Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The basic helix-loop-helix PAS (bHLH-PAS) transcription factors SIM1 and arylhydrocarbon receptor (AHR) are involved in the control of feeding behavior. Sim1 haploinsufficiency causes hyperphagia in mice and humans, most likely by perturbing the hypothalamus function. The administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AHR, causes severe anorexia, which also appears to be of central origin. Both SIM1 and AHR require heterodimerization either with ARNT or ARNT2 to function. Here, we characterize the promoter for Sim1 and show that a consensus AHR-ARNT/2 binding site positively regulates its activity in the context of transfection experiments in Neuro-2A cells. A gel shift assay indicated that AHR-ARNT/2 can bind its putative site in the Sim1 promoter. Overexpression of Arnt, Arnt2, or Ahr increased the activity of a reporter construct containing the Sim1 promoter by 1.8-, 1.5-, and 2.2-fold, respectively, but failed to do so when the AHR-ARNT/2 binding site was mutated. Similarly, TCDD increased the activity of the reporter construct by 1.8-fold but not that of its mutated version. Finally, we found that TCDD increased Sim1 expression in Neuro-2A cells and in mouse kidney and hypothalamus by 4-, 3-, and 2-fold, respectively. We conclude that Sim1 expression is regulated by AHR-ARNT/2. This result raises the possibility that Sim1 mediates the effect of TCDD on feeding and points to a complex network of regulatory interactions between bHLH-PAS proteins.
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PMID:Regulatory interaction between arylhydrocarbon receptor and SIM1, two basic helix-loop-helix PAS proteins involved in the control of food intake. 1466 Jun 29

Haploinsufficency of Sim1, which codes for a basic helix-loop-helix-PAS (PER-ARNT-SIM) transcription factor, causes hyperphagia in mice and humans, without decrease in energy expenditure. Sim1 is expressed in several areas of the brain, including the developing and postnatal paraventricular nucleus (PVN), a region of the hypothalamus that controls food intake. We have previously found that the number of PVN cells is decreased in Sim1+/- mice, suggesting that their hyperphagia is caused by a developmental mechanism. However, the possibility that Sim1 functions in the postnatal PVN to control food intake cannot be ruled out. To explore this hypothesis, we used adenoviral vectors to modulate Sim1 expression in the postnatal PVN of wild-type mice. Unilateral stereotaxic injection into the PVN of an adenoviral vector producing a short hairpin RNA directed against Sim1 resulted in a significant increase in food intake, which peaked to 22% 6 d after the procedure, compared with the injection of a control virus. In contrast, injection of an adenovirus that expresses Sim1 induced a decrease in food intake that was maximal on the seventh day after the procedure, reaching 20%. The impact of bilateral injections of these vectors into the PVN was not greater than that of unilateral injections. Together, these results strongly suggest that Sim1 functions along a physiological pathway to control food intake.
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PMID:Adenoviral-mediated modulation of Sim1 expression in the paraventricular nucleus affects food intake. 1680 40

Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a member of the basic helix-loop-helix/PER-ARNT-SIM (bHLH/PAS) transcription factor family. ARNT2 heterodimerizes with several members of the family, including single-minded homolog-1 (SIM1) and neuronal PAS domain protein 4 (NPAS4), primarily in neurons of the central nervous system. We screened 64,424 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea (ENU)-mutagenized great-grandsires for weight abnormalities. Among 17 elevated body weight phenotypes identified and mapped, one strongly correlated with an induced missense mutation in Arnt2 using a semidominant model of inheritance. Causation was confirmed by CRISPR/Cas9 gene targeting to recapitulate the original ENU allele, specifying Arg74Cys (R74C). The CRISPR/Cas9-targeted (Arnt2 R74C/R74C) mice demonstrated hyperphagia and increased adiposity as well as hepatic steatosis and abnormalities in glucose homeostasis. The mutant ARNT2 protein showed decreased transcriptional activity when coexpressed with SIM1. These findings establish a requirement for ARNT2-dependent genes in the maintenance of the homeostatic feeding response, necessary for prevention of obesity and obesity-related diseases.
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PMID:A viable hypomorphic Arnt2 mutation causes hyperphagic obesity, diabetes and hepatic steatosis. 3056 51