fat-preference-a-novel-model-of-eating-behavior-in-rats

Fat Preference: A Novel Model of Eating Behavior in Rats

Obesity is a growing problem in the United States of America, with more than a third of the population classified as obese. One factor contributing to ...

Conditional mutant techniques that allow spatial and temporal control over gene expression can be used to create mice with restricted genetic modifications. These mice serve as powerful disease models in which gene function in adult tissues can be specifically dissected. Current strategies for conditional genetic manipulation are inefficient, however, and often lack sufficient spatial control. Here we use viral-mediated RNA interference (RNAi) to generate a specific knockdown of Th, the gene encoding the dopamine synthesis enzyme tyrosine hydroxylase, within midbrain neurons of adult mice. This localized gene knockdown resulted in behavioral changes, including a motor performance deficit and reduced response to a psychostimulant. These results underscore the potential of using viral-mediated RNAi for the rapid production and testing of new genetic disease models. Similar strategies may be used in other model species, and may ultimately find applications in human gene therapy.

Local gene knockdown in the brain using viral-mediated RNA interference.

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide with a prominent role in feeding and energy homeostasis. The rodent MCH receptor (MCH1R) is highly expressed in the nucleus accumbens shell (AcSh), a region that is important in the regulation of appetitive behavior. Here we establish a role for MCH and MCH1R in mediating a hypothalamic-limbic circuit that regulates feeding and related behaviors. Direct delivery of an MCH1R receptor antagonist to the AcSh blocked feeding and produced an antidepressant-like effect in the forced swim test, whereas intra-AcSh injection of MCH had the opposite effect. Expression studies demonstrated that MCH1R is present in both the enkephalin- and dynorphin-positive medium spiny neurons of the AcSh. Biochemical analysis in AcSh explants showed that MCH signaling blocks dopamine-induced phosphorylation of the AMPA glutamate receptor subunit GluR1 at Ser845. Finally, food deprivation, but not other stressors, stimulated cAMP response element-binding protein-dependent pathways selectively in MCH neurons of the hypothalamus, suggesting that these neurons are responsive to a specific set of physiologically relevant conditions. This work identifies a novel hypothalamic-AcSh circuit that influences appetitive behavior and mediates the antidepressant activity of MCH1R antagonists.

The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance.

Previous research has shown that cAMP response element (CRE)-mediated transcription is activated in the nucleus accumbens, a major brain reward region, by a variety of environmental stimuli and contributes to neuroadaptations to these stimuli. CRE-binding protein (CREB) is the most studied activator of CRE transcription and has been implicated in this brain region as a gating mechanism for behavioral responses to emotional stimuli. Little attention, however, has been given to naturally occurring inhibitors of CRE-mediated transcription, such as the inducible cAMP early repressor (ICER), an inhibitory product of the CRE modulator gene. In the present study, we investigated the extent to which ICER is induced in the nucleus accumbens by two types of environmental stimuli, stress and amphetamine, and characterized how induction of ICER in this region affects complex behavior. We show that stress and amphetamine each induces ICER expression and that overexpression of ICER in the nucleus accumbens, using viral-mediated gene transfer, increases behavioral responses to both rewarding and aversive emotional stimuli. For example, ICER overexpression increases sensitivity to amphetamine-stimulated locomotor activity as well as to natural rewards such as sucrose and social grooming. However, ICER overexpression also increases measures of anxiety in the elevated plus maze and neophobia to novel tastes. Finally, ICER produces an antidepressant-like effect in the forced swim test, further indication of an enhanced active response to stress. These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens.

Induction of inducible cAMP early repressor expression in nucleus accumbens by stress or amphetamine increases behavioral responses to emotional stimuli.

The leptin hormone is critical for normal food intake and metabolism. While leptin receptor (Lepr) function has been well studied in the hypothalamus, the functional relevance of Lepr expression in the ventral tegmental area (VTA) has not been investigated. The VTA contains dopamine neurons that are important in modulating motivated behavior, addiction, and reward. Here, we show that VTA dopamine neurons express Lepr mRNA and respond to leptin with activation of an intracellular JAK-STAT pathway and a reduction in firing rate. Direct administration of leptin to the VTA caused decreased food intake while long-term RNAi-mediated knockdown of Lepr in the VTA led to increased food intake, locomotor activity, and sensitivity to highly palatable food. These data support a critical role for VTA Lepr in regulating feeding behavior and provide functional evidence for direct action of a peripheral metabolic signal on VTA dopamine neurons.

Leptin receptor signaling in midbrain dopamine neurons regulates feeding.

