• BMB Reports
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• v.50 no.1
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• pp.31-36
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• 2017

High-dose caffeine uptake is a developmental stressor and causes food-avoidance behavior (aversion phenotype) in C. elegans, but its mode of action is largely unknown. In this study, we investigated the molecular basis of the caffeine-induced aversion behavior in C. elegans. We found that aversion phenotype induced by 30 mM caffeine was mediated by JNK/MAPK pathway, serotonergic and dopaminergic neuroendocrine signals. In this process, the dopaminergic signaling appears to be the major pathway because the reduced aversion behavior in cat-2 mutants and mutants of JNK/MAPK pathway genes was significantly recovered by pretreatment with dopamine. RNAi depletion of hsp-16.2, a cytosolic chaperone, and cyp-35A family reduced the aversion phenotype, which was further reduced in cat-2 mutants, suggesting that dopaminergic signal is indeed dominantly required for the caffeine-induced food aversion. Our findings suggest that aversion behavior is a defense mechanism for worms to survive under the high-dose caffeine conditions.

• Molecules and Cells
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• v.26 no.5
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• pp.427-435
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• 2008

In this review, we discuss the genes and the related signal pathways that regulate aging and longevity by reviewing recent findings of genetic longevity models in rodents in reference to findings with lower organisms. We also paid special attention to the genes and signals mediating the effects of calorie restriction (CR), a powerful intervention that slows the aging process and extends the lifespan in a range of organisms. An evolutionary view emphasizes the roles of nutrient-sensing and neuroendocrine adaptation to food shortage as the mechanisms underlying the effects of CR. Genetic and non-genetic interventions without CR suggest a role for single or combined hormonal signals that partly mediate the effect of CR. Longevity genes fall into two categories, genes relevant to nutrient-sensing systems and those associated with mitochondrial function or redox regulation. In mammals, disrupted or reduced growth hormone (GH)-insulin-like growth factor (IGF)-1 signaling robustly favors longevity. CR also suppresses the GH-IGF-1 axis, indicating the importance of this signal pathway. Surprisingly, there are very few longevity models to evaluate the enhanced anti-oxidative mechanism, while there is substantial evidence supporting the oxidative stress and damage theory of aging. Either increased or reduced mitochondrial function may extend the lifespan. The role of redox regulation and mitochondrial function in CR remains to be elucidated.

• Korean Journal of Psychosomatic Medicine
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• v.7 no.2
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• pp.149-157
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• 1999

Food intake and body weight are determined by a complex interaction of regulatory pathways. Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes, that signals the amount of adipose tissue energy stores to the brain and exerts major effects on energy homeostasis and neuroendocrine function. In addition, leptin has recently been shown to affect reproductive function in rodents and humans. The study of leptin and its effectors in the hypothalamus may provide important insights with respect to the interplay of several hypothalamic neuropeptides in regulating feeding as well as the interaction of genetics and environment in the regulation of energy homeostasis. In this review we summarise the action of leptin in the regulation of food intake and highlight a working model of the effects of environmental factors on the leptin system.

• Development and Reproduction
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• v.11 no.1
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• pp.13-20
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• 2007

In all female mammals, reproductive system is one of the first biological systems to show age-related decline. Female mammals in reproductive aging, though the phenomena is somewhat species-specific, start to show declining fertility and changes of numerous physiological functions. This review will present a current information on the aging of the female reproductive hormonal axis and introduce three useful rodent models for studying this field. Middle age($8{\sim}12$ months old) in female rats and mice is comparable to the stage prior to the entry of menopause in human. In this period pulsatile and surge GnRH secretion from hypothalamus gradually attenuated, then reduced pulsatile and surge LH secretion is followed consequently. This age-related defects in GnRH-LH neuroendocrine axis seem to be highly correlated with the defects in brain signals which modulate the activities of GnRH neuron. Many researchers support the idea which the age-related hypothalamic defects are the main cause of reproductive aging, but some ovarian factors such as inhibin response also could contribute to the induction of reproductive senescence. Some rodent models are quite valuable in studying the reproductive aging. The follitropin receptor knockout(FORKO) mice, both of null and haploinsufficient state, could produce depletion of oocyte/follicle with age. Dioxin/aryl hydrocarbon receptor(AhR) knockout mice also show severe ovarian defects and poor reproductive success early in their life compared to the age-matched normal mice. Further studies on the reproductive aging will be a great help to evaluate the benefits and risks of hormone replacement therapy(HRT) and to improve the safety of HRT.

