Fto colocalizes with a satiety mediator oxytocin in the brain and upregulates oxytocin gene expression.

Single nucleotide polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. Alterations in Fto expression in transgenic animals affect body weight, energy expenditure and food intake. Fto, a nuclear protein and proposed transcription co-factor, has been speculated to affect energy balance through a functional relationship with specific genes encoding feeding-related peptides. Herein, we employed double immunohistochemistry and showed that the majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto in the brain of male and female mice. We then overexpressed Fto in a murine hypothalamic cell line and, using qPCR, detected a 50% increase in the level of oxytocin mRNA. Expression levels of several other feeding-related genes, including neuropeptide Y (NPY) and Agouti-related protein (AgRP), were unaffected by the FTO transfection. Addition of 10 and 100 nmol oxytocin to the cell culture medium did not affect Fto expression in hypothalamic cells. We conclude that Fto, a proposed transcription co-factor, influences expression of the gene encoding a satiety mediator, oxytocin.

Feeding behavior, obesity, and neuroeconomics.

For the past 50 years, the most prevalent theoretical models for regulation of food intake have been based in the physiological concept of energy homeostasis. However, several authors have noted that the simplest form of homeostasis, stability, does not accurately reflect the actual state of affairs and most notably the recent upward trend in body mass index observed in the majority of affluent nations. The present review argues that processes of natural selection have more likely made us first and foremost behavioral opportunists that are adapted to uncertain environments, and that physiological homeostasis is subservient to that reality. Examples are presented from a variety of laboratory studies indicating that food intake is a function of the effort and/or time required to procure that food, and that economic decision-making is central to understanding how much and when organisms eat. The discipline of behavioral economics has developed concepts that are useful for this enterprise, and some of these are presented. Lastly, we present demonstrations in which genetic or physiologic investigations using environmental complexity will lead to more realistic ideas about how to understand and treat idiopathic human obesity. The fact is that humans are eating more and gaining weight in favorable food environments in exactly the way predicted from some of these models, and this has implications for the appropriate way to treat obesity.

Effects of central and peripheral injections of apelin on fluid intake and cardiovascular parameters in rats.

Previous studies have indicated that apelin, a novel peptide suggested to have some actions related to angiotensin peptides, has either a dipsogenic or an antidipsogenic effect and either increases or decreases blood pressure. The present study attempts to provide replication or understanding of these disparate effects. Neither central (lateral or third cerebral ventricle) nor peripheral (intravenous) administration of apelin induced water intake in sated rats, nor did it decrease water intake in deprived rats. It also had no effect on sodium appetite. Peripherally injected apelin had a hypotensive action in anesthetized rats, but had no consistent effect in awake, unrestrained rats. We conclude that apelin does not have reliable or robust effects on fluid intake or blood pressure in Sprague-Dawley rats under normal conditions, but discuss the possibility for a role of apelin in fluid homeostasis in selected physiological states.

Expression levels of genes encoding melanin concentrating hormone (MCH) and MCH receptor change in taste aversion, but MCH injections do not alleviate aversive responses.

Melanin concentrating hormone (MCH) stimulates feeding driven by energy needs and reward and modifies anxiety behavior. Orexigenic peptides of similar characteristics, including nociceptin/orphanin FQ, Agouti-related protein and opioids, increase consumption also by reducing avoidance of potentially tainted food in animals displaying a conditioned taste aversion (CTA). Herein, using real-time PCR, we assessed whether expression levels of genes encoding MCH and its receptor, MCHR1, were affected in CTA in the rat. We also investigated whether injecting MCH intracerebroventricularly (ICV) during the acquisition and retrieval of LiCl-induced CTA, would alleviate aversive responses. MCHR1 gene was upregulated in the hypothalamus and brain stem of aversive animals, MCH mRNA was significantly higher in the hypothalamus, whereas a strong trend suggesting upregulation of MCH and MCHR1 genes was detected in the amygdala. Despite these expression changes associated with aversion, MCH injected prior to the induction of CTA with LiCl as well as later, during the CTA retrieval upon subsequent presentations of the aversive tastant, did not reduce the magnitude of CTA. We conclude that MCH and its receptor form an orexigenic system whose expression is affected in CTA. This altered MCH expression may contribute to tastant-targeted hypophagia in CTA. However, changing the MCH tone in the brain by exogenous peptide was insufficient to prevent the onset or facilitate extinction of LiCl-induced CTA. This designates MCH as one of many accessory molecules associated with shaping an aversive response, but not a critical one for LiCl-dependent CTA to occur.

