Ovarian-adrenal interactions in regulation of body weight by female rats.

Conducted 7 experiments with a total of 40 female Sherman albino rats. Ovariectomy induced an increase, and estrogen treatment after ovariectomy a decrease, in the level at which Ss regulated their body weights. Food-intake changes were transient, intake returning toward normal values as terminal body weight was approached. Results suggest these intake changes were probably secondary to effects on the weight-regulating system itself. Adrenalectomy blocked or reversed the weight gain which followed ovariectomy. This effect was not a matter of incapacity but seemed to reflect a resetting of the weight-regulating system so that a low weight level was voluntarily maintained. (20 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

How should the efficacy of prenatal care be tested in twin gestations?

The aim of the present study was to test the hypothesis that the decreased renal tubular reabsorption of calcium observed in estrogen deficiency is associated with a local regulation of either PTHrP or PTH/PTHrP receptor genes in the kidney. Rats were randomly sham-operated (S) or ovariectomized receiving either vehicle (OVX) or 4 microg E2/kg/day (OVX+E4) or 40 microg E2/kg/d (OVX+E40) during 14 days using alzet minipumps. Plasma PTH and calcium levels were lower in untreated OVX animals than in all other groups (P < 0.01). Plasma PTH was higher in OVX+E40 than in OVX+E4 (P < 0.05). PTHrP mRNA expression in the kidney was unaffected by ovariectomy but was increased in OVX+E40 (0.984 +/- 0.452 for PTHrP/GAPDH mRNAs expression vs. 0.213 +/- 0.078 in sham, P < 0.01). PTH/PTHrP receptor mRNA expression and the cAMP response of renal membranes to PTH were unaffected by ovariectomy and estrogen substitution. In conclusion, renal PTHrP and PTH/PTHrP receptor mRNAs are not modified by ovariectomy. However, 17beta-estradiol increases renal expression of PTHrP mRNA without evident changes in its receptor expression and function. This may help to explain the pharmacological action of estrogen in the kidney, especially how it prevents the renal leak of calcium in postmenopausal women.     

Leptin and corticosterone have opposite effects on food intake and the expression of UCP1 mRNA in brown adipose tissue of lep(ob)/lep(ob) mice

The present study was conducted to assess the interaction effect of leptin and corticosterone on food intake and the expression of uncoupling protein 1 (UCP1) mRNA in interscapular brown adipose tissue (IBAT). To this end, a 3 x 3 factorial experiment was designed in which adrenalectomized (ADX) lep(ob)/lep(ob) mice were subjected to three doses of corticosterone and three doses of leptin. The results confirm the anorectic and orexigenic effects of leptin and corticosterone, respectively. The results also emphasize the abilities of leptin and corticosterone to respectively increase and reduce the expression of UCP1 mRNA in IBAT. The effects of leptin and corticosterone on food intake and the expression of UCP1 mRNA translated into effects on body weight and body composition; leptin reduced body weight and corticosterone increased the weight of IBAT. The present results do not provide evidence for leptin-corticosterone interactions in the control of food intake and thermogenesis. Corticosterone increased food intake and reduced the expression of IBAT UCP1 regardless of the leptin status, and leptin reduced food intake and induced the expression of IBAT UCP1 independently of the corticosterone levels.     

Evidence suggesting that galanin (GAL), melanin-concentrating hormone (MCH), neurotensin (NT), proopiomelanocortin (POMC) and neuropeptide Y (NPY) are targets of leptin signaling in the hypothalamus

Leptin (OB protein) reduces food intake by acting at the hypothalamic level. The purpose of the present study was to identify potential targets of leptin signaling in the hypothalamus in ad-lib fed rats. Central administration of leptin (5 microg) for 3 days decreased food intake and body weight gain in association with a decrease in hypothalamic galanin (GAL), melanin-concentrating hormone (MCH), proopiomelanocortin (POMC) and neuropeptide Y (NPY) gene expression and with an increase in neurotensin (NT) gene expression. In pair-fed rats, NPY gene expression was increased and there was no change in either MCH, GAL, POMC or NT gene expression. This study identifies GAL, MCH, POMC and NT as non-NPY targets of leptin signaling and suggests that leptin's action on food intake and body weight is most likely mediated by inhibiting excitatory (e.g. NPY, MCH, GAL, POMC) and stimulating inhibitory (e.g., NT) signals in the feeding circuitry.     

