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Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature.

ABSTRACT: Estrogen withdrawal in menopausal women leads to hot flushes, a syndrome characterized by the episodic activation of heat dissipation effectors. Despite the extraordinary number of individuals affected, the etiology of flushes remains an enigma. Because menopause is accompanied by marked alterations in hypothalamic kisspeptin/neurokinin B/dynorphin (KNDy) neurons, we hypothesized that these neurons could contribute to the generation of flushes. To determine if KNDy neurons participate in the regulation of body temperature, we evaluated the thermoregulatory effects of ablating KNDy neurons by injecting a selective toxin for neurokinin-3 expressing neurons [NK(3)-saporin (SAP)] into the rat arcuate nucleus. Remarkably, KNDy neuron ablation consistently reduced tail-skin temperature (T(SKIN)), indicating that KNDy neurons facilitate cutaneous vasodilatation, an important heat dissipation effector. Moreover, KNDy ablation blocked the reduction of T(SKIN) by 17β-estradiol (E(2)), which occurred in the environmental chamber during the light phase, but did not affect the E(2) suppression of T(SKIN) during the dark phase. At the high ambient temperature of 33 °C, the average core temperature (T(CORE)) of ovariectomized (OVX) control rats was significantly elevated, and this value was reduced by E(2) replacement. In contrast, the average T(CORE) of OVX, KNDy-ablated rats was lower than OVX control rats at 33 °C, and not altered by E(2) replacement. These data provide unique evidence that KNDy neurons promote cutaneous vasodilatation and participate in the E(2) modulation of body temperature. Because cutaneous vasodilatation is a cardinal sign of a hot flush, these results support the hypothesis that KNDy neurons could play a role in the generation of flushes.

SUBMITTER: Mittelman-Smith MA

PROVIDER: S-EPMC3511761 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other

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Project description:The neuronal regulation of metabolic and behavioral responses to different diets and feeding regimens is an important research area. Herein, we investigated if the opioid peptide dynorphin modulates feeding behavior and metabolism. Mice lacking dynorphin peptides (KO) were exposed to either a normal diet (ND) or a high-fat diet (HFD) for a period of 12 weeks. Additionally, mice had either time-restricted (TR) or ad libitum (AL) access to food. Body weight, food intake and blood glucose levels were monitored throughout the 12-week feeding schedule. Brain samples were analyzed by immunohistochemistry to detect changes in the expression levels of hypothalamic peptides. As expected, animals on HFD or having AL access to food gained more weight than mice on ND or having TR access. Unexpectedly, KO females on TR HFD as well as KO males on AL ND or AL HFD demonstrated a significantly increased body weight gain compared to the respective WT groups. The calorie intake differed only marginally between the genotypes: a significant difference was present in the female ND AL group, where dynorphin KO mice ate more than WT mice. Although female KO mice on a TR feeding regimen consumed a similar amount of food as WT controls, they displayed significantly higher levels of blood glucose. We observed significantly reduced levels of hypothalamic orexigenic peptides neuropeptide Y (NPY) and orexin-A in KO mice. This decrease became particularly pronounced in the HFD groups and under AL condition. The kappa opiod receptor (KOR) levels were higher after HFD compared to ND feeding in the ventral pallidum of WT mice. We hypothesize that HFD enhances dynorphin signaling in this hedonic center to maintain energy homeostasis, therefore KO mice have a more pronounced phenotype in the HFD condition due to the lack of it. Our data suggest that dynorphin modulates metabolic changes associated with TR feeding regimen and HFD consumption. We conclude that the lack of dynorphin causes uncoupling between energy intake and body weight gain in mice; KO mice maintained on HFD become overweight despite their normal food intake. Thus, using kappa opioid receptor agonists against obesity could be considered as a potential treatment strategy.

Project description:BackgroundPolycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, anovulation, and polycystic ovaries. Electroacupuncture (EA) can effectively improve hyperandrogenism and increase ovulation frequency in patients with PCOS. Pieces of suggest that androgen activity in the brain is associated with impaired steroid negative feedback in such patients. Studies have shown that EA regulated androgen receptor (AR) expression and local factor levels (such as anti-Müllerian hormone and inhibin B) in the ovary of PCOS rats. However, few studies have explored the effect of EA on androgen activity in the brain.ObjectiveThis study investigated the effect of EA on the kisspeptin-gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) neural circuit and sex hormone receptor expression in the hypothalamus of PCOS rats.MethodsPCOS signs were induced by letrozole administration, and the induced rats were treated with low-frequency EA at Guan Yuan acupoint (CV4). The effect of EA on PCOS-like signs was evaluated by observing changes in the body weight, ovarian quality, ovarian morphology, and serum sex hormone levels in rats. To explore the mechanism of the effect of EA on PCOS-like signs, the neuropeptide content of the kisspeptin-GnRH/LH neural circuit was assessed using enzyme-linked immunosorbent assay(ELISA); AR and estrogen receptor α (ERα) coexpression on kisspeptin/neurokinin B/dynorphin (KNDy) neurons was determined via triple-label immunofluorescence; and protein and mRNA expression of Kiss1, Ar, Esr1, and kisspeptin receptor (Kiss1r) was evaluated via western blotting and Reverse Transcription-Polymerase Chain Reaction (RT-PCR).ResultsThe results revealed that the estrous cycle of rats in the EA treatment group recovered, and their body and ovary weight reduced; ovarian morphology improved; serum testosterone and LH levels significantly decreased; and kisspeptin, GnRH, and dynorphin levels in hypothalamic arcuate nucleus significantly decreased. Compared with controls, the number of AR/Kiss1-positive cells increased, number of ERα/Kiss1-positive cells decreased, and protein and mRNA expression of Kiss1, Ar, and Kiss1r significantly increased in PCOS rats. However, EA treatment reversed these changes and reduced the expression of Kiss1, Ar, and Kiss1r significantly.ConclusionImprovement in the reproductive hallmarks of PCOS rats via EA may be achieved by regulating the kisspeptin-GnRH/LH circuit via androgen activity attenuation. Thus, the results provide an experimental basis for acupuncture as an adjuvant medical therapy on PCOS.

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Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature.

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