Abstract
IGF-I is considered a primary inhibitor of GH secretion. Insulin may also play an important role in regulating GH levels because insulin, like IGF-I, can suppress GH synthesis and release in primary pituitary cell cultures and insulin is negatively correlated with GH levels in vivo. However, understanding the relative contribution insulin and IGF-I exert on controlling GH secretion has been hampered by the fact that circulating insulin and IGF-I are regulated in parallel and insulin (INSR) and IGF-I (IGFIR) receptors are structurally/functionally related and ubiquitously expressed. To evaluate the separate roles of insulin and IGF-I in directly regulating GH secretion, we used the Cre/loxP system to knock down the INSR and IGFIR in primary mouse pituitary cell cultures and found insulin-mediated suppression of GH is independent of the IGFIR. In addition, pharmacological blockade of intracellular signals in both mouse and baboon cultures revealed insulin requires different pathways from IGF-I to exert a maximal inhibitory effect on GH expression/release. In vivo, somatotrope-specific knockout of INSR (SIRKO) or IGFIR (SIGFRKO) increased GH levels. However, comparison of the pattern of GH release, GH expression, somatotrope morphometry, and pituitary explant sensitivity to acute GHRH challenge in lean SIRKO and SIGFRKO mice strongly suggests the primary role of insulin in vivo is to suppress GH release, whereas IGF-I serves to regulate GH synthesis. Finally, SIRKO and/or SIGFRKO could not prevent high-fat, diet-induced suppression of pituitary GH expression, indicating other factors/tissues are involved in the decline of GH observed with weight gain.
Highlights
Circulating GH levels are negatively associated with body mass index [1, 2]
Challenges arise when trying to determine the specific contributions of insulin in directly modulating GH production in response to changes in the metabolic environment because of the following: 1) insulin and bioavailable IGF-I are regulated in parallel in metabolic extremes [12], 2) IGF-I, as well as insulin, can suppress somatotrope function in vitro [10, 13], 3) the pituitary gland expresses both insulin receptor (INSR) and the IGF-I receptor (IGFIR) [10, 11], 4) INSR is structurally and functionally related to IGFIR, in which these receptors have been reported to form hybrids [14], 5) insulin and IGF-I, at high concentrations, can bind and activate each other’s receptor [15], and 6) insulin/INSR and IGF-I/IGFIR can modulate cell function via similar intracellular signaling processes [15]
Infection of Insrfl/fl pituitary cultures with CMV-Cre Ad reduced the expression of Insr but did not alter IgfIr (Figure 1A), whereas infection of IgfIrfl/fl pituitary cultures with CMV-Cre Ad reduced the expression of IgfIr but did not alter Insr (Figure 1A)
Summary
Circulating GH levels are negatively associated with body mass index [1, 2]. Given the antilipogenic, prolipolytic, and anabolic actions of GH, it has been proposed that the low levels of GH observed in obesity contribute to the progression of metabolic disease. Challenges arise when trying to determine the specific contributions of insulin in directly modulating GH production in response to changes in the metabolic environment because of the following: 1) insulin and bioavailable IGF-I are regulated in parallel in metabolic extremes [12], 2) IGF-I, as well as insulin, can suppress somatotrope function in vitro [10, 13], 3) the pituitary gland expresses both insulin receptor (INSR) and the IGF-I receptor (IGFIR) [10, 11], 4) INSR is structurally and functionally related to IGFIR, in which these receptors have been reported to form hybrids [14], 5) insulin and IGF-I, at high concentrations, can bind and activate each other’s receptor [15], and 6) insulin/INSR and IGF-I/IGFIR can modulate cell function via similar intracellular signaling processes [15]. Pharmacological blockade of intracellular signals was used to identify the key pathways required for insulin and IGF-I actions
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