Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by type 2 deiodinase (D2). Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here, we report that D2 is a cargo protein in ER Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92-to-Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR). Ala92-D2 accumulated in the trans-Golgi and generated less T3, which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more, and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2.

The hypothalamic-pituitary-thyroid axis is affected by acute exercise, but the mechanisms underlying thyroid function changes after exercise remain to be defined. The aim of this study was to elucidate the effects of a session of acute exercise on the treadmill at 75% of maximum oxygen consumption on thyroid function of rats. Male Wistar rats were divided into five groups: control (without exercise), and killed immediately after (0 min) or 30, 60, and 120 min after the end of the exercise session. A significant increase in serum tri-iodothyronine (T 3 ) occurred immediately after the exercise, with a gradual decrease thereafter, so that 120 min after the end of the exercise, serum T 3 was significantly lower than that in controls. Total thyroxine (T 4 ) increased progressively reaching values significantly higher than that in the control group at 120 min. T 3 /T 4 ratio was significantly decreased 60 and 120 min after the exercise, indicating impaired T 4 -to-T 3 conversion. Liver type 1 deiodinase activity (D1) significantly decreased at 60 and 120 min, while pituitary D1 increased progressively from 30 to 120 min after the exercise, and thyroid D1 was increased only immediately after the end of the exercise. Brown adipose tissue (BAT) type 2 deiodinase activity (D2) was significantly lower at 30 min, but pituitary D2 remained unchanged. No change in serum thyrotropin was detected, while serum corticosterone was significantly higher 30 min after the exercise. Our results demonstrate that decreased liver D1 and BAT D2 might be involved in the decreased T 4 -to-T 3 conversion detected after an exercise session on the treadmill.

Type 2 deiodinase (D2) converts the prohormone thyroxine (T4) to the metabolically active molecule 3,5,3′-triiodothyronine (T3), but its global inactivation unexpectedly lowers the respiratory exchange rate (respiratory quotient [RQ]) and decreases food intake. Here we used FloxD2 mice to generate systemically euthyroid fat-specific (FAT), astrocyte-specific (ASTRO), or skeletal-muscle-specific (SKM) D2 knockout (D2KO) mice that were monitored continuously. The ASTRO-D2KO mice also exhibited lower diurnal RQ and greater contribution of fatty acid oxidation to energy expenditure, but no differences in food intake were observed. In contrast, the FAT-D2KO mouse exhibited sustained (24 h) increase in RQ values, increased food intake, tolerance to glucose, and sensitivity to insulin, all supporting greater contribution of carbohydrate oxidation to energy expenditure. Furthermore, FAT-D2KO animals that were kept on a high-fat diet for 8 weeks gained more body weight and fat, indicating impaired brown adipose tissue (BAT) thermogenesis and/or inability to oxidize the fat excess. Acclimatization of FAT-D2KO mice at thermoneutrality dissipated both features of this phenotype. Muscle D2 does not seem to play a significant metabolic role given that SKM-D2KO animals exhibited no phenotype. The present findings are unique in that they were obtained in systemically euthyroid animals, revealing that brain D2 plays a dominant albeit indirect role in fatty acid oxidation via its sympathetic control of BAT activity. D2-generated T3 in BAT accelerates fatty acid oxidation and protects against diet-induced obesity.

The type 2 deiodinase (D2) activates the prohormone T4 to T3. D2 is expressed in skeletal muscle (SKM), and its global inactivation (GLOB-D2KO mice) reportedly leads to skeletal muscle hypothyroidism and impaired differentiation. Here floxed Dio2 mice were crossed with mice expressing Cre-recombinase under the myosin light chain 1f (cre-MLC) to disrupt D2 expression in the late developmental stages of skeletal myocytes (SKM-D2KO). This led to a loss of approximately 50% in D2 activity in neonatal and adult SKM-D2KO skeletal muscle and about 75% in isolated SKM-D2KO myocytes. To test the impact of Dio2 disruption, we measured soleus T3 content and found it to be normal. We also looked at the expression of T3-responsive genes in skeletal muscle, ie, myosin heavy chain I, α-actin, myosin light chain, tropomyosin, and serca 1 and 2, which was preserved in neonatal SKM-D2KO hindlimb muscles, at a time that coincides with a peak of D2 activity in control animals. In adult soleus the baseline level of D2 activity was about 6-fold lower, and in the SKM-D2KO soleus, the expression of only one of five T3-responsive genes was reduced. Despite this, adult SKM-D2KO animals performed indistinguishably from controls on a treadmill test, running for approximately 16 minutes and reached a speed of about 23 m/min; muscle strength was about 0.3 mN/m·g body weight in SKM-D2KO and control ankle muscles. In conclusion, there are multiple sources of D2 in the mouse SKM, and its role is limited in postnatal skeletal muscle fibers.

