leptin and Euthyroid-Sick-Syndromes

The mechanisms behind the changes in serum triiodothyronine (T(3)), thyroxine (T(4)) and TSH that occur in the non-thyroidal illness syndrome (NTIS) are becoming clearer. Induction of a central hypothyroidism occurs due to a diminution in hypothalamic thyrotropin-releasing hormone. This can be signalled by a decrease in leptin caused by malnutrition and possibly a localised increase in hypothalamic T(3) catalyzed by altered expression of hypothalamic iodothyronine deiodinases D2 and D3. Data from D1 and D2 knockout mice suggest that these enzymes may have little contribution to the low serum T(3) found in acute illness. The decline in serum T(3) and T(4) in models of acute illness precedes the fall in hepatic D1, suggesting that much of the initial fall in these hormones may be attributable to an acute phase response giving rise to a reduction in the thyroid hormone binding capacity of plasma. When measured by reliable methods, changes in serum free T(4) and free T(3) are modest in comparison to the fall seen in total thyroid hormone. Thyroid hormone transporter expression is up-regulated in many models of the NTIS, thus if diminished tissue uptake of hormone occurs in vivo, it is likely to be the result of impaired transporter function caused by diminished intracellular ATP or plasma inhibitors of transporter action. In man, chronic illness leads to an upregulation of thyroid hormone receptor (THR) expression at least in liver and renal failure. In contrast, human and animal models of sepsis and trauma indicate that expression of THRs and their coactivators are decreased in acute illness.

Topics: Animals; Disease Models, Animal; Euthyroid Sick Syndromes; Hormone Replacement Therapy; Humans; Iodide Peroxidase; Leptin; Mice; Mice, Knockout; Receptors, Thyroid Hormone; Thyroid Hormones; Thyrotropin-Releasing Hormone

Both starvation and critical illness are hallmarked by changes in circulating thyroid hormone parameters with typically low T(3) concentrations in the absence of elevated TSH. This constellation is labeled nonthyroidal illness (NTI). Because critical illness is often accompanied by anorexia and a failing gastrointestinal tract, the NTI of critical illness may be confounded by nutrient deficiency. In an experimental study performed in a rabbit model, we investigated the impact of nutritional deficit on the NTI of sustained critical illness. Critically ill rabbits were randomly allocated to parenteral nutrition (moderate dose 270 kcal/d) initiated on the day after injury and continued until d 7 of illness or to infusing a similar volume of dextrose 1.4% (14 kcal/d). With early parenteral nutrition during illness, the decrease in serum T(3) observed with fasting was reversed, whereas the fall in T(4) was not significantly affected. The rise in T(3) with parenteral nutrition paralleled an increase of liver and kidney type-1 and a decrease of liver and kidney type-3 deiodinase activity and an increase in circulating and central leptin. Nuclear staining of constitutive androstane receptor and its downstream expression of sulfotransferases were reduced in fasting ill animals. TRH expression in the hypothalamus was not different in fasted and fed ill rabbits, although circulating TSH levels were higher with feeding. In conclusion, in this rabbit model of sustained critical illness, reduced circulating T(3), but not T(4), levels could be prevented by parenteral nutrition, which may be mediated by leptin and its actions on tissue deiodinase activity.

Topics: Animals; Constitutive Androstane Receptor; Critical Illness; Disease Models, Animal; Dithiothreitol; Euthyroid Sick Syndromes; Gene Expression Regulation; Hypothalamo-Hypophyseal System; Iodide Peroxidase; Leptin; Male; Nutrition Disorders; Parenteral Nutrition Solutions; Rabbits; Random Allocation; Receptors, Cytoplasmic and Nuclear; Thyroid Gland; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

During illness, thyroid parameters undergo acute changes, which are known as non-thyroidal illness syndrome, the cause of which has not been elucidated. In vitro and in vivo data demonstrate that leptin regulates the expression of thyrotropin-releasing hormone (TRH)-mRNA in the paraventricular nucleus as well as the secretion of thyrotropin (TSH) in response to fasting in humans and animals. Moreover, in healthy adults, TSH and leptin have almost identical circadian rhythms. Our aim was to investigate the secretion of leptin and TSH, and their probable interaction, during the acute stress that is induced by surgery.. We studied 18 severely obese but otherwise healthy men. All participants were admitted to the hospital in the morning after an overnight fast. On the following day, 14 of the participants underwent bariatric surgery at 0900. The remaining four participants did not undergo surgery and served as controls. Serum samples to measure the levels of TSH and leptin were collected from all participants, as follows: upon admission to the hospital (baseline values) and on the following day at 0900 and every 10 min, thereafter for 9 h.. The serum TSH increased during the first hour after skin incision (si) and then decreased gradually throughout the rest of the observation period. In contrast, during the first hour after si, the leptin levels remained unaltered. The leptin levels then decreased and reached a nadir at 4 h and 10 min post si after which they remained constant for approximately 1 h. Thereafter, while TSH continued to decrease, leptin started to increase and reached baseline values at 9 h post si. In control subjects, the TSH and leptin profiles seemed parallel each other.. During acute surgical stress, the secretion of TSH and leptin in severely obese men is asynchronous and causality could not be proven.

Topics: Adult; Bariatric Surgery; Circadian Rhythm; Euthyroid Sick Syndromes; Fasting; Humans; Leptin; Male; Obesity, Morbid; Thyrotropin; Time Factors

Topics: Animals; Arcuate Nucleus of Hypothalamus; Critical Illness; Disease Models, Animal; Euthyroid Sick Syndromes; Fasting; Gene Expression; Homeostasis; Humans; Hypothalamus; Intensive Care Units; Leptin; Mice; Rabbits; Rats; Syndrome; Thyroid Hormones

Leptin is an adipose tissue-secreted hormone, which decreases caloric intake and increases energy expenditure. Some effects of leptin on energy balance seem to be mediated by the hypothalamo-pituitary-thyroid axis. The present study was designed to ascertain whether i) rat thyroid gland expresses the long form of leptin receptor (ObRb) and ii) the prolonged leptin administration (daily subcutaneous injections of 24 nmol/kg leptin for 6 consecutive days) affects thyroid-gland function in this species. Coupled RT-PCR, Western blotting and immunocytochemical findings demonstrated the expression of Ob-Rb as mRNA and protein in the thyroid gland of normal rats. Prolonged leptin treatment raised thyroid-gland weight, and morphometry showed that in the enlarged glands the volume of the follicle epithelium was increased, while that of colloid remained unchanged, so that epithelium/colloid ratio was markedly lowered. In leptin-administered rats, the plasma concentration of TSH was decreased, while those of thyroid hormones (free T3 and total T4) were notably raised. Collectively, these findings suggest that systemically administered leptin stimulates growth and secretion of thyroid gland in the rat, through a direct mechanism involving Ob-Rb.

Topics: Animals; Blotting, Western; Carrier Proteins; Euthyroid Sick Syndromes; Female; Immunoenzyme Techniques; Leptin; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Thyroid Gland

Topics: Euthyroid Sick Syndromes; Female; Humans; Leptin; Male; Proteins; Thyrotropin; Triiodothyronine