Endocrine Abstracts

GH levels decline with age and weight gain and are enhanced in response to nutrient deprivation. Under these circumstances, GH levels are negatively correlated with IGF1 and insulin levels. Since IGF1 and insulin can directly inhibit GH synthesis and release from primary pituitary cells of different species, it is commonly accepted that changes in circulating IGF1 and insulin serve to directly regulate somatotrope function in response to metabolic extremes. However, teasing apart the relative contribution of IGF1 and insulin has been hampered by the fact that: i) the receptors for both hormones (IGFIR and INSR) are structurally/functionally related (i.e. high insulin levels can activate IGFIR), ii) INSR and IGFIR are expressed in the pituitary at comparably high levels; and iii) INSR and IGFIR can interact by forming hybrid receptors or via crosstalk of downstream intracellular signaling pathways, thereby modifying the response to their respective ligands. In order to evaluate the separate roles of insulin and IGF1 in regulating somatotrope function, we have used the Cre/loxP system to inactivate INSR or/and IGFIR in the somatotropes, in vitro and in vivo. Several novel concepts have emerged from this series of studies. First, although insulin and IGF1 ultimately inhibit GH synthesis/secretion, the in vitro and in vivo mechanisms of action are distinct. Second, somatotrope-specific loss of INSR or/and IGFIR increases GH levels, which cannot be completely compensated for by an intact hypothalamic feedback system, thereby establishing the somatotrope as a primary sensor for changes in circulating insulin/IGF1 levels. Third, under lean conditions, somatotrope-specific loss of INSR has a more profound effect on circulating GH/IGF1 than loss of IGFIR, suggesting insulin plays a primary role in regulating short-term changes in GH secretion. Finally, in the context of diet-induced obesity, the direct effects of insulin (or IGF1) on somatotrope function cannot fully account for the fall in GH levels and therefore, must be driven by insulin-induced changes in hypothalamic function or other systemic factors that act centrally or directly on the somatotrope to reduce GH output.