title: Latanoprost effectively ameliorates glucose and lipid disorders in db/db and ob/ob mice.
abstract: OBJECTIVE
  Improvement of glucose and lipid metabolic dysfunctions is a potent therapeutic strategy against type 2 diabetes mellitus, and identifying new functions for existing drugs may help accelerate the speed of new drug development. Here, we report that latanoprost, a clinical drug for treating primary open-angle glaucoma and intraocular hypertension, effectively ameliorated glucose and lipid disorders in two mouse models of type 2 diabetes. In addition, the glucose-lowering mechanisms of latanoprost were intensively investigated.
  
  
  METHODS
  A binding-affinity assay and enzymatic tests were used to determine the targets of latanoprost. Cell-based assays on 3T3-L1 adipocytes and C2C12 myotubes and animal model-based assays with db/db and ob/ob mice were further performed to clarify the mechanisms underlying latanoprost-regulated glucose and lipid metabolism.
  
  
  RESULTS
  Latanoprost functioned as both an indirect activator of AMP-activated protein kinase and a selective retinoid X receptor α (RXRα) antagonist able to selectively antagonise the transcription of a RXRα/peroxisome proliferator-activated receptor γ heterodimer. It promoted glucose uptake, inhibited pre-adipocyte differentiation and regulated the main genes responsible for glucose and lipid metabolism, including Fas, Scd1, Perilipin (also known as Plin1), Lpl and Pdk4. Chronic administration of latanoprost in mice potently decreased the levels of fasting blood glucose, HbA1c, fructosamine (FMN), NEFA and total cholesterol, and effectively improved glucose tolerance and glucose/lipid metabolism-related genes in vivo.
  
  
  CONCLUSIONS
  Our studies demonstrate that the existing eye drug latanoprost is both an indirect activator of AMP-activated protein kinase and a selective RXRα antagonist. Latanoprost effectively ameliorated glucose and lipid disorders in diabetic mice, which strongly highlights the potential of latanoprost in the treatment of type 2 diabetes mellitus.
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People's Republic of China.
authors.forename: Gaihong
authors.initials: G
authors.lastname: Wang
authors.forename: Xing
authors.initials: X
authors.lastname: Xu
authors.forename: Xingang
authors.initials: X
authors.lastname: Yao
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhu
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D015195:Drug Design; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000077338:Latanoprost; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D008820:Mice, Obese; D018485:Muscle Fibers, Skeletal; D047495:PPAR gamma / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology*; D012074:Remission Induction; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D011461:Prostaglandins F, Synthetic; D047490:Retinoid X Receptor alpha; D000077338:Latanoprost; D055372:AMP-Activated Protein Kinases; D005947:Glucose