Thyroid hormone-independent interaction between the thyroid hormone receptor beta2 amino terminus and coactivators.

Thyroid hormone receptors (TRs) mediate hormone action by binding to DNA response elements (TREs) and either activating or repressing gene expression in the presence of ligand, T(3). Coactivator recruitment to the AF-2 region of TR in the presence of T(3) is central to this process. The different TR isoforms, TR-beta1, TR-beta2, and TR-alpha1, share strong homology in their DNA- and ligand-binding domains but differ in their amino-terminal domains. Because TR-beta2 exhibits greater T(3)-independent activation on TREs than other TR isoforms, we wanted to determine whether coactivators bound to TR-beta2 in the absence of ligand. Our results show that TR-beta2, unlike TR-beta1 or TR-alpha1, is able to bind certain coactivators (CBP, SRC-1, and pCIP) in the absence of T(3) through a domain which maps to the amino-terminal half of its A/B domain. This interaction is specific for certain coactivators, as TR-beta2 does not interact with other co-factors (p120 or the CBP-associated factor (pCAF)) in the absence of T(3). The minimal TR-beta2 domain for coactivator binding is aa 21-50, although aa 1-50 are required for the full functional response. Thus, isoform-specific regulation by TRs may involve T(3)-independent coactivator recruitment to the transcription complex via the AF-1 domain.

Time relationship between circadian variation of serum levels of leptin, insulin and cortisol in healthy subjects.

BACKGROUND: Leptin is involved in the regulation of eating behavior. Its serum levels are determined by fat mass but a diurnal rhythm is also described. It is not clear whether leptin levels are also controlled in vivo by hormonal stimuli, like insulin or cortisol. METHODS AND RESULTS: This possible temporal relation was investigated by serial measurements during 24 h (group A) and 46 h (group B) in 15 healthy volunteers and another 10 subjects (group C) while fasting for 72 h. Maximal leptin levels were observed at 4:00 a.m. and 4:00 p.m. in subjects on a normal diet. During 24 h starvation (group B), there was a 40% decrease of mean leptin concentration when compared to baseline values. In group C, the leptin concentration under starvation dropped to 25% of basal levels after 72 h. Pooled data from group A and the nonfasting data from group B showed an insulin increase preceding leptin increase by 6 h (r = 0.405, p < 0.0001), while cortisol decreased 4 h (r = 0.361, p < 0.001) after leptin decrease. CONCLUSION: Starvation results in a fall of circulating leptin, ending leptin rhythmicity. Food intake is causally involved in the fluctuation of leptin levels in serum. Presumably this effect is mediated by insulin, while cortisol does not seem to affect leptin release directly in vivo.

Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart.

Glucose enters the heart via GLUT1 and GLUT4 glucose transporters. GLUT4-deficient mice develop striking cardiac hypertrophy and die prematurely. Whether their cardiac changes are caused primarily by GLUT4 deficiency in cardiomyocytes or by metabolic changes resulting from the absence of GLUT4 in skeletal muscle and adipose tissue is unclear. To determine the role of GLUT4 in the heart we used cre-loxP recombination to generate G4H(-/-) mice in which GLUT4 expression is abolished in the heart but is present in skeletal muscle and adipose tissue. Life span and serum concentrations of insulin, glucose, FFAs, lactate, and beta-hydroxybutyrate were normal. Basal cardiac glucose transport and GLUT1 expression were both increased approximately 3-fold in G4H(-/-) mice, but insulin-stimulated glucose uptake was abolished. G4H(-/-) mice develop modest cardiac hypertrophy associated with increased myocyte size and induction of atrial natriuretic and brain natriuretic peptide gene expression in the ventricles. Myocardial fibrosis did not occur. Basal and isoproterenol-stimulated isovolumic contractile performance was preserved. Thus, selective ablation of GLUT4 in the heart initiates a series of events that results in compensated cardiac hypertrophy.

Serum insulin-like growth factors IGF-I and IGFBP-3 in children with slipped capital femoral epiphysis.

Hormonal imbalance in puberty and biomechanical overload due to obesity have been implied in the still unknown cause of slipped capital femoral epiphysis (SCFE). Local mediators of growth hormone (GH) action, such as insulin-like growth factor I (IGF-I), play a crucial role in the development of the growth plate cartilage. Concentrations of IGF-I and its binding protein 3 (IGFBP-3) were measured in the serum of 19 SCFE children without endocrine disorders. Standing height and body weight were determined. The results were related to the bone age. Concentrations for IGF-I and IGFBP-3 were predominantly within the normal ranges for chronologic age and bone age. The correlation of IGF-I and IGFBP-3 serum levels was high. Standing height and body weight showed a tendency toward the higher percentile ranges. Ten of 19 patients were above the 97th percentile concerning their weight for height. Bone age did not differ significantly from chronologic age. Serum concentrations of IGF-I and IGFBP-3 provided no evidence of a disturbance of the somatotropic axis in SCFE children. Increased body weight associated with normal skeletal maturation implies a mechanical stress factor in the cause of SCFE in these children.

Circadian plasma leptin levels in patients with anorexia nervosa: relation to insulin and cortisol.

In anorexia nervosa, underweight results from a loss of body mass due to a restricted energy intake. Circulating leptin levels have been shown to be low in the acute stage of the disorder. We studied diurnal secretion characteristics of leptin, insulin and cortisol in a study group of anorectic patients prior to refeeding, a second study group of anorectic patients after initiation of refeeding and study groups of healthy underweight and normal-weight controls. Spontaneous secretion of leptin, insulin and cortisol was measured by drawing blood samples every 2 h for 24 h. The temporal relationships between the diurnal secretion patterns of the three hormones were assessed by cross-correlation analysis in every study group. Plasma levels of leptin and cortisol were secreted with a specific circadian rhythmicity and displayed an intricate temporal relationship in anorectic patients. Semistarvation in the non-refed patients was associated with (1) exceedingly low plasma leptin levels, (2) a qualitative alteration in the circadian rhythm of leptin and cortisol levels and (3) an alteration in the temporal coupling between cortisol and leptin. In contrast, in the patients who had gained weight, leptin levels were higher; furthermore, the diurnal pattern of leptin and the temporal relationship between leptin and cortisol were similar to controls. Increments in insulin secretion preceded those of leptin by 4-6 h in both anorectic patients and in controls. Leptin levels increased 4 h prior to those of cortisol in controls and in refed patients, whereas in the non-refed patients cortisol increased prior to leptin. Thus, anorexia nervosa leads to pronounced, albeit reversible changes in the secretion dynamics of leptin and cortisol.