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Binge eating disorder (BED) is characterized by excessive food intake during a short period of time and is often associated with obesity. Mouse models of binge‐like eating behavior are lacking making it difficult to employ genetic models in the identification of mechanisms regulating excessive eating. We report a rapid and simple model to induce binge‐like eating behavior in mice that does not require food deprivation or exogenous stressors. Weekly 24 h access to a nutritionally complete high energy diet (HED), along with continuous access to standard chow, resulted in a significant increase in HED intake following its presentation compared to mice that had continuous access to both diets. Mice exhibiting binge‐like eating consumed one‐third of their normal total daily caloric intake within 2.5 h of HED presentation. Moreover, total 24‐h caloric intakes were increased by 50% in mice exhibiting binge‐like eating. Following repeated cycles, binge‐like eating of the HED was maintained over several weeks with no evidence of habituation or significant alterations in body weight and adiposity. Pharmacological evaluation of binge‐like eating behavior was performed using clinically employed compounds. Interestingly, binge‐like eating was dose‐dependently decreased by fluoxetine, but not baclofen or topiramate. These data support clinical validation of this mouse model of binge‐like eating behavior, as fluoxetine has been shown to reduce binge frequency in human subjects with BED. The availability of transgenic and knockout mice will allow for the determination of genes that are involved in the initiation and maintenance of binge‐like eating behavior.

Statnick MA. Genetic ablation of myelin protein zero-like 3 in mice increases energy expenditure, improves glycemic control, and reduces hepatic lipid synthesis. Am J Physiol Endocrinol Metab 305: E282-E292, 2013. First published May 28, 2013; doi:10.1152/ajpendo.00228.2013.-Obesity continues to be a global health problem, and thus it is imperative that new pathways regulating energy balance be identified. Recently, it was reported: (Hayashi K, Cao T, Passmore H, Jourdan-Le Saux C, Fogelgren B, Khan S, Hornstra I, Kim Y, Hayashi M, Csiszar K. J Invest Dermatol 123: 864 -871, 2004) that mice carrying a missense mutation in myelin protein zero-like 3 (Mpzl3 rc ) have reduced body weight. To determine how Mpzl3 controls energy balance in vivo, we generated mice deficient in myelin protein zero-like 3 (Mpzl3-KO). Interestingly, KO mice were hyperphagic yet had reduced body weight and fat mass. Moreover, KO mice were highly resistant to body weight and fat mass gain after exposure to a high-fat, energydense diet. These effects on body weight and adiposity were driven, in part, by a pronounced increase in whole body energy expenditure levels in KO mice. KO mice also had reduced blood glucose levels during an intraperitoneal glucose challenge and significant reductions in circulating insulin levels suggesting an increase in insulin sensitivity. In addition, there was an overall increase in oxidative capacity and contractile force in skeletal muscle isolated from KO mice. Hepatic triglyceride levels were reduced by 92% in livers of KO mice, in part due to a reduction in de novo lipid synthesis. Interestingly, Mpzl3 mRNA expression in liver was increased in diet-induced obese mice. Moreover, KO mice exhibited an increase in insulin-stimulated Akt signaling in the liver, further demonstrating that Mpzl3 can regulate insulin sensitivity in this tissue. We have determined that Mpzl3 has a novel physiological role in controlling body weight regulation, energy expenditure, glycemic control, and hepatic triglyceride synthesis in mice. skeletal muscle; rough coat (rc/rc), Akt; immunoglobulin-like V-type domain; nonalcoholic fatty liver disease OBESITY CONTINUES TO BE a major healthcare challenge in the United States and developing countries all over the world. The overall prevalence of overweight and obese individuals with a body mass index of Ն25 kg/m 2 in the United States is 68%, and this number is expected to rise (16). The limited availability of safe and clinically efficacious pharmacological agents for weight loss can be attributed in part to the relative scarcity of knowledge about body weight regulatory mechanisms. Thus, there is an urgent need to understand the complexity of energy balance and to identify novel pathways regulating body weight.Myelin protein zero-like 3 (Mpzl3) encodes a predicted type I transmembrane protein and was named after its closest homolog Mpzl2 (also referred to as EVA1). MPZL3 and EVA1 share roughly 60% similarity in their amino acid sequences (7). Similar to EVA1, MPZL3 has a predicted extr...

The results of the microdialysis experiments suggest that periadolescent ethanol drinking by P rats increases basal DA neurotransmission (as indicated by higher DA clearance while maintaining the same extracellular DA concentrations) and prolongs the response of DA neurotransmission to ethanol.

Sahr AE, Sindelar DK, Alexander-Chacko JT, Eastwood BJ, Mitch CH, Statnick MA. Activation of mesolimbic dopamine neurons during novel and daily limited access to palatable food is blocked by the opioid antagonist LY255582. Am J Physiol Regul Integr Comp Physiol 295: R463-R471, 2008. First published June 4, 2008 doi:10.1152/ajpregu.00390.2007.-An analog of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine series (LY255582) exhibits high in vitro binding affinity and antagonist potency for the -, ␦-, and -opioid receptors. In vivo, LY255582 exhibits potent effects in reducing food intake and body weight in several rodent models of obesity. In the present study, we evaluated the effects of LY255582 to prevent the consumption of a highly palatable (HP) diet (a high-fat/ high-carbohydrate diet) both when the food was novel and following daily limited access to the HP diet. Additionally, we examined the effects of consumption of the HP diet and of LY255582 treatment on mesolimbic dopamine (DA) signaling by in vivo microdialysis. Consumption of the HP diet increased extracellular DA levels within the nucleus accumbens (NAc) shell. Increased DA in the NAc shell was not related to the quantity of the HP diet consumed, and the DA response did not habituate following daily scheduled access to the HP diet. Interestingly, treatment with LY255582 inhibited consumption of the HP diet and the HP diet-associated increase in NAc shell DA levels. Moreover, the increased HP diet consumption observed following daily limited access to the HP diet was completely prevented by LY255582 treatment. LY255582 may be a useful tool in understanding the neural mechanisms involved in the reinforcement mechanisms regulating food intake. opiate; nucleus accumbens; obesity; food intake; microdialysis INVOLVEMENT OF THE CENTRAL opioid system in the regulation of food intake is well established (for review, see Refs. 22 and 49). Many studies have demonstrated that agonists at all three opioid receptor subtypes, , ␦, and , increase food intake (26, 44), whereas antagonists decrease food intake (22, 49). More specifically, manipulations of the opioid system regulate hedonic feeding or the intake and response to highly palatable (HP) macronutrients (high-fat and/or high-sucrose) (5, 6, 33, 37). The acquisition of hedonic feeding appears to involve activation of the mesolimbic dopamine (DA) system, the dopaminergic projection from the ventral tegmental area to the nucleus accumbens (NAc) (8,11,17,21,41,42). This pathway is a key component of the brain reward circuit (33, 60) that consists of neural pathways strongly implicated in reward and reinforcement mechanisms of drugs of abuse, as well as vital behaviors, including feeding and sexual behavior. Several neurotransmitter and neuropeptide systems that modulate feeding do so, at least in part, by acting through the mesolimbic DA pathway (1, 36, 59). Endogenous opioids regulate the mesolimbic DA projection at both the level of the ventral tegmental area and NAc (30, 54), providing a potential mech...