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Dive into the research topics where H.David McCarthy is active.

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Featured researches published by H.David McCarthy.


European Journal of Pharmacology | 1994

Megestrol acetate stimulates food and water intake in the rat: effects on regional hypothalamic neuropeptide Y concentrations

H.David McCarthy; Rachel E. Crowder; Simon Dryden; Gareth Williams

Megestrol acetate, a synthetic progestogen, stimulates appetite through an unknown mechanism. We tested the hypothesis that it might act, at least in part, by stimulating the activity of hypothalamic pathways containing neuropeptide Y, a potent central appetite stimulant in rats. Administration of megestrol acetate (50 mg/kg/day, n = 8) for 9 days significantly increased food and water intake compared with untreated controls (n = 8). Treated rats showed significant (90-140%) increases in neuropeptide Y concentrations in the arcuate nucleus (where neuropeptide Y is synthesized), in the lateral hypothalamic area (through which arcuate neurones project) and in the medial preoptic area, ventromedial nucleus and dorsomedial nucleus. The latter are sites of neuropeptide Y release and sensitive to neuropeptide Y-induced hyperphagia. Megestrol acetate may therefore stimulate neuropeptide Y synthesis, transport and release, and this could contribute to its appetite-stimulating effects.


Peptides | 1992

Insulin deficiency is a specific stimulus to hypothalamic neuropeptide Y: A comparison of the effects of insulin replacement and food restriction in streptozocin-diabetic rats ☆

Pauline E. McKibbin; H.David McCarthy; Paul Shaw; Gareth Williams

Untreated insulin-deficient diabetes causes hyperphagia and neuroendocrine disturbances that may be partly mediated by increased hypothalamic activity of neuropeptide Y (NPY), a potent central appetite stimulant. The metabolic signal that stimulates hypothalamic NPY is unknown. This study aimed to determine whether insulin deficiency or hyperglycemia was responsible. Regional hypothalamic NPY concentrations were compared in streptozocin-diabetic (STZ-D) rats rendered nearly normoglycemic by either insulin replacement or food restriction. Untreated STZ-D rats were hyperphagic and showed significantly increased (p less than 0.01) hypothalamic NPY concentrations in the arcuate nucleus and lateral hypothalamic area. Once-daily ultralente insulin injections corrected hypoinsulinemia and hyperglycemia, abolished hyperphagia, and normalized NPY concentrations in all hypothalamic regions. By contrast, food restriction effectively lowered glycemia without raising insulin levels. In these underfed diabetic rats, NPY concentrations rose further and were significantly higher than nondiabetic and untreated diabetic levels in most hypothalamic regions. We conclude that insulin deficiency is a major stimulus to hypothalamic NPY in STZ-D, whereas hyperglycemia may exert an inhibitory influence. These findings support the hypothesis that hypothalamic NPY responds to specific metabolic cues and is involved in regulating energy balance and conserving body weight.


Life Sciences | 1991

Hypothalamic neuropeptide Y receptor characteristics and NPY-induced feeding responses in lean and obese Zucker rats

H.David McCarthy; Pauline E. McKibbin; Brian Roy Holloway; Rachel M. Mayers; Gareth Williams

Increased hypothalamic neuropeptide Y levels have previously been demonstrated in several hypothalamic nuclei of the (fa/fa) Zucker rat. This study set out to characterise hypothalamic NPY receptors in both genotypres and to study the effect of exogenous NPY on feeding behavior in these rats. Spontaneous daytime food intake was raised in the obese rat (p less than 0.05). Total hypothalamic receptor density (Bmax) was reduced in the obese rat compared with the lean rat (by 56%, p less than 0.005), but affinity remained unaltered. The lowest dose of NPY tested (23.5 pmol) stimulated daytime feeding in lean rats after 1, 2 and 3 hours but was inaffective in the obese rat (p less than 0.05). At two higher doses (235 pmol and 2.35 nmol), NPY was equipotent in both genotypes over 1 and 2 hours but NPY-induced feeding was attenuated over 3 hours in the obese rat. These results suggest an overactive endogenous NPYergic system in the obese (fa/fa) rat which might contribute to hyperphagia and obesity in this strain.


