ZFR
Zinc finger RNA-binding protein (hZFR) (M-phase phosphoprotein homolog)
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Avoiding insulin resistance (IR) associated with aging might lengthen life span based on previous studies using caloric-restricted animals. We assessed whether consuming niacin-bound chromium (NBC) alone or in a formula containing other so-called "insulin sensitizers" would overcome various manifestations of aging and extend life span in Zucker Fatty Rats (ZFR). We compared many metabolic parameters of ZFR fed NBC alone (n=12) or NBC in a unique formula (n=10) to a control group (n=10). In addition to NBC, the formula contained Allium sativum, Momordica charantia, Trigonella foenum-graecum and Gymnema sylvestre. The formula group received roughly 1/2 as much NBC daily as the NBC group. At week 44, all rats still lived, and no abnormalities in blood count (CBC), renal, or liver functions were found. In the two treatment groups compared to control, circulating glucose levels were significantly lower, with a trend toward lower HbA1C. Relatively elevated cholesterol and triglyceride concentrations occurred in the formula group. Compared to control, the NBC group had increased average lifespan (21.8%), median lifespan (14.1%), 30th percentile survival (19.6%), and maximum lifespan (22%). Despite similar beneficial effects on the glucose and blood pressure systems, a difference in aging was also found when the NBC group was compared to the formula group. When all rats in the other two groups had died, four in the NBC group continued to live at least a month longer. We attribute lack of a similar aging effect in the formula group to either lower dosing of NBC and/or that various ingredients in the formula counteracted the antiaging effect(s) of NBC.
MeSH Terms
- Aging
- Animals
- Blood Glucose
- Chromium
- Glycated Hemoglobin A
- Niacin
- Rats
- Rats, Zucker
The evolution with ageing of insulin resistance, body weight (BW) and mean arterial pressure (MAP) was studied in a group of Zucker fatty rats (ZFRs, n = 22), between 7 and 16 weeks of age, compared with an age-matched control group of Zucker lean rats (ZLRs, n = 22). The minimal model of glucose kinetics was applied to estimate glucose effectiveness, S(G), and insulin sensitivity, S(I), from insulinaemia and glycaemia measured during a 70 min intravenous glucose tolerance test. No correlation was found between S(G) and age in both ZFR and ZLR groups. No significant changes in mean S(G) between the two groups indicated no alteration of glucose-mediated glucose disposal. Estimates of S(I) from individual ZFRs were independent of age and, on average, showed 83% reduction (P < 0.001) compared with the ZLR group. Despite the lack of alteration of S(I) with age, the ZFR group showed an age-related increase of MAP, which correlated with increasing BW (r = 0.71 and P < 0.001). These results support the hypothesis that in our ZFRs, as a suitable genetic model of obesity and hypertension, insulin resistance is fully established at the age of 7 weeks and remains practically unaltered until at least the sixteenth week. An age-related increase in arterial pressure, observed in this strain, relates more properly to increasing BW, rather than insulin resistance. Development of hypertension with increasing age and BW may result from an enhanced insulin-mediated activity of the sympathetic nervous system, as observed in our previously reported study.
MeSH Terms
- Aging
- Animals
- Blood Pressure
- Body Weight
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Glucose
- Hypertension
- Insulin Resistance
- Male
- Obesity
- Rats
- Rats, Zucker
The roles of age and prolactin (PRL) in regulating glucocorticoid secretion in diestrous rats were investigated. Adrenal zona fasciculata-reticularis (ZFR) cells from young, adult, middle (mid)-aged, and old female rats were isolated. Estrous cycle stage was determined by light microscopy after vaginal smears. Blood samples were collected from right jugular vein at 0, 30, 60, and 120 min after challenge with adrenocorticotropin (ACTH). During the diestrous phase, plasma levels of estradiol and progesterone were lower in mid-aged and old rats than in either young or adult rats. Age-dependent increases of the basal levels of plasma PRL and corticosterone were observed. No difference of ACTH-increased plasma concentrations of corticosterone was observed among young, adult, mid-aged, and old rats. Aging increased the basal, ACTH-, PRL-, forskolin (an adenylate cyclase activator)-, and 3-isobutyl-l-methylxanthine (IBMX, a non-selective phosphodiesterase inhibitor)-stimulated release of corticosterone and production of adenosine 3', 5'-cyclic monophosphate (cAMP) in ZFR cells. However, the 8-Br-cAMP (a membrane-permeable cAMP)-stimulated release of corticosterone was not affected by age. Taken together, these data indicated that aging increased corticosterone secretion in female rats during diestrous phase, which is in part due to an increase in cAMP accumulation. In conclusion, aging and PRL play a stimulatory role in the co-regulation of corticosterone secretion.
