Polymorphism in the FTO gene is strongly associated with obesity, but little is known about the molecular bases of this relationship. We investigated whether hypothalamic FTO is involved in energy-dependent overconsumption of food. We determined FTO mRNA levels in rodent models of short- and long-term intake of palatable fat or sugar, deprivation, diet-induced increase in body weight, baseline preference for fat versus sugar as well as in same-weight animals differing in the inherent propensity to eat calories especially upon availability of diverse diets, using quantitative PCR. FTO gene expression was also studied in organotypic hypothalamic cultures treated with anorexigenic amino acid, leucine. In situ hybridization (ISH) was utilized to study FTO signal in reward- and hunger-related sites, colocalization with anorexigenic oxytocin, and c-Fos immunoreactivity in FTO cells at initiation and termination of a meal.

Previous work from our laboratory indicates that when rats are given a choice between a high-fat and a high-sucrose diet, opioid blockade with naltrexone (NTX) in a reward-related site (central amygdala) inhibits intake of the preferred diet only, whereas NTX injected into a homeostasis-related site, such as the hypothalamic paraventricular nucleus (PVN), inhibits intake of both diets. However, other work suggests that opioids increase intake of fat specifically. The present study further investigates the role of PVN opioids in food choices made by calorically-replete animals. We used a binge model with chow-maintained rats given 3-h access to a choice of a high-fat or high-sucrose diet 3 days a week. We hypothesized that intra-PVN injection of the μ-opioid agonist, DAMGO (0, 0.025, 0.25, and 2.5 nmol) would enhance, and NTX (0, 10, 30, and 100 nmol) would inhibit intake of both diets to an equal extent. We found that when animals were divided into groups according to sucrose or fat preference, DAMGO increased fat intake in fat-consuming animals, while having no effect on intake of either diet in sucrose-consuming animals. NTX, however, inhibited fat intake in both groups. Intra-PVN NTX did not inhibit intake of sucrose when presented in the absence of a fat choice, but did so when injected peripherally. Furthermore, intra-PVN and systemic NTX inhibited intake of chow by 24-h-food-deprived animals. These results indicate a complex role for PVN opioids in food intake with preference, nutrient type, and energy state affecting the ability of these compounds to change behavior.

This study experimentally examined the effects of repeated exposure to different meal portion sizes on energy intake.

Oxytocin (OT) facilitates feeding termination stemming from high osmolality, stomach distention, and malaise. Recent knockout (KO) studies suggested a crucial function for OT in carbohydrate intake: OT^−/− mice had increased preference for carbohydrates, including sucrose, but not fat (Intralipid). In striking contrast, sugar appetite was unaffected in the OT receptor KO mouse; data from wild-type animals have been insufficient. Therefore, we examined the involvement of OT in the regulation of sucrose vs. fat intake in C57BL/6 mice that served as a background KO strain. We exposed mice to a meal of sucrose or Intralipid and determined that the percentage of c-Fos-immunoreactive paraventricular hypothalamic OT neurons was elevated at termination of intake of either of the tastants, but this increase was 2-fold higher in sucrose-fed mice. A 48-h exposure to sucrose compared with Intralipid caused up-regulation of OT mRNA, whereas inherent individual preferences for sucrose vs. fat were not associated with differences in baseline OT expression as established with quantitative PCR. We found that L-368,899, an OT receptor antagonist, increased sugar intake when sucrose was presented alone or concurrently with Intralipid; it had no effect on Intralipid or total calorie consumption. L-368,899 affected Fos immunoreactivity in the paraventricular hypothalamus, arcuate nucleus, amygdala, and nucleus of the solitary tract, areas involved in aversion, satiety, and reward. This pattern serves as neuroanatomical basis of OT’s complex role in food intake, including sucrose intake. The current findings expand our knowledge on OT and suggest that it acts as a carbohydrate-specific inhibitor of feeding.