Peptides | 1992

Hypothalamic neuropeptide Y disturbances in the obese (cp/cp) JCR:LA corpulent rat

Gareth Williams; Lyndsey Shellard; Diane E. Lewis; Pauline E. McKibbin; H.David McCarthy; Dorothy G. Koeslag; James C. Russell

Regional hypothalamic neuropeptide Y (NPY) concentrations were compared between cp/cp JCR:LA corpulent rats, which were grossly obese, hyperphagic, and hyperinsulinemic, and lean (+/+) controls. In freely fed cp/cp rats, NPY levels in the arcuate nucleus (ARC) were 31% higher than in lean rats (p less than 0.001). In lean rats, chronic food restriction significantly raised NPY levels by 22% in the ARC (p less than 0.05) and by 44% in the dorsomedial nucleus (DMH; p less than 0.05). By contrast, food-restricted cp/cp rats showed no change in the ARC, but NPY levels rose in the DMH (by 36%; p less than 0.05) and ventromedial nucleus (31%; p less than 0.05). Increased NPY levels in the ARC, the major site of hypothalamic NPY synthesis, suggests increased NPYergic activity in cp/cp rats; given the central actions of NPY, this could contribute to hyperphagia, obesity, and hyperinsulinemia in this syndrome. Abnormal NPY responses to food deprivation further suggest dysregulation of NPY in cp/cp rats.


Peptides | 1992

Peripheral insulin administration attenuates the increase in neuropeptide Y concentrations in the hypothalamic arcuate nucleus of fasted rats

Usman H. Malabu; H.David McCarthy; Pauline E. McKibbin; Gareth Williams

Fasting increases neuropeptide Y (NPY) concentrations in the arcuate nucleus (ARC), its site of synthesis, and in other regions of the rat hypothalamus. Neuropeptide Y is a potent central orexigenic agent and may therefore stimulate appetite during fasting. We tested the hypothesis that low plasma insulin levels stimulate ARC levels of NPY in fasted rats. Compared with freely fed controls (n = 8), rats fasted for 72 h (n = 8) showed significantly lower plasma insulin levels (28.9 +/- 1.6 vs. 52.6 +/- 5.7 pmol/l; p < 0.001) and higher ARC NPY concentrations (14.2 +/- 1.8 vs. 8.4 +/- 2.2 fmol/micrograms protein; p < 0.001). Fasted rats treated with subcutaneous insulin (5 U/kg/day; n = 10), which nearly normalized plasma insulin (46.6 +/- 2.8 pmol/l), showed intermediate ARC NPY levels (11.2 +/- 1.4 fmol/micrograms protein; p < 0.01 vs. controls and untreated fasted rats). Insulin administered peripherally, therefore, attenuates fasting-induced NPY increases in the ARC, supporting the hypothesis that hypoinsulinemia stimulates hypothalamic NPY.


Peptides | 1993

Increased neuropeptide Y concentrations in specific hypothalamic nuclei of the rat following treatment with methysergide: evidence that NPY may mediate serotonin's effects on food intake.

Simon Dryden; H.David McCarthy; Usman H. Malabu; M. Ware; Gareth Williams

Neuropeptide Y (NPY) is a potent central appetite stimulant found in hypothalamic neurons that have close anatomical associations with neurons containing serotonin, a powerful anorectic agent. To determine whether the two neurotransmitters interact functionally, we have studied the effects on regional hypothalamic NPY concentrations of acute and chronic administration of methysergide, a 5-HT1BC/serotonin receptor antagonist. Chronic methysergide treatment (10 mg/kg/day) was given by subcutaneously implanted osmotic minipumps (n = 8). Acute effects of methysergide were determined 4 h after a single injection (10 mg/kg) in a separate group (n = 8). Controls (n = 8) had implanted minipumps delivering saline, and also received a saline injection 4 h before sacrifice. Food intake was significantly increased (p < 0.01) by both acute and chronic methysergide treatment. In the chronically treated rats, NPY levels were significantly increased over controls in the arcuate nucleus (ARC; by 41%, p = 0.02) and paraventricular nucleus (PVN; by 40%, p < 0.01). Acute methysergide treatment also increased NPY concentrations in the ARC (by 81%, p < 0.01) and PVN (by 30%, p < 0.01). Methysergide administration, which stimulated feeding, therefore raised NPY concentrations in the ARC, where NPY is synthesized, and in the PVN, a major site of NPY release where NPY injection induces hyperphagia. These findings suggest that NPYergic and serotoninergic innervations in the hypothalamus interact to regulate food intake, and raise the possibility that increased NPY release may mediate the hyperphagic effect of serotoninergic 5-HT1BC/receptor blockade.


