The satiety molecule nesfatin-1 is co-expressed with melanin concentrating hormone in tuberal hypothalamic neurons of the rat

Fort, Patrice; Salvert, Denise; Hanriot, Lucie; Jego, Sonia; Shimizu, Hiroyuki; Hashimoto, Kazuhito; Mori, Masataka; Luppi, Pierre‐Hervé

doi:10.1016/j.neuroscience.2008.05.035

Cited by 109 publications

(86 citation statements)

References 36 publications

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“…1 A and B). Neuropeptide-glutamic acid-isoleucine (n ϭ 9), cocaine-and amphetamine-regulated transcript (n ϭ 11) and nesfatin (n ϭ 10) had no effect on MCH responsive or nonresponsive vGluT2-GnRH neurons; all three peptides can be produced by MCH neurons (51,53,54). Similarly, leptin (n ϭ 5) and NPY (n ϭ 19), which also signal availability of energy stores, had no effect on the kisspeptin-activated vGluT2-GnRH neurons.…”

Section: Mch Inhibits Vglut2-gnrh Neurons Via a Mchr1-transduced Directmentioning

confidence: 99%

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction

Dumalska²,

Morozova³

et al. 2009

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

104

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A link between energy balance and reproduction is critical for the survival of all species. Energy-consuming reproductive processes need to be aborted in the face of a negative energy balance, yet knowledge of the pathways mediating this link remains limited. Fasting and food restriction that inhibit fertility also upregulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure; MCH knockout mice are lean and have a higher metabolism but remain fertile. MCH also modulates sleep, drug abuse behavior, and mood, and MCH receptor antagonists are currently being developed as antiobesity and antidepressant drugs. Despite the clinical implications of MCH, the direct postsynaptic effects of MCH have never been reported in CNS neurons. Using patch-clamp recordings in brain slices from multiple lines of transgenic GFP mice, we demonstrate a strong inhibitory effect of MCH on an exclusive population of septal vGluT2-GnRH neurons that is activated by the puberty-triggering and preovulatory luteinizing hormone surge-mediating peptide, kisspeptin. MCH has no effect on kisspeptin-insensitive GnRH, vGluT2, cholinergic, or GABAergic neurons located within the same nucleus. The inhibitory effects of MCH are reproducible and nondesensitizing and are mediated via a direct postsynaptic Ba 2؉ -sensitive K ؉ channel mechanism involving the MCHR1 receptor. MCH immunoreactive fibers are in close proximity to vGluT2-GFP and GnRH-GFP neurons. Importantly, MCH blocks the excitatory effect of kisspeptin on vGluT2-GnRH neurons. Considering the role of MCH in regulating energy balance and of GnRH and kisspeptin in triggering puberty and maintaining fertility, MCH may provide a critical link between energy balance and reproduction directly at the level of the kisspeptin-activated vGluT2-GnRH neuron.fertility ͉ gonadotropins ͉ HPG axis ͉ obesity ͉ starvation N utritional status and availability of energy stores exert a profound impact on reproductive function (1-3). Reproduction is an expensive energy-consuming process, and thus it is important that puberty, pregnancy, and lactation occur only when metabolic fuel is available (4). Availability of metabolic fuel is conveyed to the brain by peripherally generated signals, such as leptin, insulin, and ghrelin, as well as by centrally released peptides such as neuropeptide Y, melanocortins, and melanin-concentrating hormone (MCH). One or more of these signals can directly or indirectly link energy balance with reproduction at one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis. Thus, insulin and leptin may indirectly influence GnRH neurons (2, 5-7); leptin could regulate the HPG axis via kisspeptin-containing hypothalamic neurons (8, 9). Kisspeptin and its receptor are critical for reproduction (10-12); both kisspeptin and kisspeptin receptor knockout mice fail to enter puberty, and humans with loss of function mutations in the kisspeptin receptor exhibit hypogonadotropic hypogonadism and are infertile (13-15). Mechanisti...

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Section: Mch Inhibits Vglut2-gnrh Neurons Via a Mchr1-transduced Directmentioning

confidence: 99%

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction

Dumalska²,

Morozova³

et al. 2009

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

104

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“…Thus, nesfatin-1 was found highly co-expressed with the orexigenic peptide, melanin-concentrating hormone (MCH), in neurons at the lateral portion of the tuberal hypothalamic area in rats (Fort et al 2008); however, the functional relevance of such potential nesfatin-MCH interaction is yet to be evaluated. In addition, electrophysiological studies revealed that nesfatin-1 is capable of inhibiting neuropeptide Y (NPY) neurons at the ARC, as a potential mechanism for its anorectic effects (Price et al 2008).…”

Section: Reproductive Organsmentioning

confidence: 99%

Expanding roles of NUCB2/nesfatin-1 in neuroendocrine regulation

García-Galiano

Navarro

Gaytán

et al. 2010

Journal of Molecular Endocrinology

118

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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.

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“…So far, only one study described the occurrence of mature nesfatin-1 peptide in the cerebrospinal fluid of rats, whereas in brain nuclei only full length NUCB2 was detected [24]. In all subsequent reports, only full length NUCB2 was detected by Western blot [8,27,36] or studies performing immunostaining did not distinguish between NUCB2 protein and nesfatin-1 peptide [5,6,8,10,13,14,16,18,25,32,34,42,43]. Since also full length NUCB2 exerts an anorexigenic effect it is also possible that this protein is the active circulating form.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Increases Gastric and Circulating NUCB2/Nesfatin-1 Concentrations in Rats

Stengel¹,

Goebel²,

Jawien³

et al. 2011

Gastroenterology

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The satiety molecule nesfatin-1 is co-expressed with melanin concentrating hormone in tuberal hypothalamic neurons of the rat

Cited by 109 publications

References 36 publications

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction

Expanding roles of NUCB2/nesfatin-1 in neuroendocrine regulation

Lipopolysaccharide Increases Gastric and Circulating NUCB2/Nesfatin-1 Concentrations in Rats

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