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Yan-Chuan Shi,
Jackie Lau,
Zhou Lin,
Hui Zhang,
Lei Zhai,
Guenther Sperk,
Regine Heilbronn,
Mario Mietzsch,
Stefan Weger,
Xu-Feng Huang,
Ronaldo F Enriquez,
Paul A Baldock, Lei Zhang,
Amanda Sainsbury,
Herbert Herzog,
Shu Lin
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ABSTRACT: Neuropepetide Y (NPY) is best known for its powerful stimulation of food intake and its effects on reducing energy expenditure. However, the pathways involved and the regulatory mechanisms behind this are not well understood. Here we demonstrate that NPY derived from the arcuate nucleus (Arc) is critical for the control of sympathetic outflow and brown adipose tissue (BAT) function. Mechanistically, a key change induced by Arc NPY signaling is a marked Y1 receptor-mediated reduction in tyrosine hydroxylase (TH) expression in the hypothalamic paraventricular nucleus (PVN), which is also associated with a reduction in TH expression in the locus coeruleus (LC) and other regions in the brainstem. Consistent with this, Arc NPY signaling decreased sympathetically innervated BAT thermogenesis, involving the downregulation of uncoupling protein 1 (UCP1) expression in BAT. Taken together, these data reveal a powerful Arc-NPY-regulated neuronal circuit that controls BAT thermogenesis and sympathetic output via TH neurons.
Cell metabolism 02/2013; 17(2):236-48. · 17.35 Impact Factor
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ABSTRACT: 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.
Neuropeptides 05/2012; 46(4):173-82. · 1.55 Impact Factor
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ABSTRACT: The neuropeptide Y system has emerged as one of the major neural signalling pathways regulating bone homeostasis. Absence of Y1 receptor signalling from bone forming osteoblasts is responsible for an enhancement on bone mass in mice, suggesting that pharmacological blockade of Y1 receptors may offer a novel anabolic treatment option for improving bone mass. Here we show that oral administration of the selective Y1 receptor antagonist BIBO3304 for 8 weeks dose-dependently increases bone mass in mice. Histomorphometric analysis revealed a significant 1.5-fold increase in cancellous bone volume in the femora of mice treated with BIBO3304. Furthermore, bone microarchitecture was improved, with greater trabecular number and trabecular thickness. This increase in bone mass was associated with a significant increase in bone anabolic activity of osteoblasts and, interestingly, was evident despite a coincident increase in bone resorption, as evidenced by an increase in the number of the osteolytic osteoclasts. Changes were also evident in cortical bone, with a significant increase in periosteal mineral apposition rate. Importantly, no adverse extra-skeletal side effects were observed through Y1 receptor antagonism over the 8-week treatment period, with no effects of even the higher BIBO3304 dose on body weight, adiposity, energy metabolism or circulating corticosterone levels. Taken together, this work describes the first NPY-based anabolic treatment for improving bone mass, and highlights the therapeutic potential of blocking Y1 receptor signalling for the prevention of, or recovery from, degenerative skeletal diseases.
Bone 03/2012; 51(1):8-16. · 4.02 Impact Factor
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L Zhang,
A D Nguyen,
I-C J Lee,
E Yulyaningsih,
S J Riepler,
B Stehrer,
R F Enriquez,
S Lin,
Y-C Shi,
P A Baldock,
A Sainsbury,
H Herzog
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ABSTRACT: Both the neuronal-derived neuropeptide Y (NPY) and the gut hormone peptide YY (PYY) have been implicated in the regulation of energy balance and glucose homeostasis. However, despite similar affinities for the same Y receptors, the co-ordinated actions of these two peptides in energy and glucose homeostasis remain largely unknown.
To investigate the mechanisms and possible interactions between PYY with NPY in the regulation of these processes, we utilized NPY/PYY single and double mutant mouse models and examined parameters of energy balance and glucose homeostasis.