Life Sciences | 1992

The effect of dexamethasone on neuropeptide y concentrations in specific hypothalamic regions

Pauline E. McKibbin; Stephen J. Cotton; H.David McCarthy; Gareth Williams

Neuropeptide Y (NPY) is a major hypothalamic peptide which is implicated in the regulation of energy balance and in the activation of the hypothalamo-pituitary adrenal axis. This study aimed primarily to determine the effects on regional hypothalamic NPY levels, of catabolism and weight loss induced in rats by the synthetic glucocorticoid, dexamethasone, injected daily at a dose of 0.4 mg/kg for 7 days. NPY concentrations were significantly raised in the paraventricular nucleus (PVN) of male Wistar rats (45%, p = 0.009; n = 10) compared with saline-injected controls (n = 10). Body weight (p less than 0.001) and food intake (p less than 0.001) were significantly reduced, plasma insulin concentrations were increased (p less than 0.001), but there was no change in glucose concentrations. Chronic dexamethasone treatment did not cause the marked NPY increases in the arcuate nucleus (ARC) and other hypothalamic regions which have been observed in other catabolic states causing weight loss. One possible explanation is the high insulin levels induced by dexamethasone, which may have prevented compensatory hyperphagia by suppressing an increase in hypothalamic NPYergic activity. We also examined the acute effects of a single dexamethasone injection on regional hypothalamic levels, to determine whether the drug had a direct action separate from that due to sustained weight loss. In the acute study, groups of rats (n = 7) were examined at 4 h after a single injection of dexamethasone or saline. NPY concentrations were significantly increased in the lateral hypothalamic area (LHA), (60%, p = 0.008) when compared with saline-injected controls, but there was no change in body weight or glucose or insulin concentrations during the 4h interval. Altered transport or release of NPY in the lateral hypothalamic area may be a result of acute feedback regulation by glucocorticoids on the hypothalamus.


Peptides | 1991

Unchanged hypothalamic neuropeptide Y concentrations in hyperphagic, hypoglycemic rats: Evidence for specific metabolic regulation of hypothalamic NPY

Susan E. Corrin; H.David McCarthy; Pauline E. McKibbin; Gareth Williams

Hypothalamic concentrations of neuropeptide Y (NPY), a potent central appetite stimulant, increase dramatically in food-restricted and insulin-deficient diabetic rats. This suggest that NPY may drive hyperphagia in these conditions, which are characterized by weight loss and insulin deficiency. To test the hypothesis that insulin deficiency and weight loss are specific stimuli to hypothalamic NPY, we measured NPY concentrations in individual hypothalamic regions in rats with hyperphagia caused by insulin-induced hypoglycemia. Groups of 8 male Wistar rats were injected with ultralente insulin (20-60 U/kg) to induce either acute hypoglycemia (7 h after a single injection) or chronic hypoglycemia (8 days with daily injections). In hypoglycemic rats, plasma insulin concentrations were increased 6- to 7-fold compared with saline-injected controls; food intake was significantly increased with acute and chronic hypoglycemia and weight gain was significantly increased in the chronically hypoglycemic group. NPY concentrations were measured by radioimmunoassay in 8 hypothalamic regions microdissected from fresh brain slices. NPY concentrations were not increased in any region in either acute or chronic hypoglycemia. NPY therefore seems unlikely to mediate hyperphagia in hyperinsulinemia-induced hypoglycemia, supporting the hypothesis that weight loss is a specific stimulus to hypothalamic NPY and that insulin deficiency may be the metabolic signal responsible.


Peptides | 1993

Neuropeptide Y receptor numbers are reduced in the hypothalamus of streptozotocin-diabetic and food-deprived rats: Further evidence of increased activity of hypothalamic NPY-containing pathways

Helen M. Frankish; H.David McCarthy; Simon Dryden; A. Kilpatrick; Gareth Williams


Proceedings of the Nutrition Society | 1991

Neuropeptides and intestinal tract in the control of glucose Homeostasis Hypothalamic regulatory peptides and the regulation of food intake and energy balance: signals or noise?

Gareth Williams; Pauline E. McKibbin; H.David McCarthy

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Simon Dryden

University of Liverpool

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Brian Roy Holloway

Imperial Chemical Industries

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M. Ware

University of Liverpool

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