Reduced voluntary activity precedes adult-onset obesity in Nhlh2 knockout mice

Coyle, Christopher A.; Jing, Enxuan; Hosmer, Trina; Powers, J.Bradley; Wade, George N.; Good, Deborah J.

doi:10.1016/s0031-9384(02)00885-5

Cited by 52 publications

(81 citation statements)

References 36 publications

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“…Interestingly, Liu et al[ 41] demonstrated that the transcription factor Sim1 regulates the expression of several potential obesity genes such as the Mc3r and thyroid hormone receptor β 2 . The Nhlh2 transcription factor was recently implicated in the regulation of body weight in rodents, as the Nhlh2 knock-out mice demonstrate an obesity phenotype similar to that of the MC4R knock-out mouse [11]. …”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the Nhlh2 knock-out mouse demonstrates an obesity phenotype characterised by slightly elevated food intake, lack of physical activity and adult-onset obesity, which are features similar to those present in the MC4R knock-out mouse [11]. Nhlh2 is a DNA-binding protein, belonging to the basic helix-loop-helix (bHLH) family of transcription factors and is expressed in all regions of the hypothalamus involved in body weight control [10].…”

Section: Introductionmentioning

confidence: 99%

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A Two-Base Deletion –439delGC in the Melanocortin-4 Receptor Promoter Associated with Early-Onset Obesity

et al. 2006

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Background/Aims: Mutations in melanocortin-4 receptor (MC4R) are the most common genetic cause of human obesity. Mutations in MC4R promoter could also underlie obesity, but have so far not been reported. Transcription factor nescient helix-loop-helix 2 (Nhlh2) is a novel obesity candidate gene. We searched for mutations in MC4R promoter and Nhlh2 gene in 152 children with severe early-onset obesity. Lean subjects (n = 447) served as controls. Methods: MC4R promoter and Nhlh2 gene were investigated by sequencing. Gel shifts and reporter gene assays were used to investigate a deletion in MC4R promoter. Mutation carriers were carefully characterised. Weight charts from index patients and relatives were analysed. Results: We identified a deletion, –439delGC, in MC4R promoter in 2 severely obese, unrelated children and their family members, but not in controls. Index patients and mutation-carrying relatives were affected by early-onset obesity, while non-carriers had normal childhood weight development. The deletion is located at a potential Nhlh2-binding site and gel shift assays showed that Nhlh2 binds to this site. No significant differences in mutant compared to wild-type MC4R promoter activities were detected. No mutations were identified in Nhlh2 gene. Conclusion: We report an MC4R promoter mutation, –439delGC, associated with early-onset obesity and show that transcription factor Nhlh2 recognises this site in vitro. Nhlh2 mutations unlikely underlie severe human obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Two-Base Deletion –439delGC in the Melanocortin-4 Receptor Promoter Associated with Early-Onset Obesity

et al. 2006

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“…Our laboratory has confirmed that Nhlh2 plays a key role in the regulation of adult body weight by showing that mice with a targeted deletion of the Nhlh2 gene show adult onset obesity due not to increased food intake or decreased body temperature, but rather to the lack of voluntary physical activity (Coyle et al 2002). This rare phenotype, where only one side of the energy balance equation is altered, has given us the opportunity to understand the molecular mechanisms underlying the role of exercise in body weight regulation.…”

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confidence: 74%

Genetic analysis of NHLH2 and its putative role in bovine body weight control

Brennan

Vella

Good³

2006

Animal Genetics

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SummaryThe control of energy balance is fundamental to adult animals and is necessary for weight gain/loss, reproductive capacity and general health. In mice, targeted deletion of the neuronal transcription factor Nhlh2 results in adult-onset obesity because of reduced exercise and infertility because of reduced sexual behaviour. Nhlh2 (NHLH2 for humans) is expressed in the hypothalamus, particularly in neurons that have been shown to regulate energy balance. We have cloned the bovine Nhlh2 gene (bNHLH2) and we have shown that bNHLH2 is also expressed in the hypothalamus. Phylogenetic analysis of Nhlh2 reveals that it is very highly conserved in humans, mice, chimps and cattle, and found in organisms with simpler nervous systems, including Caenorhabditis elegans and Drosophila. Using a cattle-human comparative map and online databases, we have evidence that bNHLH2 is located near a quantitative trait locus for marbling on bovine chromosome 3 between microsatellite markers BM723 and BMS963. Cloning of the bNHLH2 gene from Holstein cattle and a mixed breed individual and comparison with Hereford sequences shows that the gene is highly conserved among bovine breeds.

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“…In addition, N2KO mice also display adult-onset obesity with significant increases in their fat depots, abnormal responses to cold exposure, and reduced spontaneous physical activity levels (Good et al 2008). Unlike other mouse obesity models, N2KO mice gain weight due to reduction in spontaneous physical activity, which precedes body weight gain and mild hyperphagia in older animals (Coyle et al 2002). Exercise effectively promotes neurogenesis by effectively facilitating the release of serotonin (5-hydroxytryptamine) in the brain (Fig.…”

Section: Molecular Mechanisms Associated With the Effect Of Exercise mentioning

confidence: 99%

Effect of Exercise on Neurodegeneration in Neurological Disorders

Farooqui¹

2014

Inflammation and Oxidative Stress in Neurological Disorders

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Reduced voluntary activity precedes adult-onset obesity in Nhlh2 knockout mice

Cited by 52 publications

References 36 publications

A Two-Base Deletion –439delGC in the Melanocortin-4 Receptor Promoter Associated with Early-Onset Obesity

A Two-Base Deletion –439delGC in the Melanocortin-4 Receptor Promoter Associated with Early-Onset Obesity

Genetic analysis of NHLH2 and its putative role in bovine body weight control

Effect of Exercise on Neurodegeneration in Neurological Disorders

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