Modulation of estrogen action in the rat pituitary and mammary glands by dietary energy consumption.
We are investigating the mechanisms through which estrogens induce development of prolactin (PRL)-producing pituitary tumors and mammary carcinomas in rats and how these mechanisms are affected by dietary energy consumption. The hypothesis under examination is that dietary energy restriction inhibits tumorigenesis in estrogen-responsive tissues by altering cellular responsiveness to estrogenic hormones. In the Fischer 344 (F344) rat strain, a 40% restriction of energy consumption virtually abolishes development of estrogen-induced pituitary tumors. Inhibition of pituitary tumorigenesis in the F344 strain by energy restriction results from modulation of estrogen regulation of cell survival, not cell proliferation. In contrast, energy restriction has no inhibitory effect on estrogen-induced pituitary tumor development in the ACI rat strain. However, energy restriction markedly inhibits induction of mammary carcinomas in female ACI rats treated with 17beta-estradiol. Data presented herein indicate that dietary energy restriction modulates the responsiveness of specific cell populations to estrogenic hormones and thereby inhibits estrogen-induced tumorigenesis in a manner specific to both rat strain and tissue. (+info)
Cells within the lateral hypothalamic area (LHA) are important in eating control. Glutamate or its analogs, kainic acid (KA) and N-methyl-D-aspartate (NMDA), elicit intense eating when microinjected there, and, conversely, LHA-administered NMDA receptor antagonists suppress deprivation- and NMDA-elicited eating. The subunit composition of LHA NMDA receptors (NMDA-Rs) mediating feeding, however, has not yet been determined. Identifying this is important, because distinct second messengers/modulators may be activated by NMDA-Rs with differing compositions. To begin to address this, we detected LHA NR2A and NR2B subunits by immunoblotting and NR2B subunits by immunohistochemistry using subunit-specific antibodies. To help determine whether NMDA-Rs mediating feeding might contain these subunits, we conducted behavioral studies using LHA-administered ifenprodil, an antagonist selective for NR2A- and/or NR2B-containing NMDA-Rs at the doses we used (0.001-100 nmol). Ifenprodil maximally suppressed NMDA- and deprivation-elicited feeding by 63 and 39%, respectively, but failed to suppress KA-elicited eating, suggesting its actions were behaviorally specific. Collectively, these results suggest that LHA NMDA-Rs, some of which contribute to feeding control, are composed of NR2A and/or NR2B subunits, and implicate NR2A- and/or NR2B-linked signal transduction in feeding behavior. (+info)
Effect of long-term food restriction on pituitary sensitivity to cLHRH-I in broiler breeder females.
The effect of long-term food restriction on the sensitivity of the pituitary to exogenously administered chicken luteinizing hormone releasing hormone I (cLHRH-I) was investigated in three groups of broiler breeder females fed ad libitum, fed a restricted quantity of food or fed a restricted quantity of food to obtain an intermediate body weight between those of the first two groups. At 16 weeks of age, basal FSH release was higher in ad libitum fed birds, culminating in ovarian development and subsequent oestradiol production by the small follicles. At this age, LH secretion was independent of ovarian feedback factors. In all groups, cLHRH-I was most active in releasing LH in intact and ovariectomized animals and, to a lesser extent, in releasing FSH in ovariectomized birds. At 39 weeks of age, basal FSH concentrations were similar among intact animals of all groups, whereas LH concentrations differed among groups, with higher values in the restricted birds. This food effect was enhanced in ovariectomized birds. Furthermore, the high response to cLHRH-I in the ovariectomized, restricted birds compared with the ad libitum, ovariectomized group suggests an improved sensitivity of the hypothalamic-pituitary axis. In conclusion, birds fed ad libitum showed the highest responsiveness to ovarian factors and to cLHRH-I in releasing FSH in the period before sexual maturity. No effect of amount of feeding could be observed for LH. However, during the egg laying period, LH release by cLHRH-I was highly dependent on amount of feeding and on ovarian feedback regulation. This finding indicates that the amount of feeding can modify the sensitivity of the pituitary to cLHRH-I, and possibly to gonadal hormones, during the laying period. (+info)
Expression of T lymphocyte p56(lck), a zinc-finger signal transduction protein, is elevated by dietary zinc deficiency and diet restriction in mice.
