Ontogenetic characteristics of enzyme activities and plasma metabolites in C57BL/6J:Jcl mice deficient in insulin receptor substrate 2

We have established an inbred line of mice deficient in insulin receptor substrate 2 (IRS2) on a C57BL/6J Jcl genetic background (B6J-IRS2(-/-) mice) as an animal model for typical type 2 diabetes mellitus (DM). We investigated the effect of age and sex on glucose tolerance and insulin resistance and on the activities of enzymes related to lipid metabolism in the liver and skeletal muscle of B6J-IRS2( -/-) mice. Glucose tolerance tests (GTT), insulin tolerance tests (ITT), and sampling for chemical analysis were performed at ages of 6,14, and 24 wk. GTT showed that both genders of B6J-IRs2(-/-) mice had impaired glucose tolerance at the ages of 6 and 14 wk, whereas 24-wk-old female B6J-IRs2(-/-) mice showed glucose tolerance almost comparable to that of wild-type mice; 24-wk-old male B6J-IRs2(-/-) mice still showed impaired glucose tolerance. ITT revealed that both male and female B6J-IRS2(-/-) mice remained insulin-resistant at all time points. Hepatic lipogenetic enzyme activities were higher in B6J-IRS2(-/-) mice than in wild-type mice at 6, 14 and 24 wk of age. In addition, plasma glucose, triglyceride, free fatty acid, total cholesterol, and insulin concentrations in B6J-IRS2(-/-) mice were significantly higher than those in wild-type mice at most time points; plasma triglycerides in 14-wk-old B6J-IRS2(-/-) mice were lower than those of wild-type mice. These findings suggest that young B6J-IRS2(-/-) mice are useful as type 2 DM models.     

Severe pulmonary hypertension in aging female apolipoprotein E-deficient mice is rescued by estrogen replacement therapy

Corticotropin-releasing factor overexpressing (CRF-OE) male mice showed an inhibited feeding response to a fast, and lower plasma acyl ghrelin and Fos expression in the arcuate nucleus compared to wild-type (WT) mice. We investigated whether hormones and hypothalamic feeding signals are impaired in CRF-OE mice and the influence of sex. Male and female CRF-OE mice and WT littermates (4–6 months old) fed ad libitum or overnight fasted were assessed for body, adrenal glands and perigonadal fat weights, food intake, plasma hormones, blood glucose, and mRNA hypothalamic signals. Under fed conditions, compared to WT, CRF-OE mice have increased adrenal glands and perigonadal fat weight, plasma corticosterone, leptin and insulin, and hypothalamic leptin receptor and decreased plasma acyl ghrelin. Compared to male, female WT mice have lower body and perigonadal fat and plasma leptin but higher adrenal glands weights. CRF-OE mice lost these sex differences except for the adrenals. Male CRF-OE and WT mice did not differ in hypothalamic expression of neuropeptide Y (NPY) and proopiomelanocortin (POMC), while female CRF-OE compared to female WT and male CRF-OE had higher NPY mRNA levels. After fasting, female WT mice lost more body weight and ate more food than male WT, while CRF-OE mice had reduced body weight loss and inhibited food intake without sex difference. In male WT mice, fasting reduced plasma insulin and leptin and increased acyl ghrelin and corticosterone while female WT showed only a rise in corticosterone. In CRF-OE mice, fasting reduced insulin while leptin, acyl ghrelin and corticosterone were unchanged with no sex difference. Fasting blood glucose was higher in CRF-OE with female > male. In WT mice, fasting increased hypothalamic NPY expression in both sexes and decreased POMC only in males, while in CRF-OE mice, NPY did not change, and POMC decreased in males and increased in females. These data indicate that CRF-OE mice have abnormal basal and fasting circulating hormones and hypothalamic feeding-related signals. CRF-OE also abolishes the sex difference in body weight, abdominal fat, and fasting-induced feeding and changes in plasma levels of leptin and acyl ghrelin.     

Type 2 diabetes mellitus in obese mouse model induced by monosodium glutamate.

