Mother or Father: Who Is in the Front Line? Mechanisms Underlying the Non-Genomic Transmission of Obesity/Diabetes via the Maternal or the Paternal Line

Abstract

Extensive epidemiological and experimental evidence have shown that exposure to an adverse intrauterine environment as observed in offspring of pregnancies complicated by obesity or diabetes, can program susceptibility to metabolic, endocrine and cardiovascular disorders later in life. Although most studies have concentrated on the maternal environment, it is also becoming evident that paternal exposure to obesity or diabetes can result in the later development of metabolic disorders in the offspring. Such programmed effects might not be limited to the first directly exposed generation, but could be transmitted to subsequent generations. This suggests the existence of mechanisms by which metabolic changes in parental phenotype are transmissible to offspring. The mechanisms which underpin the transmission of the programmed effects across generations are still unclear. However, epigenetic regulation of transcription has emerged as a strong candidate for mediating the heritability of metabolic diseases. Here, we review the most relevant evidence from human and animal studies showing transmission of programming effects of obesity or diabetes across generations, and the current mechanisms underlying either maternal or paternal influences on the metabolic status of offspring.

Keywords: DOHaD; diabetes; germ cell epigenome; maternal and paternal metabolic imprinting; obesity; sncRNAs.

Figure 1

Parental contribution for programming adult obesity/diabetes in the offspring. The preconception (oocyte maturation, follicular development), conception (fertilization and embryo growth until implantation), gestational and suckling periods are critical time-windows for maternal obesity/diabetes (brown rodent) to shape the risk for the offspring to develop obesity or diabetes (left panel). The preconception period (sperm cell maturation) is a critical period for paternal obesity/diabetes (brown rodent) to shape the risk for the offspring to develop obesity or diabetes (right panel).

Figure 2

Non-genetic transmission of parental programming effects. Left panel: Maternal exposure to a metabolic insult (such as an unbalanced diet, obesity, diabetes) (brown rodent) influences both her developing fetus in utero (F1) as well as the developing germ cells in the fetus which later give rise to F2, both of which are present at the time of environmental exposure. When phenotypes do not persist after F1 or F2, such a programming effect is referred to as intergenerational inheritance (c,d). However, the cells which form the F3 generation are not present at the time of environmental exposure. If they still carry phenotypes in the F3 generation, they do so by transgenerational inheritance (a). This transgenerational inheritance (non-genetic) appears to be mediated through the transmission of epigenetic information through the germline [6,80,81]. Another mechanism for the transmission of programming effects is that programmed changes in the F1 mother (maternal physiology and behavior) influence the F2 offspring development, and so on. In this case, the metabolic insult is the altered maternal phenotype and the altered phenotype is established de novo in each new generation (b). Such a programming effect is referred to as maternal phenotype intergenerational inheritance (b). Right panel: For paternal exposure to a metabolic insult (brown rodent), only the sperm cells which form the F1 generation are present and directly exposed to the insult. When phenotypes do not persist after F1, the programming effect is referred to as intergenerational inheritance (f). When phenotypes persist into F2 and beyond, it is referred to as transgenerational inheritance (e). This transgenerational inheritance (non-genetic) appears to be mediated through the transmission of epigenetic information through the paternal sperm cells [6,80,81].

Figure 3

Metabolic and endocrine phenotypes of young male rats issued from crosses (F1) between normal Wistar (mW) or diabetic (mGK) mothers and normal (pW) or diabetic (pGK) fathers. Indices of glucose tolerance (rate of glucose disappearance, K_G), after an in vivo glucose charge) (A), and of insulin secretion (insulinogenic index, ΔI/ΔG), in response to an in vivo glucose charge (B), have been evaluated. (a) p < 0.01 versus pW/mW, pGK/mW and mGK/pW. (b) p < 0.001 versus pW/mW and pGK/mGK. Adapted from [108]. The Goto-Kakizaki (GK) rat is one of the best characterized animal models of spontaneous type 2 diabetes (T2D) model. It has provided new insights into the pathogenesis of T2D as the rats develop spontaneous defects in insulin secretion and action and long-standing diabetes complications that, in many ways, resemble those described in human T2D [53,54].