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      Arcuate Nucleus Ablation Prevents Fasting-Induced Suppression of ProTRH mRNA in the Hypothalamic Paraventricular Nucleus

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          Fasting results in reduced thyroid hormone levels and inappropriately low or normal thyroid-stimulating hormone (TSH), partly attributed to central hypothyroidism due to suppression of pro TRH gene expression in the hypothalamic paraventricular nucleus. Recently, we demonstrated that the systemic administration of leptin to fasting animals restores plasma thyroxine (T<sub>4</sub>) and proTRH mRNA in the paraventricular nucleus to normal, suggesting that the fall in circulating leptin levels during fasting acts as a signal to hypophysiotropic neurons in the paraventricular nucleus to reset the set point for feedback regulation of pro TRH mRNA by thyroid hormone. To determine whether the effect of fasting on the hypothalamic-pituitary-thyroid axis is mediated through the hypothalamic arcuate nucleus where leptin receptors are highly concentrated, we studied the effect of fasting and exogenous leptin administration on plasma thyroid hormone levels and proTRH mRNA concentration in the paraventricular nucleus in adult animals with arcuate nucleus lesions induced pharmacologically by the neonatal administration of monosodium L-glutamate (MSG). In normal animals, fasting reduced plasma T<sub>4</sub> and TSH levels and the concentration of proTRH mRNA in the hypothalamic paraventricular nucleus. In contrast, neither fasting nor leptin administration to fasting MSG-treated animals had any significant effects on plasma thyroid hormone and TSH levels and proTRH mRNA in the paraventricular nucleus. These studies suggest that during fasting, the arcuate nucleus is essential for the normal homeostatic response of the hypothalamic-pituitary-thyroid axis and may serve as a critical locus to mediate the central actions of leptin on proTRH gene expression in the paraventricular nucleus.

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          The role of neuropeptide Y in the antiobesity action of the obese gene product.

          Recently Zhang et al. cloned a gene that is expressed only in adipose tissue of the mouse. The obese phenotype of the ob/ob mouse is linked to a mutation in the obese gene that results in expression of a truncated inactive protein. Human and rat homologues for this gene are known. Previous experiments predict such a hormone to have a hypothalamic target. Hypothalamic neuropeptide Y stimulates food intake, decreases thermogenesis, and increases plasma insulin and corticosterone levels making it a potential target. Here we express the obese protein in Escherichia coli and find that it suppresses food intake and decreases body weight dramatically when administered to normal and ob/ob mice but not db/db (diabetic) mice, which are thought to lack the appropriate receptor. High-affinity binding was detected in the rat hypothalamus. One mechanism by which this protein regulated food intake and metabolism was inhibition of neuropeptide-Y synthesis and release.
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            Melanocortin receptors in leptin effects.

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              Hormonal and metabolic adaptations to fasting in monosodium glutamate-obese rats.

              The effect of fasting on hormonal and metabolic variables was evaluated in normal rats and in rats with obesity induced by neonatal treatment with monosodium glutamate (MSG). The hyperinsulinemia of the fed obese rats was reversed by fasting. Plasma corticosterone was also high in the fed obese and decreased to levels similar to fed controls, while it increased in the latter group during fasting. In contrast, thyroid hormone levels decreased in controls but increased in the obese rats in response to fasting. The fed obese group had lower carcass protein and higher carcass lipid contents than controls. In response to fasting, the decrements of the initial amount of both protein and fat were lower in MSG than in controls. Fasting induced a sustained increase in plasma free fatty acids only in the obese rats, although a single 100 mumol.l-1 dose of norepinephrine stimulated in vitro glycerol release more pronouncedly in epididymal adipocytes from control than obese rats. The results indicate that MSG-obese rats were able to mobilize fat stores during prolonged fasting. The high availability of lipid fuels and the sharp and sustained decrease in circulating corticosterone in the MSG group were probably important in diminishing body protein consumption during fasting.

                Author and article information

                S. Karger AG
                August 1998
                21 August 1998
                : 68
                : 2
                : 89-97
                Department of Medicine, Division of Endocrinology, a New England Medical Center, b Beth Israel-Deaconess Medical Center, andDepartments of c Community Health and d Neuroscience, Tufts University School of Medicine, Boston, Mass., e Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, Mass., USA
                54354 Neuroendocrinology 1998;68:89–97
                © 1998 S. Karger AG, Basel

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                Page count
                Pages: 9
                Regulation of Hypothalamic Neurons


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