The number of diabetic patients is increasing every year, and new model animals are required to study the diverse aspects of this disease. An experimental obese animal model has reportedly been obtained by injecting monosodium glutamate (MSG) to a mouse. We found that ICR-MSG mice on which the same method was used developed glycosuria. Both female and male mice were observed to be obese but had no polyphagia, and were glycosuric by 29 weeks of age, with males having an especially high rate of incidence (70.0%). Their blood concentrations of glucose, insulin, total cholesterol, and triglycerides were higher than in the control mice at 29 weeks. These high concentrations appeared in younger males more often than in females, and were severe in adult males. Also, the mice at 54 weeks of age showed obvious obesity and increased concentrations of glucose, insulin, and total cholesterol in the blood. The pathological study of ICR-MSG female and male mice at 29 weeks of age showed hypertrophy of the pancreatic islet. This was also observed in most of these mice at 54 weeks. It was recognized as a continuation of the condition of diabetes mellitus. From the above results, these mice are considered to be useful as new experimental model animals developing a high rate of obese type 2 (non-insulin dependent) diabetes mellitus without polyphagia.     

Gender difference in ICER Igamma transgenic diabetic mouse

Few studies have been done to examine gender differences in diabetic mouse models. Here we examined a gender difference in Inducible cAMP Early Repressor (ICER) transgenic (Tg) mice, a diabetic mouse model. Longitudinal changes in diabetes and nephropathy were investigated in male and female Tg mice. Both male and female Tg mice developed severe diabetes early in life due to severely impaired insulin synthesis and decreased beta-cell numbers, but only female Tg mice became less hyperglycemic later in life, and most female Tg mice did not develop diabetic nephropathy. Even some female Tg mice that remained hyperglycemic showed less renal expansion than age-matched male Tg mice. Thus the gender difference in the severity of diabetes and diabetic nephropathy was evident with age in this model. This study indicates that sex hormones may play a role in glucose metabolism in diabetic conditions.     

Testosterone and estrogen differently effect Th1 and Th2 cytokine release following trauma-haemorrhage.

The object of the study was to determine whether male and female sex steroids produce divergent effects on Th1 and Th2 cytokine release following trauma-haemorrhage. Recent studies indicate that androgens are responsible for the depressed splenocyte Th1 cytokine release in males following trauma-haemorrhage. In contrast, female mice maintain their Th1 cytokine release capacity following trauma-haemorrhage. Nonetheless, the effect of male and female sex steroids on Th1 and Th2 cytokine release following trauma-haemorrhage remains unknown. Male C3H/HeN mice were castrated and treated with pellets containing either vehicle, 5alpha-dihydrotestosterone (DHT), 17beta-estradiol (estradiol), or a combination of both steroid hormones, for 14 days prior to soft-tissue trauma (i.e. laparotomy) and haemorrhagic shock (35+/-5 mmHg for 90 min followed by adequate fluid resuscitation) or sham operation. Untreated male and female mice, as well as DHT treated female mice, served as control groups. Twenty-four hours later the animals were sacrificed, plasma obtained and splenocytes harvested. Plasma DHT and estradiol levels in treated animals were comparable with intact male and female mice, respectively. A significant depression of splenocyte Th1 cytokines, i.e. IL-2, IFN-gamma, was observed in DHT treated castrated animals, DHT treated females, and untreated males following trauma-haemorrhage, as opposed to maintained Th1 cytokine release in estradiol treated and estradiol/DHT treated castrated animals and females. The release of the anti-inflammatory cytokine IL-10 was markedly increased in DHT treated mice and males subjected to trauma-haemorrhage compared to shams, but decreased in estrogen treated mice and females under such conditions. These results suggest that male and female sex steroids differentially affect the release of Th1 and Th2 cytokines following trauma-haemorrhage and should be further studied for their potential to modulate splenocyte function in trauma victims.     