Compromised immune function is common to Zn deficiency, protein and energy malnutrition; however, the causative mechanisms at the molecular level have not been elucidated. The T lymphocyte signal transduction pathway contains several Zn-finger proteins, and it is possible that the in vivo functioning of these proteins could be affected by dietary deficiency of Zn and amino acids. Thus, the objective was to investigate the effects, on expression of the T lymphocyte signal transduction proteins p56(lck), phospholipase Cgamma1 (PLCgamma1) and protein kinase C (PKCalpha), of dietary Zn deficiency (ZnDF, < 1 mg Zn/kg diet) and protein-energy malnutrition syndromes [2% protein deficiency (LP), combined Zn and 2% protein deficiency (ZnDF+LP), and diet restriction (DR, body weight equal to ZnDF)] compared with control (C) mice. Indices of nutritional status and splenocyte counts were also determined. Based on serum albumin and liver lipid concentrations, the ZnDF+LP and LP groups had protein-type malnutrition, whereas the ZnDF and DR groups had energy-type malnutrition. For Western immunoblotting of the signal transduction proteins, mouse splenic T lymphocytes were isolated by immunocolumns. The expression of T lymphocyte p56(lck) was significantly elevated in the ZnDF+LP, ZnDF and DR groups compared to the C group. In contrast, the expression of PLCgamma1 and PKC was unaffected. There was a significant negative correlation between T lymphocyte p56(lck) expression and serum Zn (r= -0.65, P = 0.0007) or femur Zn (r = -0.73, P = 0.0001) concentrations. We propose that elevated T lymphocyte p56(lck) may contribute to altered thymoctye maturation, apoptosis and lymphopenia in Zn deficiency and protein-energy malnutrition syndromes. (+info)
Interaction between genetic and dietary factors determines beta-cell function in Psammomys obesus, an animal model of type 2 diabetes.
The gerbil Psammomys obesus develops nutrition-dependent diabetes. We studied the interaction between diet and diabetic predisposition for beta-cell function. A 4-day high-energy (HE) diet induced a 3-, 4-, and 1.5-fold increase in serum glucose, insulin, and triglycerides, respectively, in diabetes-prone (DP) but not diabetes-resistant (DR) P. obesus. Hyperglycemia and concurrent 90% depletion of islet immunoreactive insulin stores were partially corrected by an 18-h fast. In vitro early insulin response to glucose was blunted in both DR and DP perifused islets. The HE diet augmented early and late insulin response in DR islets, whereas in DP islets, secretion progressively declined. Dose-response studies showed a species-related increase in islet glucose sensitivity, further augmented in DP P. obesus by a HE diet, concomitant with a decreased threshold for glucose and a 55% reduction in maximal response. These changes were associated with a fourfold increase in glucose phosphorylation capacity in DP islets. There were no differences in islet glucokinase (GK) and hexokinase (HK) Km; however, GK Vmax was 3.7- to 4.6-fold higher in DP islets, and HK Vmax was augmented 3.7-fold by the HE diet in DP islets. We conclude that the insulin-resistant P. obesus has an inherent deficiency in insulin release. In the genetically predisposed P. obesus (DP), augmented islet glucose phosphorylation ability and diet-induced reduction of the glucose threshold for secretion may lead to inadequate insulin secretion and depletion of insulin stores in the presence of caloric abundance. Thus, genetic predisposition and beta-cell maladaptation to nutritional load seem to determine together the progression to overt diabetes in this species. It is hypothesized that similar events may occur in obese type 2 diabetic patients. (+info)
Phosphate depletion in the rat: effect of bisphosphonates and the calcemic response to PTH.
