Declining fertility, insulin resistance and fatty acid metabolism in dairy cows: developmental consequences for the oocyte and pre-implantation embryo

ABSTRACT

Background: The fertility of contemporary high-yielding dairy cows is in decline and herd health and lifespan are decreasing. Over-conditioned peri-parturient cows are more insulin resistant than lean cows and this leads to an increase in body fat mobilisation, in the form of free fatty acids (FFA). This, in turn, can increase the risk of a number of disorders including fatty liver syndrome, ketosis, milk fever and infertility. In humans, the accumulation of fat in non-adipose tissues and excess accumulation of fat in visceral adipose depots also contribute to peripheral insulin resistance. The delivery of FFA to the liver from visceral adipose tissue is now believed to be the primary contributor to the pathological symptoms of hepatic lipidosis, hyperinsulinaemia and glucose intolerance. The current article develops the hypothesis that the modern high-yielding dairy cow has inadvertently been selected to become increasingly insulin resistant, in part, as a consequence of a regional re-distribution in body fat towards intra-abdominal depots. In turn, this contributes to greater lipolysis and mobilisation of FFA during early lactation with implications for cow metabolism and fertility. These ideas are developed in the context of recent data on the effects of insulin and fatty acids on oocyte and early embryo development, with reference to mice and humans where mechanistic insights from ruminants are lacking. Review Relative to non-ruminants, cattle and sheep are insulin resistant, but the mechanisms of insulin action in ruminants are believed to be similar to those of other species. Key insulin signalling pathways have been identified in both physiological and pathological conditions in humans and mice, but these mechanisms are poorly understood in ruminants. FFA are key inflammatory signals which, together with specific adipokines, can induce insulin resistance. Again, the mechanisms of action for these factors are poorly understood in ruminants. However, obesity is associated with hyperinsulinaemia and impaired egg quality in all species studied. Insulin sensitising agents in obese mice have been found to improve the post-fertilisation developmental potential of oocytes. In cattle, the detrimental effects of hyperinsulinaemia on oocyte quality are cumulative over time, suggesting that exposure to high levels of insulin during pre-antral follicular development is particularly harmful. Insulin resistance can also manifest in the pre-implantation embryo. In the mouse this leads to apoptotic cell death and lower pregnancy rates. The mechanisms of fatty acid-induced insulin resistance in the oocyte and embryo are currently not known. However, the follicle-enclosed oocyte preferentially accumulates saturated fatty acids, and high levels of palmitic (c160) and stearic (c180) acid impair maturation and postfertilisation development. In contrast, specific polyunsaturated fatty acids (PUFA) (e.g. α-linolenic acid (c183n-3)) can improve oocyte maturation and embryo development in vitro, but the effects of n-6 PUFA are generally inhibitory. However, it has been difficult to reproduce these findings in lactating cows. This is possibly due to selective uptake mechanisms in the ovary and high levels of relatively saturated FFA in peripheral circulation at this time. Conclusion: Insulin resistance in modern high-yielding dairy cows contributes to reduced fertility and there is evidence that this effect presents as reduced oocyte quality and impaired embryo development. Detailed mechanistic studies in cattle are lacking, but the level and nature of FFA (particularly PUFA) may be key in determining the extent of insulin resistance and oocyte/early embryo development.