Thyroid hormone action: The p43 mitochondrial pathway. Methods

The possibility that several pathways are involved in the multiplicity of thyroid hormone physiological influences led to searches for the occurrence of T3 extra nuclear receptors. The existence of a direct T3 mitochondrial _pathway is now well established. The demonstration that TR.al mRNA encodes not only a nuclear thyroid hormone receptor but also two proteins imported into ttùtochondria with molecular masses of 43 and 28 kDa has provided new clues to understand the pleiotropic influence of iodinated hormones. The use of a T3 photo affinity label derivative (T3-PAL) allowed detectiug two mitochondrial T3 binding proteins. In association with western blots using antibodies raised against the T3 nuclear receptor TRal, mitochondrial T3 receptors were identified as truncated T.Ral forms. Import and in organello transcription experiments performed in isolated mitochondria led to the conclusion that p43 is a transcription factor of the mitochondrial genome, inducing changes in the mitochondrial/nuclear crosstalk. Invitro experiments indicated that this T3 mitochondrial pathway affects cell differentiation, apoptosis, andtransformation. Generation of transgenic mice demonstrated the involve1nent of this mitochondrial pathwayin the determination of muscle phenotype, glucose metabolism, and thermogenesis

Programming of obesity and cardiovascular disease.

BACKGROUND: There is evidence that malnutrition in early life induces a growth retardation leading, in adult life, to manifest components of the metabolic syndrome. However, the impact on obesity seems less clearly established. OBJECTIVE: To review the effects of foetal and postnatal malnutrition on the programming of obesity in the context of the metabolic syndrome, as well as the link between central obesity and cardiovascular diseases. METHODS: Included in the review were recent papers exploring the mechanisms linking maternal nutrition with impaired foetal growth and later obesity, cardiovascular disease, hypertension and diabetes in humans and animals. RESULTS: The programming of obesity during foetal and early postnatal life depends of the timing of maternal malnutrition as well as the postnatal environment. Obesity arises principally in offspring submitted to malnutrition during early stages of gestation and which presented early catch-up growth. The programming may involve the dysregulation of appetite control or the hormonal environment leading to a context favourable to obesity development (hypersecretion of corticosteroids, hyperinsulinaemia and hyperleptinaemia and anomalies in the IGF axis). Adipose tissue secretes actively several factors implicated in inflammation, blood pressure, coagulation and fibrinolysis. The programmed development of intra-abdominal obesity after early growth restriction may thus favour higher prevalence of hypertension and cardiovascular diseases. CONCLUSIONS: Abdominal obesity appears in malnourished offspring and is aggravated by early catch-up growth. Higher rates of intra-abdominal obesity observed after growth restriction may participate to hypertension and create atherothrombotic conditions leading to the development of cardiovascular diseases