BACKGROUND: The removal of phosphate from the diet of the growing rat rapidly produces hypercalcemia, hypophosphatemia, hypercalciuria, and hypophosphaturia. Increased calcium efflux from bone has been shown to be the important cause of the hypercalcemia and hypercalciuria. It has been proposed that the increased calcium efflux from bone is osteoclast mediated. Because bisphosphonates have been shown to inhibit osteoclast-mediated bone resorption, this study was performed to determine whether bisphosphonate-induced inhibition of osteoclast function changed the biochemical and bone effects induced by phosphate depletion. METHODS: Four groups of pair-fed rats were studied: (a) low-phosphate diet (LPD; phosphate less than 0.05%), (b) LPD plus the administration of the bisphosphonate Pamidronate (APD; LPD + APD), (c) normal diet (ND, 0.6% phosphate), and (d) ND + APD. All diets contained 0.6% calcium. A high dose of APD was administered subcutaneously (0.8 mg/kg) two days before the start of the study diet and on days 2, 6, and 9 during the 11 days of the study diet. On day 10, a 24-hour urine was collected, and on day 11, rats were either sacrificed or received an additional APD dose before a 48-hour parathyroid hormone (PTH) infusion (0.066 microgram/100 g/hr) via a subcutaneously implanted miniosmotic pump. RESULTS: Serum and urinary calcium were greater in the LPD and LPD + APD groups than in the ND and ND + APD groups [serum, 11.12 +/- 0.34 and 11.57 +/- 0.45 vs. 9.49 +/- 0.17 and 9.48 +/- 0.15 mg/dl (mean +/- SE), P < 0.05; and urine, 8.78 +/- 2.74 and 16.30 +/- 4.68 vs. 0.32 +/- 0.09 and 0.67 +/- 0.28 mg/24 hr, P < 0.05]. Serum PTH and serum and urinary phosphorus were less in the LPD and LPD + APD than in the ND and ND + APD groups (P < 0.05). The calcemic response to PTH was less (P < 0.05) in the LPD and LPD + APD groups than in the ND group and was less (P = 0.05) in the LPD + APD than in the ND + APD group. Bone histology showed that phosphate depletion increased the osteoblast and osteoclast surface, and treatment with APD reduced the osteoblast surface (LPD vs. LPD + APD, 38 +/- 4 vs. 4 +/- 2%, P < 0.05, and ND vs. ND + APD, 20 +/- 2 vs. 5 +/- 2%, P < 0.05) and markedly altered osteoclast morphology by inducing cytoplasmic vacuoles. CONCLUSIONS: (a) Phosphate depletion induced hypercalcemia and hypercalciuria that were not reduced by APD administration. (b) The calcemic response to PTH was reduced in phosphate-depleted rats and was unaffected by APD administration in normal and phosphate-depleted rats, and (c) APD administration markedly changed bone histology without affecting the biochemical changes induced by phosphate depletion. (+info)
Growth hormone promotes somatic and skeletal muscle growth recovery in rats following chronic protein-energy malnutrition.
The efficacy of recombinant human growth hormone (GH) and/or a diet enriched in protein and energy to improve growth recovery following prolonged malnutrition was examined in male rats food-restricted from birth until 120 d of age. At d 121, restricted rats were randomly assigned to recovery groups receiving either a control or enriched diet with or without daily subcutaneous injections of GH. Rats were killed after 16 or 47 d of recovery. At d 16, GH treatment stimulated liver, heart, plantaris, soleus, carcass and body weight gain and inhibited fat gain when compared to recovery controls. Rats receiving GH also exhibited the highest serum insulin-like growth factor-I (IGF-I) concentrations and total muscle protein. At d 47, GH effects on body and muscle recovery were minimal, and differences among recovery groups in serum IGF-I concentration and total muscle protein were no longer present. Consumption of an enriched diet increased fat pad and liver mass, but did not promote muscle recovery. There were no differences among treatment groups in skeletal muscle IGF-I mRNA levels at d 16 or 47. In summary, GH had positive effects on somatic and skeletal muscle growth early in the recovery process, possibly via endocrine IGF-I-stimulated protein accretion. In contrast, the enriched diet promoted fat deposition with no impact on skeletal muscle growth recovery. (+info)
Feed deprivation affects crop environment and modulates Salmonella enteritidis colonization and invasion of leghorn hens.
Leghorn hens over 50 weeks of age were assigned to two treatment groups designated as either unmolted controls or molted. A forced molt was induced by a 9-day feed withdrawal, and each hen was challenged orally with 10(5) Salmonella enteritidis organisms on day 4 of feed withdrawal. On days 4 and 9 of molt, the numbers of lactobacilli and the concentrations of lactate, acetate, propionate, and butyrate, and total volatile fatty acids in the crops decreased while crop pH increased significantly (P < 0.05) in the molted hens compared to the controls. S. enteritidis crop and cecal colonization, in addition to spleen and liver invasion, increased significantly (P < 0.05) in the molted hens compared to the controls. The invasive phenotype of Salmonella spp. is complex and requires several virulence genes which are regulated by the transcriptional activator HilA. Samples of the crop contents from the molted and unmolted birds were pooled separately, centrifuged, and filter sterilized. The sterile crop contents were then used to measure the expression of hilA. By using a lacZY transcriptional fusion to the hilA gene in S. enteritidis, we found that hilA expression was 1.6- to 2.1-fold higher in the crop contents from molted birds than in those from control birds in vitro. The results of the study suggest that the changes in the microenvironment of the crop caused by feed deprivation are important regulators of S. enteritidis survival and influence the susceptibility of molted hens to S. enteritidis infections. Furthermore, our in vitro results on the expression of hilA suggest that the change in crop environment during feed withdrawal has the potential to significantly affect virulence by increasing the expression of genes necessary for intestinal invasion. (+info)