Effect of LPS treatment on tyrosine hydroxylase expression and Parkinson-like behaviors

Puberty is a critical period of development during which the brain undergoes reorganizing and remodeling. Exposure to stress during this period is thought to interfere with normal brain development and increase susceptibility to mental illnesses. In female mice, pubertal exposure to lipopolysaccharide (LPS), a bacterial endotoxin, has been shown to alter sexual, anxiety-like, and depression-like behaviors and cognition in an enduring manner. However, the mechanisms underlying these effects remain unknown. The present study examined age and sex difference in tyrosine hydroxylase (TH) expression and dopamine-dependent and Parkinson-like behaviors following LPS treatment. The results show that LPS treatment during adulthood causes an enduring increase in TH expression in many of the brain regions examined. In contrast, there is no change in TH expression following LPS treatment during puberty. However, pubertal LPS treatment induces enduring behavioral deficits in tests of Parkinson-like behaviors, more so in male than in female mice. These results suggest that the low levels of TH following exposure to pubertal immune challenge may predispose mice to Parkinson-like behavior. These findings add to our understanding of stress and immune responses during puberty and their impact on mental health later in life.     

Season of birth modifies puberty in female and male goats raised under subtropical conditions

In seasonal goats and sheep breeds, onset of puberty is modified by the season of birth. As adult does and bucks from subtropical Mexico display seasonal variation in their reproductive behaviour, this study was carried out to determine the effect of season of birth on puberty. Three groups of each sex born in January, May and October were used. During the seasons, does and bucks were weaned at an age of 30 days and offered ad libitum alfalfa hay and 100 g of commercial concentrate. In the female kids, the onset of ovulatory activity was determined by progesterone plasma concentrations once in a week from 3 months of age until the onset of puberty. In the male kids, the onset of puberty was individually recorded by observing the ability to mount and intromit an induced oestrous female goat aged 3 months and the presence of spermatozoa in the ejaculate obtained in an artificial vagina 1 week after the first mount. In female kids, there was an effect of the season on the date of first ovulation (P < 0.001). In the May group, ovulatory activity commenced at an earlier age (201 ± 3 days) compared with January (264 ± 5 days) and October (344 ± 5 days) groups (P < 0.001). In the January group also, the ovulatory activity commenced earlier than the October group (P < 0.001). In males, an effect of the season of birth on the first mounting was observed (P < 0.001). The male kids that were born in May (111 ± 3) and October (112 ± 5 days) attained puberty earlier than those born in January (131 ± 4 days; P < 0.001). The time of onset of puberty did not differ between groups of May and October. All males showed the presence of spermatozoa in the first ejaculate obtained 1 week after the first mount. The spermatozoa in all ejaculates were immobile. It was concluded that the season of birth modified the onset of puberty in both genders, but these modifications were more pronounced in the female than in the male kid goats.     

Insulinotropic effect of ovarian steroid hormones in streptozotocin diabetic female mice

To investigate the protective effect of ovarian sex steroids against streptozotocin diabetes, groups of ovariectomized streptozotocin diabetic female mice were treated orally with estradiol-17 beta (5 and 500 ug/kg/day) or progesterone (1 mg/kg/day) for 10 weeks. Streptozotocin produced a more severe hyperglycaemia and a greater fall in plasma insulin concentrations in ovariectomized mice than intact female mice. The estradiol-17 beta and progesterone treatments reduced both the severity of the hyperglycaemia and the fall in plasma insulin. Loss of pancreatic insulin after streptozotocin administration was reduced in intact mice and in mice treated with estradiol-17 beta. These observations suggest that ovarian sex steroids reduce the severity of streptozotocin diabetes at least partly by countering the cytotoxic effect of the drug on the islet B-cells, thereby reducing the fall in pancreatic and plasma insulin.     

四氧嘧啶诱发糖尿病模型效果的性别差异

目的了解性别因素对四氧嘧啶诱发糖尿病动物模型的影响,为提高动物模型的复制效率提供实验依据。方法分别给雌、雄比格犬和昆明小鼠注射不同剂量的四氧嘧啶,药后3、7、14、21 d测定血糖值,同时统计实验期间动物的死亡情况。结果给予同等剂量的四氧嘧啶,雌性比雄性动物的血糖升高更快,浓度更高。雌性犬四氧嘧啶的最适造模剂量为40 mg/kg,而雄性犬在此剂量下的模型成功率只有40%,二者差异极显著（70%VS40%,P〈0.01）;雄性犬的最适使用剂量为50 mg/kg,但在此剂量下有高达30%的雌性犬因高血糖而死亡。四氧嘧啶对小鼠的影响与犬基本一致,雌雄鼠的最佳剂量分别为200 mg/kg和250 mg/kg。结论雌性动物对四氧嘧啶的敏感性较雄性动物高,雄性动物在使用四氧嘧啶复制糖尿病模型时,其剂量通常需要较雌性动物高20%左右。     