PYY(-/-) mice exhibited increased fasting-induced food intake, enhanced fasting and oral glucose-induced serum insulin levels, and an impaired insulin tolerance, - changes not observed in NPY(-/-) mice. Interestingly, whereas PYY deficiency-induced impairment in insulin tolerance remained in NPY(-/-) PYY(-/-) mice, effects of PYY deficiency on fasting-induced food intake and serum insulin concentrations at baseline and after the oral glucose bolus were absent in NPY(-/-) PYY(-/-) mice, suggesting that NPY signalling may be required for PYY's action on insulin secretion and fasting-induced hyperphagia. Moreover, NPY(-/-) PYY(-/-) , but not NPY(-/-) or PYY(-/-) mice had significantly decreased daily food intake, indicating interactive control by NPY and PYY on spontaneous food intake. Furthermore, both NPY(-/-) and PYY(-/-) mice showed significantly reduced respiratory exchange ratio during the light phase, with no additive effects observed in NPY(-/-) PYY(-/-) mice, indicating that NPY and PYY may regulate oxidative fuel selection via partly shared mechanisms. Overall, physical activity and energy expenditure, however, are not significantly altered by NPY and PYY single or double deficiencies.
These findings show significant and diverse interactions between NPY and PYY signalling in the regulation of different aspects of energy balance and glucose homeostasis.
Diabetes Obesity and Metabolism 02/2012; 14(8):727-36. · 3.38 Impact Factor
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Amy D Nguyen,
Natalie F Mitchell,
Shu Lin,
Laurence Macia,
Ernie Yulyaningsih,
Paul A Baldock,
Ronaldo F Enriquez, Lei Zhang,
Yan-Chuan Shi,
Serge Zolotukhin,
Herbert Herzog,
Amanda Sainsbury
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ABSTRACT: Neuropeptide Y (NPY) acting in the hypothalamus is one of the most powerful orexigenic agents known. Of the five known Y receptors, hypothalamic Y1 and Y5 have been most strongly implicated in mediating hyperphagic effects. However, knockout of individual Y1 or Y5 receptors induces late-onset obesity--and Y5 receptor knockout also induces hyperphagia, possibly due to redundancy in functions of these genes. Here we show that food intake in mice requires the combined actions of both Y1 and Y5 receptors. Germline Y1Y5 ablation in Y1Y5(-/-) mice results in hypophagia, an effect that is at least partially mediated by the hypothalamus, since mice with adult-onset Y1Y5 receptor dual ablation targeted to the paraventricular nucleus (PVN) of the hypothalamus (Y1Y5(Hyp/Hyp)) also exhibit reduced spontaneous or fasting-induced food intake when fed a high fat diet. Interestingly, despite hypophagia, mice with germline or hypothalamus-specific Y1Y5 deficiency exhibited increased body weight and/or increased adiposity, possibly due to compensatory responses to gene deletion, such as the decreased energy expenditure observed in male Y1Y5(-/-) animals relative to wildtype values. While Y1 and Y5 receptors expressed in other hypothalamic areas besides the PVN--such as the dorsomedial nucleus and the ventromedial hypothalamus--cannot be excluded from having a role in the regulation of food intake, these studies demonstrate the pivotal, combined role of both Y1 and Y5 receptors in the mediation of food intake.
PLoS ONE 01/2012; 7(6):e40191. · 4.09 Impact Factor
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Yan-Chuan Shi,
Shu Lin,
Lesley Castillo,
Aygul Aljanova,
Ronaldo F Enriquez,
Amy D Nguyen,
Paul A Baldock, Lei Zhang,
Martijn S Bijker,
Laurence Macia,
Ernie Yulyaningsih,
Hui Zhang,
Jackie Lau,
Amanda Sainsbury,
Herbert Herzog
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ABSTRACT: Y2 receptors, particularly those in the brain, have been implicated in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone mass. Recent evidence also indicates a role for Y2 receptors in peripheral tissues in this process by promoting adipose tissue accretion; however their effects on energy balance remain unclear. Here, we show that adult-onset conditional knockdown of Y2 receptors predominantly in peripheral tissues results in protection against diet-induced obesity accompanied by significantly reduced weight gain, marked reduction in adiposity and improvements in glucose tolerance without any adverse effect on lean mass or bone. These changes occur in association with significant increases in energy expenditure, respiratory exchange ratio, and physical activity and despite concurrent hyperphagia. On a chow diet, knockdown of peripheral Y2 receptors results in increased respiratory exchange ratio and physical activity with no effect on lean or bone mass, but decreases energy expenditure without effecting body weight or food intake. These results suggest that peripheral Y2 receptor signaling is critical in the regulation of oxidative fuel selection and physical activity and protects against the diet-induced obesity. The lack of effects on bone mass seen in this model further indicates that bone mass is primarily controlled by non-peripheral Y2 receptors. This study provides evidence that novel drugs that target peripheral rather than central Y2 receptors could provide benefits for the treatment of obesity and glucose intolerance without adverse effects on lean and bone mass, with the additional benefit of avoiding side effects often associated with pharmaceuticals that act on the central nervous system.
