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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 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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PMID:Genetic analysis of NHLH2 and its putative role in bovine body weight control. 1688 99

In mice, targeted deletion of the basic helix-loop-helix transcription factor, nescient helix-loop-helix 2 (Nhlh2), leads to adult-onset obesity and reduced physical activity. We propose the novel hypothesis that transcriptional activity by Nhlh2 (NHLH2 in humans) controls either the ability or the motivation for exercise.
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PMID:Nhlh2: a basic helix-loop-helix transcription factor controlling physical activity. 1881 87

Nescient helix-loop-helix 2 (NHLH2/NSCL2) is a neuronal transcription factor originally thought to be involved in neuronal development and childhood neuroblastomas. Accumulating evidence has since identified roles for NHLH2 in adult phenotypes of obesity and fertility. We summarize these findings here and attempt to link genotype with phenotype in mouse models and humans. In particular, NHLH2 (Nhlh2 in mice) is one of only two genes that are genetically linked to physical activity levels. Nhlh2 also controls obesity and fertility, with strong sexual dimorphism for both phenotypes in Nhlh2 mutant animals. We propose that Nhlh2 might function as a molecular sensor in different adult hypothalamic neurons to regulate energy balance, leading to normal body weight and reproduction.
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PMID:NHLH2: at the intersection of obesity and fertility. 2368 66

Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.
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PMID:Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome. 2794 Dec 49

Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 cluster of noncoding RNAs encoded within the Prader-Willi minimal deletion critical region have previously been reported to show growth retardation and hyperphagia. Here, consistent with previous reports, we observed growth retardation in Snord116+/-P mice with a congenital paternal Snord116 deletion. However, these mice neither displayed increased food intake nor had reduced hypothalamic expression of the proprotein convertase 1 gene PCSK1 or its upstream regulator NHLH2, which have recently been suggested to be key mediators of PWS pathogenesis. Specifically, we disrupted Snord116 expression in the mediobasal hypothalamus in Snord116fl mice via bilateral stereotaxic injections of a Cre-expressing adeno-associated virus (AAV). While the Cre-injected mice had no change in measured energy expenditure, they became hyperphagic between 9 and 10 weeks after injection, with a subset of animals developing marked obesity. In conclusion, we show that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS.
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PMID:Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome. 2947 10

Hypothalamic pro-opiomelanocortin (POMC) neurons are key sensory neurons for energy balance. The basic helix-loop-helix transcription factor NHLH2 is expressed in POMC neurons, and Nhlh2 knockout mice show adult-onset obesity with low exercise behavior. Evidence is presented to explore the hypothesis that NHLH2 transcriptional activity within POMC neurons is crucial for maintaining motivated spontaneous activity and enforced exercise.
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PMID:Pro-opiomelanocortin Neurons and the Transcriptional Regulation of Motivated Exercise. 3216 70