Food intake, body weight, and adiposity in female rats: actions and interactions of progestins and antiestrogens

A series of experiments examined the effects of two progestins, progesterone and R 5020, and two nonsteroidal antiestrogens, nafoxidine and MER-25, on body weight and composition in female rats. Both progesterone and R 5020 increased food intake, body weight, and carcass adiposity in ovariectomized (OVX) rats treated with estradiol benzoate (EB), but neither progestin had any effect on these measures in OVX rats not treated with EB. R 5020 was substantially more effective than progesterone on all end points. Nafoxidine and MER-25 mimicked the actions of estradiol and decreased adipose tissue lipoprotein lipase (LPL) activity by 75-80%. For adipose tissue LPL activity, both nafoxidine and MER-25 were full estrogen agonists and without antiestrogenic activity. Nafoxidine also mimicked the effects of EB by reducing food intake, body weight, and carcass adiposity in OVX rats. In contrast, nafoxidine antagonized the induction of cytoplasmic progestin ([3H]R 5020) binding sites by EB in parametrial adipose tissue of OVX rats. In nafoxidine-treated OVX rats, concurrent progesterone administration had no effect on adipose tissue LPL activity, but progesterone did increase food intake, body weight, and carcass fat content. Some physiological mechanisms by which gonadal steroids may act to influence eating and adiposity are discussed.     

Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice

Correction of the obese state induced by genetic leptin deficiency reduces elevated levels of both blood glucose and hypothalamic neuropeptide Y (NPY) mRNA in ob/ob mice. To determine whether these responses are due to a specific action of leptin or to the reversal of the obese state, we investigated the specificity of the effect of systemic leptin administration to ob/ob mice (n = 8) on levels of plasma glucose and insulin and on hypothalamic expression of NPY mRNA. Saline-treated controls were either fed ad libitum (n = 8) or pair-fed to the intake of the leptin-treated group (n = 8) to control for changes of food intake induced by leptin. The specificity of the effect of leptin was further assessed by 1) measuring NPY gene expression in db/db mice (n = 6) that are resistant to leptin, 2) measuring NPY gene expression in brain areas outside the hypothalamus, and 3) measuring the effect of leptin administration on hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Five daily intraperitoneal injections of recombinant mouse leptin (150 micrograms) in ob/ob mice lowered food intake by 56% (P < 0.05), body weight by 4.1% (P < 0.05), and levels of NPY mRNA in the hypothalamic arcuate nucleus by 42.3% (P < 0.05) as compared with saline-treated controls. Pair-feeding of ob/ob mice to the intake of leptin-treated animals produced equivalent weight loss, but did not alter expression of NPY mRNA in the arcuate nucleus. Leptin administration was also without effect on food intake, body weight, or NPY mRNA levels in the arcuate nucleus of db/db mice. In ob/ob mice, leptin did not alter NPY mRNA levels in cerebral cortex or hippocampus or the expression of CRH mRNA in the hypothalamic paraventricular nucleus (PVN). Leptin administration to ob/ob mice also markedly reduced serum glucose (8.3 +/- 1.2 vs. 24.5 +/- 3.8 mmol/l; P < 0.01) and insulin levels (7,263 +/- 1,309 vs. 3,150 +/- 780 pmol/l), but was ineffective in db/db mice. Pair-fed mice experienced reductions of glucose and insulin levels that were < 60% of the reduction induced by leptin. The results suggest that in ob/ob mice, systemic administration of leptin inhibits NPY gene overexpression through a specific action in the arcuate nucleus and exerts a hypoglycemic action that is partly independent of its weight-reducing effects. Furthermore, both effects occur before reversal of the obesity syndrome. Defective leptin signaling due to either leptin deficiency (in ob/ob mice) or leptin resistance (in db/db mice) therefore leads directly to hyperglycemia and the overexpression of hypothalamic NPY that is implicated in the pathogenesis of the obesity syndrome.     

Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake

Genetic studies in mice have identified the ob gene product as a potential signaling factor regulating body weight homeostasis and energy balance. It is suggested that modulation of ob gene expression results in changes in body weight and food intake. Glucocorticoids are shown to have important metabolic effects and to modulate food intake and body weight. In order to test the hypothesis that these metabolic effects of glucocorticoids are linked to changes in the expression of the ob gene, ob mRNA levels were evaluated in rats treated with different glucocorticosteroids at catabolic doses and correlated to the kinetics of changes in body weight gain and food intake. Results from time course experiments demonstrate that adipose tissue ob gene expression is rapidly induced by glucocorticosteroids. This induction is followed by a concordant decrease in body weight gain and food consumption. These data suggest that the catabolic effects of corticosteroids on body weight mass and food intake might be mediated by changes in ob expression. Modulation of ob expression may therefore constitute a mechanism through which hormonal, pharmacological, or other factors control body weight homeostasis.     

Neuropeptide Y and corticotropin-releasing hormone concentrations within specific hypothalamic regions of lean but not ob/ob mice respond to food-deprivation and refeeding

Leptin is proposed to control food intake at least in part by regulating hypothalamic neuropeptide Y (NPY), a stimulator of food intake, and corticotropin-releasing hormone (CRH), an inhibitor of food intake. Ob/ob mice are leptin-deficient and would thus be expected to exhibit alterations in hypothalamic NPY and CRH. We therefore measured concentrations of NPY and CRH in discrete regions of the hypothalamus (i.e., ARC, arcuate nucleus; PVN, paraventricular nucleus; VMH, ventromedial nucleus; DMH, dorsomedial nucleus; and SCN, suprachiasmatic nucleus) of 6.5-7-wk-old ob/ob and lean mice with free access to stock diet, 24 h after food deprivation, and 1 h after refeeding. Fed ob/ob mice had 55-75% higher concentrations of NPY in the ARC, VMH and SCN than lean mice. Food deprivation increased NPY concentrations approximately 70% in the ARC, PVN and VMH of lean mice, and refeeding lowered NPY concentrations approximately 70% in the PVN of these mice. NPY in these hypothalamic regions of ob/ob mice was unresponsive to food deprivation or refeeding. The most pronounced change in CRH concentrations within the regions examined (i.e., ARC, PVN and VMH) occurred in the ARC of lean mice where refeeding lowered CRH concentrations by 75% without influencing ARC CRH concentrations in ob/ob mice. The hypothalamic concentrations of two neuropeptides involved in body weight regulation (i.e., NPY and CRH) in leptin-deficient ob/ob mice respond abnormally to abrupt changes in nutritional status.     

Nicotinic agonists competitively antagonize serotonin at mouse 5-HT3 receptors expressed in Xenopus oocytes

Leptin is an adipocyte-derived blood-borne satiety factor that decreases food intake and increases energy expenditure, thereby leading to a substantial decrease in body weight. To explore the possible roles of the hypothalamic melanocortin system in leptin action, we examined the effects of intracerebroventricular (i.c.v.) injection of leptin with or without SHU9119, a potent antagonist of alpha-melanocyte stimulating hormone, on food intake, body weight, and mitochondrial uncoupling protein-1 (UCP-1) mRNA expression in the brown adipose tissue (BAT) in rats. A single i.c.v. injection of leptin decreased cumulative food intake and body weight gain, and increased UCP-1 mRNA expression during 3 h at the onset of the dark phase. Inhibition of food intake and body weight change with leptin was reversed by co-injection of SHU9119 in a dose-dependent manner. Co-injection of SHU9119 also inhibited completely the leptin-induced increase in UCP-1 mRNA expression in the BAT. Treatment with SHU9119 alone did not affect food intake, body weight, and UCP-1 mRNA expression in rats. The present study provides evidence that the hypothalamic melanocortin system plays a central role in both satiety effect and sympathetic activation of leptin.     

