title: Male-lineage transmission of an acquired metabolic phenotype induced by grand-paternal obesity.
abstract: OBJECTIVE
  Parental obesity can induce metabolic phenotypes in offspring independent of the inherited DNA sequence. Here we asked whether such non-genetic acquired metabolic traits can be passed on to a second generation that has never been exposed to obesity, even as germ cells.
  
  
  METHODS
  We examined the F1, F2, and F3 a/a offspring derived from F0 matings of obese prediabetic A (vy) /a sires and lean a/a dams. After F0, only lean a/a mice were used for breeding.
  
  
  RESULTS
  We found that F1 sons of obese founder males exhibited defects in glucose and lipid metabolism, but only upon a post-weaning dietary challenge. F1 males transmitted these defects to their own male progeny (F2) in the absence of the dietary challenge, but the phenotype was largely attenuated by F3. The sperm of F1 males exhibited changes in the abundance of several small RNA species, including the recently reported diet-responsive tRNA-derived fragments.
  
  
  CONCLUSIONS
  These data indicate that induced metabolic phenotypes may be propagated for a generation beyond any direct exposure to an inducing factor. This non-genetic inheritance likely occurs via the actions of sperm noncoding RNA.
authors.affiliation: Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia; Faculty of Medicine, University of New South Wales, Kensington, NSW, 2052, Australia. Electronic address: j.cropley@victorchang.edu.au.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Cropley
authors.affiliation: Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia; Faculty of Medicine, University of New South Wales, Kensington, NSW, 2052, Australia.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Eaton
authors.affiliation: Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia.
authors.forename: Alastair
authors.initials: A
authors.lastname: Aiken
authors.affiliation: Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Young
authors.affiliation: Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia.
authors.forename: Eleni
authors.initials: E
authors.lastname: Giannoulatou
authors.affiliation: Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia; Faculty of Medicine, University of New South Wales, Kensington, NSW, 2052, Australia.
authors.forename: Joshua W K
authors.initials: JWK
authors.lastname: Ho
authors.affiliation: Brain and Mind Research Institute, University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Buckland
authors.affiliation: Faculty of Engineering and Information Technology, Centre of Health Technologies, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Keam
authors.affiliation: Faculty of Engineering and Information Technology, Centre of Health Technologies, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Hutvagner
authors.affiliation: Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia.
authors.forename: David T
authors.initials: DT
authors.lastname: Humphreys
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Diabetes and Heart Research Institute, Melbourne, VIC, 3004, Australia.
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Langley
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Diabetes and Heart Research Institute, Melbourne, VIC, 3004, Australia.
authors.forename: Darren C
authors.initials: DC
authors.lastname: Henstridge
authors.affiliation: Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia; Children's Hospital Oakland Research Institute, Oakland, CA, 94609, USA.
authors.forename: David I K
authors.initials: DIK
authors.lastname: Martin
authors.affiliation: Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.affiliation: Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia; Faculty of Medicine, University of New South Wales, Kensington, NSW, 2052, Australia. Electronic address: c.suter@victorchang.edu.au.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Suter
keywords: Epigenetic inheritance; Noncoding RNA; Paternal effects; Sperm RNA