Changes in renal hemodynamics and excretory function induced by a reduction of ANG II effects during renal development

The aim was to evaluate whether blockade of ANG II effects during renal development modifies the renal response to an increment of plasma amino acid concentration. It was also examined in anesthetized rats whether the reduction of the renal ability to eliminate an acute volume expansion (VE), elicited by blockade of ANG II during renal development, is sex and/or age dependent. Newborn Sprague-Dawley rats were treated with vehicle or an AT(1)-receptor antagonist (ARA) during postnatal nephrogenesis. Amino acid infusion induced increments (P < 0.05) of glomerular filtration rate (31 +/- 6%) and renal plasma flow (26 +/- 5%) in male but not in female vehicle-treated rats. Natriuretic and diuretic responses to amino acid infusion were similar in male and female vehicle-treated rats. These renal hemodynamics and excretory responses to amino acid infusion were abolished in ARA-treated rats. Renal responses to VE were evaluated at 3-4 and 9-10 mo of age in vehicle and ARA-treated rats. VE-induced natriuresis and diuresis were reduced by more than 38% (P < 0.05) in 3- to 4-mo-old male and female ARA-treated rats. An age-dependent reduction (P < 0.05) in the renal ability to eliminate VE was found in male but not in female rats treated with ARA. Our results demonstrate that the renal effects induced by an increment in amino acids are abolished when ANG II effects have been reduced during nephrogenesis. In addition, this reduction of ANG II effects elicits an impairment of the renal ability to eliminate an acute VE in males and females, which is aggravated by age only in male rats.     

Long-term effects of accelerated or delayed sexual maturation on reproductive output in wild female house mice (Mus musculus)

The effects of acceleration and delay of puberty in female house mice on survival and reproduction were tested using 6 experimental groups: (1) control females mated at the time of first oestrus, (2) females mated at weaning, (3) females treated with male urine starting at weaning and mated at first oestrus, (4) females housed in groups and mated at first oestrus, (5) females housed alone, treated with urine from grouped females and mated at first oestrus, and (6) females housed alone and mated at 68 days of age. Females caged with males at weaning or treated with male urine and mated at puberty had lower rates of survival to 180 days of age, but did not differ in rates of fertility from mice in the other four treatments. Those females that were housed with males from weaning or treated with male urine also had smaller total numbers of litters, fewer total young, and smaller average litter sizes than did females for which the age of mating was delayed, by grouping or treatment with urine from grouped females, or by being held until age 68 days before mating. Control females mated at first oestrus generally were intermediate or did not differ from the male treatments on these dependent variables. There were no differences in the average number of female young/litter across the 6 treatments. However, females that were delayed in age of first mating had significantly more male young/litter than did females that were accelerated in their sexual development or control females.(ABSTRACT TRUNCATED AT 250 WORDS)     

Delay in the age of balano-preputial skinfold cleavage and alterations in serum profiles of testosterone, 5 alpha-androstane-3 alpha,17 beta-diol, and gonadotropins in adult rats treated during puberty with luteinizing hormone releasing hormone