Operant responding for sucrose by rats bred for high or low saccharin consumption.

The use of rats differing in the intake of sweet substances has highlighted some interesting parallels between taste preferences and drug self-administration. For example, rats selectively bred to consume high (HiS) or low (LoS) amounts of a 0.1% saccharin solution (when compared to water consumption), show corresponding differences across several measures of cocaine self-administration (HiS>LoS). In this study, we measured whether the two strains also differ when response requirements are imposed for obtaining a sucrose reinforcer. Male HiS and LoS rats were measured for operant responding for sucrose pellets under fixed-ratio (FR) schedules of 1, 3, 5 and 10 and under a progressive-ratio (PR) schedule, during which the response requirement for each successive pellet increased exponentially. The effect of systemic naltrexone (0.3, 1 and 3mg/kg) on PR responding for sucrose pellets was also tested. Under all FR and PR schedules, the number of pellets obtained by the LoS rats were significantly lower than those obtained by the HiS rats. Although the LoS weighed more than the HiS rats, this difference does not appear to explain differences in operant behavior. No strain differences in the effect of naltrexone were observed; the 3mg/kg dose reduced the number of pellets obtained in both strains. Measures of locomotor activity taken prior to operant trials suggest that the differences in responding were not due to differences in general activity levels. These studies provide further characterization of the HiS and LoS rat lines by demonstrating that motivation to consume sucrose is greater in HiS than in LoS rats.

Chronic sugar intake dampens feeding-related activity of neurons synthesizing a satiety mediator, oxytocin.

Increased tone of orexigens mediating reward occurs upon repeated consumption of sweet foods. Interestingly, some of these reward orexigens, such as opioids, diminish activity of neurons synthesizing oxytocin, a nonapeptide that promotes satiety and feeding termination. It is not known, however, whether consumption-related activity of the central oxytocin system is modified under chronic sugar feeding reward itself. Therefore, we examined how chronic consumption of a rewarding high-sucrose (HS) vs. bland cornstarch (CS) diet affected the activity of oxytocin cells in the hypothalamus at the time of meal termination. Schedule-fed (2h/day) rats received either a HS or CS powdered diet for 20 days. On the 21st day, they were given the same or the opposite diet, and food was removed after the main consummatory activity was completed. Animals were perfused 60 min after feeding termination and brains were immunostained for oxytocin and the marker of neuronal activity, c-Fos. The percentage of c-Fos-positive oxytocin cells in the hypothalamic paraventricular nucleus was significantly lower in rats chronically exposed to the HS than to the CS diet, regardless of which diet they received on the final day. A similar pattern was observed in the supraoptic nucleus. We conclude that the chronic rather than acute sucrose intake reduces activity of the anorexigenic oxytocin system. These findings indicate that chronic consumption of sugar blunts activity of pathways that mediate satiety. We speculate that a reduction in central satiety signaling precipitated by regular intake of foods high in sugar may lead to generalized overeating.

Effect of high-fat diet during gestation, lactation, or postweaning on physiological and behavioral indexes in borderline hypertensive rats.

Maternal obesity is becoming more prevalent. We used borderline hypertensive rats (BHR) to investigate whether a high-fat diet at different stages of development has adverse programming consequences on metabolic parameters and blood pressure. Wistar dams were fed a high- or low-fat diet for 6 wk before mating with spontaneously hypertensive males and during the ensuing pregnancy. At birth, litters were fostered to a dam from the same diet group as during gestation or to the alternate diet condition. Female offspring were weaned on either control or "junk food" diets until about 6 mo of age. Rats fed the high-fat junk food diet were hyperphagic relative to their chow-fed controls. The junk food-fed rats were significantly heavier and had greater fat pad mass than those rats maintained on chow alone. Importantly, those rats suckled by high-fat dams had heavier fat pads than those suckled by control diet dams. Fasting serum leptin and insulin levels differed as a function of the gestational, lactational, and postweaning diet histories. Rats gestated in, or suckled by high-fat dams, or maintained on the junk food diet were hyperleptinemic compared with their respective controls. Indirect blood pressure did not differ as a function of postweaning diet, but rats gestated in the high-fat dams had lower mean arterial blood pressures than those gestated in the control diet dams. The postweaning dietary history affected food-motivated behavior; junk food-fed rats earned less food pellets on fixed (FR) and progressive (PR) ratio cost schedules than chow-fed controls. In conclusion, the effects of maternal high-fat diet during gestation or lactation were mostly small and transient. The postweaning effects of junk food diet were evident on the majority of the parameters measured, including body weight, fat pad mass, serum leptin and insulin levels, and operant performance.