RESUMO
Glucocorticoid (GC) excess promotes adipose tissue accumulation, and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) plays an important role in the local amplification of GC. Therefore, in this study, we investigated the effects of carbenoxolone (CBX), an 11ß-HSD1 inhibitor, on morphological changes in visceral fat, and the expression of genes involved in adipogenesis and lipid metabolism in high-fat (HF) diet-fed mice. Mice were fed a HF diet from 5 weeks of age. At 10 weeks of age, the mice received an intraperitoneal injection of CBX or vehicle every day for 2 weeks. CBX decreased body weight and visceral fat mass, and improved insulin sensitivity in HF-fed mice. This was accompanied by reduced adipocyte size and a decrease in large-sized adipocytes in visceral fat. The expression of adipogenesis (PPARγ and C/EBPα), glucose transport (GLUT4) and lipid metabolism (LPL, ATGL, and HSL)-related genes were suppressed in CBX mice. CBX treatment induced beneficial morphological changes in visceral fat and decreased the expression of adipogenesis, glucose transport and lipid metabolism-related genes. These findings reveal a potential mechanism underling the effects of CBX on reduced fat accumulation and improved insulin sensitivity.
Assuntos
Adipogenia/genética , Tecido Adiposo/anatomia & histologia , Tecido Adiposo/metabolismo , Carbenoxolona/farmacologia , Regulação para Baixo/efeitos dos fármacos , Glucose/metabolismo , Metabolismo dos Lipídeos/genética , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Animais , Transporte Biológico/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Regulação para Baixo/genética , Comportamento Alimentar/efeitos dos fármacos , Teste de Tolerância a Glucose , Insulina/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Intrauterine growth restriction (IUGR) is associated with a substantially greater incidence of metabolic syndrome in adulthood. Animal studies have shown that IUGR offspring are hyperphagic during the early postnatal period and therefore exhibit obesity. The molecular mechanisms underlying food intake regulation in the gastrointestinal tract have not been clarified in IUGR. In the present study, we utilized a rat model of IUGR by restricting the food intake of the mother (50% of the normal intake, ad libitum; FR group) from day 7 of gestation until delivery. Pups from undernourished mothers were fostered by control mothers. We examined the food intake and assessed the gene expressions of ghrelin, peptide YY (PYY), and cholecystokinin (CCK) in the alimentary tract of male newborns (postnatal day1) and adult offspring (age, 7 months). Compared to the offspring whose mothers received the standard diet ad libitum (CON offspring), FR offspring were hyperphagic from the weaning time until the end of the experiment, and resulted in a heavier final weight. Both newborn and adult FR offspring had higher ghrelin gene expression in the stomach and higher ghrelin plasma levels than did the controls. Although the gastrointestinal gene expressions and plasma levels of the anorexic peptides, PYY and CCK, were elevated in the FR newborns, they decreased in the FR adults. Our findings suggest that the altered gene expressions of orexigenic and anorexigenic gut peptides in the gastrointestinal tract in the maternal undernutrition-induced IUGR offspring provide a potential mechanism to explain hyperphagia and obesity seen in these offspring.
