Lycopene inhibits proinflammatory cytokine and chemokine expression in adipose tissue.

Obesity is associated with a low-grade inflammation which is correlated with an increased secretion of pro-inflammatory cytokines and chemokines by adipose tissue, suspected to contribute to the development of insulin resistance. Because lycopene is mostly stored in adipose tissue and possesses anti-inflammatory properties, we hypothesize that lycopene could reduce the production of proinflammatory markers in adipose tissue. In agreement with this hypothesis, we observed a decrease of inflammatory markers such as IL-6, MCP-1 and IL-1ß at both the mRNA and protein level when explants of epididymal adipose tissue from mice fed with a high-fat diet were incubated with lycopene ex vivo. The same effect was reproduced with explants of adipose tissue preincubated in lycopene and then subjected to TNFα stimulation. The contribution of adipocytes and preadipocytes was evaluated. In both preadipocytes and differentiated 3T3-L1 adipocytes, lycopene preincubation for 24 h decreased the TNFα-mediated induction of IL-6 and MCP-1. Finally, the same results were reproduced with human adipocyte primary cultures. The molecular mechanism was also studied. In transient transfections, a decrease of the luciferase gene reporter under control of NF-κB responsive element was observed for cells incubated in the presence of lycopene and TNFα compared to TNFα alone. The involvement of the NF-κB pathway was confirmed by the modulation of IKKα/ß phosphorylation by lycopene. Altogether, these results showed for the first time a limiting effect of lycopene on adipose tissue proinflammatory cytokine and chemokine production. Such an effect could prevent or limit the prevalence of obesity-associated pathologies, such as insulin resistance.

A novel mutation (E333D) in the thyroid hormone beta receptor causing resistance to thyroid hormone syndrome.

Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone beta receptor (TRbeta). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRbeta. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRbeta gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue (E333D). Further functional analyses of the novel TRbeta mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRbeta mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.

[Identification of eight new mutations in the c-erbAB gene of patients with resistance to thyroid hormone]. / Identification de huit nouvelles mutations dans le gène c-erbAB chez des patients atteints de résistance aux hormones thyroïdiennes.

Resistance to thyroid hormone (RTH) is a rare genetic disorder, usually associated with different mutations in the c-erbAB gene that encodes the beta type receptor of thyroid hormone (TRB). It is characterized by elevated serum thyroid hormone and inappropriate TSH secretion. The numerous mutations so far detected are clustered in three hot spot areas in the ligand binding domain of TRB. In the context of a national survey we have detected 16 different mutations in the c-erbAB gene, in 22 families presenting with RTH. Eight of these mutations had not been described previously. Two are located in an area not known to harbor naturally occurring mutations. This observation could lead to define a fourth cluster of mutations in the c-erbAB gene.

A novel resistance to thyroid hormone associated with a new mutation (T329N) in the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH) is a syndrome of elevated serum thyroxine, inappropriately "normal" serum thyrotropin (TSH) and reduced thyroid hormone responsiveness associated with point mutations in the thyroid hormone receptor-beta (TRbeta) gene. We describe a novel point mutation resulting in a cytosine for adenine substitution at nucleotide 1271 (exon 9) that results in the substitution of threonine for asparagine (T329N). This mutation was identified in a 30-year-old woman who was investigated for recurrent spontaneous abortions and was found to have RTH. Dextrothyroxine (D-T4) therapy was instituted. At 8 mg per day 2 pregnancies followed with the delivery of a healthy boy and an RTH-affected girl another miscarriage occurred on D-T4 treatment at 6 mg per day. The T329N mutation, which was also identified in the daughter, markedly reduces the affinity of TRbeta for triiodothyronine (T3). Formation of T329N mutant TR homodimers and heterodimers with RXRalpha on thyroid hormone response element F2 (TRE F2) was not affected, but the ability of T3 to interrupt T329N mutant TRbeta homodimerization was markedly reduced. The T329N mutant TRbeta was transcriptionally inactive in transient expression assays. In cotransfection assays with wild-type TRbeta1, the mutant TRbeta1 functioned in a dominant negative manner. The results suggest that the T329N mutation in the T3-binding domain of TRbeta is responsible for RTH in the proposita's family.

Localization of the thyroglobulin gene by in situ hybridization to human chromosomes.

The human thyroglobulin gene was mapped by in situ hybridization whereby a 3H-labeled recombinant plasmid DNA containing a fragment of 2.3 kilobases of human thyroglobulin gene was hybridized to human chromosome preparations. A high proportion (25%) of hybridized metaphases exhibited silver grains at the distal portion of the long arm of chromosome 8. Analysis of the grain position at this site indicated that the chromosomal localization of the human thyroglobulin gene was 8q242-8q243.