Alterations in the postovariectomy increases in gonadotropin secretion in middle-aged persistent-estrous rats: correlation with pituitary gonadotropin subunit gene expression

This study compared the changes in pituitary and serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) at various times following ovariectomy (OVX) between young cyclic and middle-aged persistent-estrous (PE) rats and related these to the relative gene expression of the pituitary gonadotropin subunits. In intact animals, both pituitary and serum levels of LH were similar between these two age groups, while the LH beta mRNA expression was significantly (p < 0.05) greater in young rats. Following OVX in young rats, the serum LH levels markedly increased (p < 0.05) beginning on day 7 and reaching a maximum fourfold increase by day 9. In contrast, the post-OVX increases in serum LH in middle-aged females were significantly delayed. OVX significantly (p < 0.05) increased pituitary LH contents of young rats by day 5, but had no effect on LH contents in middle-aged females until day 30 post-OVX. These changes were associated with increases in LH beta mRNA expression in both young and middle-aged females, but the levels were significantly (p < 0.05) lower in middle-aged females. Both pituitary and serum levels of FSH were significantly (p < 0.05) higher in middle-aged PE than in young rats prior to OVX, while the FSH beta mRNA expression was similar in both age groups. Following OVX in young rats, serum FSH levels rapidly increased (p < 0.05) on day 3 and attained tenfold higher values by day 30.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperphagia induced by hypoglycemia in rats is independent of leptin and hypothalamic neuropeptide Y (NPY)

Hypoglycemia causes hyperphagia and weight gain, through unknown peripheral and central signals. We investigated the effect of hypoglycemia on NPY and leptin expression and the ability of leptin to inhibit hypoglycemia-induced hyperphagia. Acute hypoglycemia (60 U/kg SC insulin; n = 8) increased food intake (p < 0.01) compared with controls (n = 8). Insulin- and leptin-treated rats (300 microg/kg IP leptin; n = 8) had reduced hyperphagia (p < 0.05 vs. controls; p < 0.05 vs. insulin alone) and a 15% fall in NPY mRNA levels compared with controls (p < 0.01). Chronic hypoglycemia, (20-60 U/kg/day insulin; n = 8) increased food intake compared with vehicle-treated controls (p < 0.01). Leptin and insulin administration (300 microg/kg/day IP leptin; n = 8) reduced hyperphagia (p < 0.01 vs. controls, p < 0.05 vs. insulin alone), and NPY mRNA fell by 18% vs. controls (p < 0.01). We conclude that hypoglycemia-induced hyperphagia is not mediated by either a fall in leptin or an increase in hypothalamic NPY mRNA. Leptin can inhibit feeding in hyperphagic hypoglycemic rats, and this may partly be attributable to its inhibition of the NPY neurons.     

Effect of cimetidine on weight gain in rats

Effect on food intake and body weight was studied in rats after oral administration of cimetidine. Rats in experimental (E) group exhibited less increase in food intake (20%) compared to control (C) rats (43.8%). Mean body weight showed first reduction (-9.56%) and then very small increment in experimental animals compared to gradual gain in body weight in control animals. At the end of 6 weeks, total gain in body weight was 22.5 gm in rats of E group against 53.8 gm in rats of C group. Food efficiency ratio (FER) showed much reduction (1.13) in E group against 2.07 in C group. These results demonstrate that cimetidine (H2-receptor blocker) may have ability to reduce food intake and body weight in rats.     

