RESUMO
Neuropeptide Y receptors are critical regulators of energy homeostasis and are well known for their powerful influence on feeding, but their roles in other important aspects of energy homeostasis, such as energy expenditure and their functional interactions in these processes, are largely unknown. Here we show that mice lacking both Y2 and Y4 receptors exhibited a reduction in adiposity, more prominent in intra-abdominal vs. subcutaneous fat, and an increase in lean mass as determined by dual-energy X-ray absorptiometry. These changes were more pronounced than those seen in mice with Y2 or Y4 receptor single deletion, demonstrating the important roles and synergy of Y2 and Y4 signaling in the regulation of body composition. These changes in body composition occurred without significant changes in food intake, but energy expenditure and physical activity were significantly increased in Y4(-/-) and particularly in Y2(-/-)Y4(-/-) but not in Y2(-/-) mice, suggesting a critical role of Y4 signaling and synergistic interactions with Y2 signaling in the regulation of energy expenditure and physical activity. Y2(-/-) and Y4(-/-) mice also exhibited a decrease in respiratory exchange ratio with no further synergistic decrease in Y2(-/-)Y4(-/-) mice, suggesting that Y2 and Y4 signaling each play important and independent roles in the regulation of substrate utilization. The synergy between Y2 and Y4 signaling in regulating fat mass may be related to differences in mitochondrial oxidative capacity, since Y2(-/-)Y4(-/-) but not Y2(-/-) or Y4(-/-) mice showed significant increases in muscle protein levels of peroxisome proliferator-activated receptor (PPAR)γ coactivator (PGC)-1α, and mitochondrial respiratory chain complexes I and III. Taken together, this work demonstrates the critical roles of Y2 and Y4 receptors in the regulation of body composition and energy metabolism, highlighting dual antagonism of Y2 and Y4 receptors as a potentially effective anti-obesity treatment.
Assuntos
Metabolismo Energético/fisiologia , Atividade Motora/fisiologia , Receptores de Neuropeptídeo Y/metabolismo , Absorciometria de Fóton , Análise de Variância , Animais , Western Blotting , Composição Corporal/fisiologia , Calorimetria Indireta , Ingestão de Alimentos/fisiologia , Masculino , Camundongos , Camundongos Knockout , Receptores de Neuropeptídeo Y/genética , Transdução de Sinais/fisiologiaRESUMO
Peptide YY (PYY) is best known for its important role in appetite regulation, but recent pharmacological studies have suggested that PYY is also involved in regulating energy balance and glucose homeostasis. However, the mechanism behind the regulation of these parameters by PYY is less clear. Here, by utilising an inducible transgenic mouse model where PYY overexpression is induced in adult animals (PYYtg) and release of mature PYY peptides is controlled by endogenous machineries, we show that elevating PYY levels leads to reduced food intake after a 24-h fast. Furthermore, PYYtg mice, although not significantly different from WT with respect to body weight, adiposity, lean mass, physical activity or energy expenditure, exhibited a significantly increased respiratory exchange ratio (RER), indicating decreased lipid oxidation and/or increased lipogenesis. Importantly, PYYtg mice showed a 25% reduction in liver protein levels of phosphorylated acetyl-CoA carboxylase (pACC) in the absence of changes in total ACC levels compared to those of WT mice. Moreover, liver protein levels of AMP-activated kinase (AMPK) in PYYtg mice were 25% lower than those of WT mice, consistent with a reduced pACC in these mice. These data suggest that elevation of PYY levels as seen after a meal can increase lipogenic capacity, which is likely a key contributor to the increased RER seen in PYYtg mice. In addition, PYYtg mice exhibited comparable insulin tolerance and oral glucose tolerance to those of WT, but showed a trend towards decreased insulin levels in response to an oral glucose challenge, indicating that PYY could improve insulin action. Taken together, these findings demonstrate that under physiological conditions, PYY reduces food intake while enhancing lipogenic capacity and insulin action, likely contributing to fuel assimilation in the postprandial state.
