Mutations in the human melanocortin (MC)4 receptor have been associated with obesity, which underscores the relevance of this receptor as a drug target to treat obesity. Infusion of MC4R agonists decreases food intake, whereas inhibition of MC receptor activity by infusion of an MC receptor antagonist or with the inverse agonist AgRP results in increased food intake. This review addresses the role of the MC system in different aspects of feeding behaviour. MC4R activity affects meal size and meal choice, but not meal frequency, and the type of diet affects the efficacy of MC4R agonists to reduce food intake. The central sites involved in the different aspects of feeding behaviour that are affected by MC4R signalling are being unravelled. The paraventricular nucleus plays an important role in food intake per se, whereas MC signalling in the lateral hypothalamus is associated with the response to a high fat diet. MC4R signalling in the brainstem has been shown to affect meal size. Further genetic, behavioural and brain-region specific studies need to clarify how the MC4R agonists affect feeding behaviour in order to determine which obese individuals would benefit most from treatment with these drugs. Application of MCR agonists in humans has already revealed side effects, such as penile erections, which may complicate introduction of these drugs in the treatment of obesity.

Objectives: One of the main causes of obesity is overconsumption of diets high in fat and sugar. We studied the metabolic changes and food-motivated behavior when rats were subjected to a choice diet with chow, lard and a 30% sucrose solution (high fat high sugar (HFHS)-choice diet). Because rats showed considerable variations in the feeding response to HFHS-choice diet and in food-motivated behavior, we investigated whether the motivation to obtain a sucrose reward correlated with the development of obesity when rats were subsequently subjected to HFHS-choice diet. Method: We first studied feeding, locomotor activity and body temperature, fat weights and hormonal concentrations when male Wistar rats were subjected to HFHS-choice diet for 1 week. Second, we studied sucrose-motivated behavior, using a progressive ratio (PR) schedule of reinforcement in rats that were subjected to the HFHS-choice diet for at least 2 weeks, compared to control rats on a chow diet. Third, we measured motivation for sucrose under a PR schedule of reinforcement in rats that were subsequently subjected to HFHS-choice diet or a chow diet for 4 weeks. Fat weights were measured and correlated with the motivation to obtain sucrose pellets. Results: One week on the HFHS-choice diet increased plasma concentrations of glucose and leptin, increased fat stores, but did not alter body temperature or locomotor activity. Moreover, consuming the HFHS-choice diet for several weeks increased the motivation to work for sucrose pellets. Furthermore, the motivation to obtain sucrose pellets correlated positively with abdominal fat stores in rats subsequently subjected to the HFHS-choice diet, whereas this correlation was not found in rats fed on a chow diet. Conclusion: Our data suggest that the motivation to respond for palatable food correlates with obesity due to an obesogenic environment. Conversely, the HFHS-choice diet, which results in obesity, also increased the motivation to work for sucrose. Thus, being motivated to work for sucrose results in obesity, which, in turn, increases food-motivated behavior, resulting in a vicious circle of food motivation and obesity. IntroductionObesity is one of the fastest growing medical problems in modern society. It contributes to the development of chronic disorders such as cardiovascular disease, type 2 diabetes, hypertension and some cancers. 1 For healthy body weight regulation, it is important to balance energy intake and energy expenditure. Modern society, however, is characterized by a sedentary lifestyle and a calorie intake, which is not adjusted for that. Although regulatory mechanisms that balance intake and expenditure are known , 2,3 it still remains unclear why this fails in obese individuals. It has been postulated that the ability to overconsume high-energy dense foods (in the face of plentiful food availability) was selected during evolution. Thus, under conditions when food availability is uncertain and scarce, consuming highenergy dense foods is an adequate adaptation (for a review see Uli...

It is well known that neuropeptide Y (NPY) increases food intake. The hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) are both involved in the acute, hyperphagic effects of NPY. Although it is obvious that increased energy intake may lead to obesity, it is less understood which aspects of feeding behavior are affected and whether one or multiple neural sites mediate the effects of long-term increased NPY signaling. By long-term overexpressing NPY in either the PVN or the LH, we uncovered brain site-specific effects of NPY on meal frequency, meal size, and diurnal feeding patterns. In rats injected with adeno-associated virus-NPY in the PVN, increased food intake resulted from an increase in the amount of meals consumed, whereas in rats injected in the LH, increased food intake was attributable to increased meal size. Interestingly, food intake and body weight gain were only temporarily increased in PVN-injected rats, whereas in LH-injected rats hyperphagia and body weight gain remained for the entire 50 d. Moreover, in LH-NPY rats, but not in PVN-NPY rats, diurnal rhythmicity with regard to food intake and body core temperature was lost. These data clearly show that the NPY system differentially regulates energy intake and energy expenditure in the PVN and LH, which together adjust energy balance.

