In mammals, circadian oscillators exist not only in the suprachiasmatic nucleus, which harbors the central pacemaker, but also in most peripheral tissues. It is believed that the SCN clock entrains the phase of peripheral clocks via chemical cues, such as rhythmically secreted hormones. Here we show that temporal feeding restriction under light–dark or dark–dark conditions can change the phase of circadian gene expression in peripheral cell types by up to 12 h while leaving the phase of cyclic gene expression in the SCN unaffected. Hence, changes in metabolism can lead to an uncoupling of peripheral oscillators from the central pacemaker. Sudden large changes in feeding time, similar to abrupt changes in the photoperiod, reset the phase of rhythmic gene expression gradually and are thus likely to act through a clock-dependent mechanism. Food-induced phase resetting proceeds faster in liver than in kidney, heart, or pancreas, but after 1 wk of daytime feeding, the phases of circadian gene expression are similar in all examined peripheral tissues.

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Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus

Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.

Physiological and molecular basis of thyroid hormone action.

The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T3 production. We discuss the pathological role of D3 overexpression causing “consumptive hypothyroidism” as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium. (Endocrine Reviews 23: 38–89, 2002)

Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.

In adult mammals, the adipocyte-derived hormone leptin acts on the brain to reduce food intake by regulating the activity of neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we report that neural projection pathways from the ARH are permanently disrupted in leptin-deficient (Lepob/Lepob) mice and leptin treatment in adulthood does not reverse these neuroanatomical defects. However, treatment of Lepob/Lepob neonates with exogenous leptin rescues the development of ARH projections, and leptin promotes neurite outgrowth from ARH neurons in vitro. These results suggest that leptin plays a neurotrophic role during the development of the hypothalamus and that this activity is restricted to a neonatal critical period that precedes leptin's acute regulation of food intake in adults.

https://science.sciencemag.org/content/sci/304/5667/108.full.pdf

Trophic Action of Leptin on Hypothalamic Neurons That Regulate Feeding

I. Introduction THE biological importance of the thyroid gland has been recognized for centuries (1). The realization in the late 19th century that cretinism and myxedema result from loss of thyroid function led to the discovery of T4 (2) and T3 (3) as the predominant and most potent thyroid hormones, respectively. During the ensuing decades the plasma membrane (4), synapse (5), endoplasmic reticulum (6), and mitochondria (7) have all been considered as potential cellular sites of action of the thyroid hormones. In the 1960s, however, it was noted that many of the physiological actions of T3 were preceded by nuclear RNA transcription (8, 9), and high-affinity nuclear receptors for T3 were discovered soon thereafter (10,11). The specificity of the nuclear T3 receptors (TRs) for thyroid hormone analogs closely parallels the biological potency of the compounds (12, 13), and the levels of the nuclear TRs correlate well with the developmental and tissue-specific effects of T3 in most cases (14, 15). Thus, alth...

Thyroid hormone receptors : multiple forms, multiple possibilities

Introduction DESPITE the fact that the clinical and biological importance of the thyroid hormones have been recognized for approximately 100 yr (1–3), until recently our understanding of the biological effects of these hormones has been largely descriptive and based on a catalog of effects observed to accompany an excess or deficiency of these hormones. In the past 15 yr, however, there has been substantial progress in defining the molecular basis of thyroid hormone action at the nuclear level. In the mid-60s Tata and colleagues (4, 5) first proposed that the nucleus might be the target for thyroid hormone action. This inference was based on sequential measurements of thyroid hormone effects in thyroidectomized animals treated with T4. Nevertheless, the importance and uniqueness of this pathway were not fully appreciated (6). Full understanding of the nuclear site of initiation of thyroid hormone action was dependent on the recognition that T3 was the active hormone, that T4 largely served as a precursor ...

Advances in our understanding of thyroid hormone action at the cellular level.