Assuntos
Colecistocinina/genética , Retardo do Crescimento Fetal/genética , Trato Gastrointestinal/metabolismo , Grelina/genética , Hiperfagia/genética , Peptídeo YY/genética , Regulação para Cima , Adulto , Animais , Animais Recém-Nascidos , Peso Corporal , Colecistocinina/sangue , Modelos Animais de Doenças , Ingestão de Alimentos , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/fisiopatologia , Trato Gastrointestinal/crescimento & desenvolvimento , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Grelina/sangue , Humanos , Hiperfagia/sangue , Hiperfagia/fisiopatologia , Masculino , Peptídeo YY/sangue , Ratos , Ratos Sprague-DawleyRESUMO
Peroxisomal proliferator-activated receptors (PPARs) play an important role in the regulation of lipid metabolism. The aim of this study was to investigate the effects of a maternal high-fat (HF) diet on serum lipid concentration and PPAR gene expression in liver and adipose tissue in the early life of the rat offspring. Female Sprague-Dawley rats were fed either an HF or control (CON) diet 6 weeks before mating and throughout gestation and lactation. Blood and tissue samplings of male offspring were carried out at birth or weaning. Birth weights were similar and serum triglyceride (TG) and nonesterified fatty acid (NEFA) levels showed no significant difference between HF and CON newborns, despite greatly increased hepatic PPARα mRNA expression in the HF newborns (p<0.05). Both HF newborns and weanlings revealed significantly decreased hepatic PPARγ expression compared with controls (p<0.0001). Hepatic PPARα expression in the HF weanlings was reduced markedly compared with CON weanlings (p<0.0001) and showed a negative correlation with serum TG levels (r=-0.743, p<0.05). However, epididymal expression of PPARγ in the HF weanlings was upregulated significantly compared with controls (p<0.05) and demonstrated a positive correlation with epididymal fat mass (r=0.733, p<0.05). These were accompanied by obesity as well as a rise in serum TG by 79% (p<0.05) and NEFA concentration by 36% (p<0.05) in these HF weanlings. Our findings suggest that maternal HF diet leads to alterations in PPAR gene expression in the weanling offspring, which is associated with the disturbed lipid homeostasis.
Assuntos
Gorduras na Dieta/farmacologia , Lipídeos/sangue , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Feminino , Ratos , Ratos Sprague-DawleyAssuntos
Corticosteroides/uso terapêutico , Betametasona/uso terapêutico , Dermatite Atópica/sangue , Dermatite Atópica/tratamento farmacológico , Hidrocortisona/uso terapêutico , Imunoglobulina E/sangue , Administração Tópica , Corticosteroides/administração & dosagem , Betametasona/administração & dosagem , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Hidrocortisona/administração & dosagem , Lactente , Masculino , Estudos RetrospectivosRESUMO
AIM: Leptin is one of the factors affecting serum lipid profile. We investigated the association between serum lipids and leptin/leptin receptor (LEPR) gene polymorphisms in obese Japanese children. METHODS: One hundred and thirty-six obese children (99 males and 37 females, relative weight over than 20%) from 5 to 17 years of age were recruited from 10 institutes. Four known polymorphisms in leptin gene [(+19)A G, (-2548)G A, (-188)C A, (-633)C T] and four known polymorphisms in LEPR gene [Lys109Arg, Gln223Arg, Pro(G)1019Pro(A), Ser(T)343Ser(C)] were determined using polymerase chain reaction-restriction fragment length polymorphism-based analyses. RESULTS: No associations were found between leptin gene polymorphisms and serum lipid profile. On the other hand, Lys109Arg and Ser343Ser polymorphism in LEPR gene, but not Gln223Arg or Pro1019Pro, had significant relationships with serum lipid profile; lower total and low-density lipoprotein cholesterol levels in Arg109Arg homozygotes, and lower TG levels in Ser343Ser(C/C) homozygotes. In addition, LEPR gene also associated with relative weight; Arg109Arg homozygotes had higher relative weight and Ser343Ser(C/C) homozygotes had lower one. CONCLUSION: These results suggest that LEPR gene polymorphisms may partly contribute to serum lipid profile in obese children.
