title: Prenatal metformin exposure in mice programs the metabolic phenotype of the offspring during a high fat diet at adulthood.
abstract: OBJECTIVE
  The antidiabetic drug metformin is currently used prior and during pregnancy for polycystic ovary syndrome, as well as during gestational diabetes mellitus. We investigated the effects of prenatal metformin exposure on the metabolic phenotype of the offspring during adulthood in mice.
  
  
  METHODS
  Metformin (300 mg/kg) or vehicle was administered orally to dams on regular diet from the embryonic day E0.5 to E17.5. Gene expression profiles in liver and brain were analysed from 4-day old offspring by microarray. Body weight development and several metabolic parameters of offspring were monitored both during regular diet (RD-phase) and high fat diet (HFD-phase). At the end of the study, two doses of metformin or vehicle were given acutely to mice at the age of 20 weeks, and Insig-1 and GLUT4 mRNA expressions in liver and fat tissue were analysed using qRT-PCR.
  
  
  RESULTS
  Metformin exposed fetuses were lighter at E18.5. There was no effect of metformin on the maternal body weight development or food intake. Metformin exposed offspring gained more body weight and mesenteric fat during the HFD-phase. The male offspring also had impaired glucose tolerance and elevated fasting glucose during the HFD-phase. Moreover, the expression of GLUT4 mRNA was down-regulated in epididymal fat in male offspring prenatally exposed to metformin. Based on the microarray and subsequent qRT-PCR analyses, the expression of Insig-1 was changed in the liver of neonatal mice exposed to metformin prenatally. Furthermore, metformin up-regulated the expression of Insig-1 later in development. Gene set enrichment analysis based on preliminary microarray data identified several differentially enriched pathways both in control and metformin exposed mice.
  
  
  CONCLUSIONS
  The present study shows that prenatal metformin exposure causes long-term programming effects on the metabolic phenotype during high fat diet in mice. This should be taken into consideration when using metformin as a therapeutic agent during pregnancy.
authors: Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.
authors: Henriikka
authors: H
authors: Salomäki
authors: Laura H
authors: LH
authors: Vähätalo
authors: Kirsti
authors: K
authors: Laurila
authors: Norma T
authors: NT
authors: Jäppinen
authors: Anna-Maija
authors: AM
authors: Penttinen
authors: Liisa
authors: L
authors: Ailanen
authors: Juan
authors: J
authors: Ilyasizadeh
authors: Ullamari
authors: U
authors: Pesonen
authors: Markku
authors: M
authors: Koulu
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D004435:Eating / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000235:genetics; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000254:growth & development; D008297:Male; D018811:Maternal Exposure; D008565:Membrane Proteins / Q000235:genetics; D008687:Metformin / Q000097:blood / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects
chemical_list: D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; C506119:Insig1 protein, mouse; D008565:Membrane Proteins; D008687:Metformin