Glucose-dependent insulinotropic
polypeptide (GIP) promotes
glucose-dependent insulin secretion. However, GIP also enhances
glucocorticoid secretion and promotes adiposity. Because
obesity and diabetes are
glucocorticoid dependent, we examined whether the effects of GIP on energy balance and glycemia are regulated by
glucocorticoids using pharmacological activation of
GIP receptor (GIPR) signaling with [d-Ala(2)]GIP in mice and in Y1 adrenocortical cells. Genetic elimination of GIPR activity was also studied in normal- and high-fat (HF)-fed Gipr-deficient (Gipr(-/-)) mice. [d-Ala(2)]GIP increased murine
corticosterone levels in a GIPR-dependent manner. Conversely, basal
corticosterone levels were reduced, whereas food deprivation resulted in significantly enhanced plasma
corticosterone levels in Gipr(-/-) mice. [d-Ala(2)]GIP increased cAMP levels, activated extracellular signal\x{2013}related
kinase (ERK)1/2, increased expression of steroidogenic genes, and increased neutral
lipid storage in Y1GIPR cells. Gipr(-/-) adrenal glands demonstrated a twofold upregulation of the
ACTH receptor mRNA and increased sensitivity to
ACTH ex vivo. Although HF-fed Gipr(-/-) mice exhibited significantly lower plasma
corticosterone,
glucocorticoid-treated HF-fed Gipr(-/-) mice had similar energy balance and glycemia compared with Gipr(+)(/+) controls. Hence, although the Gipr is essential for adrenal steroidogenesis and links HF feeding to increased levels of
corticosterone, reduced
glucocorticoid levels do not significantly contribute to the enhanced metabolic phenotypes in HF-fed Gipr(-/-) mice.