Obesity 05/2011; 19(11):2137-48. · 4.28 Impact Factor
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ABSTRACT: The neuropeptide Y system has proven to be one of the most important regulators of feeding behaviour and energy homeostasis, thus presenting great potential as a therapeutic target for the treatment of disorders such as obesity and at the other extreme, anorexia. Due to the initial lack of pharmacological tools that are active in vivo, functions of the different Y receptors have been mainly studied in knockout and transgenic mouse models. However, over recent years various Y receptor selective peptidic and non-peptidic agonists and antagonists have been developed and tested. Their therapeutic potential in relation to treating obesity and other disorders of energy homeostasis is discussed in this review.
British Journal of Pharmacology 03/2011; 163(6):1170-202. · 4.41 Impact Factor
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ABSTRACT: The neuropeptide Y (NPY) system--comprising of neuropeptide Y, peptide YY, pancreatic polypeptide and the corresponding Y receptors through which they act (Y1, Y2, Y4, Y5 and y6)--is well known for its role in the regulation of energy homeostasis and associated processes. Dysfunctions of the system have been implicated in human diseases such as obesity and cancer, raising the possibility that correction of the system may provide therapeutic benefits for these diseases. In addition to the regulation of appetite and satiety that has attracted most attention during the past years, insight has also been gained into the critical role of NPY in the control of energy expenditure, oxidative fuel selection and bone metabolism. Studies using conditional knockout models further shed light on the central versus peripheral, and hypothalamic versus extra-hypothalamic mechanisms of these regulatory effects of NPY. Moreover, a role of NPY family peptides and Y receptors in modulating the growth of tumours has emerged. These findings provide the basis for novel NPY system-targeted strategies to treat obesity as well as cancer. Such strategies include modifying both sides of the energy balance equation--energy intake versus energy expenditure--to achieve a greater weight/fat loss by particularly modulating peripheral Y receptor(s) to ameliorate metabolic conditions without interfering with central functions of Y receptors. In addition, targeting multiple Y receptors and/or multiple systems involved in the regulation of energy balance will have greater beneficial effects. However, long-term interference with the NPY system to target obesity or cancer related aspects needs to consider potential side effects on bone health.
Pharmacology [?] Therapeutics 03/2011; 131(1):91-113. · 8.56 Impact Factor
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ABSTRACT: 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.
AJP Regulatory Integrative and Comparative Physiology 09/2010; 299(6):R1618-28. · 3.34 Impact Factor
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ABSTRACT: Peptide YY (PYY) is released following food intake and regulates intestinal function and glucose homeostasis, but the mechanisms underpinning these processes are unclear. Enteroendocrine L cells contain PYY and express the acylethanolamine receptor, Gpr119. Here, we show that Gpr119 activation inhibited epithelial electrolyte secretion in human and mouse colon in a glucose-sensitive manner. Endogenous PYY selectively mediated these effects, since PYY(-/-) mice showed no Gpr119 response, but responses were observed in NPY(-/-) mice. Importantly, Gpr119 responses in wild-type (WT) mouse tissue and human colon were abolished by Y(1) receptor antagonism, but were not enhanced by dipeptidylpeptidase IV blockade, indicating that PYY processing to PYY(3-36) was not important. In addition, Gpr119 agonism reduced glycemic excursions after oral glucose delivery to WT mice but not PYY(-/-) mice. Taken together, these data demonstrate a previously unrecognized role of PYY in mediating intestinal Gpr119 activity and an associated function in controlling glucose tolerance.
Cell metabolism 06/2010; 11(6):532-42. · 17.35 Impact Factor
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ABSTRACT: Gut-derived peptides are known to regulate food intake by activating specific receptors in the brain, but the target nuclei and neurons influenced are largely unknown. Here we show that peripherally administered pancreatic polypeptide (PP) stimulates neurons in key nuclei of the hypothalamus critical for appetite and satiety regulation. In the lateral hypothalamic area (LHA), also known as the feeding center, neurons expressing the orexigenic neuropeptide orexin co-localize with the early neuronal activation marker c-Fos upon i.p. injection of PP into mice. In the ventromedial hypothalamus (VMH), also known as the satiety center, neurons activated by PP, as indicated by induction of c-Fos immunoreactivity, express the anorexigenic brain-derived neurotrophic factor (BDNF). Activation of neurons in the LHA and VMH in response to PP occurs via a Y4 receptor-dependent process as it is not seen in Y4 receptor knockout mice. We further demonstrate that in response to i.p. PP, orexin mRNA expression in the LHA is down-regulated, with Y4 receptors being critical for this effect as it is not seen in Y4 receptor knockout mice, whereas BDNF mRNA expression is up-regulated in the VMH in response to i.p. PP in the fasted, but not in the non-fasted state. Taken together these data suggest that PP can regulate food intake by suppressing orexigenic pathways by down-regulation of orexin and simultaneously increasing anorexigenic pathways by up-regulating BDNF.
