially regulated by MGF. Among those 87 proteins, 50% of them are involved in two major processes, energy metabolism and biosynthesis of metabolites. Further classification indicated that MGF increased proteins important for mitochondrial biogenesis and oxidative activity including oxoglutarate dehydrogenase E1 (Dhtkd1) and cytochrome c oxidase subunit 6B1 (Cox6b1). Conversely, MGF reduced proteins critical for lipogenesis such as fatty acid stearoyl-CoA desaturase 1 (Scd1) and acetyl-CoA carboxylase 1 (Acac1). These mass spectrometry data were confirmed and validated by western blot assays. Together, data indicate that MGF upregulates proteins pivotal for mitochondrial bioenergetics and downregulates proteins controlling de novo lipogenesis. This novel mode of dual pharmacodynamic actions enables MGF to enhance energy expenditure and inhibit lipogenesis, and thereby correct HFD induced liver steatosis and prevent adiposity. This provides a molecular basis supporting development of MGF or its metabolites into therapeutics to treat metabolic disorders.
authors.affiliation: The Laboratory for Macromolecular Analysis & Proteomics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America; Department of Pathology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America.
authors.forename: Jihyeon
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America.
authors.forename: Zhongbo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America.
authors.forename: Pasha
authors.initials: P
authors.lastname: Apontes
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America.
authors.forename: Daorong
authors.initials: D
authors.lastname: Feng
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America; Department of Molecular Pharmacology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Pessin
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Sauve
authors.affiliation: The Laboratory for Macromolecular Analysis & Proteomics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America; Department of Pathology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Angeletti
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chi
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects*; D004734:Energy Metabolism / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D053858:Metabolic Networks and Pathways; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D009929:Organ Size / Q000187:drug effects; D020543:Proteome / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019440:Anti-Obesity Agents; D008055:Lipids; D020543:Proteome; D044004:Xanthones; C013592:mangiferin