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Urocortins: Emerging Metabolic and Energy Homeostasis Perspectives

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Urocortins: Emerging Metabolic and Energy Homeostasis Perspectives Review Urocortins: emerging metabolic and energy homeostasis perspectives Yael Kuperman and Alon Chen Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel The effects of stress on energy balance and the through the expression of neuropeptide Y and agouti-related pep- involvement of the neuropeptide corticotropin releasing tide. The Arc is accessible to circulating signals of energy balance, factor in modulating the anorexia of stress and sympath- through the underlying median eminence, because this region of the etic nervous system tone are well recognized. Currently, brain is not protected by the blood–brain barrier. Thus, the Arc serves as an integrative center responsible for information processing and studies centered on the roles of the more recently coordinating appropriate output [58]. described members of this family of ligands, the urocor- Bed nucleus of the stria terminalis (BNST): the BNST is located within tins, and their preferred receptor, the corticotropin the basal forebrain and is considered to be the extended amygdala. It releasing factor type 2 receptor, suggest that they are seems to be involved in a number of complex functions, including important modulators of centrally controlled metabolic sexual behavior, autonomic function, anxiety and aversiveness of opiate withdrawal [58]. functions. In addition, urocortins also regulate fuel util- Dorsal raphe nucleus (DRN): the raphe nuclei are located in the ization in the periphery by acting locally within key midbrain and provide the major ascending serotonergic projection metabolic tissues through autocrine and/or paracrine to the forebrain. The raphe projects to the striatum, amygdala, mechanisms. Recent findings have demonstrated that caudate putamen, hippocampus, substantia nigra and locus coeru- urocortin 2 and urocortin 3, by acting through their leus. The dorsal and medial raphe nuclei receive substantial afferents from the parabrachial nucleus and the hypothalamic nuclei. The DRN specific receptor in peripheral tissues, are novel modu- contains the largest and densest 5-hydroxytryptamine (5-HT) aggre- lators of glucose homeostasis and metabolic functions. gate in the brain. In contrast to the median raphe nucleus, there is no age-related loss of 5-HT neurons within the DRN, although 5-HT- Introduction producing cell size and dendritic length decline with age [58]. The maintenance of energy homeostasis in the presence of Dorso-medial hypothalamic nucleus (DMH): the DMH receives affer- ents from the BNST, from many parts of the brain stem and from most physiologically or psychologically stressful stimuli requires parts of the hypothalamus. The projections of the DMH are mostly the activation of coordinated adaptive responses, with regu- intrahypothalamic. The DMH has been implicated in the regulation of latory and functional changes in both central and peripheral ingestive behavior, stress, reproduction, circadian rhythms and systems. Although the roles of the corticotropin releasing thermogenesis [58]. Lateral septum (LS): the LS nucleus is the largest nucleus of the septum (the medial interventricular wall of the telencephalon). Most of the septal region develops morphofunctional links with the hippo- Glossary campus and the amygdala. The septal region is rich in g-aminobutyric acid (GABA)-ergic neurons. The septal region does not form a func- Amygdala: the amygdala consists of a heterogeneous gray complex tional unit by itself, but it comprises complex and parallel circuits that which is divided to nuclear groups on the basis of cytoarchitectonic, might form loops with the hippocampal formation and the hypothala- histochemical, immunocytochemical and hodological studies. The mus [58]. amygdala has been shown to be involved in the modulation of Paraventicular nucleus (PVN): The PVN is located in the anterior part neuroendocrine function, visceral effector mechanisms and complex of the hypothalamic periventricular zone. The PVN contains magno- patterns of integrated behavior, such as defense, ingestion, aggres- cellular neurosecretory cells, which produce oxytocin and vasopressin sion, reproduction, memory and learning. Such a modulation is and whose axons extend into the posterior pituitary, and parvocellular exercised, at least in part, through a vast network of connections neurosecretory cells, which produce CRF, vasopressin and thyrotro- with other brain regions, such as the hypothalamus, the brain stem pin-releasing hormone. The parvocellular neurons project to the and spinal cord autonomic cell aggregates [58]. median eminence, and the secreted peptides are carried to the anterior Arcuate nucleus (Arc): the Arc is