Assuntos
Peso Corporal/genética , Ingestão de Alimentos , Metabolismo dos Lipídeos/genética , Obesidade/genética , Peptídeo YY/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Animais Geneticamente Modificados , Peso Corporal/fisiologia , Jejum/metabolismo , Teste de Tolerância a Glucose , Homeostase/genética , Homeostase/fisiologia , Masculino , Camundongos , Obesidade/metabolismo , Peptídeo YY/genéticaRESUMO
The neuropeptide Y (NPY) system has been implicated in the regulation of bone homeostasis and osteoblast activity, but the mechanism behind this is unclear. Here we show that Y1 receptor signaling is directly involved in the differentiation of mesenchymal progenitor cells isolated from bone tissue, as well as the activity of mature osteoblasts. Importantly, the mRNA levels of two key osteogenic transcription factors, runx2 and osterix, as well as the adipogenic transcription factor PPAR-gamma, were increased in long bones of Y1(-/-) mice compared with wild-type mice. In vitro, bone marrow stromal cells (BMSCs) isolated from Y1(-/-) mice formed a greater number of mineralized nodules under osteogenic conditions and a greater number of adipocytes under adipogenic conditions than controls. In addition, both the number and size of fibroblast colony-forming units formed in vitro by purified osteoprogenitor cells were increased in the absence of the Y1 receptors, suggestive of enhanced proliferation and osteogenesis. Furthermore, the ability of two specific populations of mesenchymal progenitor cells isolated from bone tissue, an immature mesenchymal stem cell population and a more committed osteoprogenitor cell population, to differentiate into osteoblasts and adipocytes in vitro was enhanced in the absence of Y1 receptor signaling. Finally, Y1 receptor deletion also enhanced the mineral-producing ability of mature osteoblasts, as shown by increased in vitro mineralization by BMSCs isolated from osteoblast-specific Y1(-/-) mice. Together these data demonstrate that the NPY system, via the Y1 receptor, directly inhibits the differentiation of mesenchymal progenitor cells as well as the activity of mature osteoblasts, constituting a likely mechanism for the high-bone-mass phenotype evident in Y1(-/-) mice.
Assuntos
Diferenciação Celular , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Adipócitos/citologia , Adipogenia , Animais , Células da Medula Óssea/citologia , Osso e Ossos/metabolismo , Calcificação Fisiológica , Contagem de Células , Ensaio de Unidades Formadoras de Colônias , Feminino , Deleção de Genes , Masculino , Camundongos , Neuropeptídeo Y/deficiência , Neuropeptídeo Y/metabolismo , Osteogênese/genética , Receptores de Neuropeptídeo Y/deficiência , Células Estromais/citologia , Células Estromais/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima/genéticaRESUMO
BACKGROUND: Y2 receptor signalling is known to be important in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone physiology. Y2 receptors are located post-synaptically as well as acting as auto receptors on NPY-expressing neurons, and the different roles of these two populations of Y2 receptors in the regulation of energy homeostasis and body composition are unclear. METHODOLOGY/PRINCIPAL FINDINGS: We thus generated two conditional knockout mouse models, Y2(lox/lox) and NPYCre/+;Y2(lox/lox), in which Y2 receptors can be selectively ablated either in the hypothalamus or specifically in hypothalamic NPY-producing neurons of adult mice. Specific deletion of hypothalamic Y2 receptors increases food intake and body weight compared to controls. Importantly, specific ablation of hypothalamic Y2 receptors on NPY-containing neurons results in a significantly greater adiposity in female but not male mice, accompanied by increased hepatic triglyceride levels, decreased expression of liver carnitine palmitoyltransferase (CPT1) and increased expression of muscle phosphorylated acetyl-CoA carboxylase (ACC). While food intake, body weight, femur length, bone mineral content, density and cortical bone volume and thickness are not significantly altered, trabecular bone volume and number were significantly increased by hypothalamic Y2 deletion on NPY-expressing neurons. Interestingly, in situ hybridisation reveals increased NPY and decreased proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus of mice with hypothalamus-specific deletion of Y2 receptors in NPY neurons, consistent with a negative feedback mechanism between NPY expression and Y2 receptors on NPY-ergic neurons. CONCLUSIONS/SIGNIFICANCE: Taken together these data demonstrate the anti-obesogenic role of Y2 receptors in the brain, notably on NPY-ergic neurons, possibly via inhibition of NPY neurons and concomitant stimulation of POMC-expressing neurons in the arcuate nucleus of the hypothalamus, reducing lipogenic pathways in liver and/or skeletal muscle in females. These data also reveal as an anti-osteogenic effect of Y2 receptors on hypothalamic NPY-expressing neurons on trabecular but not on cortical bone.