ReviewInterface between metabolic balance and reproduction in ruminants: Focus on the hypothalamus and pituitary
Introduction
Reproductive function and metabolic function are intimately linked for the simple reason that the former comes at a cost. This is especially the case for females, who need to source energy for pregnancy and lactation. Central regulation of both reproduction and metabolic function provides a means whereby adequate energy or energy deficit can be sensed, such that food intake and energy expenditure can be modulated. In the past three decades, our understanding of the central regulation of food intake and energy expenditure has increased due to the identification of a range of neuronal systems within the brain. In addition, the relatively recent identification of neuropeptides that modulate reproductive function has provided a new layer of knowledge. In particular, kisspeptin and gonadotropin inhibitory hormone (GnIH) stand out as key factors in the regulation of reproduction. Not surprisingly, the neural elements within the brain that control metabolic function and those that control reproduction are inter-connected.
The focus of this article is on ruminant species, particularly sheep and cattle. Other excellent reviews deal with the topic as it pertains to rodents (True et al., 2011a), but large animal models provide special opportunities to gain knowledge of the subject. In particular, the sheep is the species of choice for the real-time measurement of the secretion of gonadotropin releasing hormone (GnRH) and the blood volume and passive nature of sheep allow serial measurement of circulating hormones. Sheep are not nocturnal, as are rodents, and they are able to undergo remarkable variations in live-weight (adiposity). Nevertheless, rodent models provide opportunities to manipulate genetic makeup and also have a much shorter generation interval than ruminant animals. Excellent studies in rodent species have been reviewed in this volume (Bellefontaine N & Elias CF (2014 Minireview: Metabolic control of the reproductive physiology: Insights from genetic mouse models)). Ruminants present a special case in terms of metabolic function because their digestive system is different to that of monogastric species and they derive energy from the diet in terms of volatile fatty acids rather than carbohydrates and proteins, both of which are digested in the rumen. In spite of this, these animals have very efficient gluconeogenic function and maintain blood glucose levels within a narrow range. There is a paucity of information on the interaction between the reproductive and metabolic systems in bovine species but there are some interesting issues, especially in relation to the high-producing dairy cow.
Firstly, I outline reproductive and metabolic function in ruminants and consider the impact of altered energy balance on reproductive function, especially in terms of the synthesis and secretion of GnRH. I review information on the neural connections within the hypothalamus that allow the reproductive axis to be influenced by metabolic state. This will include information on connectivity of neural elements within the hypothalamus and how these connections translate into function. With this framework, I then consider the regulation of metabolic function in ruminants, with particular reference to hypothalamic systems. The specific cases of how growth hormone (GH) and thyroid hormones are affected by metabolic perturbation and how this affects the reproductive axis are considered and the particular implications of seasonality and lactation are reviewed. This article focusses on the hypothalamic and pituitary components of the reproductive axis, although it is recognised that metabolic state also impacts directly on the function of the gonads.
Section snippets
Relationship between GnRH and gonadotropins
The primary driver of reproduction is GnRH, secreted from the brain into the hypophysial portal system in a pulsatile manner (Clarke and Cummins, 1982). In sheep, the majority of GnRH cells are found in the preoptic area of the brain, as in rodent species (Lehman et al., 1986). GnRH is mandatory for the synthesis and secretion of gonadotropins in the gonadotropes of the anterior pituitary, but there are important distinctions in the way this is effected (Clarke et al., 2011). Luteinising
Seasonality of breeding and metabolic function in sheep
Sheep are seasonal breeders and also display seasonality of metabolic function; this provides a useful adjunct to their utility as a model for both reproduction and energy balance. The annual cycle of reproductive activity and inactivity differs between breeds (Hafez, 1952). Reproductive seasonality is discussed briefly here and the photoperiodic regulation of appetite and energy expenditure is considered below. Seasonality is due to the action of melatonin, functioning as a ‘zeitgeber’ of the
Brain sensing of metabolic state — historical perspective
An appreciation of the regulation of food intake and energy expenditure was rudimentary until approximately 30 years ago. Whereas it was known that lesions in the ventromedial nucleus of the hypothalamus cause hyperphagia and obesity (Hetherington and Ranson, 1939) and lesions in the lateral hypothalamus caused hypophagia (Anand and Brobeck, 1951), the neural substrates (appetite regulating peptides — ARP) in these regions of the brain were not identified for another 30 years. In relation to farm
GH in relation to metabolic state and reproduction
The GH axis and the reproductive axis are intimately linked in terms of function at various levels (Veldhuis et al., 2006). Circulating GH levels are elevated in lean sheep, due to increased expression of the gene for GH releasing hormone neurons in the arcuate nucleus and reduced somatostatin gene expression (Henry et al., 2001c) and circulating plasma GH levels are elevated in cattle (Blum et al., 1985) and sheep (Barker-Gibb and Clarke, 1996). At least part of this response is presumably due
Photoperiodic effects on metabolic status
As indicated earlier, there is a circannual cycle of metabolic function in sheep. This has been reviewed in detail elsewhere (Clarke, 2008, Rhind et al., 2002). The circannual cycle of food intake and change in body weight is driven by changes, within the brain, in the expression of NPY and POMC gene expression (Anukulkitch et al., 2009, Clarke et al., 2000, Clarke et al., 2003, Lincoln et al., 2001). There are also changes in the expression of pre-pro-ORX and MCH, but how this relates to food
Effects of ARP on the reproductive axis
As indicated above, ghrelin is a potent stimulator of food intake and a suppressor of reproductive function. In relation to ARP that are found in the brain, the same general rule applies, with orexigens inhibiting reproduction and anorexigens having a stimulatory effect.
