Corticotropin-releasing Factor and Adrenocorticotrophic Hormone as Potential Central Mediators of OB Effects

Abstract

OB (leptin) has been identified as a factor that suppresses appetite and stimulates metabolism. Attention has focused on the hypothalamus as its potential site of action, but OB could also act on other brain regions. In addition, the paradox of high OB levels in obese humans remains unresolved. Here we show in mice that both the long and short form of the OB receptor are expressed not only in the hypothalamus but also in the amygdala and pituitary. Recombinant murine OB elicited the release of corticotropin-releasing factor from superfused brain slice preparations containing hypothalamus or amygdala. Because corticotropin-releasing factor inhibits appetite and stimulates metabolism, it may be a key mediator of central OB effects. Recombinant OB also induced pituitary release of adrenocorticotrophic hormone. Because adrenocorticotrophic hormone-induced elevation of plasma glucocorticoid levels can inhibit corticotropin-releasing factor release via negative feedback, the OB effects on pituitary adrenocorticotrophic hormone release may be pertinent to human obesity, which combines increased plasma glucocorticoid levels with elevated levels of OB. An imbalance between the effects of OB on corticotropin-releasing factor release from the hypothalamus and on adrenocorticotrophic hormone release from the pituitary could contribute to obesity.Obesity is a cause of serious health problems, and new research on the ob gene, which encodes an adipose tissue-derived hormone (OB or leptin) that suppresses appetite and stimulates metabolism (1, 2), raises hopes for therapeutical intervention. Little is known about the molecular factors mediating OB effects. Increasing evidence supports a central site of action for OB. Infusion of OB into the lateral ventricles of normal or OB-deficient ob/ob mice decreases feeding (3). Although the hypothalamus has been identified as a potential site of action of OB (4), OB may also act on other regions. Short and long forms of the OB receptor (OB-R) 1 differing in the length of their intracellular domain are formed by differential splicing, but only the long OB-R form can activate janus kinase (JAK) and lead to phosphorylation of signal transducers and activators of transcription (STAT) proteins. The JAK/STAT pathway has been proposed to mediate the effects of OB on body weight (5). The function of the short OB-R form has not been identified yet, but this form could also have an important role in mediating central effects of OB.Although neuropeptide Y has been implicated as a potential central mediator of OB effects (4), recent evidence indicates that additional factors may be involved (6). OB-deficient ob/ob mice treated with OB show strong Fos protein immunoreactivity in the paraventricular nucleus (PVN) (7). It is interesting in this context that corticotropin-releasing factor (CRF) acting at the PVN inhibits food intake and stimulates metabolic rate in genetically obese animals and lean controls (8 -10). Furthermore, conditions that increase hypothalamic CRF production also diminish food in...

Quantitative Expression Analysis of Genes Regulated by Both Obesity and Leptin Reveals a Regulatory Loop between Leptin and Pituitary-derived ACTH

“…It has been reported that both leptin and ACTH appear in the circulation in a negatively correlated pulsatile fashion (36). In contrast to this negative correlation between leptin and ACTH and the results described here, it has been reported that leptin induces release of ACTH from pituitary fragments in culture (37). There may be differences between the relatively acute effect of leptin as detected in the study by Raber et al (37) and the more chronic effects reported here.…”

“…In a direct analysis by RTQ-PCR on an independent set of RNA samples, there was no significant difference in the expression of i0 m0-307 between lean and obese mice in fat, liver, or muscle ( For the two genes tested there was no evidence that leptin directly and acutely altered pituitary gene expression. The mRNA encoding the leptin receptor is present on pituitary cells, although the identity of the relevant cells is not known (37,53,54). It is possible that leptin directly alters the expression of the genes identified in this study, but we were not able to detect these changes under the culture and leptin exposure conditions used.…”

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

“…Interestingly, leptin appears to be both upstream and downstream of hypothalamic CRF 2 action, perhaps providing a physiological context for the current findings. Leptin has receptors on CRFergic hypothalamic neurons (Hakansson et al, 1998), provokes secretion of CRF receptor agonists from hypothalamic explants (Costa et al, 1997;Raber et al, 1997), and stimulates PVN CRF (Schwartz et al, 1996) and VMH CRF 2 mRNA synthesis (Hashimoto et al, 2004). Conversely, Zucker obese (fa/fa) rats, which lack a fully functional leptin receptor, have reduced VMH CRF 2 mRNA expression (Richard et al, 1996).…”

Regulation of corticotropin-releasing factor and urocortin 2/3 mRNA by leptin in hypothalamic N39 cells

“…Leptin has been reported to increase CRF secretion from the rat hypothalamus in in intro and ex vivo [49,12]. CRF neurons in the PVN and VMH are considered to be an important mediator for leptin that contribute to regulation of feeding and adiposity [40].…”