Reciprocal regional changes in brain NPY receptor density during dietary restriction and dietary-induced obesity in the rat

Widdowson, Peter; Upton, R; Henderson, Lynne; Buckingham, Robin E.; Wilson, Shelagh; Williams, Gareth

doi:10.1016/s0006-8993(97)81680-0

Cited by 89 publications

(48 citation statements)

References 24 publications

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“…The altered NPY production may modulate NPY receptor expression, as increased hypothalamic Y 2 and Y 5 receptor expression was observed in dietary obese rodents. 43,45 In keeping with this, we have previously found exaggerated responses to exogenous NPY administration in diet-induced obese rats. 38 Furthermore, previously we observed a reduced PVN amelanocyte-stimulating hormone, together with reduced NPY peptide, after chronic high-fat feeding in the rat, 21 which may explain the prolonged hyperphagia.…”

Section: Npy Cck and Adipokines In Dietary Obesity Mj Morris Et Alsupporting

confidence: 70%

Brain neuropeptide Y and CCK and peripheral adipokine receptors: temporal response in obesity induced by palatable diet

et al. 2007

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Objective: Palatable food disrupts normal appetite regulation, which may contribute to the etiology of obesity. Neuropeptide Y (NPY) and cholecystokinin play critical roles in the regulation of food intake and energy homeostasis, while adiponectin and carnitine palmitoyltransferase (CPT) are important for insulin sensitivity and fatty acid oxidation. This study examined the impact of short-and long-term consumption of palatable high-fat diet (HFD) on these critical metabolic regulators. Methods: Male C57BL/6 mice were exposed to laboratory chow (12% fat), or cafeteria-style palatable HFD (32% fat) for 2 or 10 weeks. Body weight and food intake were monitored throughout. Plasma leptin, hypothalamic NPY and cholecystokinin, and mRNA expression of leptin, adiponectin, their receptors and CPT-1, in fat and muscles were measured. Results: Caloric intake of the palatable HFD group was 2-3 times greater than control, resulting in a 37% higher body weight. Fat mass was already increased at 2 weeks; plasma leptin concentrations were 2.4 and 9 times higher than control at 2 and 10 weeks, respectively. Plasma adiponectin was increased at 10 weeks. Muscle adiponectin receptor 1 was increased at 2 weeks, while CPT-1 mRNA was markedly upregulated by HFD at both time points. Hypothalamic NPY and cholecystokinin content were significantly decreased at 10 weeks. Conclusion: Palatable HFD induced hyperphagia, fat accumulation, increased adiponectin, leptin and muscle fatty acid oxidation, and reduced hypothalamic NPY and cholecystokinin. Our data suggest that the adaptive changes in hypothalamic NPY and muscle fatty acid oxidation are insufficient to reverse the progress of obesity and metabolic consequences induced by a palatable HFD.

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Section: Npy Cck and Adipokines In Dietary Obesity Mj Morris Et Alsupporting

confidence: 70%

Brain neuropeptide Y and CCK and peripheral adipokine receptors: temporal response in obesity induced by palatable diet

et al. 2007

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“…46 The increased NPY levels produced by energy deprivation are associated with decreased NPY Y 5 and=or NPY Y 2 receptor density in the hypothalamus (lateral (perifornical)), dorsal, ventromedial, hippocampus (CA3 region) thalamus (paraventricular and reuniens nuclei) and amygdala (centromedial nucleus). 47,48 In ob=ob mice that have high brain NPY levels, similarly decreased receptor density has been shown in the hypothalamus, thalamus (midline group), cortex (cingulate, retrosplenal and granular) and hippocampus. 49 In contrast, animals made obese by feeding a high-fat diet, in which hypothalamic NPY levels are low, increased NPY Y 5 and=or NPY Y 2 receptor density has been shown in the hypothalamus, amygdala and thalamus.…”

