Thyroid hormone action is predominantly mediated by thyroid hormone receptors (THRs), which are encoded by the thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) genes. Patients with mutations in THRB present with resistance to thyroid hormone β (RTHβ), which is a disorder characterized by elevated levels of thyroid hormone, normal or elevated levels of TSH and goitre. Mechanistic insights about the contributions of THRβ to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THRβ alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology. These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THRα have since been described. These patients have RTHα and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic–pituitary–thyroid axis in these individuals is minimally affected, which suggests that the central T3 feedback loop is not impaired in patients with RTHα, in stark contrast to patients with RTHβ.
Pendred's syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the PDS/SLC26A4 gene that encodes pendrin. Functionally, pendrin is a transporter of chloride and iodide in Xenopus oocytes and heterologous mammalian cells and a chloride/base exchanger in -intercalated cells of the renal cortical collecting duct. The partially impaired thyroidal iodide organification in Pendred's syndrome suggests a possible role of pendrin in iodide transport at the apical membrane of thyroid follicular cells, but experimental evidence for this concept is lacking. The iodide transport properties of pendrin were determined in polarized Madin-Darby canine kidney cells expressing the sodium iodide symporter (NIS), pendrin, or NIS and pendrin using a bicameral system-permitting measurement of iodide content in the basal, intracellular, and apical compartments. Moreover, we determined the functional consequences of two naturally occurring mutations (L676Q and FS306>309X). In polarized Madin-Darby canine kidney cells, NIS mediates uptake at the basolateral membrane. Only minimal amounts of iodide reach the apical compartment in the absence of pendrin. In cells expressing NIS and pendrin, pendrin mediates transport of iodide into the apical chamber. Wild type pendrin also mediates iodide efflux in transiently transfected cells. In contrast, both pendrin mutants lose the ability to promote iodide efflux. These results provide evidence that pendrin mediates apical iodide efflux from polarized mammalian cells loaded with iodide. Consistent with the partial organification defect observed in patients with Pendred's syndrome, naturally occurring mutations of pendrin lead to impaired transport of iodide.
Hypothalamic malonyl-CoA has been shown to function in global energy homeostasis by modulating food intake and energy expenditure. Little is known, however, about the regulation of malonyl-CoA concentration in the central nervous system. To address this issue we investigated the response of putative intermediates in the malonyl-CoA pathway to metabolic and endocrine cues, notably those provoked by glucose and leptin. Hypothalamic malonyl-CoA rises in proportion to the carbohydrate content of the diet consumed after food deprivation. Malonyl-CoA concentration peaks 1 h after refeeding or after peripheral glucose administration. This response depends on the dose of glucose administered and is blocked by the i.c.v. administration of an inhibitor of glucose metabolism, 2-deoxyglucose (2-DG). The kinetics of change in hypothalamic malonyl-CoA after glucose administration is coincident with the suppression of phosphorylation of AMP kinase and acetyl-CoA carboxylase. Blockade of glucose utilization in the CNS by i.c.v. 2-DG prevented the effects of glucose on 5AMP-activated protein kinase, malonyl-CoA, hypothalamic neuropeptide expression, and food intake. Finally, we showed that leptin can increase hypothalamic malonyl-CoA and that the increase is additive with glucose administration. Leptin-deficient ob/ob mice, however, showed no defect in the glucose-or refeeding-induced rise in hypothalamic malonyl-CoA after food deprivation, demonstrating that leptin was not required for this effect. These studies show that hypothalamic malonyl-CoA responds to the level of circulating glucose and leptin, both of which affect energy homeostasis.acetyl-CoA carboxylase ͉ AMP kinase ͉ carnitine palmitoyl-transferase 1c ͉ fatty acid synthase A n interconnected endocrine and neuroendocrine system controls food intake and energy expenditure (1). Recently, a new pathway for maintaining energy homeostasis has become evident that relies on an ancient nutrient-sensing pathway whereby the CNS directly monitors energy needs by sampling cellular adenine nucleotide levels and responds by directing hunger and peripheral energy expenditure (2, 3). Neural cellular energy status is monitored through AMPK, which directly senses the [AMP]/[ATP] ratio. The AMPK system provides a rapid means of detecting energy status not reliant directly on endocrine signals. The activation of AMPK leads to the inhibition of the key regulatory enzyme of fatty acid synthesis, acetyl-CoA carboxylase (ACC). The activity of this enzyme is an indicator of energy surplus and is thought to be one of the mechanisms by which energy homeostasis is mediated. Several enzymes that are involved in fatty acid metabolism have been implicated in the CNS control of energy homeostasis including AMPK (4-7), ACC (8, 9), fatty acid synthase (FAS) (8, 10), carnitine palmitoyltransferase 1 (CPT1) (11, 12), and stearoyl-CoA desaturase 1 (13). Because fatty acid synthesis is a process that occurs primarily during energy surplus, it is not surprising that this system has evolved as a means to r...
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