MeSH Terms
- 1-Methyl-3-isobutylxanthine
- 8-Bromo Cyclic Adenosine Monophosphate
- Adrenocorticotropic Hormone
- Aging
- Animals
- Colforsin
- Corticosterone
- Cyclic AMP
- Diestrus
- Estradiol
- Female
- Progesterone
- Prolactin
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
The effect of muscle fiber type and maturation on intramyocellular lipid (IMCL) content and its relationship to insulin resistance was investigated. Intramyocellular lipid content in slow-twitch (soleus) and fast-twitch (tibialis anterior, TA) muscles of fa/fa (Zucker fatty rat, ZFR) and age-matched lean (Zucker lean rat, ZLR) Zucker rats were repeatedly measured over 3 months. Intramyocellular lipid levels in both the soleus and the TA were significantly higher in the ZFR relative to the ZLR. For the ZFR, IMCL TA increased by approximately 2-fold from 5.3 to 8.4 weeks of age. No subsequent accumulation of IMCL TA occurred in ZFR from 8.4 up to 13.1 weeks of age. For ZLR, IMCL TA contents steadily decreased from 6.6 to 13.1 weeks of age (-77%, P<.05). In contrast, IMCL levels in the soleus were not significantly altered in either rat strain over the course of the study. Maximum impairment in whole-body insulin sensitivity in ZFR was observed at 9-weeks of age, concomitant with peak IMCL TA accumulation. Insulin-stimulated 2-deoxy-D-glucose (2DG) transport in the TA muscle of 10.2- and 14.1-week-old ZFR was significantly impaired relative to age-matched ZLR. Insulin-stimulated glucose uptake in the soleus of ZFR and ZLR decreased (P<.05) as the animals matured (ZFR, -49%; ZLR, -69%). Overall, these results support the hypothesis that fast-twitch glycolytic muscles play a major role during the onset of insulin resistance. In addition, proper timing may govern the success of a pharmacological studies aimed at measuring the impact of insulin-sensitizing drugs on IMCL.
MeSH Terms
- Aging
- Animals
- Biological Transport
- Blood Glucose
- Deoxyglucose
- Glucose Tolerance Test
- Glycolysis
- Insulin
- Insulin Resistance
- Kinetics
- Lipids
- Muscle Cells
- Muscle Fibers, Fast-Twitch
- Muscle Fibers, Slow-Twitch
- Muscle, Skeletal
- Obesity
- Rats
- Rats, Zucker
Previous studies in our laboratories have demonstrated that niacin-bound chromium (NBC), Maitake mushroom and (-)-hydroxycitric acid (HCA-SX) can ameliorate hypertension, dyslipidemias and diabetes mellitus, and therefore may be useful in weight management. In the present study, we used aged, diabetic Zucker fatty rats (ZFR) (70-75 weeks) in order to determine whether NBC, fraction SX of Maitake mushroom (MSX) and 60% (-)-hydroxycitric acid (HCA-SX) from Garcinia cambogia, alone or in combination, can affect certain aspects of the metabolic syndrome. Syndrome X or metabolic syndrome has been described as a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, mild dyslipidemia, and hypertension, which are associated with subsequent development of type 2 diabetes mellitus and cardiovascular disease. Four groups of eight ZFR were gavaged daily with different supplements. For the initial three weeks, the control group of ZFR received only water, the second group received NBC 40 mcg elemental chromium/day, the third group received MSX 100 mg/day and the last group