title: Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice.
abstract: Type 2 diabetes (T2D) has reached an epidemic level globally. Most current treatments ameliorate the hyperglycemic symptom of the disease but are not effective in correcting its underlying cause. One important causal factor of T2D is ectopic accumulation of lipids in metabolically sensitive organs such as liver and muscle. Mitochondrial uncoupling, which reduces cellular energy efficiency and increases lipid oxidation, is an appealing therapeutic strategy. The challenge, however, is to discover safe mitochondrial uncouplers for practical use. Niclosamide is an anthelmintic drug approved by the US Food and Drug Administration that uncouples the mitochondria of parasitic worms. Here we show that niclosamide ethanolamine salt (NEN) uncouples mammalian mitochondria at upper nanomolar concentrations. Oral NEN increases energy expenditure and lipid metabolism in mice. It is also efficacious in preventing and treating hepatic steatosis and insulin resistance induced by a high-fat diet. Moreover, it improves glycemic control and delays disease progression in db/db mice. Given the well-documented safety profile of NEN, our study provides a potentially new and practical pharmacological approach for treating T2D.
authors.affiliation: Department of Pharmacology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Hanlin
authors.initials: H
authors.lastname: Tao
authors.affiliation: Department of Pharmacology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of Pharmacology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA. [2] Zhejiang Key Laboratory of Applied Enzymology, Yangtze Delta Region Research Institute of Tsinghua University, Jiaxing, Zhejiang, China.
authors.forename: Xiangang
authors.initials: X
authors.lastname: Zeng
authors.affiliation: 1] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. [2] Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA. [3] Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Department of Pharmacology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Shengkan
authors.initials: S
authors.lastname: Jin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005215:Fasting / Q000097:blood; D005234:Fatty Liver / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D015309:Glucose Clamp Technique; D056945:Hep G2 Cells; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008322:Mammals / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D041681:NIH 3T3 Cells; D009534:Niclosamide / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014475:Uncoupling Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D014475:Uncoupling Agents; D009534:Niclosamide