Resistance to thyroid hormone, and peroxisome-proliferator-activated receptor gamma resistance

Resistance to thyroid hormone (RTH) is usually inherited in a dominant fash ion, and is characterized by elevated serum thyroid hormone levels and fail ure to suppress pituitary secretion of thyroid-stimulating hormone, with va riable refractoriness to hormone action in peripheral tissues. Two major fo rms of the disorder are recognized: asymptomatic individuals with generaliz ed resistance (GRTH) and patients with thyrotoxic features suggesting predo minant pituitary resistance (PRTH). In over 100 families with GRTH or PRTH, we have identified heterozygous mutations in the thyroid hormone receptor beta isoform (TR beta), which localize to three regions (amino acids 231-28 2, 310-353 and 429-461) of the hormone-binding domain of the receptor. The mutant receptors are transcriptionally impaired, due either to reduced liga nd binding or to attenuated interaction with co-activators, and inhibit wil d-type TR action in a dominant-negative manner. In the TR beta crystal stru cture, most RTH mutations cluster around the hormone-binding pocket, with r eceptor regions that mediate functions (DNA binding, dimerization, corepres sor recruitment) required for dominant-negative activity being devoid of na tural mutations. The pathogenesis of variable tissue resistance is not full y understood, but may be related to the differing tissue distributions of T R alpha and TR beta, and to variable dominant-negative activity of mutant r eceptors on different target genes. The nuclear receptor peroxisome-prolife rator-activated receptor gamma (PPAR gamma) regulates adipogenesis and medi ates the action of thiazolidinediones - novel antidiabetic agents which enh ance tissue insulin sensitivity. The PPAR gamma gene was screened in 85 sub jects with severe insulin resistance, and two different heterozygous recept or mutations (P467L and V290M) were identified in three affected individual s. The PPAR gamma mutants are markedly transcriptionally impaired due to al tered ligand binding and co-activator recruitment. Analogous to RTH, they i nhibit the function of wild-type PPAR gamma when co-expressed, and such dom inant-negative inhibition is linked to their ability to silence basal gene transcription via aberrant interaction with co-repressors. In addition to i nsulin resistance, all three affected subjects developed Type II diabetes m ellitus and hypertension at an unusually early age. Our findings provide co mpelling evidence that PPAR gamma is important in the control of insulin se nsitivity, glucose homoeostasis and blood pressure in humans. Future studie s aim to elucidate the mechanism by which this receptor regulates insulin a ction and vascular tone.