Neuropeptides 06/2010; 44(3):261-8. · 1.55 Impact Factor
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ABSTRACT: The hypothalamus regulates the skeleton and adipose tissue via endocrine mechanisms. Changes in sex steroid levels in menopause and aging are central to the associated changes in bone mass and adiposity. Whereas many of these effects occur via direct actions on osteoblasts or adipocytes, sex hormones can also mediate effects on bone and adipose tissue via interaction with neuronal pathways. A key hypothalamic regulator of bone and adipose tissue is neuropeptide Y (NPY), which coordinately influences these tissues via effects on neuroendocrine and sympathetic nervous output. Better understanding of the interaction between NPY and sex steroids in regulating skeletal and energy homeostasis could lead to more effective treatments for osteoporosis and obesity.
Trends in Endocrinology and Metabolism 03/2010; 21(7):411-8. · 8.11 Impact Factor
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Yan-Chuan Shi,
Shu Lin,
Iris P L Wong,
Paul A Baldock,
Aygul Aljanova,
Ronaldo F Enriquez,
Lesley Castillo,
Natalie F Mitchell,
Ji-Ming Ye, Lei Zhang,
Laurence Macia,
Ernie Yulyaningsih,
Amy D Nguyen,
Sabrina J Riepler,
Herbert Herzog,
Amanda Sainsbury
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ABSTRACT: 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.
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.
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.
PLoS ONE 01/2010; 5(6):e11361. · 4.09 Impact Factor
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Shu Lin,
Yan-Chuan Shi,
Ernie Yulyaningsih,
Aygul Aljanova, Lei Zhang,
Laurence Macia,
Amy D Nguyen,
En-Ju Deborah Lin,
Matthew J During,
Herbert Herzog,
Amanda Sainsbury
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ABSTRACT: Pancreatic polypeptide (PP) is a potent anti-obesity agent known to inhibit food intake in the absence of nausea, but the mechanism behind this process is unknown.
Here we demonstrate that in response to i.p. injection of PP in wild type but not in Y4 receptor knockout mice, immunostaining for the neuronal activation marker c-Fos is induced specifically in neurons of the nucleus tractus solitarius and the area postrema in the brainstem, notably in cells also showing immunostaining for tyrosine hydroxylase. Importantly, strong c-Fos activation is also detected in the arcuate nucleus of the hypothalamus (ARC), particularly in neurons that co-express alpha melanocyte stimulating hormone (alpha-MSH), the anorexigenic product of the proopiomelanocortin (POMC) gene. Interestingly, other hypothalamic regions such as the paraventricular nucleus, the ventromedial nucleus and the lateral hypothalamic area also show c-Fos induction after PP injection. In addition to c-Fos activation, PP injection up-regulates POMC mRNA expression in the ARC as detected by in situ hybridization. These effects are a direct consequence of local Y4 signaling, since hypothalamus-specific conditional Y4 receptor knockout abolishes PP-induced ARC c-Fos activation and blocks the PP-induced increase in POMC mRNA expression. Additionally, the hypophagic effect of i.p. PP seen in wild type mice is completely absent in melanocortin 4 receptor knockout mice.
Taken together, these findings show that PP reduces food intake predominantly via stimulation of the anorexigenic alpha-MSH signaling pathway, and that this effect is mediated by direct action on local Y4 receptors within the ARC, highlighting a potential novel avenue for the treatment of obesity.
