A Reproductive Endocrine Profile in the Diabetes (db) Mutant Mouse1

Johnson, Linda Marlene; Sidman, Richard L.

doi:10.1095/biolreprod20.3.552

Cited by 108 publications

(59 citation statements)

References 12 publications

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“…In contrast, and in agreement with our findings, the absence of a clear morphological abnormality in the reproductive tract of LepR-deficient male mice has also been reported by others (53,103). But intriguingly, reexpression of LepR in the PMV of LepR-null mice did not ameliorate male fertility.…”

Section: Discussionsupporting

confidence: 93%

“…Thus, our findings indicate that PMV neurons may serve as an alternative pathway in this circuitry, conveying inputs on changing levels of leptin directly to GnRH neurons. As observed in db/db and ob/ob mice (53,54), LepR-null mice displayed no deficits in GnRH neuronal migration, GnRH gene expression, or peptide production. We also noticed that LepR-null mice show modest or undetectable changes in Kiss1 gene expression compared with control littermates.…”

Section: Discussionsupporting

confidence: 51%

“…Together, these data suggest that the infertility phenotype of the LepR-null mice is not caused by deficient expression of Gnrh or Kiss1 genes. Rather, the leptin-signaling deficient mice display increased GnRH content in the median eminence/mediobasal hypothalamus, strengthening the model that GnRH secretion is inhibited in females with leptin-signaling deficiency (53,54). This elevated GnRH content is not observed in the infertile Kiss1 gene knockout mice (73,74), suggesting that the disruption in the normal pubertal development observed in Kiss1 and in leptin-signaling deficiencies is caused by dissociated mechanisms.…”

Section: Discussionmentioning

confidence: 71%

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Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons

Donato¹,

Cravo²,

Frazão³

et al. 2011

J. Clin. Invest.

305

292

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Studies in humans and rodents indicate that a minimum amount of stored energy is required for normal pubertal development. The adipocyte-derived hormone leptin is a key metabolic signal to the neuroendocrine reproductive axis. Humans and mice lacking leptin or the leptin receptor (LepR) (ob/ob and db/db mice, respectively) are infertile and fail to enter puberty. Leptin administration to leptin-deficient subjects and ob/ob mice induces puberty and restores fertility, but the exact site or sites of leptin action are unclear. Here, we found that genetic deletion of LepR selectively from hypothalamic Kiss1 neurons in mice had no effect on puberty or fertility, indicating that direct leptin signaling in Kiss1 neurons is not required for these processes. However, bilateral lesions of the ventral premammillary nucleus (PMV) of ob/ob mice blunted the ability of exogenous leptin to induce sexual maturation. Moreover, unilateral reexpression of endogenous LepR in PMV neurons was sufficient to induce puberty and improve fertility in female LepR-null mice. This LepR reexpression also normalized the increased hypothalamic GnRH content characteristic of leptin-signaling deficiency. These data suggest that the PMV is a key site for leptin's permissive action at the onset of puberty and support the hypothesis that the multiple actions of leptin to control metabolism and reproduction are anatomically dissociated. IntroductionThe existence of a fundamental link between nutrition and reproduction is well established. Early studies in humans and rodents suggested that a minimum amount of stored energy is required for normal pubertal development and to maintain the tone of the reproductive system (1, 2). This concept is based on the idea that when survival is threatened by scarcity of food or increased energy demands, males and females of most species divert energy away from reproduction. This includes sexual maturation, the production of reproductive hormones and gametes, and the maintenance of pregnancy and lactation. On the other hand, excess energy may have a negative impact on the reproductive physiology. For example, elevated adiposity in women aggravates polycystic ovarian syndrome and ovulatory dysfunctions and may induce hypothalamic hypogonadism (3, 4). Moreover, the increasing rates of childhood obesity have been associated with the advance in the timing of pubertal maturation and its deleterious consequences (5-8). Earlier menarche in girls is correlated with increased risk of adult obesity, type 2 diabetes, and breast cancer (9, 10). Thus, changing levels of key metabolic cues is an essential signal for the onset of puberty. But the assessment of the mechanisms underlying puberty initiation has been obstructed by the lack of information on the brain sites in which this event is integrated.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 71%

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Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons

Donato¹,

Cravo²,

Frazão³

et al. 2011

J. Clin. Invest.

305

292

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“…Female rats with streptozotocin-induced diabetes present diminution in the secretion of gonadotropins due to inadequate GnRH release, or a reduction in normal pituitary response when subjected to stimulation with this hormone (18).…”

mentioning

confidence: 99%

Reproductive physiology, and physical and sexual development of female offspring born to diabetic dams

