Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adipose (adp) is an obesity gene in Drosophila and mice with crucial functions in fat metabolism. We investigated the correlation between genetic variation of the WDTC1 locus, the ortholog of adp, and human obesity. Five WDTC1 single-nucleotide polymorphisms (SNPs) were genotyped in 935 and 1,115 adults of two ethnically diverse US populations. In the Boston Puerto Rican population, we demonstrated that two WDTC1 SNPs strongly associated with obesity. Homozygote and heterozygote carriers of the major allele i22835A, representing approximately 96% of the population, had significantly higher mean BMI (31.5 and 31.0 kg/m(2), respectively) than noncarriers (28.6 kg/m(2)). Conversely, homozygotes of the minor allele i22835G were leaner and were 74% less likely to be overweight or obese (odds ratio (OR) = 0.26, P = 0.003) compared to homozygote carriers of the major allele. Haplotype analyses based on two SNPs further supported these findings. In addition, we found a strong interaction of monounsaturated fatty acid (MUFA) intake by genotype in this population. As dietary MUFA intake increased, minor allele carriers of SNP i22835A>G had higher BMIs, whereas major allele carriers had lower BMIs. A white population also exhibited a pattern of association between WDTC1 genotypes and obesity although of a different nature. Those WDTC1 variants which associated with obesity likely have experienced strong positive selection in human history, when food supply was unpredictable. Given the high frequency of the major alleles in both populations, we suggest that WDTC1 variation may be an important risk factor contributing to obesity in these populations.
Obesity (Silver Spring) 2009 Mar
PMID:WDTC1, the ortholog of Drosophila adipose gene, associates with human obesity, modulated by MUFA intake. 1923 44

WDTC1/Adp encodes an evolutionarily conserved suppressor of lipid accumulation. While reduced WDTC1 expression is associated with obesity in mice and humans, its cellular function is unknown. Here, we demonstrate that WDTC1 is a component of a DDB1-CUL4-ROC1 (CRL4) E3 ligase. Using 3T3-L1 cell culture model of adipogenesis, we show that disrupting the interaction between WDTC1 and DDB1 leads to a loss of adipogenic suppression by WDTC1, increased triglyceride accumulation and adipogenic gene expression. We show that the CRL4(WDTC) (1) complex promotes histone H2AK119 monoubiquitylation, thus suggesting a role for this complex in transcriptional repression during adipogenesis. Our results identify a biochemical role for WDTC1 and extend the functional range of the CRL4 complex to the suppression of fat accumulation.
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PMID:The antiobesity factor WDTC1 suppresses adipogenesis via the CRL4WDTC1 E3 ligase. 2711 64

ASG2 (Altered Seed Germination 2) is a prenylated protein in Arabidopsis thaliana that participates to abscisic acid signaling and is proposed to act as a substrate adaptor for the DDB1 (DNA damage-binding protein 1)-CUL4 (Cullin 4) E3 ubiquitin ligase complex. ASG2 harbors WD40 and TetratricoPeptide Repeat (TPR) domains, and resembles the well-conserved animal gene called ADP (antiobesity factor ADIPOSE) in fly and WDTC1 (WD40 and TPR 1) in humans. Loss of function of WDTC1 results in an increase in adipocytes, fat accumulation, and obesity. Antiadipogenic functions of WDTC1 involve regulation of fat-related gene transcription, notably through its binding to histone deacetylases (HDACs). Our sequence and phylogenetic analysis reveals that ASG2 belongs to the ADP/WDTC1 cluster. ASG2 and WDTC1 share a highly conserved organization that encompasses structural and functional motifs: seven WD40 domains and WD40 hotspot-related residues, three TPR protein-protein interaction domains, DDB1-binding elements [H-box and DWD (DDB1-binding WD40 protein)-box], and a prenylatable C-terminus. Furthermore, ASG2 involvement in fat metabolism was confirmed by reverse genetic approaches using asg2 knockout Arabidopsis plants. Under limited irradiance, asg2 mutants produce "obese" seeds characterized by increased weight, oil body density, and higher fatty acid contents. In addition, considering some ASG2- and WDTC1-peculiar properties, we show that the WDTC1 C-terminus is prenylated in vitro and HDAC-binding capability is conserved in ASG2, suggesting that the regulation mechanism and targets of ADP/WDTC1-like proteins may be conserved features. Our findings reveal the remarkable evolutionary conservation of the structure and the physiological role of ADIPOSE homologs in animals and plants.
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PMID:Remarkable Evolutionary Conservation of Antiobesity ADIPOSE/WDTC1 Homologs in Animals and Plants. 2866 38