The mature male sheep: a model to study the effects of nutrition on the reproductive axis

We have been using mature male sheep to study the ways in which nutrition affects reproduction, with a focus on the brain-pituitary axis and, in particular, GnRH activity. The sheep model has four major advantages for such studies. Firstly, sheep are large enough to support long periods of frequent serial sampling of peripheral blood, hypophyseal portal blood and cerebrospinal fluid from the cerebral ventricles. Importantly, this can be done with freely moving animals and, thus, avoids many of the potential complications associated with restraint. The second advantage, particularly relevant to nutrition-reproduction interactions, is the vast history of nutritional research for this species, providing us with techniques (for example, gut cannulation) and an extensive database on the requirements of sheep for energy, protein and specific dietary components such as amino acids, fatty acids and trace elements. Thirdly, subtle manipulations of diet can be used that cover the range seen in the real world, where animals (including humans) rarely encounter the uninterrupted, ad libitum food supplies that are normal for laboratory animals. Within this normal range of conditions, clear reproductive outcomes can be measured without resorting to starvation and both short- and long-term responses can be studied. Finally, the sheep model has an intrinsic economic relevance and findings from sheep can be transposed readily to other agricultural mammals. The sheep model is also relevant to human biology, often directly, but also indirectly because it often leads us to question the significance of findings from studies with rodents. Using mature male sheep to study the reproductive endocrine responses to acute and chronic changes in diet, we have shown that glucose does not appear to be involved directly, but that fatty acids can stimulate GnRH-dependent pathways that initiate changes in testicular function. Our work also indicates that GnRH-independent (perhaps also neuroendocrine) mechanisms may be involved. In the brain, it seems likely that intracerebral insulin and orexin are important mediators of the GnRH response to nutritional changes, but it is unlikely that leptin plays a role, at least in mature animals.