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Ghrelin is a 28-amino acid peptide, recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin derived from both hypothalamus and stomach was found to regulate pituitary growth hormone (GH) secretion in a distinct dose-dependent manner (Kojima & Kanjawa., 2005). Ghrelin was also found in the pituitary gland where it acts as an autocrine or endocrine regulator of GH release (Garcia et al., 2007). GHS-R is a G protein-coupled receptor which is expressed at high levels in the hypothalamus and pituitary. Moreover, GHS- R expression has also been found in testis, ovary, pituitary, heart, lung, liver, kidney, pancreas, stomach, adipose tissue, and immune cells. Therefore, ghrelin, through operating at different levels, was reported to be involved in many biological functions including energy homeostasis and reproduction (Kojima & Kanjawa., 2005).

Ghrelin expression in the cyclic and pregnant rat ovary changes throughout pregnancy and during oestrus, with the lowest level during proestrus and maximum values in dioestrus. This cyclic change of ghrelin expression with the maximum level

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detected during the luteal stages in parallel with progesterone profile suggests a possible effect in the development and function of the corpus luteum in rat (CL; Caminos et al., 2003). During the course of pregnancy ghrelin was detected at its highest level in an early stage and it decreased gradually during the latter half of pregnancy. The function of the CL required for maintaining pregnancy during the first week of gestation is regulated by LH and prolactin (PRL), while the second half of pregnancy is regulated both by the action of lactogen and androgen produced by the placenta, and by oestrogen and progesterone produced by CL. Therefore, it has been suggested that ovarian ghrelin expression during early pregnancy is modulated by the action of LH and prolactin while placental lactogen is primarily involved in placental ghrelin expression during the latter half of pregnancy (Caminos et al., 2003). Moreover, ghrelin expression in testis is highly selective for Leydig cells and under the hormonal control of pituitary LH. LH administration raises levels of testicular ghrelin RNA. Conversely, ghrelin inhibits pulsatile LH in female rat, and testosterone secretion in male rat. Therefore, elevated ghrelin levels may result in suppression of the reproductive axis (Garcia et al., 2007).

Ghrelin expression in the hypothalamic nucleus, which has important effects on food intake, is highly suggestive of a possible role of ghrelin in food intake. Peripherally or centrally injected ghrelin in freely-fed rats results in an increase in food intake and GH secretion (Wren, et al., 2000). Tschöp et al. (2000) showed that continuous central administration of ghrelin results in a dose-dependent increase in food intake and body weight. In addition, there is a fluctuation in plasma ghrelin associated with feeding status, increasing during fasting and decreasing after feeding. In beef cattle, Wertz-Lutz et al. (2006) suggested that ghrelin plays an important role in feeding behaviour and energy homeostasis. An increase in plasma ghrelin concentrations was observed prior to feeding in cattle, followed by a postprandial decrease. Roche et al. (2006) reported a positive relationship between genetic selection for increased milk production and plasma ghrelin concentration, dry matter intake, and GH level. Therefore, NEB in lactating cows was proposed to stimulate ghrelin and GH secretion (Bardford & Allen, 2008). Taking into account the impact of nutritional status on reproduction prompted the idea that ghrelin may operate at central and peripheral levels as a key signal for energy status to the reproductive axis.

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Collectively, ghrelin was recognized as a potent orexigenic agent by acting at central endocrine levels, providing a link between the stomach, hypothalamus and pituitary and playing an important role in EB through stimulating food intake and adiposity (Garcia et al., 2007).

1.4.3 Conclusion

The decline in fertility in modern dairy cattle is complex and many factors have been suggested to have an effect on this trait (Figure 1.4). Most of these factors can be categorized as pathological (mastitis, lameness), physiological (high milk yield, reproduction hormones), and managerial (nutrition, oestrous detection). So, different genes that play a role in these pathways may be expected to have an impact on fertility, resulting in hundreds of genes potentially being involved in reproduction in dairy cattle (which is clearly a polygenic trait). In addition, there are complicated interactions among these factors and many of these genes have multiple effects. For example, the incidence of lameness is associated with lower oestrus expression and lower fertility (Dobson et al., 2008). On the other hand, high producing cows were found to be more susceptible to lameness and this was associated with the low BCS in these cows (Espejo et al., 2006). Furthermore, nutritional status of the cows, which is affected by management and genetics, has major effects on fertility in dairy cattle. For instance, cows overconditioned at calving or in a state of undernutrition early lactation will develop more sever NEB and subsequently lower fertility through reducing LH and FSH pulse frequency (Butler and Smith, 1989; Butler, 2003). Many genes that have direct effects on feeding behaviour also have significant effects on fertility (leptin, ghrelin etc.). The effects of some of the genes that affect fertility are investigated in more detail in the following chapters.

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Figure 1.4 Different factors affecting fertility in dairy cattle.

Selection indices are used to describe the magnitudes of genetic effects of the kind described above (which will be covered exensively in the following chapter). This approach has been used successfully in the dairy industry, as described in the following section.