A spontaneous binge-like eating model in mice using unpredictable once weekly access to palatable diets.

Many pre-clinical models of binge-like eating involve predictable, scheduled, access to a palatable diet high in fat (HF), where access may be preceded by anticipatory behaviour. Here, to introduce spontaneity into the binge-type consumption of palatable diets, mice were allowed 2 h access on a random day once per week and at a random time within an 8 h window either side of the transition from dark phase to light phase. Despite normal intake of a stock diet prior to unpredictable access to HF diet, mice immediately initiated a substantial eating episode when presented with HF diet. Following this consumption, compensatory hypophagia was observed relative to stock diet-fed controls, and cumulative energy intakes converged. There were no effects of HF diet on body weight or body composition over a 12-week period. Binge-like consumption was also observed on unpredictable access to the complete liquid diet, chocolate Ensure, but not with a 10% sucrose solution. Binge-like responses to unpredictable access to HF diet or Ensure were similar in male and female mice, although there were effects of sex on caloric consumption from stock diet in the compensatory period following palatable diet intake, with higher intakes in females. The timing of the 2h access period relative to light phase transition affected intake of palatable diets, but less robustly than the equivalent effect on stock diet intake during the same timed periods - the diurnal patterning of energy intake was diet sensitive. The large spontaneous binge-like consumption on unpredictable access to either solid or liquid palatable diets in mice of either sex offers the potential to combine these attributes with other manipulations where a developing obesity is part of the binge-like eating phenotype.

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

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.

Repletion of TNFα or leptin in calorically restricted mice suppresses post-restriction hyperphagia.

The causes of post-restriction hyperphagia (PRH) represent a target for drug-based therapies to prevent obesity. However, the factors causing PRH are poorly understood. We show that, in mice, the extent of PRH was independent of the time under restriction, but depended on its severity, suggesting that PRH was driven by signals from altered body composition. Signals related to fat mass were important drivers. Circulating levels of leptin and TNFα were significantly depleted following caloric restriction (CR). We experimentally repleted their levels to match those of controls, and found that in both treatment groups the level of PRH was significantly blunted. These data establish a role for TNFα and leptin in the non-pathological regulation of energy homeostasis. Signals from adipose tissue, including but not limited to leptin and TNFα, regulate PRH and might be targets for therapies that support people engaged in CR to reduce obesity.