Previous work has shown that chronic treatment of intact, immature male rats with luteinizing hormone releasing hormone (LHRH) decreases sex accessory gland weights and results in retardation of the normal developmental increase in the ratio of serum testosterone (T)/5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-Diol) via an apparent enhancement of testicular 5 alpha-reductase or 3 alpha-hydroxysteroid oxidoreductase activities. In the present work, androgen dependent balano-preputial skinfold cleavage was significantly delayed by approximately one week in intact, immature male rats which were treated daily for two weeks with either 1.0 micrograms, 2.5 micrograms or 5.0 micrograms of LHRH during a discrete phase of pubertal development (28-41 days of age). In intact, adult (62 day old) animals which received LHRH treatments during pubertal development, serum T concentrations and sex accessory gland weights were reduced compared to control animal values. Serum 3 alpha-Diol content in the adult rats was either unaltered or increased significantly depending on the LHRH dosage employed during sexual development. Serum luteinizing hormone concentrations were not different between control and LHRH-pretreated adult rats whereas the highest dosage of LHRH employed (5.0 micrograms) during puberty resulted in a significant elevation of adult serum follicle stimulating hormone levels. It is suggested that chronic LHRH treatment of the male rat during puberty results in a perturbation in testicular androgen biosynthetic activities and an impairment of pituitary-testicular hormone feedback mechanisms which persist at least through early adulthood.     

Gonadal hormone effects on entrained and free-running circadian activity rhythms in the developing diurnal rodent Octodon degus

The slowly maturing, long-lived rodent Octodon degus (degu) provides a unique opportunity to examine the development of the circadian system during adolescence. These studies characterize entrained and free-running activity rhythms in gonadally intact and prepubertally gonadectomized male and female degus across the first year of life to clarify the impact of sex and gonadal hormones on the circadian system during adolescence. Gonadally intact degus exhibited a delay in the phase angle of activity onset (Psi(on)) during puberty, which reversed as animals became reproductively competent. Gonadectomy before puberty prevented this phase delay. However, the effect of gonadal hormones during puberty on Psi(on) does not result from changes in the period of the underlying circadian pacemaker. A sex difference in Psi(on) and free-running period (tau) emerged several months after puberty; these developmental changes are not likely to be related, since the sex difference in Psi(on) emerged before the sex difference in tau. Changes in the levels of circulating hormones cannot explain the emergence of these sex differences, since there is a rather lengthy delay between the age at which degus reach sexual maturity and the age at which Psi(on) and tau become sexually dimorphic. However, postnatal exposure to gonadal hormones is required for sexual differentiation of Psi(on) and tau, since these sex differences were absent in prepubertally gonadectomized degus. These data suggest that gonadal hormones modulate the circadian system during adolescent development and provide a new model for postpubertal sexual differentiation of a central nervous system structure.     

Distinctive stress effects on learning during puberty

Puberty is a time of significant change in preparation for adulthood. Here, we examined how stressful experience affects cognitive and related hormonal responses in male and female rats prior to, during and after puberty. Groups were exposed to an acute stressor of brief periodic tailshocks and tested 24 h later in an associative memory task of trace eyeblink conditioning. Exposure to the stressor did not alter conditioning in males or females prior to puberty but enhanced conditioning in both males and females during puberty. The enhancement occurred in pubescent females irrespective of the estrous cycle. In adulthood, sex differences in trace conditioning and the response to stress emerged: females outperformed males under unstressed conditions, but after stressor exposure, trace conditioning in females was impaired whereas that in males was enhanced. These differences were not related to changes in gross motor activity or other nonspecific measures of performance. The effects of acute stress on corticosterone, estradiol, progesterone, and testosterone were also measured. Stressor exposure increased the concentration of corticosterone in all age groups, although sex differences were only evident in adults. All reproductive hormones except estradiol increased with age in a predictable and sex dependent fashion and none were affected by stressor exposure. Estradiol decreased in male rats across age, and remained stable for female rats. Together, these data indicate that males and female respond similarly to learning opportunities and stressful experience before and during puberty; it is in adulthood that sex differences and the opposite responses to stress arise.     

Postnatal profile of plasma leptin concentrations in male and female rats: relation with the maturation of the pituitary-gonadal axis

Leptin, the ob gene product, has been implicated in the initiation of puberty in mice and humans. However, it is not yet clear whether leptin also plays a pivotal role in promoting sexual maturation in rats. Based on the assumption that circulating leptin levels would increase during the peripubertal period if this hormone triggers puberty, we examined the developmental profile of plasma leptin from neonatal (day 1) through adult (day 85) age in both male and female rats and simultaneously monitored several important indices of pituitary-gonadal function. A significant elevation of plasma leptin during the peripubertal period was not observed in either male or female rats. Although this finding may not support leptin as a humoral factor triggering puberty, we observed a rise in leptin in both sexes from the second postnatal week, which clearly preceded the first significant elevations of luteinizing hormone and gonadal steroids. Therefore, it is still possible that leptin may play a role in promoting sexual maturation in rats of both sexes already from an early postnatal period. It seems that the role for leptin in sexual development is permissive, but not decisive, in rats.     

