Low Liver-Derived IGF-1 Drives the Alterations in Growth Hormone Secretion in Food-Restricted Male Mice

Chronic food restriction (FR) changes growth hormone (GH) secretion from a pulsatile pattern, observed in ad libitum–fed mice, to a tonic secretion, in which basal (nonpulsatile) 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 FR mice. To test this possibility, GH secretion patterns were investigated in ad libitum–fed hepatocyte-specific GH receptor (GHR) knockout (KO) (Albumin^ΔGHR) male mice and compared to those of ad libitum–fed and FR control male mice. As expected, serum IGF-1 and liver Igf1 messenger RNA (mRNA) expression were similarly suppressed in Albumin^ΔGHR-fed and FR wild-type (WT) mice. Plasma ghrelin did not differ between ad libitum–fed control and Albumin^ΔGHR mice, but increased in FR control mice. Like the results observed in FR animals, Albumin^ΔGHR-fed mice exhibited increases in total and basal (nonpulsatile) GH secretion without alterations in GH pulse amplitude compared to control mice. Although Albumin^ΔGHR-fed and FR WT mice both 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–induced expression of IGF-1 increased circulating IGF-1 levels and prevented most changes in the pattern of GH secretion in FR WT mice. In conclusion, suppressed liver-derived IGF-1 is the primary mechanism behind the changes in the GH secretion pattern observed in FR male mice.