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Central urocortin 3 and type 2 corticotropin-releasing factor receptor in the regulation of energy homeostasis: critical involvement of the ventromedial hypothalamus.

Chen P, Hover CV, Lindberg D, Li C - Front Endocrinol (Lausanne) (2013)

Bottom Line: The effects of CRF are mediated by two G-protein-coupled receptors, type 1 and type 2 CRF receptors (CRF(1) and CRF(2)).Ucn 3 is the latest addition of the CRF family of peptides and is highly selective for CRF(2).The brain loci that mediate the central effects of Ucn 3 remain to be fully determined.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Virginia Health System Charlottesville, VA, USA.

ABSTRACT
The vital role of the corticotropin-releasing factor (CRF) peptide family in the brain in coordinating response to stress has been extensively documented. The effects of CRF are mediated by two G-protein-coupled receptors, type 1 and type 2 CRF receptors (CRF(1) and CRF(2)). While the functional role of CRF(1) in hormonal and behavioral adaptation to stress is well-known, the physiological significance of CRF(2) remains to be fully appreciated. Accumulating evidence has indicated that CRF(2) and its selective ligands including urocortin 3 (Ucn 3) are important molecular mediators in regulating energy balance. Ucn 3 is the latest addition of the CRF family of peptides and is highly selective for CRF(2). Recent studies have shown that central Ucn 3 is important in a number of homeostatic functions including suppression of feeding, regulation of blood glucose levels, and thermoregulation, thus reinforcing the functional role of central CRF(2) in metabolic regulation. The brain loci that mediate the central effects of Ucn 3 remain to be fully determined. Anatomical and functional evidence has suggested that the ventromedial hypothalamus (VMH), where CRF(2) is prominently expressed, appears to be instrumental in mediating the effects of Ucn 3 on energy balance, permitting Ucn 3-mediated modulation of feeding and glycemic control. Thus, the Ucn 3-VMH CRF(2) system is an important neural pathway in the regulation of energy homeostasis and potentially plays a critical role in energy adaptation in response to metabolic perturbations and stress to maintain energy balance.

No MeSH data available.


Related in: MedlinePlus

(A) Darkfield photomicrograph showing CRFR2 mRNA signal revealed by in situ hybridization in the basal hypothalamic area of a transgenic mouse expressing Cre recombinase (Cre) and enhanced yellow fluorescent protein (EYFP) in SF1-positive cells. Note that CRFR2 mRNA hybridization signal (white clusters) was abundant in the dorsomedial part of the VMH (VMHdm). (B) Bright field photomicrograph of the same area in (A) showing SF1-positive cells, revealed by immunostaining with anti-green fluorescent protein antibody (darkbrown precipitates) in the VMH. (C) High magnification of boxed area in (A) showing colocalization of CRFR2 (black dot clusters) and SF1 (brown precipitates) in the VMH. ARH, arcuate nucleus of hypothalamus; V3, third ventricle; VMHc, central part of the VMH; VMHdm, dorsomedial part of the VMH; VMHvl, ventrolateral part of the VMH. Scale bar = 50 μm (B), 20 μm (C).
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Figure 2: (A) Darkfield photomicrograph showing CRFR2 mRNA signal revealed by in situ hybridization in the basal hypothalamic area of a transgenic mouse expressing Cre recombinase (Cre) and enhanced yellow fluorescent protein (EYFP) in SF1-positive cells. Note that CRFR2 mRNA hybridization signal (white clusters) was abundant in the dorsomedial part of the VMH (VMHdm). (B) Bright field photomicrograph of the same area in (A) showing SF1-positive cells, revealed by immunostaining with anti-green fluorescent protein antibody (darkbrown precipitates) in the VMH. (C) High magnification of boxed area in (A) showing colocalization of CRFR2 (black dot clusters) and SF1 (brown precipitates) in the VMH. ARH, arcuate nucleus of hypothalamus; V3, third ventricle; VMHc, central part of the VMH; VMHdm, dorsomedial part of the VMH; VMHvl, ventrolateral part of the VMH. Scale bar = 50 μm (B), 20 μm (C).

Mentions: Currently, detailed neurochemical phenotypes of CRF2-positive cells within the VMH remain unclear. Several proteins have been found to be expressed in the VMH including SF1, pituitary adenylate cyclase-activating polypeptide, the leptin receptor, and VGLUT2 (Fei et al., 1997; Elmquist et al., 1998; Ziegler et al., 2002; Segal et al., 2005; Kurrasch et al., 2007). It has been shown that CRF2 extensively colocalizes with VGLUT2 in the VMH (Chen et al., 2010). VGLUT2 mediates glutamate uptake into synaptic vesicles of excitatory neurons (Fremeau et al., 2001; Herzog et al., 2001; Takamori et al., 2001) and has been used extensively as a marker for excitatory glutamatergic neurons. The colocalization of CRF2 and VGLUT2 suggests that CRF2 is expressed predominately in excitatory neurons in the VMH. As mentioned above, SF1 is a nuclear receptor that regulates the transcription of key genes involved in sexual development and reproduction (Parker et al., 2002). In adults, SF1 expression is specifically confined to the VMH (Parker et al., 2002). In SF1 mice, CRF2 mRNA expression is nearly undetectable in the VMH (Luo et al., 1994; Sadovsky et al., 1995; Shinoda et al., 1995), suggesting CRF2 is expressed in SF1 cells in the VMH. Consistent with this notion, it was found that more than 90% of CRF2 neurons in the dorsomedial part of the nucleus are also SF1-positive (Figure 2) with less colocalization of these two materials in the VMHvl (Digruccio et al., 2007).