Transient sex-related changes in the mice hypothalamo-pituitary-adrenal (HPA) axis during the acute phase of the inflammatory process

The potential role of endogenous sex hormones in regulating hypothalamo-pituitary-adrenal (HPA) axis function was investigated after a single injection of endotoxin in adult (8 week old) BALB/c mice of both sexes. The effect of LPS on plasma ACTH, corticosterone (B), testosterone and oestradiol (E) levels and on anterior pituitary (AP) ACTH and adrenal B contents at different times after treatment was studied. The results indicate that: (a) basal B but not ACTH plasma levels were significantly higher in female than in male mice; (b) LPS significantly increased both ACTH and B plasma levels over the baseline 2 h after injection, both hormone levels being higher in female than in male mice; (c) although plasma ACTH concentrations recovered the basal value at 72 h after LPS in animals of both sexes, plasma B levels returned to the baseline only at 120 h after treatment; (d) E plasma levels significantly increased 2 h after LPS and returned to the baseline at 72 h post-treatment, in both sexes; (e) at 2 h after LPS, testosterone plasma levels significantly decreased in male mice and increased in female mice, recovering the baseline level at 120 and 72 h after LPS, respectively; (f) AP ACTH content was similar in both sexes in basal condition and it was significantly diminished 72 h post-treatment without sex difference; whereas AP ACTH returned to basal content 120 h after LPS in males, it remained significantly decreased in females; (g) basal adrenal B content was higher in female than in male mice, and it significantly increased in both sexes 2 h post-LPS, maintaining this sex difference. Whereas adrenal B returned to basal content 72 h after treatment in male mice, it remained significantly enhanced up to 120 h post-LPS in female animals. The data demonstrate the existence of a clear sexual dimorphism in basal condition and during the acute phase response as well as in the recovery of the HPA axis function shortly after infection.     

Changes in the renin-angiotensin-aldosterone system in rats of both sexes submitted to chronic hypobaric hypoxia

The effect of moderate chronic hypobaric hypoxia (CHH) on the renin-angiotensin-aldosterone system has been analysed in male and female intact and castrated rats. The experimental animals were submitted to a simulated altitude of 4,400 m during ten weeks. Half of the experimental and half of the control animals were castrated at three weeks of age. Arterial pressure (AP) was measured once a week during the whole experimental period. Blood samples were obtained by decapitation at the end of the study. Red cell volume, plasma renin activity (PRA), plasma angiotensinogen (Ao) and aldosterone concentration (ALDO) were determined in the blood samples. Results have shown that the female animals subjected to CHH had lower levels of AP than the control female rats during all the studied periods whereas the AP of male hypoxic rats was only transiently diminished. All these changes were abolished by castration. PRA was not altered in either sex. The enzymatic complex was higher in male than in female control animals and decreased after castration in both hypoxic and control male rats. Ao was decreased by CHH in both sexes of intact rats and in female castrated animals. The renin substrate was higher in male than in female intact rats and decreased after castration in male animals. ALDO was increased after CHH only in male rats. Control female rats have higher levels of ALDO than male animals. Changes in the renin-angiotensin-aldosterone system related to CHH and also significant differences between sexes suggest that adrenal and gonadal corticosteroids may be involved in the main alterations presently observed.     