• Journal of Photoscience
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• v.9 no.2
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• pp.255-257
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• 2002

In birds, the photoperiodic seasonal breeding involves encephalic photoreception at the initial step of triggering the well-known endocrinal cascade. Especially in Japanese quail (Coturnix coturnixjaponica), the reproductive neuroendocrine function responds to a single long day, and hypothalamic regions are known to be important for the reproductive response. However, little is known about where and how the light and time signals are integrated to detect daylength information and transduced to the endocrinal responses. To gain insights into this issue, we are interested in the c-Fos expression in the hypothalamus of the Japanese quail. Meddle and Follett (1997) previously identified two hypothalamic regions where c-Fos-like immunoreactivities were induced in response to a long day by using an antibody to carboxyl terminal region of human c-Fos (Lys$^{347}$ -Leu$^{367}$ ). In the present study, we used a different anti-c-Fos antibody recognizing a region from Lys$^{128}$ to Ala$^{152}$ of human c-Fos, and found in long-day- stimulated quails many c-Fos-like immunoreactive nuclei localizing within two regions, nucleus anterior medialis hypothalami and nucleus periventricularis hypothalami, which are distinct from those identified in the previous study. Then, we focused on the difference in the cross-reactivities of the antibodies used, and determined the whole coding sequence of quail c-Fos to compare the antigenic sequences of the two antibodies with the amino acid sequence of quail c-Fos. We found that the antibody we used would recognize quail c-Fos more specifically than that used in the previous study.

• Development and Reproduction
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• v.13 no.4
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• pp.257-264
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• 2009

A neurotoxin, 6-hydroxydopamine (6-OHDA) has been widely used to create animal model for Parkinson's disease (PD) due to its specific toxicity against dopaminergic (DA) neurons. Since DA signals modulate a broad spectrum of CNS physiology, one can expect profound alterations in neuroendocrine activities of both PD patients and 6-OHDA treated animals. Limited applications of 6-OHDA injection model, however, have been made on the studies of hypothalamuspituitary neuroendocrine circuits. The present study was performed to examine whether blockade of brain catecholamine (CA) biosynthesis with 6-OHDA can make any alteration in the transcriptional activities of hypothalamus-pituitary hormone genes in adult male rats. Three-month-old male rats (SD strain) were received 6-OHDA ($200{\mu}g$ in $10{\mu}\ell$ of saline/animal) by intracerebroventricular (icv) injection, and sacrificed after two weeks. To determine the mRNA levels of hypothalamuspituitary hormone genes, total RNAs were extracted and applied to the semi-quantitative RT-PCRs. The mRNA levels of tyrosine hydroxylase (TH), the rate-limiting enzyme for the catecholamine biosynthesis, were significantly lower than those from the control group (control:6-OHDA=1:0.72${\pm}$0.02AU, p<0.001), confirming the efficacy of 6-OHDA injection. The mRNA levels of gonadotropin-releasing hormone (GnRH) and corticotropin releasing hormone (CRH) in the hypothalami from 6-OHDA group were significantly lower than those from the control group (GnRH, control:6-OHDA=1:0.39${\pm}$0.03AU, p<0.001; CRH, control:6-OHDA=1:0.76${\pm}$0.07AU, p<0.01). There were significant decreases in the mRNA levels of common alpha subunit of glycoprotein homones (Cg$\alpha$), LH beta subunit (LH-$\beta$), and FSH beta subunit (FSH-$\beta$) in pituitaries from 6-OHDA group compared to control values (Cg$\alpha$, control:6-OHDA=1:0.81${\pm}$0.02AU, p<0.001; LH-$\beta$, control:6-OHDA=1:0.68${\pm}$0.04AU, p<0.001; FSH-$\beta$, control:6-OHDA=1:0.84${\pm}$0.05AU, p<0.001). Similarly, the level of adrenocorticotrophic hormone (ACTH) transcripts from 6-OHDA group was significantly lower than that from the control group (control: 6-OHDA=1:0.86${\pm}$0.04AU, p<0.01). The present study demonstrated that centrally injected DA neurotoxin could downregulate the transcriptional activities of the two hypothalamus-pituitary neuroendocrine circuits, i.e., GnRH-gonadotropins and CRH-ACTH systems. These results suggested that hypothalamic CA input might affect on the activities of gonad and adrenal through modulation of hypothalamus-pituitary function, providing plausible explanation for frequent occurrence of sexual dysfunction and poor stress-response in PD patients.

