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Roa J.,University of Cordoba, Spain | Roa J.,University of Otago | Tena-Sempere M.,University of Cordoba, Spain | Tena-Sempere M.,CIBER ISCIII | Tena-Sempere M.,Instituto Maimonides Of Investigaciones Biomedicas Imibic
Trends in Endocrinology and Metabolism | Year: 2010

The onset of puberty is gated by body energy reserves and nutritional cues. The adipose hormone leptin is an essential signal for the metabolic control of puberty, through mechanisms that are yet to be fully characterized. Mammalian target of rapamycin (mTOR), an energetic cell sensor, operates at specific hypothalamic nuclei as a transducer for leptin effects on feeding and energy homeostasis. This review summarizes recent experimental evidence supporting a role for central mTOR signaling in puberty onset. These findings are discussed in the context of topical developments in the field, such as recognition of the roles of the cAMP responsive element-binding protein regulated transcription coactivator-1 (Crtc1) and kisspeptins in the metabolic control of reproduction, thus highlighting novel mechanisms responsible for coupling puberty and energy homeostasis. © Elsevier Ltd.

Martins L.,University of Santiago de Compostela | Martins L.,CIBER ISCIII | Fernandez-Mallo D.,University of Santiago de Compostela | Fernandez-Mallo D.,CIBER ISCIII | And 13 more authors.
PLoS ONE | Year: 2012

Current evidence suggests that ghrelin, a stomach derived peptide, exerts its orexigenic action through specific modulation of Sirtuin1 (SIRT1)/p53 and AMP-activated protein kinase (AMPK) pathways, which ultimately increase the expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARC). However, there is a paucity of data about the possible action of ghrelin on alternative metabolic pathways at this level. Here, we demonstrate that ghrelin elicits a marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signaling pathway. Of note, central inhibition of mTOR signaling with rapamycin decreased ghrelin's orexigenic action and normalized the mRNA expression of AgRP and NPY, as well as their key downstream transcription factors, namely cAMP response-element binding protein (pCREB) and forkhead box O1 (FoxO1, total and phosphorylated). Taken together, these data indicate that, in addition to previous reported mechanisms, ghrelin also promotes feeding through modulation of hypothalamic mTOR pathway. © 2012 Martins et al.

Garcia-Galiano D.,University of Cordoba, Spain | Garcia-Galiano D.,CIBER ISCIII | Navarro V.M.,University of Cordoba, Spain | Navarro V.M.,University of Washington | And 5 more authors.
Journal of Molecular Endocrinology | Year: 2010

Nesfatin-1 was originally identified as a hypothalamic neuropeptide, derived from the precursor NEFA (for DNA binding/EF-hand/acidic protein)/nucleobindin 2 (NUCB2), with the ability to suppress food intake, acting in a leptin-independent manner. Departing from this seminal finding, the patterns of expression of NUCB2/nesfatin-1 have been thoroughly characterized in different hypothalamic nuclei and brain areas with proven roles in energy homeostasis, and its potential interactions with other key neuropeptide regulators of appetite have been documented. Intriguingly, recent experimental evidence suggests that NUCB2/nesfatin-1 is also expressed in peripheral tissues with relevant metabolic functions, such as the pancreas, the adipose, and the gut. In addition, evidence is mounting that nesfatin signaling may participate in adaptative responses and in the control of body functions gated by the state of energy reserves, such as puberty onset. Altogether, these observations have broadened our perception of the biological profile of nesfatin-1 that, rather than a simple anorectic signal in the hypothalamus, might operate at different tissues as an integral regulator of energy homeostasis and closely related neuroendocrine functions. © 2010 Society for Endocrinology.

Castellano J.M.,University of Cordoba, Spain | Castellano J.M.,CIBER ISCIII | Bentsen A.H.,Copenhagen University | Mikkelsen J.D.,Copenhagen University | And 3 more authors.
Brain Research | Year: 2010

Body energy reserves and metabolic state are relevant modifiers of puberty onset and fertility; forms of metabolic stress ranging from persistent energy insufficiency to morbid obesity are frequently linked to reproductive disorders. The mechanisms for such a close connection between energy balance and reproduction have been the subject of considerable attention; however, our understanding of the neurobiological basis for this phenomenon is still incomplete. In mid 1990s, the adipose-hormone, leptin, was proven as an essential signal for transmitting metabolic information onto the centers governing puberty and reproduction; yet, the ultimate mode of action of leptin on GnRH neurons has remained contentious for years. More recently, kisspeptins, a family of neuropeptides encoded by the Kiss1 gene, have emerged as conduits for the metabolic regulation of reproduction and putative effectors of leptin actions on GnRH neurons. This review recapitulates the experimental evidence obtained to date, mostly in laboratory rodents, supporting the function of kisspeptins in bridging energy balance and reproduction, with special emphasis on recent developments in this field, such as the recognition of mTOR (mammalian target of rapamycin) and Crtc1 (Creb1-regulated transcription coactivator-1) as putative mediators for leptin regulation of Kiss1 expression, as well as the identification of other potential metabolic modulators of kisspeptin signaling, such as ghrelin, neuropeptide Y (NPY) and melanin-concentrating hormone (MCH). © 2010 Elsevier B.V.

Varela L.,University of Santiago de Compostela | Varela L.,CIBER ISCIII | Martinez-Sanchez N.,University of Santiago de Compostela | Martinez-Sanchez N.,CIBER ISCIII | And 18 more authors.
Journal of Pathology | Year: 2012

Hyperthyroidism is characterized in rats by increased energy expenditure and marked hyperphagia. Alterations of thermogenesis linked to hyperthyroidism are associated with dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism-induced hyperphagia remain largely unclear. Here, we demonstrate that hyperthyroid rats exhibit marked up-regulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti-related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of pro-opiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR co-localizes with thyroid hormone receptor-α (TRα). Central administration of thyroid hormone (T3) or genetic activation of thyroid hormone signalling in the ARC recapitulated hyperthyroidism effects on feeding and the mTOR pathway. In turn, central inhibition of mTOR signalling with rapamycin in hyperthyroid rats reversed hyperphagia and normalized the expression of ARC-derived neuropeptides, resulting in substantial body weight loss. The data indicate that in the hyperthyroid state, increased feeding is associated with thyroid hormone-induced up-regulation of mTOR signalling. Furthermore, our findings that different neuronal modulations influence food intake and energy expenditure in hyperthyroidism pave the way for a more rational design of specific and selective therapeutic compounds aimed at reversing the metabolic consequences of this disease. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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