Increased neuropeptide-Y messenger ribonucleic acid (mRNA) and decreased neurotensin mRNA in the hypothalamus of the obese (ob/ob) mouse.

Wilding, John; Gilbey, S. G.; Bailey, Clifford J.; Batt, R. A. L.; Williams, Gareth; Ghatei, Mohammad A.; Bloom, Stephen R.

doi:10.1210/endo.132.5.7682936

Cited by 222 publications

(93 citation statements)

References 36 publications

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“…The involvement of NPY in the pathophysiology of obesity is supported by the increased levels of NPY and of NPY mRNA in the hypothalamus of obese rodents (41)(42)(43)(44). The enhanced expression levels Y-1R and Y-5R in the OM rats are consistent with the susceptibility of OM rats to develop obesity.…”

Section: Discussionmentioning

confidence: 77%

Effects of a High‐Fat Diet and Strain on Hypothalamic Gene Expression in Rats

et al. 2002

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Effects of a high-fat diet and strain on hypothalamic gene expression in rats. Obes Res. 2002;10:1188 -1196. Objective: This study was designed to investigate whether dietary fat and genetic background might differentially alter the expression of hypothalamic genes involved in food intake. Research Methods and Procedures: Three-month-old Osborne-Mendel (OM) and S5B/Pl rats were fed either a high-fat or a low-fat diet for 14 days. mRNA for neuropeptide Y (NPY), corticotrophin-releasing hormone, NPY Y-1 receptor and Y-5 receptor, and serotonin 2c (5-HT2c) receptors were measured using Northern blotting or ribonuclease protection assays. Results: OM rats showed an increased expression of NPY and corticotrophin-releasing hormone compared with S5B/Pl rats. The expression of NPY-Y1 and -Y5 receptor mRNA was significantly higher in the hypothalamus of OM rats compared with S5B/Pl rats. The expression of 5HT-2c receptor mRNA was significantly reduced in both strains of rats eating a high-fat diet when compared with the animals eating the low-fat diet. Discussion: These data suggest that over activity of the NPY system may contribute to the development of obesity in OM rats and that expression of the 5HT-2c receptor gene may be modulated by dietary fat.

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Section: Discussionmentioning

confidence: 77%

Effects of a High‐Fat Diet and Strain on Hypothalamic Gene Expression in Rats

et al. 2002

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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: 85%

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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“…One potential candidate is the AgRP neuronal population, due to its role in leptin's function and the disrupted expression of AgRP mRNA and peptide of LR Δα mice (51-53). Leptin acts to downregulate AgRP expression and to inhibit AgRP cell activity (54)(55)(56). These actions of leptin require PI3K signaling (7,8).…”

Section: Discussionmentioning

confidence: 99%