Filamentous actin disruption and diminished inositol phosphate response in gingival fibroblasts caused by Treponema denticola

A large body of evidence suggests that the neuroendocrine axis plays a major role in the reproductive aging of female rats. Since increased hypothalamic neuropeptide Y (NPY) neurosecretion is crucial in the preovulatory LH discharge in young rats, we tested the hypothesis that diminution in the preovulatory LH surge in middle-aged (MA) rats may be due to altered neurosecretory activity in NPYergic neurons. In Exp 1, we examined NPY levels in six microdissected hypothalamic nuclei, including median eminence (ME), arcuate nucleus (ARC), and medial preoptic area (MPOA), at 1000, 1200, 1400, 1600, 1800, 2000, or 2200 h on the day of proestrus in young (2.5- to 3-month old) and MA (7- to 9-month old) regularly cycling rats. At 1000 h, ME NPY levels in young rats were significantly lower than those in MA rats. In young rats, the ME NPY levels were significantly increased at 1400 h before the LH surge in the afternoon and thereafter decreased progressively during the interval of the LH surge. In MA rats, however, ME NPY levels decreased in the afternoon in association with an attenuated LH surge. In addition, in the ARC and MPOA, the other hypothalamic sites associated with induction of LH surge, NPY levels increased before and during the LH surge in young rats, no change in NPY levels in these nuclei was observed in association with the attenuated LH surge in MA rats. Also, NPY levels in the ARC and MPOA during the afternoon were significantly lower in MA compared with those in young animals. These results demonstrated the absence of an antecedent increase in NPY levels, specifically in the ME and ARC, during the afternoon of proestrus in MA animals. In a second experiment, we evaluated whether the absence of dynamic changes in NPY levels in the ME and ARC in MA rats was due to altered hypothalamic NPY gene expression. Regularly cycling young (2.5- to 3-month-old) and MA (8- to 10-month-old) rats were killed at 1000, 1200, 1400, 1600, 1800, 2000, or 2200 h on the day of proestrus. The medial basal hypothalamus was processed for prepro-NPY messenger RNA (mRNA) measurement by ribonuclease protection assay. In young rats, prepro-NPY mRNA levels were significantly increased at 1200 h and remained elevated throughout the afternoon. In contrast, in MA rats prepro-NPY mRNA levels remained unchanged before and during the attenuated LH surge. These results clearly indicate that the augmentation in NPY neuronal activity before and during the LH surge seen in young rats fails to manifest itself in middle-aged rats. As hypothalamic NPY participates in the induction of LHRH surge, our results suggest that reduced LHRH and LH surges in MA rats may be due to diminution in NPY secretion in these animals.     

Determinants of successful defibrillation

The sexual difference of calcium-binding protein regucalcin mRNA expression in the liver of rats was investigated by Northern blot analysis. Liver regucalcin cDNA (0.9 kb of open reading frame) was used as a probe. The analysis of total RNAs extracted from various tissues of rats indicated that regucalcin mRNA was present primarily in the liver with a size of 1.8 kb. Hepatic regucalcin mRNA was expressed in male rats more than in females. This sexual difference was also seen in aged rats (50 weeks old), although the expression was decreased with increasing age. Ovariectomy did not cause a significant alteration in hepatic regucalcin mRNA levels. The subcutaneous administration of 17beta-estradiol (0.2 mg/100 g body weight) in ovariectomized rats did not cause an appreciable increase in hepatic mRNA levels. The results demonstrate that regucalcin mRNA expression in rat liver is based on sex, and that this difference may not be related to estrogen.     

Effectiveness of estradiol in preventing and reversing obesity induced by ovariectomy and high-caloric diet in female rats.

