Hypothalamic gene expression during voluntary hypophagia in the Sprague-Dawley rat on withdrawal of the palatable liquid diet, Ensure

Abstract

Sprague-Dawley rats over-consume calories over a 10 week period and develop diet-induced obesity (c. 100 g body weight differential vs controls) when fed a control pellet diet supplemented with chocolate Ensure liquid. Subsequent withdrawal of Ensure immediately reduces caloric intake by more than 50%, and results in weight loss, despite control pellet being available ad libitum. To assess the molecular underpinnings of this phenomenon, brains were processed for energy balance and food reward-related gene expression analysis at two time points, 24 h and 4 days after the withdrawal of Ensure, when energy intake was suppressed. Gene expression levels in hypothalamic arcuate nucleus and forebrain nucleus accumbens were compared with rats pair-fed to the same energy intake, i.e. imposed negative energy balance, and to controls fed control pellet ad libitum throughout. Cumulative energy intake was approximately 50% lower across the 4 day post-Ensure period, giving rise to a small reduction in body weight although body adiposity and blood leptin remained elevated (c. 100% and 50%, respectively vs controls) in rats that had previously been fed Ensure. In contrast, pair-feeding reduced blood insulin and leptin by 33% and 55%, respectively. Hypothalamic expression of neuropeptide Y and agouti-related peptide was down-regulated at 24 h in rats previously fed Ensure, indicative of the apparent counter-regulatory changes seen in diet-induced obesity, but was normalised between the 24 h and 4 day time points. By contrast, the effect of cumulative negative energy balance in the pair-fed groups increased with time, up-regulating expression of the orexigenic neuropeptides. There was also a reduction of suppressor of cytokine signalling-3 gene expression in pair-fed groups where leptin levels were low. There were no changes in opioid, dopamine receptor or cannabinoid receptor expression in the nucleus accumbens. Feedback from diet-induced obesity appears to drive voluntary hypophagia upon withdrawal of palatable diet, and to override signals from intake restriction that would otherwise set in train an anabolic drive.

Keywords: Agouti related peptide; Diet-induced obesity; Neuropeptide Y; Reward; SOCS3.