Assuntos
Leptina/genética , Lipídeos/sangue , Obesidade/genética , Polimorfismo Genético , Receptores para Leptina/genética , Adolescente , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Japão , Masculino , Obesidade/sangue , Reação em Cadeia da PolimeraseRESUMO
Autism spectrum disorders (ASD) are life-long neurodevelopmental conditions. The pathophysiology is poorly understood, and the clinical diagnosis can only be made through behavioural assessments. The prevalence of ASD has increased eight-fold over the last three decades. Paralleling this rise, research interest in the disorder has been accumulating, centering on two aspects: risk factors that would explain the increase in prevalence, and precursors that could predict an emergence of ASD prior to 2 years of age. As regard factors responsible for the increased prevalence, an increasing trend of low birthweight (4.2% in 1980 v. 9.6% in 2006 at Japan) and advanced paternal age at birth are potentially implicated. To explore these issues, and to yield an early diagnostic algorithm for ASD, the authors initiated the ongoing Hamamatsu Birth Cohort for Mothers and Children (HBC) in 2007. The strengths of the HBC include frequent, direct face-to-face assessments of all the participating mothers and children during the first 4 years of life (12 assessments); this depth of assessments will disclose subtle changes in the developmental domains of individuals with ASD, which might otherwise be overlooked. A total of 1200 pregnant women are to be recruited by the end of 2010. Assembled information comprises a range of variables related to the mother's characteristics and child development. The comprehensiveness of the HBC will provide an informative data source that will elucidate early trajectories of children with ASD in addition to revealing detailed, developmental properties of typically developing children.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Hormônio do Crescimento Humano/farmacologia , Fator de Crescimento Insulin-Like I/fisiologia , Regiões Promotoras Genéticas/efeitos dos fármacos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/biossíntese , Linhagem Celular , Humanos , Luciferases/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , beta-Galactosidase/metabolismoRESUMO
BACKGROUND: This study aimed to evaluate whether an ultrasound-guided technique can improve upon a landmark-guided technique in achieving femoral vein access in pediatric cardiac catheterization. METHODS: This study examined 87 consecutive subjects with a median age of 2 years (range, 1 month to 19 years) who had congenital or other heart disease. Femoral vein puncture was attempted using either an ultrasound-guided technique (US group, n = 43) or a landmark-guided technique (LM group, n = 44). The patients were assigned alternately to either an ultrasound- or landmark-guided group. Overall success and traumatic complication rates were compared between the two groups, as well as the influence of patient size and age. RESULTS: The overall rate of success in achieving femoral vein access did not differ between the two groups. Among the successful cases in the two groups, there were no significant differences in patient size or age. Inadvertent femoral artery puncture occurred with 3 (7%) of 43 patients in the US group and with 14 (31.8%) of 44 patients in the LM group, for a significantly higher complication rate in the LM group (p < 0.01). CONCLUSIONS: Ultrasound-guided access to the femoral vein minimizes the complication of inadvertent arterial puncture as compared with the landmark-guided approach.
Assuntos
Cateterismo Cardíaco/métodos , Veia Femoral/diagnóstico por imagem , Cardiopatias/diagnóstico , Punções/métodos , Ultrassonografia Doppler/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Reprodutibilidade dos TestesRESUMO
To determine the clinical relevance of in vitro drug chemoresistance in childhood acute myeloid leukemia, we used an MTT assay to test leukemic cells from 132 newly diagnosed children. Patients were diagnosed according to the French-American-British (FAB) classification as follows: M0 (n = 12), M1 (n = 16), M2 (n = 53), M4 (n = 17), M5 (n = 19) and M7 (n = 15). The results revealed that, compared to leukemic cells from complete-responders (n = 107), those from non-responders who failed induction therapy (n = 17) were 1.4 to 5.0 times more resistant in vitro to cytarabine (P = 0.005), melphalan (P = 0.003), etoposide (P = 0.011), L-asparaginase (P = 0.017), aclarubicin (P = 0.026) and dexamethasone (P = 0.039). For seven other drugs tested, the median lethal dose of 70% and leukemic cell survival of