During pregnancy, the fetus places nutritional demands on the mother. Maternal food intake and weight gain increases significantly during pregnancy. However, the mechanisms underlying these physiological changes are still poorly understood.
Two key central hormones that act on the hypothalamus, the primary brain region regulating food intake and food choice, are α-melanocyte stimulating hormone (α-MSH) and oxytocin: both hormones inhibit feeding in the non-pregnant animal. It has recently been shown that in pregnancy the inhibitory effect of α-MSH on feeding is lost.
The overarching hypothesis is that oxytocin signalling in late pregnancy is suppressed or modified to promote the consumption of food beyond homeostatic need, pushing pregnant animals into positive energy balance in preparation for parturition and lactation. We will use a mouse model to test the following hypotheses: i. hyperphagia in late pregnancy is accompanied by changes in preferences for high-calorie macronutrients (e.g. sugar, fat); ii. these behavioural changes are correlated with changes in the location and/or density of oxytocin receptor (OTR) expression in relevant brain regions during pregnancy; iii. these behaviours can be attenuated or replicated by administration of selective OTR and/or melanocortin receptor (MC) agonists or antagonists to specific brain regions; and iv. these behavioural changes can be recapitulated by targeted inhibition of oxytocin cells.
Brain OTR and MC4 expression will be mapped in pregnant mice for the first time using RNAscope. Oxytocin and/or a-MSH signalling will be manipulated by targeted icv injections of OTR and/or MC4 agonists or antagonists. Oxytocin cells will also be selectively inhibited using chemogenomic technologies. In all these manipulation studies, the main outputs assessed will be behavioural assays of eating, activity and food choice.
Understanding the key pathways involved in the physiological adaptations underlying pregnancy-induced hyperphagia and food choice potentially provides a useful physiological model to investigate increased food intake and the development of obesity.
Dr John Menzies
Dr Joanne Murray
Dr Zhuoxian Meng (Zhejiang University)