PI3K: An Attractive Candidate for the Central Integration of Metabolism and Reproduction

Acosta-Martínez, Maricedes

doi:10.3389/fendo.2011.00110

Cited by 41 publications

(58 citation statements)

References 166 publications

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“…In addition to STAT3 and mTOR signaling, phosphatidylinositol-3-kinase (PI3K) signaling is also considered a key integrator of metabolic and reproductive function. Impairments in leptin-and/or insulin-induced PI3K signaling are observed in response to chronic under-and over-nutrition, and these impairments are thought to play a role in the mechanism whereby reproductive function becomes suppressed, as reviewed by Acosta-Martinez (2011). These data, along with others, demonstrate the importance of a more complete understanding of the roles that intracellular signaling molecules play in the neuroendocrine integration of nutritional signals on fertility.…”

Section: Other Considerationsmentioning

confidence: 89%

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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Section: Other Considerationsmentioning

confidence: 89%

Neuroendocrine integration of nutritional signals on reproduction

Evans

Anderson

2017

Journal of Molecular Endocrinology

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“…The weakened Pi3K signaling may be responsible for the downregulation of Gnrh mrNa expression in LeP-immunized rats. impaired hypothalamic insulin and LeP receptor signaling is thought to be at the core of reproductive disorders associated with metabolic dysfunction [1]. Metabolic models of LeP resistance (hyperleptinemia) that are known to alter GNrH/LH release, such as diabetes dietinduced obesity, and caloric restriction, are also accompanied by impairments of Pi3K signaling in insulin-and LeP-sensitive tissues including the hypothalamus [4].…”

Section: Discussionmentioning

confidence: 99%

“…in fact, the Ca/Pi disorder is responsible for osteoporosis [12]. in neurons, as in a variety of other cell types, phosphatidylinositol-3-kinase (Pi3K) is a key intermediate that is common to the signaling pathways of a number of peripheral metabolic cues, including insulin and LeP, which are well known to regulate both metabolic and reproductive functions [1].…”

Section: Introductionmentioning

confidence: 99%

Exogenous Leptin Administered Intramuscularly Induces Sex Hormone Disorder and Ca Loss via Downregulation of <i>Gnrh</i> and PI3K Expression

Liu

Nashun³

et al. 2014

Exp. Anim.

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Obesity is a public health problem that increases the risk of metabolic disease, infertility, and other chronic health problems. The present study aimed to develop a new rat model for sex hormone disorder with overweight and Ca loss by intramuscular injection of exogenous leptin (LEP). Thirty female Sprague-Dawley (SD) rats (40 days old) were injected thrice intramuscularly with LEP or keyhole limpet hemocyanin immunogen. The following analyses were performed to determine the development of appetite, overweight, reproductive related-hormones, and calcium (Ca)/phosphorus (Pi) in SD rats: measurement of Lee's index, body weight, food intake; serum Ca, Pi, and hormone tests by enzyme-linked immunosorbent analysis; histological analysis of abdominal fat; real-time polymerase chain reaction analysis of neuropeptide Y, pro-opiomelanocortin, gonadotropin-releasing hormone (Gnrh) mRNA, and gonadotropin-releasing hormone receptor (Gnrhr) mRNA expression; and western blotting analysis of enzyme phosphatidylinositol-3-kinase (PI3K). Rats injected with LEP immunogen displayed significantly increased body weight, food intake, Lee's index, serum LEP, serum cortisol, fat deposition in the abdomen, and decreased hormones including follicle stimulating hormone, luteinizing hormone, estradiol, cholecystokinin, and Ca. Exogenous LEP administered intramuscularly also downregulate Gnrh and PI3K. In conclusion, exogenous LEP administered intramuscularly is a novel animal model for sex hormones disorder with overweight and Ca loss in SD rats. The downregulation of PI3K and Gnrh may be involved in the development of this animal model.

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“…Insulin and leptin share a presumed intracellular signaling pathway in that PI3K is activated in the presence of insulin or leptin alone, and as such PI3K represents a common pathway through which metabolism may influence reproduction (Acosta-Martinez, 2011; Carvalheira et al, 2005; Niswender et al, 2003; Niswender et al, 2001). Neurons in the ARH such as POMC neurons express both the IR and LepRb.…”

Section: Leptinmentioning

confidence: 99%

Minireview: Metabolic control of the reproductive physiology: Insights from genetic mouse models

Bellefontaine

Elias

2014

Hormones and Behavior

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Over the past two decades, and in particular over the past 5-7 years, there has been a tremendous advancement in the understanding of the metabolic control of reproductive physiology. This has been in large part due to the advancement and refinement of gene targeting tools and techniques for molecular mapping. Yet despite the emergence of exciting and often times thought-provoking data through the use of new mouse models, the heavy reliance on gene targeting strategies has become fundamental in this process and thus caution must be exercised when interpreting results. This minireview article will explore the generation of new mouse models using genetic manipulation, such as viral vector delivery and the use of the Cre/loxP system, to investigate the role of circulating metabolic hormones in the coordination of reproductive physiology. In addition, we will also highlight some of the pitfalls in the use of genetic manipulation in the current paradigms. However, it has become clear that metabolic cues employ integrated and plastic neural circuits in order to modulate the neuroendocrine reproductive axis, and despite recent advances much remains to be elucidated about this circuitry.

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PI3K: An Attractive Candidate for the Central Integration of Metabolism and Reproduction

Cited by 41 publications

References 166 publications

Neuroendocrine integration of nutritional signals on reproduction

Neuroendocrine integration of nutritional signals on reproduction

Exogenous Leptin Administered Intramuscularly Induces Sex Hormone Disorder and Ca Loss via Downregulation of <i>Gnrh</i> and PI3K Expression

Minireview: Metabolic control of the reproductive physiology: Insights from genetic mouse models

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