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Effects of ovarian hormones on internal circadian organization in rats.

ABSTRACT: The circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is the central pacemaker driving rhythms in endocrine physiology. Gonadal steroid hormones affect behavioral rhythms and clock gene expression. However, the impact of fluctuating ovarian steroid levels during the estrous cycle on internal circadian organization remains to be determined. Further, it is not known if steroid hormone depletion, as in menopause, affects the timing system. To determine the influence of estrous cycle stage and steroid depletion on circadian organization, we measured clock gene expression in the SCN and peripheral tissues from cycling and ovariectomized (OVX) period1-luciferase (per1-luc) transgenic rats. The estrous cycle had modest effects on mean phase and phase distribution of per1-luc expression in the SCN. Surprisingly, peak per1-luc expression in the SCN was widely distributed mainly at night, regardless of cycle stage, an effect eliminated by OVX. Treatment of SCN tissue explants with ovarian steroids did not significantly affect per1-luc expression, suggesting that brain regions outside the SCN mediate the phasic effects of steroids. Our data demonstrate that estrous cycle stage has tissue-dependent effects on the phase of per1-luc expression, phase synchrony among oscillators, and the phase relationship between some peripheral clocks and the light-dark cycle. They also reveal that steroid hormone depletion following OVX alters the timing system, suggesting that the decline in hormone levels, common during the transition to menopause, may be associated with irregular internal circadian organization. This effect on the timing system could contribute to the behavioral and physiological changes associated with this transition.

SUBMITTER: Murphy ZC

PROVIDER: S-EPMC4076364 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Effects of ovarian hormones on internal circadian organization in rats.

Murphy Zachary C ZC Pezuk Pinar P Menaker Michael M Sellix Michael T MT

Biology of reproduction 20130815 2

The circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is the central pacemaker driving rhythms in endocrine physiology. Gonadal steroid hormones affect behavioral rhythms and clock gene expression. However, the impact of fluctuating ovarian steroid levels during the estrous cycle on internal circadian organization remains to be determined. Further, it is not known if steroid hormone depletion, as in menopause, affects the timing system. To determine the influence of estrou ...[more]

PMID: 23843233

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Project description:In female rodents, sexual receptivity is coordinated with cyclic changes in the release of gonadal hormones. Increases in estradiol (E) and progesterone (P) during proestrus and estrus not only induce ovulation but also modulate behaviors that increase the likelihood that the female will find a mate and reproduce. This includes changes in receptive behaviors, such as lordosis, as well as changes in appetitive or proceptive behaviors, including motivation. Interestingly, the direction of these changes in motivation is dependent on the type of reward that is being pursued. While induction of sexual receptivity by E and P increases motivation for access to a male, motivation for a palatable food reward is decreased. These concurrent changes may facilitate adaptive choice across the estrous cycle; females bias their choice for sex when fertilization is most likely to occur, but for food when copulation is unlikely to result in impregnation. In order to test this hypothesis, we developed a novel paradigm to measure the motivated choice between a palatable food reward and access to a male conspecific. Ovariectomized, hormone primed females were trained to operantly respond for both food and sex on a fixed interval (FI) schedule. After training, unprimed and primed females were tested in a chamber that allows them to choose between food and sex while still requiring responding on the FI schedule for reach reward. From this we can not only determine the impact of hormone priming on female choice for food or sex, but also how this is reflected by changes in motivation for each specific reward, as measured by the average number of responses made during each fixed interval. Induction of sexual receptivity by hormone priming biases choice toward sex over food and this change is accompanied by an increase in motivation for sex but a decrease in motivation for food. This work provides evidence in support of a novel framework for understanding how the release of ovarian hormones over the course of the estrous cycle modulates adaptive behavioral choice in females by directly assessing motivation via operant responding when multiple rewards are available.

Project description:Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role.We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE.Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review.We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a central action of estrogens to increase the satiating potency of the gastrointestinal hormone cholecystokinin. Another mechanism involves a decrease in the preference for sweet foods during the follicular phase. Genetic defects in brain ?-melanocycte-stimulating hormone-melanocortin receptor (melanocortin 4 receptor, MC4R) signaling lead to a syndrome of overeating and obesity that is particularly pronounced in women and in female animals. The syndrome appears around puberty in mice with genetic deletions of MC4R, suggesting a role of ovarian hormones. Emerging functional brain-imaging data indicates that fluctuations in ovarian hormones affect eating by influencing striatal dopaminergic processing of flavor hedonics and lateral prefrontal cortex processing of cognitive inhibitory controls of eating. There is a dearth of research on the neuroendocrine control of eating after menopause. There is also comparatively little research on the effects of ovarian hormones on EE, although changes in ovarian hormone levels during the menstrual cycle do affect resting EE.The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health.

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Effects of ovarian hormones on internal circadian organization in rats.

Publications

Effects of ovarian hormones on internal circadian organization in rats.

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