PLoS ONE 01/2009; 4(12):e8488. · 4.09 Impact Factor
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Paul A Baldock,
Nicola J Lee,
Frank Driessler,
Shu Lin,
Susan Allison,
Bernhard Stehrer,
En-Ju D Lin, Lei Zhang,
Ronald F Enriquez,
Iris P L Wong, [......],
Dominique D Pierroz,
Katy Slack,
Yan C Shi,
Ernie Yulyaningsih,
Aygul Aljanova,
David G Little,
Serge L Ferrari,
Amanda Sainsbury,
John A Eisman,
Herbert Herzog
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ABSTRACT: Changes in whole body energy levels are closely linked to alterations in body weight and bone mass. Here, we show that hypothalamic signals contribute to the regulation of bone mass in a manner consistent with the central perception of energy status. Mice lacking neuropeptide Y (NPY), a well-known orexigenic factor whose hypothalamic expression is increased in fasting, have significantly increased bone mass in association with enhanced osteoblast activity and elevated expression of bone osteogenic transcription factors, Runx2 and Osterix. In contrast, wild type and NPY knockout (NPY (-/-)) mice in which NPY is specifically over expressed in the hypothalamus (AAV-NPY+) show a significant reduction in bone mass despite developing an obese phenotype. The AAV-NPY+ induced loss of bone mass is consistent with models known to mimic the central effects of fasting, which also show increased hypothalamic NPY levels. Thus these data indicate that, in addition to well characterized responses to body mass, skeletal tissue also responds to the perception of nutritional status by the hypothalamus independently of body weight. In addition, the reduction in bone mass by AAV NPY+ administration does not completely correct the high bone mass phenotype of NPY (-/-) mice, indicating the possibility that peripheral NPY may also be an important regulator of bone mass. Indeed, we demonstrate the expression of NPY specifically in osteoblasts. In conclusion, these data identifies NPY as a critical integrator of bone homeostatic signals; increasing bone mass during times of obesity when hypothalamic NPY expression levels are low and reducing bone formation to conserve energy under 'starving' conditions, when hypothalamic NPY expression levels are high.
PLoS ONE 01/2009; 4(12):e8415. · 4.09 Impact Factor
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Paul A Baldock,
Susan J Allison,
Pernilla Lundberg,
Nicola J Lee,
Katy Slack,
En-Ju D Lin,
Ronaldo F Enriquez,
Michelle M McDonald, Lei Zhang,
Matthew J During,
David G Little,
John A Eisman,
Edith M Gardiner,
Ernie Yulyaningsih,
Shu Lin,
Amanda Sainsbury,
Herbert Herzog
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ABSTRACT: The importance of neuropeptide Y (NPY) and Y2 receptors in the regulation of bone and energy homeostasis has recently been demonstrated. However, the contributions of the other Y receptors are less clear. Here we show that Y1 receptors are expressed on osteoblastic cells. Moreover, bone and adipose tissue mass are elevated in Y1(-/-) mice with a generalized increase in bone formation on cortical and cancellous surfaces. Importantly, the inhibitory effects of NPY on bone marrow stromal cells in vitro are absent in cells derived from Y1(-/-) mice, indicating a direct action of NPY on bone cells via this Y receptor. Interestingly, in contrast to Y2 receptor or germ line Y1 receptor deletion, conditional deletion of hypothalamic Y1 receptors in adult mice did not alter bone homeostasis, food intake, or adiposity. Furthermore, deletion of both Y1 and Y2 receptors did not produce additive effects in bone or adiposity. Thus Y1 receptor pathways act powerfully to inhibit bone production and adiposity by nonhypothalamic pathways, with potentially direct effects on bone tissue through a single pathway with Y2 receptors.
Journal of Biological Chemistry 07/2007; 282(26):19092-102. · 4.77 Impact Factor
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ABSTRACT: The neuropeptide Y system - comprising neuropeptide Y, peptide YY, pancreatic polypeptide and the Y receptors through which they act (Y1, Y2, Y4, Y5 and y6) - has been at the center of attention with regards to regulation of feeding behavior and its possible involvement in obesity. In the past, research has focused mainly on the orexigenic and obesogenic action of this system, with Y1 and Y5 receptors being prime candidates as mediators of neuropeptide Y-induced hyperphagia and obesity. However, in recent years, the role of other members of the neuropeptide Y family, peptide YY, pancreatic polypeptide and the Y2 and Y4 receptors through which they predominantly act, have commanded increasing attention on account of their effects to mediate satiety and promote weight loss via actions in key brain structures, such as the arcuate nucleus of the hypothalamus and the brain stem. This review focuses on the role of peptide YY- and pancreatic polypeptide-like compounds as possible antiobesity drugs, taking into account their effects, not only on energy balance, but also in the regulation of bone formation, and highlights potential benefits of using Y2 and/or Y4 antagonists (as opposed to agonists such as peptide YY or pancreatic polypeptide) in the treatment of obesity.
Expert Review of Endocrinology & Metabolism 02/2007; 2(2):163-173.