non-responders were higher than those of complete-responders, but the difference was not statistically significant. We sought correlations between FAB subtypes and in vitro drug resistance. Leukemias of the FAB M4 and M5 subtype were more sensitive to L-asparaginase (P = 0.01, P = 0.0036) than those of the FAB M2 subtype. FAB M5 leukemia was more sensitive to etoposide than were the FAB M2, M4 and M7 subtypes (P = 0.001, P = 0.034, P = 0.023, respectively). By contrast, FAB M5 leukemia was significantly more resistant to prednisolone and dexamethasone than were the FAB M0, M1, M2, M4 and M7 subtypes. We sought correlations between in vitro drug resistance and long-term clinical outcome, but found no associations in this case. These results suggest that in vitro resistance to cytarabine, melphalan, etoposide, L-asparaginase, aclarubicin and dexamethasone might represent factors that can predict response to the early course of therapy. Selecting an appropriate anti-cancer drug according to the FAB classification together with drug sensitivity testing may contribute to improved prognoses in childhood acute myeloid leukemia.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adolescente , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia Mieloide/classificação , Leucemia Mieloide/patologia , Masculino , Prognóstico , Indução de Remissão , Fatores de Tempo , Resultado do TratamentoAssuntos
Acarbose/uso terapêutico , Adenoma/etiologia , Embolização Terapêutica , Doença de Depósito de Glicogênio Tipo I/complicações , Hipoglicemiantes/uso terapêutico , Neoplasias Hepáticas/etiologia , Abdome/diagnóstico por imagem , Acarbose/administração & dosagem , Adenoma/diagnóstico , Adenoma/terapia , Adolescente , Cateterismo , Doença de Depósito de Glicogênio Tipo I/diagnóstico , Doença de Depósito de Glicogênio Tipo I/terapia , Humanos , Hipoglicemiantes/administração & dosagem , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Imageamento por Ressonância Magnética , Masculino , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
OBJECTIVE: To demonstrate sexual dimorphism in serum leptin levels not only during puberty, but also in childhood in Japan. DESIGN: Cross-sectional study. SETTING: Hamamatsu-Hokuen study in Japan. SUBJECTS: Body weight and height were measured in normal-weight Japanese children and adolescents (143 boys, 178 girls), and 161 boys and 129 girls whose percentage of overweight for the standard (%Wt) was more than+25%. Serum leptin levels were compared with %Wt. Subjects were divided into group 1 (6-10 y of age) and group 2 (11-15 y of age) according to their age. RESULTS: In overweight subjects, leptin was more highly correlated with %Wt in boys of group 2 (r=0.67, P<0.0001) than group 1 (r=0.32, P=0.004). In girls as well, a correlation coefficient was greater in group 2 (r=0.67, P<0.0001) than group 1 (r=0.44, P=0.0011). In normal-weight boys, there was no significant correlation between serum leptin and %Wt both in groups 1 and 2. On the contrary, statistical significance was demonstrated in the correlation between serum leptin and %Wt in group 1 (r=0.31, P=0.0019) and group 2 (r=0.35, P=0.0014) as well as in the total normal-weight girls (r=0.28, P=0.0011). CONCLUSIONS: It is suggested that sexual dimorphism is present in serum leptin levels, especially when compared to weight, as early as during childhood.
Assuntos
Peso Corporal/fisiologia , Leptina/sangue , Obesidade/sangue , Adolescente , Composição Corporal , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Puberdade/sangue , Caracteres SexuaisRESUMO
We describe the successful treatment of a 20-year-old patient with chronic granulomatous disease (CGD), by unrelated bone marrow transplantation (UBMT). The patient is relatively old compared to other CGD patients treated with BMT. He had had repeated serious infections from early childhood and was diagnosed as CGD, gp91-phox deficiency. Prolonged antibiotic-resistant pneumonitis worsened when the patient was 18 years old. In addition, he suffered Aspergillus osteomyelitis and acute renal failure due to amphotericin B. He received 94 granulocyte transfusions from 94 adult donors and the infections gradually improved. In September 1998, at 20 years of age, he underwent UBMT from an HLA 6 antigen-matched male donor, with CY and TBI conditioning. He received MTX and CsA as prophylaxis against GVHD. No serious complications occurred and rapid engraftment was achieved. Acute GVHD (grade 2, at day 19) and chronic GVHD (limited, at day 192) occurred. However, both were easily controlled. The patient is alive and well with no late rejection 26 months after UBMT.
