Mechanism of Programmed Obesity in Intrauterine Fetal Growth Restricted Offspring: Paradoxically Enhanced Appetite Stimulation in Fed and Fasting States

Abstract

We have shown that intrauterine fetal growth restriction (IUGR) newborn rats exhibit hyperphagia, reduced satiety, and adult obesity. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a principal metabolic regulator that specifically regulates appetite in the hypothalamic arcuate nucleus (ARC). In response to fasting, upregulated AMPK activity increases the expression of orexigenic (neuropeptide Y [NPY] and agouti-related protein [AgRP]) and decreases anorexigenic (proopiomelanocortin [POMC]) peptides. We hypothesized that IUGR offspring would exhibit upregulated hypothalamic AMPK, contributing to hyperphagia and obesity. We determined AMPK activity and appetite-modulating peptides (NPY and POMC) during fasting and fed conditions in the ARC of adult IUGR and control females. Pregnant rats were fed ad libitum diet (control) or were 50% food restricted from gestation day 10 to 21 to produce IUGR newborns. At 10 months of age, hypothalamic ARC was dissected from fasted (48 hours) and fed control and IUGR females. Arcuate nucleus messenger RNA ([mRNA] NPY, AgRP, and POMC) and protein expression (total and phosphorylated AMPK, Akt) was determined by quantitative reverse transcriptase–polymerase chain reaction and Western Blot, respectively. In the fed state, IUGR adult females demonstrated evidence of persistent appetite stimulation with significantly upregulated phospho (Thr¹⁷²)-AMPKα/AMPK (1.3-fold), NPY/AgRP (2.3/1.8-fold) and decreased pAkt/Akt (0.6-fold) and POMC (0.7-fold) as compared to fed controls. In controls though not IUGR adult females, fasting significantly increased pAMPK/AMPK, NPY, and AgRP and decreased pAkt/Akt and POMC. Despite obesity, fed IUGR adult females exhibit upregulated AMPK activity and appetite stimulatory factors, similar to that exhibited by fasting controls. These results suggest that an enhanced appetite drive in both fed and fasting states contributes to hyperphagia and obesity in IUGR offspring.