School of Veterinary and Biomedical Sciences

David Miller's Research

• Energy Balance and Fertility
• Early Life Programming
• Hormonal Control of Tissue Growth and Function

Energy Balance and Fertility

Infertility can be a symptom of inappropriate energy balance. In humans, conditions such as anorexia, obesity and even excessive exercise can have negative impacts on fertility. It has also long been known that seasonal changes in productivity and nutrition can have profound effects on various reproductive events in farmed and wild animal species. These nutritional scenarios of altered reproductive function are thought to be brought about by interactions with metabolic sensing and messaging systems in the body that are involved in the homeostatic control of energy balance.

Since appetite, growth and reproduction are regulated by nutritional feedback signals to the same brain region (hypothalamus) they share common mechanisms. Reproductive status is dictated by the activity of the gonadotrophin-releasing hormone (GnRH) ‘pulse generator’ in the hypothalamus, which is activated at puberty upon attainment of appropriate body weight, but which is subsequently disrupted if body weight or nutritional status becomes inappropriate. GnRH output therefore provides a measure of hypothalamic sensitivity to nutritional feedback from peripheral signals.

Research by us in this area is concentrating on the role of metabolic hormones in relaying information about an animal’s nutritional and body weight status, and how this information is then utilised to control energy balance, growth and fertility (GnRH secretion). Indeed, from the study of GnRH output in sheep we have recently demonstrated that the hypothalamus differentiates between two distinct components of nutritional feedback, namely short-term energy intake and long-term body fat reserves. The signals that the hypothalamus reads to make this differentiation appears to be major metabolic hormones like insulin, ghrelin and leptin interacting with neuropeptide systems such as NPY, AgRP, POMC and CART.

Other research on Neurobiology by members of the Physiology & Pharmacology can be found on the Molecular Nuerobiology Laboratory page.

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Early Life Programming

"We are what our mothers ate". This phrase describes the theory that the in utero nutrition of the fetus is very important in determining the long-term health and productivity of both humans and animals. The capacity of prenatal and early postnatal nutrition to affect adult reproductive function in sheep and other livestock species has been known since the 1970’s. More recently, epidemiological studies in humans have indicated that environmental influences, such as nutrition and endocrine disrupting compounds (EDCs) during fetal development can have long-term effects on the health of the offspring, an observation that resulted in the term ‘fetal programming’. We are investigating the critical windows during gestation (pregnancy) when deleterious nutritional and metabolic effects may have their greatest impact, not only in terms of fetal development but also in relation to lifetime performance and health. One particular focus is on the development and activity of the reproductive organs. They are particularly important in the timing of puberty, the re-commencement of ovarian function after birth, and the seasonal fluctuations in reproductive status.

Our research has shown that maternal undernutrition directly compromises ovarian development and function in sheep. Specifically, we have found that mild undernutrition during the first 95 days of gestation (term ≈ day 147) is not associated with growth retardation, but offspring have a 20% lower ovulation rate in adulthood. Furthermore, this reduction in fertility probably has fetal origins because there is an associated delay in fetal ovarian follicular development during pregnancy. Research is ongoing to fully elucidate this phenomenon and to determine the metabolic signaling pathways involved.

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Hormonal Control of Tissue Growth and Function

Much interest has recently arisen regarding the role of hormones in not only controlling central mechanisms such as energy balance, appetite and growth, but also their peripheral actions in the control of tissue growth and development. Many of the same hormones that have central metabolic actions have now been found to affect cellular differentiation, proliferation and apoptosis (cell death).

Moreover, we are now starting to understand better the paracrine and autocrine signaling systems which these metabolic hormones must ultimately interact with.

Research in progress is concerned with how nutritional changes in metabolic hormones, such as leptin and ghrelin, may interact with cellular differentiation, proliferation and apoptotic factors such as SCF, PCNA, Bax, Bcl-2 and Mcl-1 to control tissue growth and development. Moreover, these same pathways may also be involved in the altered functioning of these tissues under different physiological or environmental conditions.

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