Neuropeptide Signaling in the Integration of Metabolism and Reproduction

Crown, Angelena; Clifton, Donald K.; Steiner, Robert A.

doi:10.1159/000109095

Cited by 140 publications

(108 citation statements)

References 196 publications

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“…Indeed, prolonged hyperactivation of AgRP/NPY neurons, often associated with negative energy balance, causes not only robust hyperphagia to restore adiposity stores but also suppresses reproductive function. Although NPY has been shown to influence GnRH and gonadotrophin secretion, chronic administration of NPY delays sexual maturity and impairs reproductive function (40). Furthermore, deletion of NPY or Y4 receptor from leptindeficient mice restores fertility (17).…”

Section: Discussionmentioning

confidence: 99%

Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake

Olofsson

Pierce²,

Xu³

2009

Proc. Natl. Acad. Sci. U.S.A.

152

123

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In female mammals including rodents and humans, feeding decreases during the periovulatory period of the ovarian cycle, which coincides with a surge in circulating estrogen levels. Ovariectomy increases food intake, which can be normalized by estrogen treatment at a dose and frequency mimicking those during the estrous cycle. Furthermore, administration of estrogen to rodents potently inhibits food intake. Despite these well-known effects of estrogen, neuronal subtypes that mediate estrogen's anorexigenic effects have not been identified. In this study, we show that changes in hypothalamic expression of agouti-related protein (Agrp) and neuropeptide Y (Npy) coincide with the cyclic changes in feeding across the estrous cycle. These cyclic changes in feeding are abolished in mice with degenerated AgRP neurons even though these mice cycle normally. Central administration of 17␤-estradiol (E2) decreases food intake in controls but not in mice lacking the AgRP neurons. Furthermore, E2 treatment suppresses fastinginduced c-Fos activation in AgRP and NPY neurons and blunts the refeeding response. Surprisingly, although estrogen receptor alpha (ER␣) is the key mediator of estrogen's anorexigenic effects, we find that expression of ER␣ is completely excluded from AgRP and NPY neurons in the mouse hypothalamus, suggesting that estrogen may regulate these neurons indirectly via presynaptic neurons that express ER␣. This study indicates that neurons coexpressing AgRP and NPY are functionally required for the cyclic changes in feeding across estrous cycle and that AgRP and NPY neurons are essential mediators of estrogen's anorexigenic function.estrogen ͉ feeding P roper regulation of energy homeostasis and reproduction is fundamental for fitness and survival. Reproduction is an energy intensive process, and precise interaction of regulators for energy balance and reproduction allows coordinated regulation of these two processes. Leptin, a hormone secreted from adipose tissue, plays a critical role in both energy balance and reproduction. Leptin is produced proportional to body fat mass and it conveys the abundance of the body's energy stores to the brain, where it acts to regulate feeding and energy expenditure (1). A decline in leptin level signals a state of negative energy balance, which triggers robust counterregulatory mechanisms to increase feeding. One consequence of negative energy balance is induction of hypogonadonism and inhibition of reproductive function (2). Consistent with this notion, leptin deficiency results in profound hyperphagia and infertility in rodents and humans (1,(3)(4)(5).Estrogen, a hormone essential for sexual reproduction, plays a role in feeding and energy balance regulation. Serum levels of estrogen decline during negative energy balance (6) and estrogen deficiency or loss of function of estrogen receptor (ER) results in increased feeding and adiposity in rodents and humans (7-10). Feeding and body weight increase in ovariectomized females and estrogen replacement reverses such effects (11,1...

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Section: Discussionmentioning

confidence: 99%

Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake

Olofsson

Pierce²,

Xu³

2009

Proc. Natl. Acad. Sci. U.S.A.

152

123

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“…Galanin-like peptide (GALP)-expressing neurons represent another population of neurons that contributes to the metabolic control of fertility (Cunningham 2004, Crown et al 2007, Shioda et al 2011. Anatomically, GALP cell bodies are primarily located in the ARC, but their fibers make apparent contacts with GNRH neurons in the rat hypothalamus (Takatsu et al 2001).…”

Section: Galp-expressing Neuronsmentioning

confidence: 99%

Neuroendocrine integration of nutritional signals on reproduction

Evans

Anderson

2017

Journal of Molecular Endocrinology

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Reproductive function in mammals is energetically costly and therefore tightly regulated by nutritional status. To enable this integration of metabolic and reproductive function, information regarding peripheral nutritional status must be relayed centrally to the gonadotropin-releasing hormone (GNRH) neurons that drive reproductive function. The metabolically relevant hormones leptin, insulin and ghrelin have been identified as key mediators of this 'metabolic control of fertility'. However, the neural circuitry through which they act to exert their control over GNRH drive remains incompletely understood. With the advent of Cre-LoxP technology, it has become possible to perform targeted gene-deletion and gene-rescue experiments and thus test the functional requirement and sufficiency, respectively, of discrete hormone-neuron signaling pathways in the metabolic control of reproductive function. This review discusses the findings from these investigations, and attempts to put them in context with what is known from clinical situations and wild-type animal models. What emerges from this discussion is clear evidence that the integration of nutritional signals on reproduction is complex and highly redundant, and therefore, surprisingly difficult to perturb. Consequently, the deletion of individual hormone-neuron signaling pathways often fails to cause reproductive phenotypes, despite strong evidence that the targeted pathway plays a role under normal physiological conditions. Although transgenic studies rarely reveal a critical role for discrete signaling pathways, they nevertheless prove to be a good strategy for identifying whether a targeted pathway is absolutely required, critically involved, sufficient or dispensable in the metabolic control of fertility.

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“…3 However, mGlu receptor activation does not affect the release of this peptide from the posterior pituitary in male rats. 3 Since α-MSH inhibits the preovulatory PRL and LH surge and ovulation of female rats, 4 mGlu receptor activity at α-MSH level could lead to increased LH production.…”

Section: Actions Of Mglu Receptor Activation On Hypothalamic Factorsmentioning

confidence: 99%

mGlu receptors in endocrine organs

Durand

Carniglia

Lasaga

2011

WIREs Membr Transp Signal

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Metabotropic glutamate (mGlu) receptors in the central nervous system are known to be essential for neuroplasticity associated with normal brain functions and are also critically involved in various neurological and psychiatric disorders. A recent surge of publications supports the presence, importance, and functionality of mGlu receptors outside the central nervous system with a unique distribution within various tissues. Group I, II, and III mGlu receptors are found in a wide range of peripheral organs including parts of the peripheral nervous system and nonneural organs such as hypophysis, pancreas, adrenal medulla, and the reproductive system. The distinct distribution of mGlu receptors in peripheral tissues is discussed in terms of possible functional endocrine implications. 

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Neuropeptide Signaling in the Integration of Metabolism and Reproduction

Cited by 140 publications

References 196 publications

Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake

Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake

Neuroendocrine integration of nutritional signals on reproduction

mGlu receptors in endocrine organs

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