Genetic variation in the corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and association studies with obesity in UK Caucasians

Challis, Benjamin; Luan, Jian’an; Keogh, Julia M.; Wareham, Nick; Farooqi, I. Sadaf; O’Rahilly, Stephen

doi:10.1038/sj.ijo.0802564

Cited by 26 publications

(19 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with these findings, our results further suggest that forebrain CRHR1 inactivation increases body weight gain in chronically stressed mice,which may not be surprising since activation of central CRH receptors suppresses food intake (Bell et al, 1998; Grill et al, 2000), and the Crhr1 gene has been associated with obesity in humans (Challis et al, 2004). …”

Section: Discussionsupporting

confidence: 85%

Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling

Wang

Chen

Wolf

et al. 2011

Neurobiology of Disease

141

124

View full text Add to dashboard Cite

Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders.

show abstract

Section: Discussionsupporting

confidence: 85%

Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling

Wang

Chen

Wolf

et al. 2011

Neurobiology of Disease

141

124

View full text Add to dashboard Cite

show abstract

“…Challis and associates [19] screened 51 severely obese children (body mass index (BMI)>4 kg/m 2 standard deviations above the age-related mean), a UK Caucasian population-based cohort for genetic polymorphisms in the human CRHR2 gene. In subjects with extreme early-onset obesity, three missense mutations were found in CRHR2 (Glu220Asp, Val240Ile and Val411Met).…”

Section: Discussionmentioning

confidence: 99%

Cross Species Association Examination of UCN3 and CRHR2 as Potential Pharmacological Targets for Antiobesity Drugs

et al. 2006

View full text Add to dashboard Cite

BackgroundObesity now constitutes a leading global public health problem. Studies have shown that insulin resistance affiliated with obesity is associated with intramyocellular lipid (IMCL) accumulation. Therefore, identification of genes associated with the phenotype would provide a clear target for pharmaceutical intervention and care for the condition. We hypothesized that urocortin 3 (UCN3) and corticotropin-releasing hormone receptor 2 (CRHR2) are associated with IMCL and subcutaneous fat depth (SFD), because the corticotropin-releasing hormone family of peptides are capable of strong anorectic and thermogenic effects.Methodology/Principal FindingsWe annotated both bovine UCN3 and CRHR2 genes and identified 12 genetic mutations in the former gene and 5 genetic markers in the promoter region of the latter gene. Genotyping of these 17 markers on Wagyu×Limousin F2 progeny revealed significant associations between promoter polymorphisms and SFD (P = 0.0203−0.0685) and between missense mutations of exon 2 and IMCL (P = 0.0055−0.0369) in the bovine UCN3 gene. The SFD associated promoter SNPs caused a gain/loss of 12 potential transcription regulatory binding sites, while the IMCL associated coding SNPs affected the secondary structure of UCN3 mRNA. However, none of five polymorphisms in CRHR2 gene clearly co-segregated with either trait in the population (P>0.6000).Conclusions/SignificanceBecause UCN3 is located on human chromosome 10p15.1 where quantitative trait loci for obesity have been reported, our cross species study provides further evidence that it could be proposed as a potential target for developing antiobesity drugs. None of the markers in CRHR2 was associated with obesity-type traits in cattle, which is consistent with findings in human. Therefore, CRHR2 does not lend itself to the development of antiobesity drugs.

show abstract

“…In addition, PTSD patients with increased cortisol reactivity may be at greater risk for development of nicotine tolerance and dependence. Increased HPA axis activity in these subpopulations may result from a genetic predisposition (Kyllo et al, 1996;Witchel et al, 1997;Baghai et al, 2002;Gonzalez-Gay et al, 2003;Hernandez-Avila et al, 2003;Smoller et al, 2003;Challis et al, 2004;Charmandari et al, 2004;Oswald et al, 2004;Slawik et al, 2004;Wust et al, 2004), traumatic stress exposure, perhaps at critical periods in development (Meany et al, 2001;Rasmusson et al, 2004), or both.…”

Section: Nicotine Dependence and Ptsd: The Chicken And The Eggmentioning

confidence: 96%

Smoking as a complex but critical covariate in neurobiological studies of posttraumatic stress disorders: a review

Rasmusson

Picciotto²,

Krishnan‐Sarin

2006

J Psychopharmacol

View full text Add to dashboard Cite

As smoking rates in the general population continue to fall in response to new information and changing social values, the continued high rate of smoking among persons with psychiatric disorders has caught the attention of society at many levels: public health officials, medical and mental health care providers, and concerned family members alike. As a consequence, research studies aimed at quantifying the problem and understanding its cause have increased dramatically over the past several years. The following review first examines epidemiological studies that have revealed a bidirectional causal relationship between tobacco dependence and posttraumatic stress disorder (PTSD), one of several mental health disorders in which tobacco dependence remains prevalent and resistant to intervention. Second, we use a translational neuroscience perspective to discuss possible neurobiological mediators of the relationship between PTSD and tobacco dependence, hoping to spur further human and animal research that will elucidate pathogenetic mechanisms involved and inspire novel treatment interventions. Finally, to enable more effective clinical research in this area, we provide an overview of effective scientific methods for assessing and managing 'smoking status' as an experimental variable in clinical research studies of PTSD as well as other mental health disorders.

show abstract

Genetic variation in the corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and association studies with obesity in UK Caucasians

Cited by 26 publications

References 26 publications

Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling

Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling

Cross Species Association Examination of UCN3 and CRHR2 as Potential Pharmacological Targets for Antiobesity Drugs

Smoking as a complex but critical covariate in neurobiological studies of posttraumatic stress disorders: a review

Contact Info

Product

Resources

About