Abstract
We examined the role of hepatocyte micro-RNA-122 and hypothalamic neuropeptides, in weanling (21d) female rats exposed to calorie restriction induced growth restriction either prenatally (IUGR), postnatally (PNGR) or both (IPGR) vs. ad lib fed controls (CON). IUGR were hyperinsulinemic, hyperleptinemic and dyslipidemic with high circulating miR-122. In contrast, PNGR and IPGR displayed insufficient glucose, insulin and leptin amidst high ketones with a dichotomy in circulating miR-122 of PNGR<IPGR = CON. Examination of livers revealed a reduction in miR-122 expression in PNGR and IPGR reflecting the hepatic size. This reduction of hepatic miR-122 was associated with an increase in specific target transcripts (ALDO-A, BCKDK, PPAR-β) and those mediating fatty acid oxidation (PGC-1α, CPT-1α), with a concomitant suppression of fatty acid and cholesterol synthesizing transcripts (FAS, HMGCR). Functionally, these changes correlated with increased fatty acid oxidation and mitochondrial CPT1α enzyme activity ex vivo. In vitro physiologic (serum starvation) and genetic manipulation of miR-122 in H4IIE hepatoma cells revealed fidelity in regulating ALDO-A/BCKDK, but an infidelity in perturbing fatty acid/cholesterol synthesizing and oxidizing gene transcripts. Nevertheless, changes in endogenous miR-122 maintained singular directionality while altering FAS/HMGCR and CPT-1α/PGC-1α, almost reflecting each other, and thereby maintaining a balance in fatty acid/cholesterol supply necessary to meet the in vitro demands of these rapidly proliferating transformed cells. Successive microarray based analysis, comparing IPGR to CON demonstrated differential expression of hypothalamic genes mediating cell proliferation and survival, appetite/energy balance, circadian rhythm and obesity/diabetes. We conclude that miR-122 regulates genes mediating fatty acid/cholesterol metabolism in postnatal female rats, fueling the energy demand.