Integrating peripheral and central mechanisms that regulate growth hormone (GH) secretion during periods of altered food consumption

F.J. Steyn, J.W. Leong and C. Chen, School of Biomedical Sciences (SBMS), The University of Queensland, St. Lucia, QLD 4067, Australia.

Growth hormone (GH) has gained most of its recognition for its role in stimulating linear growth. However it is also a key anabolic hormone in the regulation of energy balance; in this role GH stimulates muscle growth and bone density, and also regulates body fat mass and lipid metabolism. Somewhat reciprocally, body composition and meal pattern are both major determinants of GH secretion in that the central and peripheral peptides normally involved in the regulation of food intake mediate GH secretion. As a result, nutritional status impacts the regulation of the GH axis culminating in reduced or increased levels of GH secretion during periods of excessive or restricted energy consumption, respectively.

To fully understand the impact of energy flux on GH secretion, one must consider interactions between multiple endocrine systems and their integration with the central mechanisms that drive GH secretion. At its core, central regulation of GH secretion from the anterior pituitary gland is modulated by stimulating GH releasing hormone (GHRH) and inhibitory somatostatin (SRIF) neurons. These neurons are dispersed between populations of orexigenic (primarily NPY and AgRP expressing neurons) and anorexigenic neurons (including neurons expressing POMC and CART). Despite the fact that direct interactions between hypothalamic appetite regulatory neurons and those regulating GH secretion are still under investigation, clear relationships between peripheral factors coupled to food intake and GH secretion have been established. For example, ghrelin - a potent orexigenic hormone secreted by the stomach - stimulates both NPY/AgRP neurons and GH secretion.

The endogenous cannabinoid system has gained favour as a central regulator of appetite. Treatment with cannabinoid receptor subtype-1 (CB1) agonist result in a biphasic response in food intake; low dosages stimulate food consumption whereas high dosages have an inhibitory effect. Of particular importance regarding GH secretion and food intake is the potential role of the endogenous cannabinoid system in integrating peripheral with central mechanisms that are involved in mediating GH secretion. Early observations suggest that activation of the CB1 receptor by exogenous cannabinoids result in suppression of GH secretion. These studies do not take into account the biphasic effects of CB1 receptor activation, and consequently do not address potential stimulatory or inhibitory effects of cannabinoids on GH secretion. Furthermore, as fasting stimulates the endogenous cannabinoid system, early attempts do not address the potential interaction of cannabinoids on GH secretion during periods of reduced food intake.

Our recent observations confirm that central activation of the CB1 receptor suppresses the initial fasting-induced increase in GH secretion. Gene analysis studies confirm that these effects are mediated via an interaction with GHRH neurons. It should be noted, however, that the impact of fasting and the mechanisms that drive GH secretion during early periods of food restriction differ from those regulating pulsatile GH secretion during times of adequate food consumption. In this scenario we observe a differential impact following CB1 activation, where low levels of cannabinoid treatment (0.5mg/kg IP) resulting in increased food intake is coupled with an increase in GHRH mRNA within the arcuate nucleus. In contrast, elevated dosages (1.0mg/kg IP) of cannabinoid treatment do not affect food intake nor do they induce any alterations in GHRH mRNA expression. This finding was surprising considering that the same dosage (1.0mg/kg IP) was sufficient to inhibit the initial fasting-induced increase observed in GHRH mRNA. We are currently extending these observations to determine whether the differential impact on GHRH neurons relates to changes in peripheral GH secretion. Overall, our observations suggest that the endogenous cannnabinoid system may prove to be yet another mechanism involved in the already complicated array of integrated systems that regulate GH secretion during periods of altered food consumption.