Section: Appetite Suppressionmentioning

confidence: 83%

“…49 In contrast, animals made obese by feeding a high-fat diet, in which hypothalamic NPY levels are low, increased NPY Y 5 and=or NPY Y 2 receptor density has been shown in the hypothalamus, amygdala and thalamus. 47 Many of these brain areas are also influenced by other regulators of food intake such as GLP-1, MC-4 receptor agonists, AGRP, leptin, CART (cocaine and amphetamine related transcript) and the orexins. 50 -53 Together, these studies strongly suggest that food intake in response to changes in energy balance may involve the coordinated activity of NPY containing neurons and receptors in many brain regions, and not just those in the hypothalamus.…”

Section: Appetite Suppressionmentioning

confidence: 99%

Appetite suppression based on selective inhibition of NPY receptors

Chamorro

Della‐Zuana

et al. 2002

Int J Obes

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AIM:The aim of this review is to critically assess available evidence that blockade of the actions of NPY at one of the five NPY receptor subtypes represents an attractive new drug discovery target for the development of an appetite suppressant drug. RESULTS: Blockade of the central actions of NPY using anti-NPY antibodies, antisense oligodeoxynucleotides against NPY and NPY receptor antagonists results in a decrease in food intake in energy-deprived animals. These results appear to show that endogenous NPY plays a role in the control of appetite. The fact that NPY receptors exist as at least five different subtypes raises the possibility that the actions of endogenous NPY on food intake can be adequately dissociated from other effects of the peptide. Current drug discovery has produced a number of highly selective NPY receptor antagonists which have been used to establish the NPY Y 1 receptor subtype as the most critical in regulating short-term food intake. However, additional studies are now needed to more clearly define the relative contribution of NPY acting through the NPY Y 2 and NPY Y 5 receptors in the complex sequence of physiological and behavioral events that underlie the long-term control of appetite. CONCLUSIONS: Blockade of the NPY receptor may produce appetite-suppressing drugs. However, it is too early to state with certainty whether a single subtype selective drug used alone or a combination of NPY receptor selective antagonists used in combination will be necessary to adequately influence appetite regulation.

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“…By contrast, dietary obesity induced by voluntary overeating of a highly-palatable diet is not accompanied by obvious increases in the activity of the ARC NPY neurones; indeed, there is some evidence that aspects of their activity are inhibited, perhaps suggesting an attempt to restrain overeating of palatable food (Wilding et al 1992;Widdowson et al 1997). On the other hand, in mice at least, dietary obesity seems to induce the emergence of 'ectopic' NPY expression in the DMH .…”

Section: Neuropeptide Y and Obesitymentioning

confidence: 93%

“…The Y5 receptor is expressed at relatively high levels in the LHA, close to the site where NPY acts most potently to simulate feeding (Gerald et al 1996). NPY receptor density in this area is decreased during starvation, which may be explained by down regulation of these receptors following increased local availability of NPY (Widdowson et al 1997); as discussed later (p. 389), NPY release is known to be enhanced during food deprivation (Kalra et al 1991b). Overall, NPY receptors (putatively Y5) in this area appear well placed to participate in mediating the increased hunger and food-seeking behaviour of the food-deprived animal.…”

Section: Neuropeptide Y and Energy Homeostasismentioning

confidence: 99%

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

2000

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The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of ‘feeding’ and ‘satiety’ centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY ‘feeding’ receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as α-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as ‘agouti’ protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find use as anti-obesity drugs in human subjects Orexins-A and -B, derived from prepro-orexin, are expressed in specific neurones of the lateral hypothalamic area (LHA). Orexin-A injected centrally stimulates eating and prepro-orexin mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose, and orexin neurones may be involved in stimulating feeding in response to falls in plasma glucose.

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Reciprocal regional changes in brain NPY receptor density during dietary restriction and dietary-induced obesity in the rat

Cited by 89 publications

References 24 publications

Brain neuropeptide Y and CCK and peripheral adipokine receptors: temporal response in obesity induced by palatable diet

Brain neuropeptide Y and CCK and peripheral adipokine receptors: temporal response in obesity induced by palatable diet

Appetite suppression based on selective inhibition of NPY receptors

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

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