Proceedings of The Physiological Society

Obesity (2014) Proc Physiol Soc 32, PC009

Poster Communications

Elevated maternal plasma DLK1/PREF-1 in pregnancy is conceptus-derived and its abrogation affects maternal metabolic adaptations to pregnancy

M. A. Cleaton1, A. C. Ferguson-Smith2, M. Charalambous3

1. Centre for Trophoblast Research, Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. 2. Deptartment of Genetics, University of Cambridge, Cambridge, United Kingdom. 3. Centre for Endocrinology, Queen Mary University of London, London, United Kingdom.

Delta-like homologue 1 (Dlk1, also called Pref-1) is a paternally-expressed imprinted gene that is present in both membrane-bound and soluble forms. Dlk1 is implicated in postnatal control of metabolic parameters, including the appropriate and timely development of brown adipose tissue (1) and the propensity to develop obesity on a high fat diet (2, 3). In the adult, Dlk1 expression is low, as is the concentration of soluble DLK1 in the plasma. However, during pregnancy maternal plasma DLK1 levels rise dramatically, with the peak concentration correlating with the number of fetuses carried (4). Thus, we hypothesised that maternal plasma DLK1 during pregnancy may be conceptus-derived. Additionally, overexpression of Dlk1 from endogenous control elements results in a switch in whole-body metabolism to favour fatty acid utilisation (3). Thus, we hypothesised that the elevation in maternal plasma DLK1 during pregnancy may occur to enable maternal metabolic adaptations to pregnancy.To test these hypotheses, we utilised genetic mouse models and the imprinting status of DLK1 to selectively abrogate Dlk1 expression in the mother, conceptus, both or neither. By measuring maternal plasma DLK1 concentrations in these crosses during pregnancy, we demonstrated that the pregnancy-induced elevation in maternal plasma DLK1 does not occur in the absence of Dlk1 expression in the conceptus. Thus, the conceptus is the source of the additional DLK1.We analysed maternal metabolic parameters in mothers in the presence and absence of pregnancy-induced elevated maternal plasma DLK1. Moreover, we utilised mothers of varying Dlk1 expression status, since membrane-bound DLK1 has been demonstrated to be required for the response to soluble DLK1 in other tissue contexts (5). Maternal resource allocation was affected by maternal plasma DLK1 levels, but only in Dlk1-null mothers. Abrogation of elevated maternal plasma DLK1 did not affect whole-body weight gain, but had maternal genotype-specific effects on tissue weight gain. Analysis of maternal plasma metabolite levels demonstrated alterations consistent with changes in cholesterol metabolism in Dlk1-null mothers but fatty acid metabolism in Dlk1-expressing mothers. Thus, elevated maternal plasma DLK1 during pregnancy affects maternal metabolic parameters in a complex, maternal expression status-dependent manner.

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