• Development and Reproduction
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• v.9 no.1
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• pp.1-5
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• 2005

The hypothalamo-pituitary-gonadal hormone axis is centrally controlled by a complex regulatory network of excitatory and inhibitory signals, that is dormant during infantile and juvenile periods and activated at puberty. The kisspeptins are the peptide products of the KiSS-1 gene and the endogenous agonists for the G protein-coupled receptor 54(GPR54). Although KiSS-1 was initially discovered as a metastasis suppressor gene, a recent evidence suggests the KiSS-1/GPR54 system is a key regulator of the reproductive system. Yet the actual role of the KiSS-1/GPR54 system in the neuroendocrine control of gonadotropin secretion remains largely unexplored, the system could be the first missing link in the reproductive hormonal axis. Central or peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal axis, increasing circulating gonadotropin levels in rodents, sheep, monkey and human models. These effects appear likely to be mediated via the hypothalamic GnRH neuron system, although kisspeptins may have direct effects on the anterior pituitary gland. The loss of function mutations of the GPR54(GPR54-/-) have been associated with lack of puberty onset and idiopathic hypogonadotropic hypogonadism(IHH). So kisspeptin infusion may provide a novel mechanism for HPG axis manipulation in disorders of the reproductive system.

• Development and Reproduction
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• v.13 no.3
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• pp.183-190
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• 2009

In mammals, puberty is a dynamic transition process from infertile immature state to fertile adult state. The neuroendocrine aspect of puberty is started with functional activation of hypothalamus-pituitary-gonadal hormone axis. The timing of puberty can be altered by many factors including hormones and/or hormone-like materials, social cues and metabolic signals. For a long time, attainment of a particular body weight or percentage of body fat has been thought as crucial determinant of puberty onset. However, the precise effect of high-fat (HF) diet on the regulation of hypothalamic GnRH neuron during prepubertal period has not been fully elucidated yet. The present study was undertaken to test the effect of a HF diet on the puberty onset and hypothalamic gene expressions in immature female rats. The HF diet (45% energy from fat, HF group) was applied to female rats from weaning to around puberty onset (postnatal days, PND 22-40). Body weight and vaginal opening (VO) were checked daily during the entire feeding period. In the second experiment, all animals were sacrificed on PND 36 to measure the weights of reproductive tissues. Histological studies were performed to assess the effect of HF diet feeding on the structural alterations in the reproductive tissues. To determine the transcriptional changes of reproductive hormone-related genes in hypothalamus, total RNAs were extracted and applied to the semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Body weights of HF group animals tend to be higher than those of control animals between PND 22 and PND 31, and significant differences were observed PND 32, PND 34, PND 35 and PND 36 (p<0.05). Advanced VO was shown in the HF group (PND $32.8{\pm}0.37$ p<0.001) compared to the control (PND $38.25{\pm}0.25$). The weight of ovaries (p<0.01) and uteri (p<0.05) from HF group animals significantly increased when compared to those from control animals. Corpora lutea were observed in the ovaries from the HF group animals but not in control ovaries. Similarly, hypertrophy of luminal and glandular uterine epithelia was found only in the HF group animals. In the semi-quantitative RT-PCR studies, the transcriptional activities of KiSS-1 in HF group animals were significantly higher than those from the control animals (p<0.001). Likewise, the mRNA levels of GnRH (p<0.05) were significantly elevated in HF group animals. The present study indicated that the feeding HF diet during the post-weaning period activates the upstream modulators of gonadotropin such as GnRH and KiSS-1 in hypothalamus, resulting early onset of puberty in immature female rats.