Î¼-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{[3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) is a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10- or 50-fold selective for human or rat MOR, respectively, compared with Îº-opioid receptors (KOR) and Î´-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with Î¼ receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.

Regulation of ingestive behaviors in the rat by GSK1521498, a novel micro-opioid receptor-selective inverse agonist.

&Mu;-Opioid-Rezeptor (MOR) Agonismus induziert schmackhaft Lebensmittelkonsum haupts&auml;chlich durch Modulation der lohnenden Eigenschaften der Lebensmittel. N-{[3,5-difluoro-3&#39;-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]Methyl}-2,3-dihydro-1H-Inden-2-Amine (GSK1521498) ist eine inverse Roman opioid-Rezeptor-Agonist, die auf der Grundlage von in-vitro-Affinit&auml;t Proben, gr&ouml;&szlig;er als 10 oder 50 - 8-fach ist selektiv f&uuml;r Mensch oder Ratte MOR, bzw. gegen&uuml;ber &kappa;-Opioid-Rezeptoren (KOR) und &delta;-Opioid-Rezeptoren (DOR). Ebenso wurde die bevorzugte MOR Belegung versus KOR und DOR durch Autoradiographie im Gehirn Scheiben aus langen Evans Ratten Oral dosiert mit der Droge beobachtet. GSK1521498 unterdr&uuml;ckt n&auml;chtlichen Nahrungsaufnahme von Standard- oder schmackhaft Chow schlank und Di&auml;t-induzierte fettleibig (DIO) lange Evans-Ratten. Die Dosis-Wirkungs-Beziehung und den zeitlichen Verlauf der Wirksamkeit bei schlanken Ratten gef&uuml;ttert schmackhaft Chow korreliert mit &mu;-Rezeptor-Belegung und die Plasma-Konzentration-Profil des Medikaments. Chronischer oraler Gabe von GSK1521498 induziert K&ouml;rper-Gewicht-Verlust bei DIO Ratten, die Masse Fettreduktion umfasste. Die Reduzierung des K&ouml;rpergewichts entsprach die kumulative Verringerung der Nahrungsaufnahme; Daher bezieht sich die Wirkung des GSK1521498 auf K&ouml;rpergewicht auf Hemmung der Nahrungsaufnahme. GSK1521498 unterdr&uuml;ckt die Vorliebe f&uuml;r Saccharose-haltige L&ouml;sungen bei schlanken Ratten. Operante Reaktion-Modelle auch mit schlanke Ratten reduziert GSK1521498 die Verst&auml;rkung-Wirksamkeit von schmackhaft Essen Belohnung und verst&auml;rkten S&auml;ttigungsgef&uuml;hl. GSK1521498 ist ein potenter, MOR-selektive inverse-Agonist, der moduliert die hedonische Aspekte der Einnahme und daher k&ouml;nnte eine pharmakologische Behandlung von Adipositas und ESSSUCHT-Erkrankungen darstellen.

Verordnung der Ansaug Verhaltensweisen bei der Ratte durch GSK1521498, einen Roman Mikro-Opioid-Rezeptor-selektive inverse Agonisten.

The prototypic second messenger cyclic AMP (cAMP) is essential for controlling cellular metabolism, including glucose and lipid homeostasis. In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs). To explore the physiological functions of Epac1, we generated Epac1 knockout mice. Here we report that Epac1 null mutants have reduced white adipose tissue and reduced plasma leptin levels but display heightened leptin sensitivity. Epac1-deficient mice are more resistant to high-fat diet-induced obesity, hyperleptinemia, and glucose intolerance. Furthermore, pharmacological inhibition of Epac by use of an Epac-specific inhibitor reduces plasma leptin levels in vivo and enhances leptin signaling in organotypic hypothalamic slices. Taken together, our results demonstrate that Epac1 plays an important role in regulating adiposity and energy balance.

Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1.

Article	Year
Local gene knockdown in the brain using viral-mediated RNA interference. Nature medicine\| PubMed ID: 14634645	2003
The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 15772353	2005
Induction of inducible cAMP early repressor expression in nucleus accumbens by stress or amphetamine increases behavioral responses to emotional stimuli. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 16899718	2006
Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron\| PubMed ID: 16982424	2006
Regulation of ingestive behaviors in the rat by GSK1521498, a novel micro-opioid receptor-selective inverse agonist. The Journal of pharmacology and experimental therapeutics\| PubMed ID: 21712426	2011
Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1. Molecular and cellular biology\| PubMed ID: 23263987	2013

Jonathan D. Hommel

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