received HCA-SX 200 mg/day. During weeks 4-6, the doses of each treatment were doubled. The control animals lost approximately 50 g body weight (BW) per rat over 6 weeks of treatment, which is characteristic of these animals in declining health. In contrast, eight ZFR receiving NBC lost approximately 9 g BW per rat, while rats consuming MSX lost 16 g BW per rat. However, ZFR receiving HCA-SX simulated the pattern in the control group because these animals lost approximately 46 g BW per rat. The wide individual variations resulted in a lack of statistical significance among groups. Nevertheless, 75% of the ZFR in the control group lost more than 50 g BW over the 6 weeks duration, whereas none of the ZFR receiving NBC, 25% of the ZFR receiving MSX and 57% of the ZFR receiving HCA-SX lost over 50 g BW over the 6 weeks of the study. ZFR in all 3 treatment groups showed significantly lower blood pressures as compared to control, which seemed to be dose related. The general trend was for renal and liver blood parameters, hepatic and renal lipid peroxidation and DNA fragmentation to improve due to the supplementation of these natural products. Treatment of animals with a combination of these three novel supplements resulted in a lower SBP and maintenance of BW compared to control animals. These results demonstrate that elderly diabetics and even aging individuals might benefit from a similar regimen.
MeSH Terms
- Agaricales
- Aging
- Animals
- Blood Pressure
- Body Weight
- Chromium
- Citrates
- DNA Fragmentation
- Drinking Behavior
- Feeding Behavior
- Kidney
- Lipid Peroxidation
- Liver
- Metabolic Syndrome
- Niacin
- Rats
- Rats, Zucker
The effects and mechanisms of aging on corticosterone secretion in zona fasciculata-reticularis (ZFR) cells of ovariectomized (Ovx) rats were studied. Young (3-month) and old (24-month) female rats were Ovx for 4 days before decapitation. ZFR cells were isolated and incubated with different hormones or reagents at 37 degrees C for 30 min. Aging increased the basal secretion of corticosterone both in vivo and in vitro. The adrenocorticotropin (ACTH)-, forskolin-, 3-isobutyl-l-methylxanthine (IBMX)-, 8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP)-, and ovine prolactin (oPRL)-stimulated release of corticosterone by ZFR cells was greater in old than in young Ovx rats. H89, an inhibitor of protein kinase A (PKA), decreased the production of corticosterone in ZFR cells from young but not old Ovx rats. Forskolin-, or IBMX-induced production of cAMP was greater in old than in young Ovx animals, which correlated with the increase of corticosterone production by aging. The activity of 11 beta-hydroxylase that converts deoxycorticosterone (DOC, 10(-9) or 10(-8) M) to corticosterone in rat ZFR cells was decreased by age. However, the corticosterone production in response to high dose of DOC (10(-7) M) was indifferent between young and old groups. These results suggest that aging increases corticosterone production in Ovx rats via a mechanism in part associated with an increase of adenylyl cyclase activity and a decrease of phosphodiesterase activity, and then an increase of the generation of cAMP, but not related to either PKA activity or 11 beta-hydroxylase.
