Neuropeptide Y Receptor Selective Ligands in the Treatment of Obesity

Kamiji, Mayra Mayumi; Inui, Akio

doi:10.1210/er.2007-0003

Cited by 80 publications

(46 citation statements)

References 292 publications

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“…NPY is a 36-amino acid neuropeptide member of the pancreatic polypeptide family that includes peptide YY (PYY) and pancreatic polypeptide (PP) (29). NPY affects a wide variety of physiological functions via the activation of a population of distinct G protein-coupled NPY receptor subtypes: Y1, Y2, Y4, and Y5 (29,35).…”

mentioning

confidence: 99%

“…NPY affects a wide variety of physiological functions via the activation of a population of distinct G protein-coupled NPY receptor subtypes: Y1, Y2, Y4, and Y5 (29,35). All NPY receptor subtypes are expressed in the hypothalamus (18,60).…”

mentioning

confidence: 99%

“…The effects of NPY on feeding and energy homeostasis are thought to be mediated largely by hypothalamic Y1 and Y5 receptors (reviewed in Ref. 29). Y2 receptors, having affinity for both NPY and PYY (35), act in an inhibitory manner on both orexigenic NPY as well as anorexigenic proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) (21).…”

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confidence: 99%

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Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats

Rojas

Stafford

Saadat

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Rojas JM, Stafford JM, Saadat S, Printz RL, Beck-Sickinger AG, Niswender KD. Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats. Am J Physiol Endocrinol Metab 303: E1479 -E1488, 2012. First published October 16, 2012; doi:10.1152/ajpendo.00351.2012.-Elevated plasma triglyceride (TG) levels contribute to an atherogenic dyslipidemia that is associated with obesity, diabetes, and metabolic syndrome. Numerous models of obesity are characterized by increased central nervous system (CNS) neuropeptide Y (NPY) tone that contributes to excess food intake and obesity. Previously, we demonstrated that intracerebroventricular (icv) administration of NPY in lean fasted rats also elevates hepatic production of very low-density lipoprotein (VLDL)-TG. Thus, we hypothesize that elevated CNS NPY action contributes to not only the pathogenesis of obesity but also dyslipidemia. Here, we sought to determine whether the effects of NPY on feeding and/or obesity are dissociable from effects on hepatic VLDL-TG secretion. Pair-fed, icv NPY-treated, chow-fed LongEvans rats develop hypertriglyceridemia in the absence of increased food intake and body fat accumulation compared with vehicle-treated controls. We then modulated CNS NPY signaling by icv injection of selective NPY receptor agonists and found that Y1, Y2, Y4, and Y5 receptor agonists all induced hyperphagia in lean, ad libitum chow-fed LongEvans rats, with the Y2 receptor agonist having the most pronounced effect. Next, we found that at equipotent doses for food intake NPY Y1 receptor agonist had the most robust effect on VLDL-TG secretion, a Y2 receptor agonist had a modest effect, and no effect was observed for Y4 and Y5 receptor agonists. These findings, using selective agonists, suggest the possibility that the effect of CNS NPY signaling on hepatic VLDL-TG secretion may be relatively dissociable from effects on feeding behavior via the Y1 receptor.brain; obesity dyslipidemia; hepatic lipid metabolism DESPITE THE FACT THAT CLINICIANS have become increasingly adept at treating classical cardiovascular risk factors (i.e., hypertension, smoking, and cholesterol) (24), cardiovascular disease remains one of the leading causes of deaths worldwide (20), potentially due to the parallel diabetes and obesity epidemics (39). The dyslipidemia associated with diabetes and obesity consists of elevated very low-density lipoprotein (VLDL)-triglyceride (TG) together with small, dense, lowdensity lipoprotein cholesterol (LDL-C) and reduced highdensity lipoprotein cholesterol (HDL-C) levels (22,23,26) and is an increasingly recognized component of cardiovascular risk, morbidity, and mortality (26).Models of obesity/diabetes dyslipidemia suggest that increased visceral fat mass and insulin resistance lead to elevated adipocyte lipolysis, which increases free fatty acid (FFA) delivery to liver, where it is efficiently cleared, reesterified to TG, and loaded onto a nascent apolipoprotein B (apoB) part...

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Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats

Rojas

Stafford

Saadat

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…LHA lateral hypothalamic area, PFA perifornicular area, VMH ventromedial hypothalamus, PVH paraventricular nucleus, Ob-R leptin receptor, NPY1/5 neuropeptide Y1 and Y5 receptors, MCR melanocortin receptor, MCHR melanin-concentrating hormone receptor, CART cocaine-amphetamine regulated transcript receptor, AgRP Agouti regulated peptide, MSH melanocyte stimulating hormone, CRF1 corticotrophin releasing factor receptor 1. Scheme modified according to [18,101,[251][252][253][254].…”

Section: Hypothalamus As a Potential Target For Drug Development In Tmentioning

confidence: 99%

“…On one hand it is regarded as the most potent endogenous orexigenic agent [102] acting via NPY1-R and NPY5-R [103]. On the other hand it was found to mediate anorexia at the NPY2-R and NPY4-R [101]. In the Arc leptin depolarizes POMC neurons but hyperpolarizes NPY/GABA/AgRP neurons reducing the transmitter release from these terminals.…”

Section: Endogenous Ligands Of Npy Receptorsmentioning

confidence: 99%

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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G‐Protein‐Coupled Receptors as Drug Targets

Miao¹,

2009

Enzyme Inhibition in Drug Discovery and Development

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Neuropeptide Y Receptor Selective Ligands in the Treatment of Obesity

Cited by 80 publications

References 292 publications

Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats

Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

G‐Protein‐Coupled Receptors as Drug Targets

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