Lactation undernutrition leads to multigenerational molecular programming of hypothalamic gene networks controlling reproduction.

Monika M. Kaczmarek,Tamra Mendoza,Leslie P. Kozak

doi:10.1186/s12864-016-2615-4

Abstract

BackgroundReproductive 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.ResultsUsing 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.ConclusionThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2615-4) contains supplementary material, which is available to authorized users.

Highlights

Reproductive success is dependent on development of hypothalamic circuits involving many hormonal systems working in concert to regulate gonadal function and sexual behavior
Hypothalamic gene expression networks altered in F1 progeny undernourished during early postnatal development Because kisspeptins are essential gatekeepers of proper reproductive maturation, including gating by metabolic factors [21] and kisspeptin neural circuits develop gradually during the first weeks of postnatal life [20], we investigated whether neonatal undernutrition during the neonatal period impacts kisspeptin-signaling related gene expression within the hypothalamus of 10- and 21day old mice (Fig. 3; Additional file 3: Table S1)
We showed that this early developmental plasticity of hypothalamus leads to transcriptomic changes in hypothalamus when challenged with undernutrition and in consequence change body composition and timing of puberty in F1 generation

Summary

Introduction

Reproductive success is dependent on development of hypothalamic circuits involving many hormonal systems working in concert to regulate gonadal function and sexual behavior. The above mentioned phenomena display sexual dimorphism, and substantial differences are detected between males and females in relation to the development of reproductive brain circuits, the timing of puberty, and the function of the HPG axis in adulthood [1, 2]. In this circuitry, the essential contribution of several neuropeptide pathways, including prominently kisspeptin neurons, has been documented [4]. The ability of high doses of leptin to increase the hypothalamic expression of Kiss gene in different models of severe metabolic stress, such as the leptin-deficient ob/ob mouse and the diabetic rat, fueled the hypothesis that leptin acts on kisspeptin neurons to conduct its stimulatory/permissive effects on GnRH neurons [6,7,8]

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