title: Lactation undernutrition leads to multigenerational molecular programming of hypothalamic gene networks controlling reproduction.
abstract: Reproductive success is dependent on development of hypothalamic circuits involving many hormonal systems working in concert to regulate gonadal function and sexual behavior. The timing of pubertal initiation and progression in mammals is likely influenced by the nutritional and metabolic state, leading us to the hypothesis that transient malnutrition experienced at critical times during development may perturb pubertal progression through successive generations. To test this hypothesis we have utilized a mouse model of undernutrition during suckling by exposing lactating mothers to undernutrition.
  
  
  
  Using a combination of transcriptomic and biological approaches, we demonstrate that molecular programming of hypothalamus may perturb gender specific phenotypes across generations that are dependent on the nutritional environment of the lactation period. Lactation undernutrition in first (F1) generation offspring affected body composition, reproductive performance parameters and influenced the expression of genes responsible for hypothalamic neural circuits controlling reproductive function of both sexes. Strikingly, F2 offspring showed phenotypes similar to F1 progeny; however, they were sex and parental nutritional history specific. Here, we showed that deregulated expression of genes involved in kisspeptin signaling within the hypothalamus is strongly associated with a delay in the attainment of puberty in F1 and F2 male and female offspring.
  
  
  
  The early developmental plasticity of hypothalamus when challenged with undernutrition during postnatal development not only leads to altered expression of genes controlling hypothalamic neural circuits, altered body composition, delayed puberty and disturbed reproductive performance in F1 progeny, but also affects F2 offspring, depending on parental malnutrition history and in sexually dimorphic manner.
authors.affiliation: Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland. m.kaczmarek@pan.olsztyn.pl.
authors.forename: Monika M
authors.initials: MM
authors.lastname: Kaczmarek
authors.affiliation: Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.
authors.forename: Tamra
authors.initials: T
authors.lastname: Mendoza
authors.affiliation: Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
authors.forename: Leslie P
authors.initials: LP
authors.lastname: Kozak
mesh_terms: D000818:Animals; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D007031:Hypothalamus / Q000254:growth & development* / Q000378:metabolism; D007774:Lactation; D044342:Malnutrition / Q000235:genetics*; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D012098:Reproduction; D012741:Sexual Maturation
keywords: Hypothalamus; Kisspeptin; Leptin; Multigenerational programming; Reproductive performance