Abnormal zinc metabolism in type II diabetes mellitus

Although thyroxine (T4) 5'-deiodinase activity is diminished in liver homogenates of starved rats, no information is available regarding the effect of starvation on net T4 to triiodothyronine (T3) conversion in the intact rat. It appeared important to clarify this relationship since rat liver homogenates are widely used as a model for the study of the factors responsible for reduced circulating T3 in chronically ill and calorically deprived patients. In contrast to the expected selective decrease in circulating T3 levels in calorically restricted humans due to diminished T4 to T3 conversion, 5 d of starvation of two groups of male Sprague-Dawley rats resulted, paradoxically, in a greater decrease in serum T4 than in serum T3 levels. Kinetic studies show that starvation is associated with no change in the metabolic clearance rate (MCR) of T3, a 20% increase in the MCR of T4, a 67% reduction in turnover rate of T4, but only a 58% reduction in the turnover rate of T3. Moreover, in the first group of rats studied, direct chromatographic analysis of the isotopic composition of total body homogenates after the injection of 125I-T4 showed that 21.8% of T4 is converted to T3 in control rats and 28.8% in starved rats, suggesting that virtually all extrathyroidal T3 in starved and control rats is derived from the peripheral conversion of T4, and that there is little or no direct thyroidal secretion of T3. Our findings strongly point to a reduced thyroidal secretion of T4 as the primary cause of the observed reduction in circulating T3. Since the mechanisms leading to reduced levels of plasma T3 differ in humans and rats, it may be important to reexamine the use of liver homogenate preparations as models for study of the pathogenesis of the "low T3 syndrome" in humans.

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Decreased serum triiodothyronine in starving rats is due primarily to diminished thyroidal secretion of thyroxine.

We have studied the effect of glucagon on the expression of a triiodothyronine (T3) and carbohydrate-inducible mRNA sequence (mRNA-S14) in rat liver that undergoes a threefold diurnal variation (peak, 2200 h; nadir, 0800 h). Glucagon injection into euthyroid rats (25 micrograms/100 g body wt i.p., three doses at 15-min intervals) during the nocturnal plateau of mRNA-S14 caused a monoexponential disappearance of this sequence (t1/2, 90 min) accompanied by a 90% reduction in the transcriptional rate in a nuclear run-off assay, indicative of a near total reduction of synthesis. This effect was markedly attenuated in rats treated with T3 (200 micrograms/100 g body wt i.p.) 24 h before glucagon injection. When T3 was given 15 min after glucagon, the glucagon-initiated decline in mRNA-S14 was reversed within 90 min, suggesting a rapid interaction between the two hormones in the evening. Curiously, administration of T3 alone at this hour did not affect a significant increase in mRNA-S14. At 0800 h, however, T3 caused the expected brisk induction of this sequence, whereas glucagon was without effect. In essence, glucagon affected mRNA-S14 synthesis only in the evening, while T3 increased levels of this sequence above the baseline only in the morning. T3, however, reversed the effect of prior glucagon injection at night. The observed alterations in hormonal responsivity could underly the diurnal variation of mRNA-S14 expression. Moreover, the data suggest the hypothesis that T3 may act on S14 gene expression by antagonizing factors that inhibit its transcription.

/pdf/opposing-effects-of-glucagon-and-triiodothyronine-on-the-1ocs24p7gh.pdf

Opposing effects of glucagon and triiodothyronine on the hepatic levels of messenger ribonucleic acid S14 and the dependence of such effects on circadian factors.

We have analyzed the factors responsible for the circadian variation in rat hepatic mRNA-S14. Regulation of this sequence, which is found in lipogenic tissues and encodes a protein (S14) believed to be associated with fatty acid synthesis, is an excellent model of the interaction of thyroid hormone and dietary factors at the hepatocellular level. The mRNA exhibits a 3-fold diurnal variation (peak, approximately 2000 h; nadir, 0800 h) in ad libitum feeding rats on a 12-h light, 12-h dark photoschedule. We studied the effects of the photoschedule, periodic food intake, hypophysectomy, and induction by thyroid hormone (T3) on the mRNA-S14 rhythm. Adaptation to feeding restricted to either light or dark periods for 15 days did not greatly affect the diurnal rhythm. Photoreversal resulted in a 180 degrees phase shift, whereas the rhythm persisted in the presence of constant light. Oscillation continued around a higher baseline after a receptor-saturating dose of T3 in both normal and hypophysectomized rats. Our results indicate primary entrainment of the mRNA-S14 diurnal rhythm to the photoperiod, rather than to periodic food intake. Moreover, the circadian regulatory signal, which probably originates in the central nervous system, appears capable of antagonizing a maximal T3-inductive stimulus and does not originate in the pituitary gland. Persistence of the oscillation in constant light rules out circulating melatonin as the mediator. Synchronization of the rhythm by the photoschedule suggests that neuroendocrine factors are important determinants of rhythmic changes in hepatic gene expression.

W B Kinlaw

Papers

Advances in our understanding of thyroid hormone action at the cellular level.

Abnormal zinc metabolism in type II diabetes mellitus

Decreased serum triiodothyronine in starving rats is due primarily to diminished thyroidal secretion of thyroxine.

Opposing effects of glucagon and triiodothyronine on the hepatic levels of messenger ribonucleic acid S14 and the dependence of such effects on circadian factors.

Diurnal variation in hepatic expression of the rat S14 gene is synchronized by the photoperiod.