Gonadectomy in Mito-Ob mice revealed a sex-dimorphic relationship between prohibitin and sex steroids in adipose tissue biology and glucose homeostasis

Background

Recently, we have developed a novel transgenic mouse model by overexpressing prohibitin (PHB) in adipocytes, which developed obesity due to upregulation of mitochondrial biogenesis in adipocytes, hence named “Mito-Ob.” Interestingly, only male Mito-Ob mice developed obesity-related impaired glucose homeostasis and insulin sensitivity, whereas female Mito-Ob mice did not. The observed sex differences in metabolic dysregulation suggest a potential involvement of sex steroids. Thus, the main aim of this study is to investigate the role of sex steroids on the overall phenotype of Mito-Ob mice through gonadectomy, as well as direct effect of sex steroids on adipocytes from Mito-Ob mice in vitro.

Methods

Mito-Ob mice and wild-type CD-1 mice were gonadectomized at 12 weeks of age. Age- and sex-matched sham-operated mice were used as controls. Body weight, white adipose tissue, glucose tolerance, and insulin sensitivity were analyzed 3 months post-surgery. Differentiation of adipocytes isolated from female and male Mito-Ob mice were studied with and without sex steroids.

Results

Gonadectomy significantly reduced body weight in Mito-Ob mice compared with sham-operated mice, whereas the opposite trend was observed in wild-type mice. These changes occurred independent of food intake. A corresponding decrease in adipose tissue weight was found in gonadectomized Mito-Ob mice, but depot-specific differences were observed in male and female. Gonadectomy improved glucose tolerance in male wild-type and Mito-Ob mice, but the effect was more pronounced in wild-type mice. Gonadectomy did not alter insulin sensitivity in male Mito-Ob mice, but it was improved in male wild-type mice. In primary cell cultures, testosterone inhibited adipocyte differentiation to a lesser extent in male Mito-Ob preadipocytes compared with the wild-type mice. On the other hand, preadipocytes from female wild-type mice showed better differentiation potential than those from female Mito-Ob mice in the presence of 17β-estradiol.

Conclusions

PHB requires sex steroids for the development of obese phenotype in Mito-Ob mice, which differentially affect glucose homeostasis and insulin sensitivity in male and female. It appears that PHB plays sex- and adipose depot-specific roles and involves additional factors. In vitro studies suggested that PHB differently influenced adipocyte differentiation in the presence and absence of sex steroids. Overall, this study along with available information in the literature indicated that a multifaceted relationship exists between PHB and sex steroids, which may work in a cell/tissue type- and sex-specific manner.

     

Ontogeny and sexual dimorphism of estradiol-2-hydroxylase activity in rat liver microsomes

A radio-enzymatic method was used to measure the activity of estradiol-2-hydroxylase in liver microsomes of male and female Wistar rats, ranging in age from 10 to 63 days. In pre-pubertal rats (10-30 days) the Vmax increased, but revealed no sex differences. After 30 days of age, however, it decreased in females. In males, on the other hand, it increased still further, reaching a maximum in adulthood. The apparent Km showed no significant sex differences in pre-pubertal rats, but appeared to decline after puberty in females. In females puberty was also associated with the appearance of important changes in the kinetic properties of estradiol-2-hydroxylase. These changes were reflected in hyperbolic Lineweaver-Burk plots. Hill plots of this data gave straight lines with slopes significantly less than one--indicating negative cooperativity. Alternatively the hyperbolic Lineweaver-Burk plots could mean that the enzyme consists of more than one form, which act on the same substrate, but with different affinities. It is concluded that development in female Wistar rats is associated with important qualitative changes in the kinetic properties of estradiol-2-hydroxylase and that factors which become operative during puberty play a key role in initiating these changes.     

Testosterone levels in plasma and testes of neonatal mice

Newborn female and male C57BL6 mice were decapitated at birth or at different times during the first 24 h after birth and testosterone was determined by radioimmunoassay in plasma and testes. In newborn females, plasma testosterone is low and does not significantly change over the first 24 h after birth. In contrast, in newborn males, plasma testosterone more than doubles during the first 2 h after birth and then falls rapidly to remain relatively low for the remainder of the 24 h period after birth. The increase in plasma testosterone is of almost certain testicular origin since it follows a decrease in testicular testosterone content. It seems likely that the increase in plasma testosterone in male mice which reaches its peak at 2 h after birth is involved in an essential way in the development of well-documented sex differences in gonadotropin secretion and behavior.