Thus, NPY suppresses reproduction (Barker-Gibb et al., 1995) (Fig. 8A), whilst melanocortins are stimulatory (Backholer et al., 2010a) (Fig. 8B). NPY does not only block pulsatile secretion of GnRH/LH in the ovariectomised ewe,
Special case of kisspeptin in relation to the lean condition
Kisspeptin cells in the ovine brain express leptin receptors and leptin treatment of lean ovariectomised ewes increases kisspeptin gene expression (Backholer et al., 2010b). It seems reasonable, therefore, to postulate that the restoration of reproductive function in lean animals, by leptin, is through this mechanism. Whereas the leptin effect is on both populations of kisspeptin cells, those of the arcuate nucleus do not project directly to the GnRH cell bodies of the preoptic area; those of
GH and kisspeptin in relation to reduced body weight
In cows, kisspeptin appears to stimulate the secretion of GH as well as gonadotropins (Kadokawa et al., 2008). In contrast to the situation in the sheep, where kisspeptin regulates GnRH secretion (Smith et al., 2008b), it appears to act on the pituitary gonadotropes in the cow (Ezzat et al., 2010). In sheep, kisspeptin gene expression is reduced in animals that are hypogonadotropic because of lean condition and this is partly corrected by leptin administration (Backholer et al., 2010b), as
GnIH as an integrator of reproduction and metabolic function
GnIH is a potent inhibitor of reproductive function in the sheep and also stimulates food intake (Clarke et al., 2012a). GnIH cells project to GnRH cells as well as to the ARP cells throughout the ovine hypothalamus (Qi et al., 2009), providing a neuronal substrate for dual effect on reproduction and regulation of food intake (Table 3).
GnIH also stimulates food intake in the rat (Johnson et al., 2007) and the non-human primate (Clarke et al., 2012a). An indication that there is an inverse
Energy expenditure and the effects of sex steroids
Ruminants are continuous grazers but can be entrained in various ways with programmed feeding. In particular, when sheep are fed during a certain window every day, a post-prandial thermogenic response is seen in fat and muscle (Henry et al., 2008). This enables a detailed study of mechanisms that regulate thermogenesis, perhaps the best known being the central effect of leptin to enhance the post-prandial thermogenic response — this was clearly seen in skeletal muscle (Henry et al., 2008),
Genetic models of obesity and reproduction
A number of rodent models of obesity are well known, but these will not be discussed here. One model of genetic ‘obesity’ in sheep is that originally described by Morris et al. (1997). Here, animals were selected for backfat thickness and then back-crossed. The main difference in composition of these animals is in the amount of retroperitoneal and omental fat (Francis et al., 2000). Whilst there are no reports in the literature regarding the fertility of these animals, the shepherds for the
Lactation
Lactation can be regarded as a state of negative energy balance and the function of ARP at this time has been well studied in the rat (Smith and Grove, 2002). The profound drain of energy that is brought about by lactation in rats is thought to cause the cessation of reproduction (Brogan et al., 1999, Tsukamura and Maeda, 2001). The effect in rats may be due to suckling, since pup-removal can restore LH levels (Smith and Grove, 2002, Tsukamura and Maeda, 2001). Energy expenditure during
Conclusions
It is clear that reproduction is dependent upon metabolic state and this can be seen at all levels of the HPG axis. Circulating metabolic factors and indicators of body stores (such as leptin) act on the brain to alter the levels of peptides that regulate appetite/energy expenditure as well as GnRH secretion and this has been the major focus of this review. The particular bias has been to examine these issues in ruminants, particularly the sheep and the cow. These species provide useful
References (276)
- et al.
A test of the lipostat theory in a seasonal (ovine) model under natural conditions reveals a close relationship between adiposity and melanin concentrating hormone expression
Domest. Anim. Endocrinol.
(2009) - et al.
Double-Ovsynch in high-producing dairy cows: effects on progesterone concentrations and ovulation to GnRH treatments
Theriogenology
(2013) - et al.
Photoperiodic control of seasonal body weight cycles in hamsters
Neurosci. Biobehav. Rev.
(1985) - et al.
Reduced and compensatory growth: endocrine and metabolic changes during food restriction and refeeding in steers
J. Nutr.
(1985) - et al.
Negative energy balance increases periprandial ghrelin and growth hormone concentrations in lactating dairy cows
Domest. Anim. Endocrinol.
(2008) The arcuate nucleus as a circumventricular organ in the mouse
Neurosci. Lett.
(2011)- et al.
Synthesis and secretion of GnRH
Anim. Reprod. Sci.
(2005) - et al.
Transcription rate of the follicle stimulating hormone (FSH) beta subunit gene is reduced by inhibin in sheep but this does not fully explain the decrease in mRNA
Mol. Cell. Endocrinol.
(1993) - et al.
Are hypothalamic neurons transsynaptically connected to porcine adipose tissue?
Biochem. Biophys. Res. Commun.
(2003) - et al.
A molecular switch for photoperiod responsiveness in mammals
Curr. Biol.
(2010)