Corticotrophin releasing factor (CRH), a 41 amino-acid peptide was isolated in 1981. Science. 1981 Sep 18;213(4514):1394-7. CRH is secreted from the paraventricular nucleus of the hypothalamus into the hypophyseal portal system. Fed Proc. 1985 Jan;44(1 Pt 2):221-7. It is then transported to the anterior pituitary where it stimulates ACTH secretion. Prog Neurobiol. 1993 May;40(5):573-629. While CRH is recognised to have a role in arousal and locomotor activity, central injection of CRH also produces anorexia in rodents.
CRH actions are to be mediated by CRH R1 Endocrinology. 1993 Dec;133(6):3058-61. and CRH R2 receptors. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):836-40 Stress Endocrinology. 1996 Nov;137(11):4786-95. and CRH infusions Endocrinology. 1996 Nov;137(11):4619-29. induce expression of CRH R1 mRNA. Abundant CRH R2 expression is demonstrated in the VMN (ventromedial nucleus). CRH-R2 expression is down-regulated by increased food intake and up-regulated by reduction in food intake.
CRH injection into the PVN inhibits NPY-induced feeding, while injection elsewhere did not, suggesting that the PVN could be the target for the actions of CRH on appetite suppression. Eur J Pharmacol. 2002 Apr 12;440(2-3):189-97. Lesions of the PVN do not prevent the CRH mediated effects of estradiol, Am J Physiol.1994 Jul;267(1 Pt 1):E32-8. suggesting that sites other than PVN may be involved in mediating the anorectic effects of CRH. Injection of alpha helical CRH, a CRH antagonist, decreased the anorexic effects evoked by CRH injection into the PVN while it fails to attenuate the effect of CRH injection into the VMN, suggesting the variations in distribution or specificity of CRH receptors. Abundant CRH R2 expression demonstrated in the VMN could suggest this as a possible alternative site of action of CRH. But at the same time VMN is not essential to produce the effects of CRH on food intake Am J Physiol. 1989 Mar;256(3 Pt 2):R751-6. or thermogenesis. Am J Physiol. 1990 Oct;259(4 Pt 2):R799-806
CRH has been shown to be involved in mediating the thermogenic actions of fenfluramine and a Serotonin 2A and 2C receptor agonist. Injection of alpha helical CRH, the CRH antagonist, blocks the anorexic effects of estradiol suggesting that CRH may mediate the anorectic effects of estradiol Brain Res Bull.1993;32(6):689-92
In the brain, CRH also binds to CRH-binding protein (CRH-BP) which inactivates CRH. Front Neuroendocrinol. 1995 Oct;16(4):362-82 CRH 6-33 an inhibitor of the CRH-BP reduces weight gain in obese fa/fa Zucker rats. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15475-80 This may suggest that there may be a deficiency of the active CRH in obesity resulting in increased food intake and obesity. Obese rats have lower levels of CRH-R2 mRNA expression in the VMN.Endocrinology. 1996 Nov;137(11):4786-95. This could further reduce the activity of CRH in obesity. Leptin on the other hand induces CRH-R2 expression in the VMN despite reduction in food intake. CRH antagonists can prevent the anorectic effects of leptin. Nat Neurosci. 1998 Jun;1(2):103. These could imply mediation of the actions of leptin at least partly through the CRH pathway. Leptin blocks the food deprivation induced CRH synthesis in the PVN in obese ob/ob mice. Endocrinology. 1998 Apr;139(4):1524-32. In keeping with this, leptin deficiency results in hyperactivity of the hypothalamic-pituitary- adrenal axis. Stress with its increased cortisol levels might decrease CRH and increase appetite leading to obesity with chronic stress due to comfort eating in a subset of individuals.Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11696-701
Not all findings have favored the likelihood of a role of CRH in appetite regulation. There is no evidence of a correlation of CRH release in the PVN to daily feeding pattern. Neuroendocrinology. 1992 Jan;55(1):74-83. Adrenalectomy, which results in increased CRH production and release is not associated with a significant decrease in daily food intake. The corticosteroid deficiency that follows adrenalectomy along with changes in the sympathetic nervous system activity probably explains most of the decrease in appetite in this state.
UROCORTIN
Urocortin (UCN), a 40 amino acid peptide, which was described in 1995, Nature. 1995 Nov 16;378(6554):287-92 decreases food intake while increasing energy expenditure. Science. 1996 Sep 13;273(5281):1561-4. Urocortin is a member of the CRH family with 45% sequence homology to CRH as well as Urotensin I. Synthetic Urocortin evokes secretion of adrenocorticotropic hormone (ACTH) both in vitro and in vivo In contrast to CRH, Urocortin cells are not found in the paraventricular nucleus, instead they are described in the lateral hypothalamus and the supraoptic nucleus. In keeping with this, microinjection of Urocortin into VMN rather than PVN inhibits feeding. Urocortin is present in the Lateral Hypothalamus, and UCN containing neurons project to the Ventromedial Hypothalamus (VMN) where abundant CRH R2 expression is demonstrated.
