No abstract

BackgroundSimilar to other systems, the endocrine system is affected by aging. Thyroid hormone, the action of which is affected by many factors, has been shown to be associated with longevity. The most useful marker for the assessment of thyroid hormone action is TSH level. Although age and gender are believed to modify the pituitary set point or response to free thyroid hormone concentration, the precise age- and gender-dependent responses to thyroid hormone have yet to be reported.MethodsWe analyzed the results of 3564 thyroid function tests obtained from patients who received medication at both out- and inpatient clinics of Shinshu University Hospital. Subjects were from among those with thyroid function test results in the normal or mildly abnormal range. Based on a log-linear relationship between the concentrations of FHs and TSH, we established the putative resistance index to assess the relation between serum FH and TSH levels.ResultsFree thyroid hormone and TSH concentration showed an inverse log-linear relation. In males, there was a negative relationship between the free T3 resistance index and age. In females, although there were no relationships between age and FHs, the indices were positively related to age.ConclusionsThese findings indicated that there is a gender-specific response to thyroid hormone with aging. Although the TSH level is a useful marker for the assessment of peripheral thyroid hormone action, the values should be interpreted carefully, especially with regard to age- and gender-related differences.

Pharmacological characteristics of the voltage-dependent calcium channel (VDCC) of the pancreatic B-cell were studied using omega-conotoxin (omega CgTX) and dihydropyridine (DHP) calcium channel blockers. High glucose and potassium (K+) depolarization were employed as the stimulant of insulin release. omega CgTX (greater than 50 nM), a blocker of neural, but not muscular, Ca2+ channels, partially blocked (27%) the second, but not the first, phase of glucose-induced insulin release without a significant effect on K+ depolarization-induced insulin release. The DHP Ca2+ channel blocker nifedipine inhibited both phases of glucose-induced insulin release (ED50 = 200 nM) and completely abolished both phases of response at 10 microM. In contrast, the DHP Ca2+ channel blocker only partially suppressed (75% at 10 microM) K+ depolarization-induced insulin release with an ED50 of 100 nM. We conclude that pancreatic B-cell possesses at least two classes of VDCCs; one is DHP sensitive, and the other DHP insensitive. Partial suppression of the second phase of glucose-induced insulin release by a high concentration of omega CgTX may be due to its toxic effect on the secretory machinery other than VDCC.

No abstract

No abstract

No abstract

Thyroid hormone receptors (TR) are members of the nuclear receptor superfamily. There are at least two TR isoforms, TR and TR , which act as mediators of thyroid hormone in tissues. However, the relative expression of each TR isoform in target tissues is still elusive. Herein, we have developed an RT-PCR and restriction enzyme digestion method to determine the expression of TR 1 and TR 1. We analyzed the expression of TR isoforms in 3T3-L1 preadipocytes induced to differentiate by an adipogenic cocktail in the presence or absence of 100 nM triiodothyronine (T 3 ). The TR 1 isoform was predominantly expressed in 3T3-L1 adipocytes, and its expression was increased at the stage of development concomitant with the emergence of lipid droplets. Little, if any, TR 1 mRNA was detected in adipocytes. Administration of T 3 to the differentiating 3T3-L1 cells enhanced the accumulation of triglyceride. The expression profile of TR 1 in T 3 -treated adipocytes was similar to that in non-treated cells. The transcripts of adipogenic factors, CCAAT/ enhancer binding protein (C/EBP ) and peroxisome proliferator activated receptor (PPAR ), were not altered by T 3 . Lipid binding protein, aP2, that is downstream of these transcription factors was also unaffected by T 3 . In contrast, the lipogenic enzyme, glyceraldehyde-3-phosphate dehydrogenase mRNA was significantly increased in the presence of T 3 . Therefore, T 3 appears to be a hormone capable of modulating the expression of lipogenic enzyme and augments the accumulation of lipid droplets. We conclude that the TR isoform might play an important role in the generation and maintenance of the mature adipocyte phenotype, regulating the expression of lipogenic enzymes.

Octamer transcription factor-1 (Oct-1) is a member of the POU (Pit-1, Oct-1, unc-86) family of transcription factors and is involved in the transcriptional regulation of a variety of gene expressions related to cell cycle regulation, development, and hormonal signals. It has been shown that Oct-1 acts not only as a transcriptional activator but also as a transcriptional repressor for certain genes. The mechanism of the repressive function of Oct-1 has not been well understood. Here we demonstrate by using the glutathione S-transferase pull-down assays and coimmunoprecipitation assays that the POU domain of Oct-1 directly interacts with a silencing mediator for retinoid and thyroid hormone receptors (SMRT). The interaction surfaces are located in the Cterminal region of SMRT, which are different from previously described silencing domains I and II or receptor interacting domains I and II. In transient transfection assays in COS1 cells, overexpression of SMRT attenuated the augmentation of Oct-1 transcriptional activity by OBF-1/OCA-B, activator for Oct-1. In pull-down assays, increasing amounts of SMRT could compete the binding of OCA-B to Oct-1 POU domain. The activity of Oct-1 could be determined by a regulated balance between SMRT and OCA-B. Furthermore, cotransfected unliganded thyroid hormone receptor enhanced the transactivation by Oct-1, and addition of 3,3,5-tri-iodo-L-thyronine obliterated the stimulatory effects. Consequently, in the presence of cotransfected thyroid hormone receptor, the octamer response element acts as an element negatively regulated by 3,3,5-tri-iodo-L-thyronine. The results suggest that the transcriptional activity of Oct-1 can be modulated by interaction through its POU domain by a silencing mediator SMRT resulting in the cross-talk between Oct-1 and nuclear receptors.Octamer transcription factor-1 (Oct-1) 1 activates the octamer motif containing gene promoters that are ubiquitously as well as tissue-specifically expressed genes such as histone H2B, the small nuclear RNA, and Ig (1-3). Oct-1 is a member of a family of transcription factors characterized by the presence of a bipartite DNA-binding domain (POU domain). The POU domain consists of two conserved regions, a POU-specific domain and a POU homeodomain (4, 5). The both subdomains have a helixturn-helix motif, acting not only as a DNA-binding domain but also as a protein-protein interaction domain. A number of transcription factors have been identified to interact with the POU domains of Oct-1 such as TBP, TFIIB, HMG2, and Oct-binding factor 1 (OBF-1) also referred to as Oct-1-associated coactivator (OCA-B) (6 -11). It has been shown that Oct-1 interacts with nuclear hormone receptors such as retinoid X receptor, thyroid hormone receptor (TR), and glucocorticoid receptor and influences their transcriptional activity (12-14). Oct-1 possesses not only transactivation function but also repression function; von Willebrand factor promoter (15), prolactin gene promoter (16), or rGH promoter (14) was shown to be down-regulated by Oct...