located in the tuberal part of the pituitary by the blood vessels of the hypothalamo–pituitary portal hypothalamic periventricular zone. The Arc receives strong input system. The PVN also contains neurons that project to regions contain- from hypothalamic structures such as the periventricular nuclei, ing preganglionic autonomic neurons. Accordingly, the PVN has a the PVN, the dorso-medial hypothalamic nucleus, the preoptic central role in mediating hypothalamic responses to stress, feeding nucleus and the premammillary nucleus. Extrahypothalamic input and drinking behavior, and participates in a variety of autonomic involves the bed nucleus of the stria terminalis, the amygdala, the responses [58]. lateral septal nucleus and the brain stem. Two primary populations of Ventro-medial hypothalamic nucleus (VMH): The VMH receives affer- Arc neurons exert opposing actions on energy balance. One neuronal ent projections from the amygdala and ventral subiculum, from many population located mainly in the ventro-lateral subdivision of the Arc hypothalamic nuclei and from the brain stem. The VMH projections are inhibits food intake through the expression of pro-opiomelanocortin- consistent with its proposed role in mediating somatomotor aspects of derived peptide, the a-melanocyte-stimulating hormone and complex motivated behavior. It shares connections with forebrain and cocaine- and amphetamine-regulated transcript. The other popu- brain stem regions that are involved in mediating reproductive beha- lation in the far ventro-medial part of the Arc stimulates food intake vior and with regions involved with appetite behaviors such as the PVN and DMH. The VMH sends massive projections to other parts of the hypothalamic medial zone, to the amygdala and the septum [58] (see Glossary Figure I). Corresponding author: Chen, A. ([email protected]). 122 1043-2760/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2007.12.002 Available online 11 March 2008 Review Trends in Endocrinology and Metabolism Vol.19 No.4 Glossary Figure I. Neuroanatomy involved in energy homeostasis and the stress response. A schematic depicting a mammalian brain, highlighting various regions implicated in energy homeostasis and the stress response. factor (CRF) peptide and its cognate type 1 CRF receptor (see Glossary) in the hypothalamus, represents the final (CRF1) in the regulation of the hypothalamic–pituitary– common pathway for the integration of the neuroendocrine adrenal (HPA) axis and stress-related behavioral responses stress response in the brain [1]. CRF has an important and are well established, the physiological roles of the related well-established role in the regulation of the HPA axis urocortin peptides and their preferred receptor, the type 2 under basal and stress conditions [2,3]. In addition to this CRF receptor (CRF2), in responses to such challenges are hypophysiotropic action, CRF integrates the behavioral, less understood. autonomic and metabolic responses to stressors [4–6]. CRF To date, the mammalian CRF–urocortin family includes is involved in the control of arousal, anxiety, cognitive four structurally related peptides (CRF, and urocortin 1, -2 functions and appetite [7–13]. Dysregulation of the stress and -3). All are encoded by separate genes and show response can have severe psychological and physiological differential expression patterns within both central and consequences [14,15], and chronic hyperactivation of the peripheral tissues. The physiological effects of these pep- CRF system has been linked to stress-related emotional tides are mediated through two related seven transmem- disorders such as anxiety, anorexia nervosa and depres- brane domain receptors (CRF1 and CRF2), which are sion [7–15]. expressed as multiple isoforms arising from alternative In addition to CRF, the CRF–urocortin family of pep- splicing of the genes. In addition to the brain and pituitary tides includes the more recently described urocortins: uro- gland, the CRF–urocortin family of peptides and receptors cortin 1 [16], urocortin 2 (or stresscopin-related peptide are highly expressed in several peripheral tissues, and an encoded by the human ortholog) [17,18] and urocortin 3 (or increasing body of evidence suggests a role for these pep- stresscopin encoded by the human ortholog) [18,19] tides and receptors in regulating energy metabolism not (Figure 1). CRF and urocortin peptides mediate their only centrally, but also by acting locally within key meta- effects through activation of two membrane-bound G- bolic tissues, including skeletal muscle and the endocrine protein-coupled receptors, CRF1 [20–23] and CRF2 [24– pancreas. Here, we discuss the recent findings demonstrat- 27] (Figure 1). CRF1 mRNA is widely expressed in mam- ing the potential for urocortin 2 and urocortin 3, acting malian brain and pituitary,
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