Urocortin is more potent than CRH in suppression of feeding in rodents, which is probably attributable to the higher affinity of Urocortin for CRH R2 and CRH R2a receptors. But weight loss induced by Urocortin is less than that seen with CRH. This is probably attributable to the lower thermogenic effect of Urocortin. Meal size rather than meal frequency is reduced by Urocortin administration.
CRH actions are to be mediated by CRH R1 Endocrinology. 1993 Dec;133(6):3058-61. and CRH R2 receptors. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):836-40 Stress Endocrinology. 1996 Nov;137(11):4786-95. and CRH infusions Endocrinology. 1996 Nov;137(11):4619-29. induce expression of CRH R1 mRNA. Abundant CRH R2 expression is demonstrated in the VMN (ventromedial nucleus). CRH-R2 expression is down-regulated by increased food intake and up-regulated by reduction in food intake.
CRH injection into the PVN inhibits NPY-induced feeding, while injection elsewhere did not, suggesting that the PVN could be the target for the actions of CRH on appetite suppression. Eur J Pharmacol. 2002 Apr 12;440(2-3):189-97. Lesions of the PVN do not prevent the CRH mediated effects of estradiol, Am J Physiol.1994 Jul;267(1 Pt 1):E32-8. suggesting that sites other than PVN may be involved in mediating the anorectic effects of CRH. Injection of alpha helical CRH, a CRH antagonist, decreased the anorexic effects evoked by CRH injection into the PVN while it fails to attenuate the effect of CRH injection into the VMN, suggesting the variations in distribution or specificity of CRH receptors. Abundant CRH R2 expression demonstrated in the VMN could suggest this as a possible alternative site of action of CRH. But at the same time VMN is not essential to produce the effects of CRH on food intake Am J Physiol. 1989 Mar;256(3 Pt 2):R751-6. or thermogenesis. Am J Physiol. 1990 Oct;259(4 Pt 2):R799-806
CRH has been shown to be involved in mediating the thermogenic actions of fenfluramine and a Serotonin 2A and 2C receptor agonist. Injection of alpha helical CRH, the CRH antagonist, blocks the anorexic effects of estradiol suggesting that CRH may mediate the anorectic effects of estradiol Brain Res Bull.1993;32(6):689-92
In the brain, CRH also binds to CRH-binding protein (CRH-BP) which inactivates CRH. Front Neuroendocrinol. 1995 Oct;16(4):362-82 CRH 6-33 an inhibitor of the CRH-BP reduces weight gain in obese fa/fa Zucker rats. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15475-80 This may suggest that there may be a deficiency of the active CRH in obesity resulting in increased food intake and obesity. Obese rats have lower levels of CRH-R2 mRNA expression in the VMN.Endocrinology. 1996 Nov;137(11):4786-95. This could further reduce the activity of CRH in obesity. Leptin on the other hand induces CRH-R2 expression in the VMN despite reduction in food intake. CRH antagonists can prevent the anorectic effects of leptin. Nat Neurosci. 1998 Jun;1(2):103. These could imply mediation of the actions of leptin at least partly through the CRH pathway. Leptin blocks the food deprivation induced CRH synthesis in the PVN in obese ob/ob mice. Endocrinology. 1998 Apr;139(4):1524-32. In keeping with this, leptin deficiency results in hyperactivity of the hypothalamic-pituitary- adrenal axis. Stress with its increased cortisol levels might decrease CRH and increase appetite leading to obesity with chronic stress due to comfort eating in a subset of individuals.Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11696-701
Not all findings have favored the likelihood of a role of CRH in appetite regulation. There is no evidence of a correlation of CRH release in the PVN to daily feeding pattern. Neuroendocrinology. 1992 Jan;55(1):74-83. Adrenalectomy, which results in increased CRH production and release is not associated with a significant decrease in daily food intake. The corticosteroid deficiency that follows adrenalectomy along with changes in the sympathetic nervous system activity probably explains most of the decrease in appetite in this state.
UROCORTIN
Urocortin (UCN), a 40 amino acid peptide, which was described in 1995, Nature. 1995 Nov 16;378(6554):287-92 decreases food intake while increasing energy expenditure. Science. 1996 Sep 13;273(5281):1561-4. Urocortin is a member of the CRH family with 45% sequence homology to CRH as well as Urotensin I. Synthetic Urocortin evokes secretion of adrenocorticotropic hormone (ACTH) both in vitro and in vivo In contrast to CRH, Urocortin cells are not found in the paraventricular nucleus, instead they are described in the lateral hypothalamus and the supraoptic nucleus. In keeping with this, microinjection of Urocortin into VMN rather than PVN inhibits feeding. Urocortin is present in the Lateral Hypothalamus, and UCN containing neurons project to the Ventromedial Hypothalamus (VMN) where abundant CRH R2 expression is demonstrated.
Urocortin is more potent than CRH in suppression of feeding in rodents, which is probably attributable to the higher affinity of Urocortin for CRH R2 and CRH R2a receptors. But weight loss induced by Urocortin is less than that seen with CRH. This is probably attributable to the lower thermogenic effect of Urocortin. Meal size rather than meal frequency is reduced by Urocortin administration.