Increased Hypothalamic Content of Preproneuropeptide Y Messenger Ribonucleic Acid in Genetically Obese Zucker Rats and Its Regulation by Food Deprivation*

Sanacora, Gerard; Kershaw, Maryann; Finkelstein, James D.; White, Jeffrey D.

doi:10.1210/endo-127-2-730

Cited by 315 publications

(125 citation statements)

References 48 publications

(45 reference statements)

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“…In the obese Zucker rat ( fa/fa), NPY secretion is increased and does not decrease significantly with food ingestion, explaining the continuous stimulation of feeding behavior observed in these animals [52]. NPY mRNA expression in the ARC is generally in good agreement with peptide content [53], being increased in fed obese Zucker rats ( fa/fa) when compared to lean Zucker rats and further increased after fasting [54].…”

Section: Discussionmentioning

confidence: 80%

Increase in Ghrelin Levels After Weight Loss in Obese Zucker Rats is Prevented by Gastric Banding

et al. 2007

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Background Gastric banding is thought to decrease appetite in addition to the mechanical effects of food restriction, although this has been difficult to demonstrate in human studies. Our aim was to investigate the changes in orexigenic signals in the obese Zucker rat after gastric banding. Methods Obese Zucker rats ( fa/fa) were submitted to gastric banding (GBP), sham gastric banding fed ad libitum (sham), or sham operation with food restriction, pair-fed to the gastric banding group (sham-PF). Lean Zucker rats ( fa/+) were used as additional controls. Body weight and food intake were daily recorded for 21 days after surgery when epididymal fat was weighed and fasting ghrelin and hypothalamic NPY mRNA expression were measured. Results Gastric banding in obese Zucker rats resulted in a significant decrease of cumulative body weight gain and food intake. Furthermore, gastric banded rats were leaner than Sham-PF, as expressed by a significantly lower epididymal fat weight. Ghrelin levels of gastric banded rats were not increased when compared to sham-operated animals fed ad libitum and were significantly lower than the levels of weight matched sham-PF rats (1116.9±103.3 g GBP vs 963.2±54.3 g sham, 3,079.5±221.6 sham-PF and 2,969.9±150.9 g lean rats, p<0.001); hypothalamic NPY mRNA expression was not increased in GBP when compared to sham-operated rats. Conclusion In obese Zucker rats, GBP prevents the increase in orexigenic signals that occur during caloric deprivation. Our data support the hypothesis that sustained weight loss observed after gastric banding does not depend solely on food restriction.

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Section: Discussionmentioning

confidence: 80%

Increase in Ghrelin Levels After Weight Loss in Obese Zucker Rats is Prevented by Gastric Banding

et al. 2007

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“…ARC NPY neuronal activity is increased in the ob/ob mouse and the fa/fa Zucker rat, similarly to the changes seen in states of energy deficits in which leptin levels fall and fat mass is depleted (Sanacora et al 1990;McKibbin et al 1991;Wilding et al 1993). NPY may partly drive the hyperphagia that contributes to obesity in these models, as food intake falls with administration of a potent Y5 antagonist (Criscione et al 1998), and in ob/ob mice that also have the NPY gene knocked out (Erickson et al 1996b).…”

Section: Neuropeptide Y and Obesitymentioning

confidence: 84%

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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“…We suggest that this combination of changes indicates inhibition of the ARC NPY neurones, and that the increased NPY levels in the PVN are due to blockade of NPY release causing its local accumulation in the PVN terminals; this will need to be con®rmed by direct measurements of NPY secretion in the PVN in vitro (Dryden et al, 1995). It has been reported previously that the obese Zucker rat shows a typical weight loss when underfed and, unlike lean rats, does not display increases in NPY mRNA or in NPY levels in the hypothalamic regions (Sanacora et al, 1990;McKibbin et al, 1991;Dryden et al, 1996). Our ®ndings are consistent with theirs.…”

Section: Discussionmentioning

confidence: 99%

The effect of moxonidine on feeding and body fat in obese Zucker rats: role of hypothalamic NPY neurones

Chen

King

Pickavance

et al. 1999

British J Pharmacology

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1 The antihypertensive agent moxonidine, an imidazoline I i -receptor agonist, also induces hypophagia and lowers body weight in the obese spontaneously hypertensive rat, but the central mediation of this action and the neuronal pathways that moxonidine may interact with are not known. We studied whether moxonidine has anti-obesity e ects in the genetically-obese and insulinresistant fa/fa Zucker rat, and whether these are mediated through inhibition of the hypothalamic neuropeptide Y (NPY) neurones. 2 Lean and obese Zucker rats were given moxonidine (3 mg kg 71 day 71 ) or saline by gavage for 21 days. 3 Moxonidine decreased food intake throughout by 20% in obese rats (P50.001) and by 8% in lean rats (P50.001), and reduced weight gain that ®nal body weight was 15% lower in obese (P50.001) and 7% lower in lean (P50.01) rats than their untreated controls. Plasma insulin and leptin levels were decreased in moxonidine-treated obese rats (P50.01 and P50.05), but unchanged in treated lean rats. Uncoupling protein-1 gene expression in brown adipose tissue was stimulated by 40 ± 50% (P40.05) in both obese and lean animals given moxonidine. Obese animals given moxonidine showed a 37% reduction in hypothalamic NPY mRNA levels (P=0.01), together with signi®cantly increased NPY concentrations in the paraventricular nucleus (P50.05), but no changes in the arcuate nucleus or other nuclei; this is consistent with reduced NPY synthesis in the arcuate nucleus and blocked release of NPY in the paraventricular nucleus. In lean animals, moxonidine did not a ect NPY levels or NPY mRNA. 4 The hypophagic, thermogenic and anti-obesity e ects of moxonidine in obese Zucker rats may be partly due to inhibition of the NPY neurones, whose inappropriate overactivity may underlie obesity in this model.

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Increased Hypothalamic Content of Preproneuropeptide Y Messenger Ribonucleic Acid in Genetically Obese Zucker Rats and Its Regulation by Food Deprivation*

Cited by 315 publications

References 48 publications

Increase in Ghrelin Levels After Weight Loss in Obese Zucker Rats is Prevented by Gastric Banding

Increase in Ghrelin Levels After Weight Loss in Obese Zucker Rats is Prevented by Gastric Banding

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

The effect of moxonidine on feeding and body fat in obese Zucker rats: role of hypothalamic NPY neurones

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