SignificanceThe only known homeostatic regulator of fat mass is the leptin system. We hypothesized that there is a second homeostat regulating body weight with an impact on fat mass. In this study we have added and removed weight loads from experimental animals and measured the effects on the biological body weight. The results demonstrate that there is a body weight homeostat that regulates fat mass independently of leptin. As the body weight-reducing effect of increased loading was dependent on osteocytes, we propose that there is a sensor for body weight in the long bones of the lower extremities acting as “body scales.” This is part of a body weight homeostat, “gravitostat,” that keeps body weight and body fat mass constant.

Meal feeding is a critical issue in the over-consumption of calories leading to human obesity. To investigate the mechanisms involved in the regulation of meal feeding in rodents, we studied a scheduled feeding regime that induces substantial food intake over short periods of time. Male Sprague-Dawley rats and C57BL6 mice were fed one of four palatable diets [45% fat pellet, 60% fat pellet or standard pellet supplemented with Ensure (EN; Abbott Laboratories, Maidenhead, UK) or 12.5% sucrose (SUC)] either ad lib. or with daily 2-h scheduled access and standard pellet available for 22 h. Energy balance gene expression in the hypothalamic arcuate nucleus (ARC) and nucleus accumbens (NAcc) reward gene expression were assessed by in situ hybridisation. Rats fed ad lib. on 45% or 60% fat diet were heavier and fatter than controls, and had reduced neuropeptide Y (NPY) gene expression in the ARC. Mice fed ad lib. on any of the palatable diets were heavier, fatter and had higher blood leptin than controls, and had reduced NPY and increased cocaine- and-amphetamine-regulated transcript mRNA in the ARC. Schedule-fed rats and mice quickly adapted their feeding behaviour to 2-h access on palatable food. Three schedule-fed groups binged: the percentage of daily calories consumed in 2 h on 45% fat diet, 60% fat diet or EN, respectively, was 55%, 63% and 49% in rats, and 86%, 86% and 45% in mice. However, changed feeding behaviour was not reflected in an induction of orexigenic neuropeptide or suppression of anorexigenic neuropeptide gene expression in the ARC, in the 2-h period prior to scheduled feeding. The mechanisms underlying large meal/binge-type eating may be regulated by nonhomeostatic processes involving other genes in the hypothalamus or other brain areas. However, assessment of opioid and dopamine receptor gene expression in the NAcc did not reveal evidence of the involvement of these genes in driving large meals, at least at the investigated time point.

Providing rats and mice with access to palatable high fat diets for a short period each day induces the consumption of substantial binge-like meals. Temporal food intake structure (assessed using the TSE PhenoMaster/LabMaster system) and metabolic outcomes (oral glucose tolerance tests [oGTTs], and dark phase glucose and insulin profiles) were examined in Sprague–Dawley rats given access to 60% high fat diet on one of 3 different feeding regimes: ad libitum access (HF), daily 2 h-scheduled access from 6 to 8 h into the dark phase (2 h-HF), and twice daily 1 h-scheduled access from both 1–2 h and 10–11 h into the dark phase (2 × 1 h-HF). Control diet remained available during the scheduled access period. HF rats had the highest caloric intake, body weight gain, body fat mass and plasma insulin. Both schedule-fed groups rapidly adapted their feeding behaviour to scheduled access, showing large meal/bingeing behaviour with 44% or 53% of daily calories consumed from high fat diet during the 2 h or 2 × 1 h scheduled feed(s), respectively. Both schedule-fed groups had an intermediate caloric intake and body fat mass compared to HF and control (CON) groups. Temporal analysis of food intake indicated that schedule-fed rats consumed large binge-type high fat meals without a habitual decrease in preceding intake on control diet, suggesting that a relative hypocaloric state was not responsible or required for driving the binge episode, and substantiating previous indications that binge eating may not be driven by hypothalamic energy balance neuropeptides. In an oGTT, both schedule-fed groups had impaired glucose tolerance with higher glucose and insulin area under the curve, similar to the response in ad libitum HF fed rats, suggesting that palatable feeding schedules represent a potential metabolic threat. Scheduled feeding on high fat diet produces similar metabolic phenotypes to mandatory (no choice) high fat feeding and may be a more realistic platform for mechanistic study of diet-induced obesity.

HighlightsRapid adaptation of feeding behaviour to scheduled palatable diet accessNo evidence of reduced feeding (hypophagia) prior to scheduled palatable mealsMice exhibit food anticipatory activity (FAA) prior to scheduled palatable mealsContinuing presence of FAA when scheduled palatable mealsare withdrawnImmediate hyperphagic response once the palatable meals are restored after 7 days

We sought to determine whether the orexigenic hormone, ghrelin, is involved in the intrinsic regulation of food choice in rats. Ghrelin would seem suited to serve such a role given that it signals hunger information from the stomach to brain areas important for feeding control, including the hypothalamus and reward system (e.g. ventral tegmental area, VTA). Thus, in rats offered a choice of palatable foods (sucrose pellets and lard) superimposed on regular chow for 2 weeks, we explored whether acute central delivery of ghrelin (intracerebroventricular (ICV) or intra-VTA) is able to redirect their dietary choice. The major unexpected finding is that, in rats with high baseline lard intake, acute ICV ghrelin injection increased their chow intake over 3-fold, relative to vehicle-injected controls, measured at both 3 hr and 6 hr after injection. Similar effects were observed when ghrelin was delivered to the VTA, thereby identifying the VTA as a likely contributing neurobiological substrate for these effects. We also explored food choice after an overnight fast, when endogenous ghrelin levels are elevated, and found similar effects of dietary choice to those described for ghrelin. These effects of fasting on food choice were suppressed in models of suppressed ghrelin signaling (i.e. peripheral injection of a ghrelin receptor antagonist to rats and ghrelin receptor (GHSR) knock-out mice), implicating a role for endogenous ghrelin in the changes in food choice that occur after an overnight fast. Thus, in line with its role as a gut-brain hunger hormone, ghrelin appears to be able to acutely alter food choice, with notable effects to promote “healthy” chow intake, and identify the VTA as a likely contributing neurobiological substrate for these effects.