Four experiments with 77 female Holtzman rats examined the effects of estradiol benzoate (EB) on food intake, body weight (BW), ano-nasal length, and BW/body length ratio in ovariectomized (OVX) and intact Ss maintained on control or high-fat diets and of OVX and intact Ss that had been reduced by deprivation. EB was highly effective in preventing the increase in food intake, BW, and ano-nasal growth after OVX; it was relatively ineffective in reversing BW gain after OVX. However, when ano-nasal length was also considered, BW was effective in returning OVX Ss to an appropriate BW for their increased ano-nasal length. Intact Ss fed a high-caloric diet did not exhibit an increased rate of ano-nasal growth, which indicates that the skeletal growth that occurred after OVX was not simply a result of increased food intake. It is concluded that EB modulates food intake and BW by multiple mechanisms, one of which is by modulating skeletal growth. The nature of the effect of EB on BW of intact Ss suggests that this effect occurs by still another mechanism. (13 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Complex probes for high-throughput parallel genetic mapping of genomic mouse BAC clones

We investigated the effect of centrally administered pituitary adenylate cyclase activating polypeptide (PACAP) on feeding in rats, and the involvement of hypothalamic neuropeptide gene expression using in situ hybridization. Intracerebroventricular injection of PACAP (1000 pmol/rat) significantly decreased food intake in a dose-dependent manner. In PACAP-treated rats, neuropeptide Y (NPY) mRNA levels in the arcuate nucleus and galanin mRNA levels in the paraventricular nucleus increased, and corticotropin-releasing hormone (CRH) mRNA levels in the paraventricular nucleus decreased. In rats fasted for 72 h, NPY mRNA levels increased, and CRH mRNA levels decreased, but galanin mRNA levels were unchanged. These results indicate that the anorectic function of PACAP is not mediated by NPY or CRH, and that PACAP increases galanin synthesis.     

Zinc deficiency increases hypothalamic neuropeptide Y and neuropeptide Y mRNA levels and does not block neuropeptide Y-induced feeding in rats

Zinc deficiency reduces intake and produces an unusual approximately 3.5-d cycle of intake in rats. The mechanism underlying the anorexia and cycling has not yet been defined; current hypotheses suggest that alterations in amino acid metabolism and neurotransmitter concentrations may be a part of this anorexia. Recent reports indicate that appetite-stimulating neuropeptide Y (NPY) may be elevated during zinc deficiency. This suggests that a resistance to NPY may exist during zinc deficiency because NPY levels are high, yet appetite is low. The purpose of this study was to measure NPY peptide and mRNA concentrations during zinc deficiency in specific nuclei of the hypothalamus in which peptide and mRNA for NPY are known to be associated with appetite, and also to determine whether zinc-deficient rats are responsive to central infusions of NPY. Both NPY peptide levels in the paraventricular nucleus and NPY mRNA levels in the arcuate nucleus were higher (P < 0.05) in zinc-deficient rats than in zinc-adequate rats. When rats were administered exogenous NPY to the paraventricular nucleus, both zinc-deficient and zinc-adequate rats responded similarly by increasing food intake. These results suggest that NPY is elevated during zinc deficiency in an attempt to restore normal food intake levels, rather than being reduced and thereby contributing to the anorexia associated with zinc deficiency. During zinc deficiency, NPY receptors are able to bind NPY and initiate an orexigenic response.     

Effects of aldosterone and deoxycorticosterone on food intake and body weight.

Conducted an experiment with 48 female adrenalectomized Sprague-Dawley rats, who were injected daily with aldosterone (.25 mg/kg) or deoxycorticosterone (3 mg/kg) in combination with corticosterone. The mineralocorticoids increased food intake and weight gain well beyond that of controls receiving only corticosterone injections. The weight gain was not wholly dependent on increased food intake, as separate groups of Ss maintained on a restricted diet (10 g of laboratory chow/day) also displayed significant mineralocorticoid-stimulated weight gain. Although carcass composition was not directly determined, the undifferentiated wet/dry tissue ratios, hematocrit values, and nasoanal lengths found across groups suggested that the observed effect of mineralocorticoids was on body fat. Aldosterone and deoxycorticosterone can have important actions on energy metabolism as well as on sodium regulation. (9 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)