Spadotto

Damasceno

Godinho

et al. 2012

Arq Bras Endocrinol Metab

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Objectives: The objective of this study was to evaluate physical and sexual development and reproductive physiology in female rat offspring that developed in hyperglycemia conditions in utero and during lactation. Materials and methods: Maternal diabetes was induced in female rats by a single IV injection of streptozotocin before mating. Female offspring development was evaluated by means of the following parameters: physical development; age of vaginal opening and first estrus; weight and histological evaluation of uterus and ovaries; duration of the estrous cycle, sexual behavior, and fertility after natural mating. Results: In the female offspring, maternal diabetes caused delays in initial physical development; diminution in ovary weight and number of follicles; and inferior reproductive performance compared with the control group. Conclusions: The exposure to hyperglycemia in uterus and during lactation caused delays in physical and sexual development, and affected the reproductive physiology of female rats negatively. Arq Bras Endocrinol Metab. 2012;56(2):96-103 Keywords Sexual behavior; physical development; diabetes; female reproductive physiology; female rat; streptozotocin RESUMO Objetivos: O objetivo deste estudo foi avaliar o desenvolvimento físico e sexual e a fisiologia reprodutiva de ratas que se desenvolveram em condições hiperglicêmicas in utero e lactação. Materiais e métodos: Para induzir o diabetes nas ratas, foi utilizada estreptozotocina em dose única via intravenosa antes do acasalamento. A prole feminina foi avaliada por meio dos seguintes parâmetros: o desenvolvimento físico; a idade de abertura vaginal e do primeiro estro, peso e avaliação histológica do útero e ovários; a duração do ciclo estral, o comportamento sexual e a fertilidade após acasalamentos naturais. Resultados: O diabetes materno provocou, na prole feminina, retardo no desenvolvimento físico; diminuição do peso dos ovários e do número de folículos; a performance reprodutiva foi inferior à do grupo controle. Conclusões: Concluiu-se que a exposição aos meios intrauterino e lactacional hiperglicêmicos provocou retardo no desenvolvimento físico e sexual e prejudicou a fisiologia reprodutiva de ratas. Arq Bras Endocrinol Metab. 2012;56(2):96-103

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“…For example, men with diabetes mellitus exhibit reproductive impairment and impotence, children manifest delayed puberty, and women have an increased prevalence of anovulation, menstrual irregularity, and infertility (4)(5)(6)(7)(8)(9)(10). Presumptive abnormalities of both pituitary and gonadal function have been described in vivo (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). However, the interpretation of these observations is limited by confounding influences of weight loss, protein catabolism, hyperglycemia, gonadal vasculopathy, and homeostatic responses of the pituitary-gonadal and adrenal axes in intact animals (15)(16)(17)(18)(19)(20)(21)(22).…”

mentioning

confidence: 99%

Mechanisms subserving the trophic actions of insulin on ovarian cells. In vitro studies using swine granulosa cells

Veldhuis¹,

Kolp²,

Toaff³

et al. 1983

J. Clin. Invest.

108

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A B S T R A C T Direct actions of insulin on gonadal tissues have been difficult to demonstrate in vivo. We have developed an in vitro system in which swine ovarian cells remain highly responsive to trophic actions of insulin. Purified porcine insulin significantly augmented the biosynthesis and secretion of progesterone by cultured granulosa cells. These stimulatory actions of insulin were dose-and time-dependent and saturable. Under serum-restricted conditions, insulin also significantly amplified the capacity of estradiol and 8-bromo cyclic AMP to stimulate progesterone production. Inhibitors of protein and RNA synthesis (cycloheximide, actinomycin D, and alpha-amanatin) inhibited insulin action. The stimulation of progesterone production by insulin was attributable to increased biosynthesis of pregnenolone, rather than diminished catabolism of progesterone to its principal metabolite, 20a-hydroxypregn-4-en-3-one. Insulin also enhanced progesterone production in the presence of a soluble sterol substrate, 5-cholesten-3j3,25-diol, which readily gains access to the mitochondrial cholesterol side-chain cleavage system. Moreover, exposure of granulosa cells to insulin produced a three-to sevenfold increase in mitochondrial content of cytochrome P-450 measured by difference spectroscopy, with a corresponding increase in mitochondrial cholesterol side-chain cleavage activity.The capacity of insulin to facilitate progesterone biosynthesis by ovarian cells was mimicked by the insulinlike somatomedin, multiplication stimulating activity, but not by epidermal growth factor, fibroblast growth factor, or porcine relaxin. Insulin's augmentation of progesterone production reflected a selective action on progestin biosynthesis, since insulin significantly suppressed estrogen biosynthesis by granulosa cells.Thus, our investigations indicate that insulin acts on ovarian cells selectively to stimulate pregnenolone (but not estrogen) biosynthesis. The actions of insulin are exerted by processes that require protein and RNA synthesis, and by mechanisms that augment mitochondrial cytochrome P-450 content and facilitate the utilization of cholesterol in the side-chain cleavage 1046 J. Clin. Invest.

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A Reproductive Endocrine Profile in the Diabetes (db) Mutant Mouse1

Cited by 108 publications

References 12 publications

Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons

Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons

Reproductive physiology, and physical and sexual development of female offspring born to diabetic dams

Mechanisms subserving the trophic actions of insulin on ovarian cells. In vitro studies using swine granulosa cells

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