RESUMO
The opioid receptors (OR) regulate food intake. Still, despite extensive pre-clinical research, the overall effects and individual contribution of the mu (MOR), kappa (KOR), and delta (DOR) OR subtypes to feeding behaviors and food intake remain unclear. To address this, we conducted a pre-registered systematic search and meta-analysis of rodent dose-response studies to evaluate the impact of central and peripheral administration of non-selective and selective OR ligands on intake, motivation, and choice of food. All studies had a high bias risk. Still, the meta-analysis confirmed the overall orexigenic and anorexigenic effects of OR agonists and antagonists, respectively. Our results support a larger orexigenic role for central MOR agonists among OR subtypes and that peripheral OR antagonists reduce motivation for and intake of preferred foods. In binary food choice studies, peripheral OR agonists selectively increase the intake of fat-preferred foods; in contrast, they did not increase the intake of sweet carbohydrate-preferred foods. Overall, these data support that OR regulation of intake, motivation, and choice is influenced by food macronutrient composition.
Assuntos
Motivação , Receptores Opioides , Analgésicos Opioides/farmacologia , Ingestão de Alimentos , Comportamento Alimentar , Ligantes , Receptores Opioides muRESUMO
The dynorphin (DYN) peptide family includes opioid and non-opioid peptides, yet the physiological role of the non-opioid DYN peptides remains poorly understood. Recent evidence shows that administering the non-opioid peptide DYN-A2-17 into the paraventricular hypothalamic nucleus (PVN) simultaneously increased short-term intake of standard rodent chow and spontaneous physical activity (SPA). The present studies aimed to expand upon the mechanisms and role of DYN-A2-17 on food intake and energy expenditure. Injection of DYN-A2-17 in PVN increased SPA, energy expenditure and wheel running in the absence of food. Repeated DYN-A2-17 injection in PVN increased short-term chow intake, but this effect habituated over time and failed to alter cumulative food intake, body weight or adiposity. Pre-treatment with a CRF receptor antagonist into PVN blocked the effects of DYN-A2-17 on food intake while injection of DYN-A2-17 in PVN increased plasma ACTH. Finally, as DYN peptides are co-released with orexin peptides, we compared the effects of DYN-A2-17 to orexin-A and the opioid peptide DYN-A1-13 on food choice and intake in PVN when palatable snacks and chow were available. DYN-A1-13 selectively increased intake of palatable snacks. DYN-A2-17 and orexin-A decreased palatable snack intake while orexin-A also increased chow intake. These findings demonstrate that the non-opioid peptide DYN-A2-17 acutely regulates physical activity, energy expenditure and food intake without long-term effects on energy balance. These data also propose different roles of opioid, non-opioid DYN and orexin peptides on food choice and intake when palatable and non-palatable food options are available.
Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Dinorfinas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Corrida , Adiposidade/efeitos dos fármacos , Adiposidade/fisiologia , Hormônio Adrenocorticotrópico/sangue , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Masculino , Camundongos Endogâmicos BALB C , Orexinas/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Corrida/fisiologiaRESUMO
Food intake and physical activity are regulated by multiple neuropeptides, including orexin and dynorphin (DYN). Orexin-A (OXA) is one of two orexin peptides with robust roles in regulation of food intake and spontaneous physical activity (SPA). DYN collectively refers to several peptides, some of which act through opioid receptors (opioid DYN) and some whose biological effects are not mediated by opioid receptors (non-opioid DYN). While opioid DYN is known to increase food intake, the effects of non-opioid DYN peptides on food intake and SPA are unknown. Neurons that co-express and release OXA and DYN are located within the lateral hypothalamus. Limited evidence suggests that OXA and opioid DYN peptides can interact to modulate some aspects of behaviors classically related to orexin peptide function. The paraventricular hypothalamic nucleus (PVN) is a brain area where OXA and DYN peptides might interact to modulate food intake and SPA. We demonstrate that injection of des-Tyr-dynorphin (DYN-A(2-17), a non opioid DYN peptide) into the PVN increases food intake and SPA in adult mice. Co-injection of DYN-A(2-17) and OXA in the PVN further increases food intake compared to DYN-A(2-17) or OXA alone. This is the first report describing the effects of non-opioid DYN-A(2-17) on food intake and SPA, and suggests that DYN-A(2-17) interacts with OXA in the PVN to modulate food intake. Our data suggest a novel function for non-opioid DYN-A(2-17) on food intake, supporting the concept that some behavioral effects of the orexin neurons result from combined actions of the orexin and DYN peptides.
Assuntos
Dinorfinas/fisiologia , Orexinas/metabolismo , Fragmentos de Peptídeos/fisiologia , Animais , Regulação do Apetite , Ingestão de Energia , Masculino , Camundongos Endogâmicos BALB C , Atividade MotoraRESUMO
Despite the increase in obesity prevalence over the last decades, humans show large inter-individual variability for susceptibility to diet-induced obesity. Understanding the biological basis of this susceptibility could identify new therapeutic alternatives against obesity. We characterized behavioral changes associated with propensity to obesity induced by cafeteria (CAF) diet consumption in mice. We show that Balb/c mice fed a CAF diet display a large inter-individual variability in susceptibility to diet-induced obesity, such that based on changes in adiposity we can classify mice as obesity prone (OP) or obesity resistant (OR). Both OP and OR were hyperphagic relative to control-fed mice but caloric intake was similar between OP and OR mice. In contrast, OR had a larger increase in locomotor activity following CAF diet compared to OP mice. Obesity resistant and prone mice showed similar intake of sweet snacks, but OR ate more savory snacks than OP mice. Two bottle sucrose preference tests showed that OP decreased their sucrose preference compared to OR mice after CAF diet feeding. Finally, to test the robustness of the OR phenotype in response to further increases in caloric intake, we fed OR mice with a personalized CAF (CAF-P) diet based on individual snack preferences. When fed a CAF-P diet, OR increased their calorie intake compared to OP mice fed the standard CAF diet, but did not reach adiposity levels observed in OP mice. Together, our data show the contribution of hedonic intake, individual snack preference and physical activity to individual susceptibility to obesity in Balb/c mice fed a standard and personalized cafeteria-style diet.