We hereby show the importance of choice in the observation of fcHFHS diet-induced hyperphagia, which results in increases in meal number due to sugar drinking without any compensatory decrease in meal size. We thus provide a novel dietary model in rats that mimics important features of human overconsumption that have been ignored in rodent models of obesity.
The role of the melanocortin (MC) system in feeding behavior is well established. Food intake is potently suppressed by central infusion of the MC 3/4 receptor agonist α-melanocyte stimulating hormone (α-MSH), whereas the MC 3/4 receptor inverse-agonist Agouti Related Peptide (AGRP) has the opposite effect. MC receptors are widely expressed in both hypothalamic and extra-hypothalamic brain regions, including nuclei involved in food reward and motivation, such as the nucleus accumbens (NAc) and the ventral tegmental area. This suggests that MCs modulate motivational aspects of food intake. To test this hypothesis, rats were injected intracerebroventricularly with α-MSH or AGRP and their motivation for sucrose was tested under a progressive ratio schedule of reinforcement. Food motivated behavior was dose-dependently decreased by α-MSH. Conversely, AGRP increased responding for sucrose, an effect that was blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast to progressive ratio responding, free intake of sucrose remained unaltered upon α-MSH or AGRP infusion. In addition, we investigated whether the effects of α-MSH and AGRP on food motivation were mediated by the NAc shell. In situ hybridization of MC3 and MC4 receptor expression confirmed that the MC4 receptor was expressed throughout the NAc, and injection of α-MSH and AGRP into the NAc shell caused a decrease and an increase in motivation for sucrose, respectively. These data show that the motivation for palatable food is modulated by MC4 receptors in the NAc shell, and demonstrate cross-talk between the MC and dopamine system in the modulation of food motivation.
Objective: Reduction of melanocortin signaling in the brain results in obesity. However, where in the brain reduced melanocortin signaling mediates this effect is poorly understood. Design: We determined the effects of long-term inhibition of melanocortin receptor activity in specific brain regions of the rat brain. Melanocortin signaling was inhibited by injection of a recombinant adeno-associated viral (rAAV) vector that overexpressed Agouti-related peptide (AgRP) into the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), the lateral hypothalamus (LH) or the accumbens shell (Acc). Results: Overexpression of AgRP in the rat PVN, VMH or LH increased bodyweight, the percentage of white adipose tissue, plasma leptin and insulin concentrations and food intake. Food intake was mainly increased because of an increase in meal size in the light and dark phases, after overexpression of AgRP in the PVN, LH or VMH. Overexpression of AgRP in the PVN or VMH reduced average body core temperature in the dark on day 40 post injection, whereas AgRP overexpression in the LH did not affect temperature. In addition, overexpression of AgRP in the PVN, LH or VMH did not significantly alter mRNA expression of AgRP, neuropeptide Y (NPY), pro-opiomelanocortin (POMC) or suppressor of cytokine signaling 3 (SOCS3) in the arcuate. Overexpression of AgRP in the Acc did not have any effect on the measured parameters. Conclusions: Reduction of melanocortin signaling in several hypothalamic regions increased meal size. However, there were brain area-specific effects on other parameters such as core temperature and plasma leptin concentrations. In a previous study, where NPY was overexpressed with an rAAV vector in the PVN and LH, meal frequency and meal size were increased respectively, whereas locomotor activity was reduced by NPY overexpression at both nuclei. Taken together, AgRP and NPY have complementary roles in energy balance.
The second-generation antipsychotic drug olanzapine has become a widely prescribed drug in the treatment of schizophrenia and bipolar disorder. Unfortunately, its therapeutic benefits are partly outweighed by significant weight gain and other metabolic side effects, which increase the risk for diabetes and cardiovascular disease. Because olanzapine remains superior to other antipsychotic drugs that show less weight gain liability, insight into the mechanisms responsible for olanzapine-induced weight gain is crucial if it is to be effectively addressed. Over the past few decades, several groups have investigated the effects of olanzapine on energy balance using rat models. Unfortunately, results from different studies have not always been consistent and it remains to be determined which paradigms should be used in order to model olanzapine-induced weight gain most accurately. This review summarizes the effects of olanzapine on energy balance observed in different rat models and discusses some of the factors that appear to contribute to the inconsistencies in observed effects. In addition it compares the effects reported in rats with clinical findings to determine the predictive validity of different paradigms.
Because the use of monoamine reuptake inhibitors as weight‐reducing agents is limited by adverse effects, novel antiobesity drugs are needed. We studied acute effects of the noradrenaline (NA) and serotonin (5‐HT) reuptake inhibitor sibutramine (SIB), alone and after pretreatment with α1‐ and α2‐adrenoceptor (AR), and 5‐HT1/2/7, 5‐HT1B and 5‐HT2C receptor antagonists in order to determine which ARs and 5‐HT receptors act downstream of SIB on feeding and locomotion. Acute effects on caloric and water intake, meal microstructure and locomotion were assessed, using an automated weighing system and telemetry in male rats with restricted 18‐h access to Western style diet. SIB 3 mg/kg reduced meal size and frequency, which suggests enhanced within‐ and postmeal satiety. Imiloxan (α2B‐AR), WB4101 (α1‐AR), SB‐224289 (5‐HT1B), and modestly BRL 44408 (α2A/D‐AR) attenuated SIB's effect on meal size, suggesting that α2B‐ and α1‐ARs and 5‐HT1B receptors mediate within‐meal satiety, with a modest role for α2A/D‐ARs. Only prazosin (α1/2B/2C‐AR) counteracted SIB's effect on meal frequency. At 3 mg/kg, SIB modestly increased locomotion. This effect was blocked by metergoline (5‐HT1/2/7), WB4101 (α1‐AR), and RX821002 (α2‐AR). Interestingly, the α2‐AR antagonists atipamezole and RX821002 enhanced SIB's effect on caloric intake, probably due to inverse agonistic actions at α2A‐autoreceptors that further enhanced release of NA that regulates caloric intake. Thus, an inverse agonist of presynaptic α2A‐ARs might beneficially enhance SIB's weight‐reducing effect and offer novel treatment for obesity. All in all, the present data supports the ARs and 5‐HT receptors involved in the effects of SIB on different aspects of caloric intake and locomotion.
This is the first study to investigate the effect of local hypothalamic knockdown of GHS-R1a on FAA. Our results implicate hypothalamic GHS-R1a signaling in the regulation of FAA. Nevertheless, some FAA remained, suggesting that a distributed network of brain areas and signaling pathways is involved in the development of FAA.
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