short communications nature publishing group integrative Physiology Long-term central administration of neuropeptide Y (NPY) results in an obese phenotype, characterized by hyperphagia, increased lipogenesis in liver and adipose tissue, and elevated plasma concentrations of leptin, insulin, and corticosterone (1-4). Obesity is also induced when NPY is overexpressed in the adult hypothalamus of mice after hypothalamic injections of recombinant adeno-associated viral (rAAV) particles (5). Recently, we have shown (with the use of rAAV-NPY injected at the site of NPY receptors in the paraventricular nucleus (PVN)) that increased NPY signaling in the rat PVN is sufficient to result in obesity (6,7). We here determine whether the obesity, induced by long-term NPY overexpression in the PVN in the adult rat, is dependent on increased food intake. Methods Rats were injected with rAAV-NPY (n = 18) or control (AAV-contr; n = 6) in the PVN of male Wistar rats (220-250 g; Crl-Wu, Charles River, Sulzfeld, Germany) and body weight gain examined for 50 days as described previously (7). Some of the rats (n = 9) were pair-fed to controls (AAV-NPY-pf) for 3 weeks. These rats obtained the same amount of food that was ingested by the AAV-contr rats the day before. Transmitters were placed under anesthesia (7) in the abdominal cavity (TA10TA-F40; Data Sciences International, St Paul, MN) to monitor locomotor activity and body temperature. Differences in body weight, food intake, body temperature, and locomotor activity were assessed using repeated measure analysis (SPSS for Windows, version 15.0; SPSS, Chicago, IL). When significant overall interactions were found, post hoc analyses were performed with t-tests or one-way ANOVA. All experimental procedures were approved by the Committee for Animal Results Viral-induced NPY expression in the PVN at 50 days after injection was confirmed by in situ hybridization on coronal sections (16 μm) of the hypothalamus as described previously (6). AAV-infected areas were considered correctly targeted when bilateral staining was detected in the PVN, with the extension to the immediate surrounding area of the PVN. Animals with incorrectly targeted injection were excluded from analysis (in total, one rat from AAV-contr, two rats from AAV-NPY-al, and three rats from AAV-NPY-pf were excluded). Food intake was analyzed over periods of 5 days. Rats that were injected with AAV-NPY and fed ad libitum (AAV-NPY-al) increased food intake during the first 3 weeks, after which it slowly decreased again. At the end of the study, food intake was no longer significantly different from controls (Figure 1a,b). Body weight gain was significantly increased in AAV-NPY-al rats compared to controls in the first part of the study; however, between day 35 and 50 the body weight gain was no longer significantly different (Figure 1c,d). AAV-NPY rats that were pair-fed to the AAV-contr rats (AAV-NPY-pf) showed a decreased body weight gain when compared to controls (Figure 1c,d). This resulted in a cumulative body Increasing n...

Disruption of melanocortin (MC) signaling, such as by ectopic Agouti overexpression, leads to an obesity syndrome with hyperphagia, obesity, and accelerated body weight gain during high-fat diet. To investigate where in the brain disruption of MC signaling results in obesity, long-term Agouti expression was induced after local injections of recombinant adeno-associated viral particles in selected brain nuclei of adult rats. Agouti expression in the paraventricular nucleus, a hypothalamic region with a high density of MC receptors, induced acute onset hyperphagia and rapid weight gain that persisted for at least 6 weeks. In contrast, obesity and hyperphagia developed with a 3 week delay when Agouti was expressed in the dorsal medial hypothalamus. Agouti expression in the lateral hypothalamus (LH) did not affect food intake and body weight during regular diet, despite the presence of MC receptors in this region. However, during exposure to a high-fat diet, animals with Agouti expression in the LH exhibited a marked increase in body weight. Here we show that the LH is important for the protection against diet-induced obesity by controlling caloric intake during consumption of a high-fat diet. Together, this study provides evidence that different aspects of the Agouti-induced obesity syndrome, such as hyperphagia and diet responsiveness, are mediated by distinct brain regions and opens challenging opportunities for further understanding of pathophysiological processes in the development of the obesity syndrome.