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Cyclic‐glycine‐proline accelerates mammary involution by promoting apoptosis and inhibiting IGF‐1 function

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Journal of Cellular Physiology

Published online on


In rodents, post‐lactational involution of mammary glands is characterized by the loss of mammary epithelial cells via apoptosis, which is associated with a decline in the expression of insulin‐like growth factor‐1 (IGF‐1). Overexpression of IGF‐1 delays involution by inhibiting apoptosis of epithelial cells and preserving the remaining secretory alveoli. Cyclic‐glycine‐proline (cGP), a metabolite of IGF‐1, normalizes IGF‐1 function under pathological conditions by regulating the bioavailability of IGF‐1. The present study investigated the effect of cGP on the physiological decline in IGF‐1 function during post‐lactational mammary involution. Rat dams were gavaged with either cGP (3 mg/kg) or saline once per day from post‐natal d8‐22. Before collecting tissue on post‐natal d23, a pair of mammary glands were sealed on d20 (72 hr‐engorgement, thus representative of late‐involution) and d22 (24 hr‐engorgement, thus representative of mid‐involution), while the remaining glands were allowed to involute naturally (early‐involution). During early‐involution, cGP accelerated the loss of mammary cells through apoptosis, resulting in an earlier clearance of intact secretory alveoli compared with the control group. This coincided with an earlier up‐regulation of the cell survival factors, Bcl‐xl and IGF‐1R, in the early‐involution cGP glands compared with the control glands. During late‐involution, cGP reduced the bioactivity of IGF‐1, which was evident through decreased phosphorylation of IGF‐1R in the regressed alveoli. Maternal administration of cGP did not alter milk production and composition during early‐, peak‐, or late‐stage of lactation. These data show that cGP accelerates post‐lactational involution by promoting apoptosis and the physiological decline in IGF‐1 function. Role of cGP in regulating IGF‐1 function during brain development and in neurological conditions is well known. This study shows that cGP accelerates the onset of post‐lactational involution in mammary glands by promoting the physiological decline in IGF‐1 function.