Central urocortin 3 and type 2 corticotropin-releasing factor receptor in the regulation of energy homeostasis: critical involvement of the ventromedial hypothalamus.

Chen P, Hover CV, Lindberg D, Li C - Front Endocrinol (Lausanne) (2013)

(A) Darkfield photomicrograph showing CRFR2 mRNA signal revealed by in situ hybridization in the basal hypothalamic area of a transgenic mouse expressing Cre recombinase (Cre) and enhanced yellow fluorescent protein (EYFP) in SF1-positive cells. Note that CRFR2 mRNA hybridization signal (white clusters) was abundant in the dorsomedial part of the VMH (VMHdm). (B) Bright field photomicrograph of the same area in (A) showing SF1-positive cells, revealed by immunostaining with anti-green fluorescent protein antibody (darkbrown precipitates) in the VMH. (C) High magnification of boxed area in (A) showing colocalization of CRFR2 (black dot clusters) and SF1 (brown precipitates) in the VMH. ARH, arcuate nucleus of hypothalamus; V3, third ventricle; VMHc, central part of the VMH; VMHdm, dorsomedial part of the VMH; VMHvl, ventrolateral part of the VMH. Scale bar = 50 μm (B), 20 μm (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3539675&req=5

Figure 2: (A) Darkfield photomicrograph showing CRFR2 mRNA signal revealed by in situ hybridization in the basal hypothalamic area of a transgenic mouse expressing Cre recombinase (Cre) and enhanced yellow fluorescent protein (EYFP) in SF1-positive cells. Note that CRFR2 mRNA hybridization signal (white clusters) was abundant in the dorsomedial part of the VMH (VMHdm). (B) Bright field photomicrograph of the same area in (A) showing SF1-positive cells, revealed by immunostaining with anti-green fluorescent protein antibody (darkbrown precipitates) in the VMH. (C) High magnification of boxed area in (A) showing colocalization of CRFR2 (black dot clusters) and SF1 (brown precipitates) in the VMH. ARH, arcuate nucleus of hypothalamus; V3, third ventricle; VMHc, central part of the VMH; VMHdm, dorsomedial part of the VMH; VMHvl, ventrolateral part of the VMH. Scale bar = 50 μm (B), 20 μm (C).
Mentions: Currently, detailed neurochemical phenotypes of CRF2-positive cells within the VMH remain unclear. Several proteins have been found to be expressed in the VMH including SF1, pituitary adenylate cyclase-activating polypeptide, the leptin receptor, and VGLUT2 (Fei et al., 1997; Elmquist et al., 1998; Ziegler et al., 2002; Segal et al., 2005; Kurrasch et al., 2007). It has been shown that CRF2 extensively colocalizes with VGLUT2 in the VMH (Chen et al., 2010). VGLUT2 mediates glutamate uptake into synaptic vesicles of excitatory neurons (Fremeau et al., 2001; Herzog et al., 2001; Takamori et al., 2001) and has been used extensively as a marker for excitatory glutamatergic neurons. The colocalization of CRF2 and VGLUT2 suggests that CRF2 is expressed predominately in excitatory neurons in the VMH. As mentioned above, SF1 is a nuclear receptor that regulates the transcription of key genes involved in sexual development and reproduction (Parker et al., 2002). In adults, SF1 expression is specifically confined to the VMH (Parker et al., 2002). In SF1 mice, CRF2 mRNA expression is nearly undetectable in the VMH (Luo et al., 1994; Sadovsky et al., 1995; Shinoda et al., 1995), suggesting CRF2 is expressed in SF1 cells in the VMH. Consistent with this notion, it was found that more than 90% of CRF2 neurons in the dorsomedial part of the nucleus are also SF1-positive (Figure 2) with less colocalization of these two materials in the VMHvl (Digruccio et al., 2007).

Bottom Line: The effects of CRF are mediated by two G-protein-coupled receptors, type 1 and type 2 CRF receptors (CRF(1) and CRF(2)).Ucn 3 is the latest addition of the CRF family of peptides and is highly selective for CRF(2).The brain loci that mediate the central effects of Ucn 3 remain to be fully determined.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Virginia Health System Charlottesville, VA, USA.

ABSTRACT
The vital role of the corticotropin-releasing factor (CRF) peptide family in the brain in coordinating response to stress has been extensively documented. The effects of CRF are mediated by two G-protein-coupled receptors, type 1 and type 2 CRF receptors (CRF(1) and CRF(2)). While the functional role of CRF(1) in hormonal and behavioral adaptation to stress is well-known, the physiological significance of CRF(2) remains to be fully appreciated. Accumulating evidence has indicated that CRF(2) and its selective ligands including urocortin 3 (Ucn 3) are important molecular mediators in regulating energy balance. Ucn 3 is the latest addition of the CRF family of peptides and is highly selective for CRF(2). Recent studies have shown that central Ucn 3 is important in a number of homeostatic functions including suppression of feeding, regulation of blood glucose levels, and thermoregulation, thus reinforcing the functional role of central CRF(2) in metabolic regulation. The brain loci that mediate the central effects of Ucn 3 remain to be fully determined. Anatomical and functional evidence has suggested that the ventromedial hypothalamus (VMH), where CRF(2) is prominently expressed, appears to be instrumental in mediating the effects of Ucn 3 on energy balance, permitting Ucn 3-mediated modulation of feeding and glycemic control. Thus, the Ucn 3-VMH CRF(2) system is an important neural pathway in the regulation of energy homeostasis and potentially plays a critical role in energy adaptation in response to metabolic perturbations and stress to maintain energy balance.

No MeSH data available.


Related in: MedlinePlus