Glucose-dependent insulinotropic polypeptide receptor regulates steroidogenic gene expression in the mouse testis and is modulated by metabolic and intracellular signaling factors.

Glucose‑dependent insulinotropic polypeptide (GIP), an incretin hormone associated with obesity and diabetes, has recently gained attention for its potential roles in reproductive physiology, although its functions in the male reproductive system remain poorly understood. This study investigated the expression and function of the GIP receptor (GIPR) in the mouse testis and examined how metabolic conditions and intracellular signaling pathways regulate Gipr expression. Immunoblotting, quantitative RT-PCR, and immunohistochemistry revealed that GIPR is expressed in Leydig cells, spermatogonia, and spermatocytes. Administration of a GIPR agonist increased the expression of steroidogenic genes, particularly Cyp11a1, in mouse testes. In MA‑10 Leydig cells, GIPR activation enhanced cAMP responsive transcription and transiently upregulated Star, Cyp11a1, Cyp17a1, and Hsd3b. Diet induced obesity resulted in increased testicular Gipr expression, whereas Gip expression remained unchanged. Pharmacological analyses demonstrated that cAMP signaling, retinoid signaling, classical and novel types of Protein Kinase C (PKC) activation, and PPARs activation modulate Gipr transcription in germ cells and Leydig cells. These findings indicate that GIP signaling directly affects Leydig cell function and suggest that metabolic conditions associated with obesity enhance GIPR responsiveness in the testis.