Low liver-derived IGF-1 drives the alterations in growth hormone secretion in food-restricted male mice

Chronic food restriction changes growth hormone (GH) secretion from a pulsatile pattern, observed in ad libitum-fed mice, to a tonic secretion, in which basal (non-pulsatile) GH secretion prevails. However, the physiological mechanisms driving this alteration are not fully understood. We hypothesize that suppressed liver-derived insulin-like growth factor 1 (IGF-1) production may be a key underlying mechanism responsible for changing the GH secretion pattern in food-restricted mice. To test this possibility, GH secretion patterns were investigated in ad libitum-fed hepatocyte-specific GH receptor (GHR) knockout (KO) (AlbuminΔGHR) male mice and compared to those of ad libitum-fed and food-restricted control male mice. As expected, serum IGF-1 and liver Igf1 mRNA expression were similarly suppressed in AlbuminΔGHR-fed and food-restricted wild-type mice. Plasma ghrelin did not differ between ad libitum-fed control and AlbuminΔGHR mice, but increased in food-restricted control mice. Like the results observed in food-restricted animals, AlbuminΔGHR-fed mice exhibited increases in total and basal (non-pulsatile) GH secretion without alterations in GH pulse amplitude compared to control mice. Although both AlbuminΔGHR-fed and food-restricted wild-type mice exhibited suppressed Ghr mRNA levels in the liver, there were significant differences in the hepatic expression of sexually dimorphic genes and those regulating GH sensitivity. Hepatocyte-specific adeno-associated virus (AAV)-induced expression of IGF-1 increased circulating IGF-1 levels and prevented most changes in the pattern of GH secretion in food-restricted wild-type mice. In conclusion, suppressed liver-derived IGF-1 is the primary mechanism behind the changes in the GH secretion pattern observed in food-restricted male mice.