Functional modulation of ovine and human somatotropes by in vitro application of leptin

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Obesity is a common disorder in developed countries and a prevalent condition which is often stigmatized. Actuarial data indicate that life expectancy is reduced when body-mass index (body mass in kg-square of the height in metres) is 20% or more above the ideal (obesity is >28% above ideal). Growth hormone (GH) from pituitary gland is the major anabolic hormone to increase muscle and reduce fat. A significant reduction in GH is found in obesity. Indeed, visceral fat mass is primary negative statistical determinant of GH secretion in middle age men and women. It is clear that the reduction in GH is due to a low sensitivity of GH cells to GH-releasing hormone (GHRH) from brain. It is therefore necessary to understand the change of pituitary GH cells in obesity. A recently identified, fat cell secreted, polypeptide (leptin) is demonstrated to reduce food intake and increase energy expenditure. Receptors for leptin have been found in pituitary gland, mainly in GH secreting cells. In our preliminary experiments, leptin reduces GH secretion by decreasing GHRH receptor synthesis. Meanwhile, this leptin treatment increased the receptors for GH-releasing peptide (GHRP), a synthetic peptide stimulating GH secretion. We aim to investigate the effect of leptin on cultured ovine and human GH cells by studying important cell functions including hormone and receptors synthesis, intracellular signaling molecules, membrane ion channels and cellular secreting machinery. The results will clarify the mechanism underlying GH deficiency in obese patients. We will also test the effect of synthetic GHRP in combination with leptin in vitro. The relationship between GHRP and leptin on the functional modification of GH cells will also be studied. It is likely to see that GHRP reduces the inhibitory effect of leptin on GH cells. This may end up an effective therapeutical use of GHRP (oral available) in the treatment of obesity.