Ovariectomy leads to significant increase in body weight, but the possible peripheral mechanisms involved in weight gain are still unknown. Since exercise and thyroid hormones modulate energy balance, we aimed to study the effect of swimming training on body weight gain and brown adipose tissue (BAT) type 2 iodothyronine deiodinase responses in ovariectomized (Ox) or sham-operated (Sh) rats. Rats were submitted to a period of 8-week training, 5 days per week with progressive higher duration of exercise protocol. Swimming training program did not totally prevent the higher body mass gain that follows ovariectomy in rats (16.5% decrease in body mass gain in Ox trained rats compared to 22% decrease in sham operated trained animals, in relation to the respective sedentary groups), but training of Ox animals impaired the accumulation of subcutaneous fat pads. Interestingly, swimming training upregulates pituitary type 1 (p<0.001 vs. all groups) and BAT type 2 iodothyronine deiodinases (p<0.05 vs. ShS and OxS) in sham operated but not in Ox rats, indicating an impaired pituitary and peripheral response to exercise in Ox rats. However, BAT mitochondrial O2 consumption significantly increased by swimming training in both sham and Ox groups, indicating that Ox BAT mitochondria responds normally to exercise stimulus, but does not result in a significant reduction of body weight. In conclusion, increased body mass gain produced by Ox is not completely impaired by 8 weeks of high intensity physical training, showing that these animals sustain higher rate of body mass gain independent of being submitted to higher energy expenditure.

The use of anabolic-androgenic steroids to improve physical performance or appearance has increased notably. The doses used are 10-to 100-fold higher than the therapeutic dose (TD), and this abuse can cause several side effects. Glucose metabolism is significantly affected by anabolic-androgenic steroid abuse, but studies about glycemic regulation during fasting are scarce. There are some evidences showing that testosterone can antagonize glucocorticoids action, which are crucial to glucose production during fasting. Thus, the aim of this study was to determine the impact of supraphysiological doses (SDs) of nandrolone decanoate (DECA) on rat glucose metabolism during fasting. Male Wistar rats were treated with i.m. injections of vehicle, a low TD (0.016 mg/100 g b.w.-TD group) or a high SD (1 mg/100 g b.w.-SD group) of DECA, once a week for 8 weeks. After 12 h fasting, we evaluated glucose and pyruvate tolerance tests, liver glycogen content, serum levels of gluconeogenic substrates, insulin and corticosterone, glucose uptake and hexokinase (HK) activity in skeletal muscle, and the adrenal catecholamine content. SD group had increased serum insulin levels and a blunted response to insulin regarding glucose uptake in skeletal muscle. Fasting serum glucose decreased significantly in SD group, as well as the pyruvate tolerance test and liver glycogen content. Moreover, serum levels of glycerol were increased in SD group. Our data indicate that SDs of DECA exert effects on different regulatory points of glucose metabolism, resulting in defective gluconeogenesis and decreased skeletal muscle glucose uptake in response to insulin.

ResumoA deficiência de esteroides gonadais femininos acelera o ganho de massa corpórea, mas os possíveis mecanismos centrais e periféricos envolvidos no aumento da ingestão alimentar e no ganho de massa adiposa que ocorrem nessa condição são pouco conhecidos. Em modelos animais, tanto a falta quanto os defeitos na ação do estrogênio causam aumento da massa corpórea, demonstrando claramente um possível papel desse esteroide no sobrepeso pós-menopausa. Sabe-se que a obesidade e o sobrepeso estão associados a diversas comorbidades que podem levar à morte prematura. Portanto, desvendar os mecanismos relacionados ao ganho de massa corpórea é de grande relevância, assim como desenvolver estratégias que possam prevenir o seu estabelecimento. A regulação do balanço energético está associada ao controle da massa corpórea, sendo o exercício físico um importante modulador desse parâmetro homeostático. Porém, a influência do exercício físico sobre o ganho de massa corpórea durante a deficiência de estrogênio é controversa e depende do protocolo de exercício utilizado. Neste estudo, pretendemos revisar os achados que relacionam a deficiência de estrogênio ao ganho de massa corpórea em animais e seres humanos. Arq Bras Endocrinol Metab. 2009;53(3):310-7. Descritores Sobrepeso; exercício; estrogênio; menopausa; ovariectomia AbstRActFemale steroid hormones deficiency leads to a significant increase in body mass, but the possible central and peripheral mechanisms involved in increased food ingestion and fat accumulation in this situation are still unknown. In animal models, the specific lack of estrogen or its action produce progressive body mass gain, clearly demonstrating the possible role of this hormone in overweight after menopause. Obesity and overweight correspond to a relevant human health problem that can lead to premature death. Therefore unraveling the mechanisms underlying body mass gain is of great relevance, as well as the development of strategies to prevent its establishment. Energy balance regulation is associated with the control of body mass, and physical exercise is an important modulator of this homeostatic parameter. However, the influence of physical exercise in mass gain development during estrogen deficiency is controversial and depends on the exercise protocol used. In this study, we intend to review the data on the effects of estrogen deficiency on body mass gain in humans and animal models. 17β-estradiol (E2), estrona (E1) e estriol (E3). Desses, o 17β-estradiol é o principal esteroide em humanos que possui propriedades estrogênicas (1).A secreção dos hormônios gonadais é regulada pelo eixo hipotálamo-adeno-hipófise. Em resposta ao hormônio liberador de gonadotrofinas (GnRH), a hipófi-

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