MeSH Terms
- 1-Methyl-3-isobutylxanthine
- 8-Bromo Cyclic Adenosine Monophosphate
- Adenylyl Cyclases
- Adrenocorticotropic Hormone
- Aging
- Animals
- Carrier Proteins
- Colforsin
- Corticosterone
- Cyclic AMP
- Cyclic AMP-Dependent Protein Kinases
- Desoxycorticosterone
- Female
- Intracellular Signaling Peptides and Proteins
- Isoquinolines
- Ovariectomy
- Phosphodiesterase Inhibitors
- Phosphoric Diester Hydrolases
- Prolactin
- Rats
- Rats, Sprague-Dawley
- Sulfonamides
- Zona Fasciculata
- Zona Reticularis
The effects of aging on zona fasciculatareticularis (ZFR) cell function in male rats were studied. Male rats 3, 6, and 22 months of age were divided into three groups, and collagenase-dispersed ZFR cells were isolated and incubated with adrenocorticotropin (ACTH), 8-bromo-adenosine 3':5'-cyclic monophosphate (8-Br-cAMP), ovine prolactin (oPRL), deoxycorticosterone (DOC), or 3-isobutyl-l-methylxanthine (IBMX) at 37 degrees C for 1 hour. Corticosterone concentrations in cell media and cAMP production in ZFR cells were measured by radioimmunoassay. Protein expression of PRL receptor in ZFR cells were analyzed by Western blot. The basal levels of plasma and medium corticosterone were higher in 22-month-old than in 3-month-old rats. In contrast, the release of corticosterone in response to ACTH, 8-Br-cAMP, and DOC was lower in 22-month-old than in 3- and 6-month-old rats. Aging decreased the oPRL-stimulated release of corticosterone but increased the protein expression of PRL receptor in ZFR cells. The basal levels of intracellular cAMP increased with age. However, the ACTH-stimulated production of intracellular cAMP decreased in 22-month-old compared with 3- or 6-month-old rats. The increment of cAMP accumulation in ZFR cells after administration of IBMX was greater in 22-month-old than in 3- or 6-month-old rats. These results suggest that the aging effects on the production of corticosterone in rat ZFR cells is associated with change of the generation of cAMP, the activity of 11 beta-hydroxylase and the protein expression of PRL receptor.
MeSH Terms
- 1-Methyl-3-isobutylxanthine
- 8-Bromo Cyclic Adenosine Monophosphate
- Adrenocorticotropic Hormone
- Aging
- Animals
- Blotting, Western
- Cells, Cultured
- Corticosterone
- Culture Media, Conditioned
- Cyclic AMP
- Desoxycorticosterone
- Male
- Prolactin
- Radioimmunoassay
- Rats
- Rats, Sprague-Dawley
- Receptors, Prolactin
- Zona Fasciculata
- Zona Reticularis
The effects of age on steroidogenesis in rat zona fasciculata-reticularis (ZFR) cells were studied. Young, adult, and middle-aged rats were ovariectomized (Ovx) and received replacement therapy with oil or estradiol benzoate ([EB] 25 microg/mL/kg). Rat ZFR cells were incubated with corticotropin (ACTH), prolactin (PRL), or forskolin at 37 degrees C for 1 hour. The effects of age on the activity of steroidogenic enzymes of ZFR cells were measured by the amount of intermediate steroidal products separated by thin-layer chromatography. Plasma levels were higher for PRL (54% to 254%) and corticosterone (179% to 257%) in middle-aged versus young rats. In oil-treated Ovx rats, basal and ACTH-stimulated corticosterone release by ZFR cells were also greater in middle-aged compared with young rats. Replacement with EB in Ovx rats increased the ACTH-stimulated release of corticosterone. Administration of ovine PRL in vitro resulted in a dose-dependent increase of corticosterone production. In oil-treated middle-aged rats, ovine PRL-stimulated corticosterone release was higher than in young rats. Forskolin-induced production of cyclic adenosine 3',5'-monophosphate (cAMP) was greater in middle-aged versus young rats and correlated with the increase of corticosterone production. The activity of steroidogenic enzymes in rat ZFR cells was unchanged by age. These results suggest that the age-related increase of corticosterone production in female rats is associated with the stimulatory effect of PRL on ZFR cells and is due in part to an increase of cAMP generation.
MeSH Terms
- 3-Hydroxysteroid Dehydrogenases
- Aging
- Animals
- Colforsin
- Corticosterone
- Cyclic AMP
- Estradiol
- Female
- Ovariectomy
- Prolactin
- Rats
- Rats, Sprague-Dawley
- Steroid 11-beta-Hydroxylase
- Steroid 21-Hydroxylase