Abstract
BackgroundY2 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 FindingsWe thus generated two conditional knockout mouse models, Y2lox/lox and NPYCre/+;Y2lox/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 cartinine 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/SignificanceTaken 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.
Highlights
Neuropeptide Y (NPY), a 36-amino acid peptide, is widely expressed in the central and peripheral nervous systems and is an important regulator of numerous physiological processes, including energy balance [1,2]
In order to evaluate the role of hypothalamic Y2 receptors in the regulation of energy balance, Y2 receptors were selectively deleted from the hypothalamus by injection of a recombinant adeno-associated viral vector expressing Cre-recombinase into the hypothalamus of adult male Y2lox/lox mice
The other organ weights as a percent of body weight in Y2hypKO mice did not differ significantly from those in control mice. These data suggests that lack of hypothalamic Y2 receptors leads to positive energy balance characterized by hyperphagia and increased body weight gain, which is consistent with the known role of Y2 receptors as a mediator of PYY3-36induced satiety [5]
Summary
Neuropeptide Y (NPY), a 36-amino acid peptide, is widely expressed in the central and peripheral nervous systems and is an important regulator of numerous physiological processes, including energy balance [1,2]. Activation of NPY/AGRP neurons leads to release of NPY and AGRP, which stimulate appetite, fat storage and weight gain [8] This occurs in association with effects of NPY on Y1 or Y5 receptors [9] and the ability of AGRP to antagonize melanocortin 3/4 (MC3/4) receptors in the paraventricular nucleus [8]. POMC/CART neurons produce alpha-melanocyte stimulating hormone (a-MSH), which acts to inhibit food intake, weight gain and energy balance by action on central MC3/4 receptors in the paraventricular nucleus [10]. Consistent with an important role of NPY in the regulation of energy homeostasis, intracerebroventricular or hypothalamusspecific administration of NPY to normal rodents leads to defects characteristic of obesity, including hyperphagia, accelerated body weight gain, hyperleptinemia, hypercorticosteronemia, hyperinsulinemia and increased adiposity [18,19,20,21]. Y2 receptors are located post-synaptically as well as acting as auto receptors on NPYexpressing neurons, and the different roles of these two populations of Y2 receptors in the regulation of energy homeostasis and body composition are unclear
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