Assuntos
Transplante de Medula Óssea/imunologia , Doença Granulomatosa Crônica/terapia , Osteomielite/etiologia , Pneumonia/etiologia , Adulto , Aspergilose/etiologia , Aspergilose/terapia , Terapia Combinada , Gerenciamento Clínico , Progressão da Doença , Intervalo Livre de Doença , Doença Granulomatosa Crônica/complicações , Antígenos HLA/imunologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Osteomielite/microbiologia , Osteomielite/terapia , Pneumonia/terapia , Doadores de TecidosAssuntos
Hiperplasia Suprarrenal Congênita/metabolismo , Metabolismo dos Lipídeos , Córtex Suprarrenal/metabolismo , Hiperplasia Suprarrenal Congênita/complicações , Animais , Colesterol/metabolismo , Feminino , Gônadas/metabolismo , Humanos , Lipidoses/etiologia , Fosfoproteínas , Placenta/metabolismo , Gravidez , Receptores de LDL/metabolismoRESUMO
Obesity during childhood is caused by both congenital and acquired causes. Obese children usually have family history, especially of their mothers. Identical twins have similar weight even if they are reared apart. In very rare cases of heritable obesity, genetic defects in leptin synthesis and its receptor, POMC, MC4 receptor, and prohormone converting enzyme have been reported. In addition, body weight of children and adolescents is related with their life styles, and the prevalence of obesity in recent years is higher than before probably due to changes in calorie intake and energy expenditure. Diagnosis of obesity is based on the assessment of overweight using BMI in most cases of adults. During childhood and adolescence, BMI can not be applied as in adults and its percentile values are useful for children. Percentage of overweight for the standard weight for height has been used as well to demonstrate over- or underweight in children and adolescents. Evaluation of fat volume and its distribution is essential for the precise diagnosis of obesity in children as well as adults.
Assuntos
Obesidade , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Obesidade/diagnósticoRESUMO
Corollosporine [(+/-)-3-hexyl-3,7-dihydroxy-1(3H)-isobenzofuran-1-one], an antibacterial metabolite of the marine fungus, Corollospora maritima, was synthesized by four different routes from 3-hydroxyphthalic anhydride or 2-methoxybenzoic acid as the starting material to verify its proposed structure.
Assuntos
Antibacterianos/síntese química , Ascomicetos/metabolismo , Anidridos Ftálicos/síntese química , Antibacterianos/química , Ascomicetos/química , Estrutura Molecular , Anidridos Ftálicos/químicaRESUMO
BACKGROUND: Mineralocorticoid hormones, which maintain electrolyte balance and blood pressure, are thought to be associated not only with the expression of renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), but also with that of intracellular mineralocorticoid receptors (MRs). The present study was designed to test whether the mineralocorticoid action of glucocorticoid corticosterone on renal MR is involved in the development of diabetes-associated hypertension by measuring the alterations of renal 11beta-HSD2. METHOD: We measured the mean systolic blood pressure, renal 11beta-HSD1, and mRNA levels in streptozotocin (STZ)-induced diabetic rats that received spironolactone, insulin, or no treatment, and in nondiabetic controls that received spironolactone. RESULTS: Four weeks after an injection of STZ, the renal 11beta-HSD2 and mRNA levels were significantly lower in diabetic rats than in control rats, and the mean systolic blood pressure was 14.8% higher in diabetic rats than in controls. Subcutaneous injections of spironolactone into diabetic rats for three weeks partially reversed the decrease in renal 11beta-HSD2 activity and gene expression, and prevented the mean systolic blood pressure elevation. Spironolactone treatment for one week also resulted in a significant reduction in mean systolic blood pressure during the development of diabetic hypertension. However, treatment with STZ did not significantly decrease the renal 11beta-HSD1 activity and mRNA expression, and spironolactone treatment did not exert a significant effect on this enzyme in STZ-induced diabetic rats. CONCLUSION: In the development of diabetes-induced hypertension, the effect of spironolactone on mean systolic blood pressure may be associated with the mineralocorticoid effects of corticosterone on renal MR, as well as an alteration of renal 11beta-HSD2 activity and its mRNA expression in insulin-dependent diabetic rats.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Espironolactona/farmacologia , Sístole/efeitos dos fármacos , 11-beta-Hidroxiesteroide Desidrogenases , Aldosterona/sangue , Animais , Corticosterona/sangue , Hidroxiesteroide Desidrogenases/genética , Hidroxiesteroide Desidrogenases/metabolismo , Masculino , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Receptores de Mineralocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/fisiologia , EstreptozocinaRESUMO
Placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) converts glucocorticoids to 11-keto-products and is believed to play an important role in protecting fetuses from higher maternal glucocorticoid levels. Recent reports have speculated that prenatal glucocorticoid exposure leads to fetal growth retardation and adult offspring hypertension and hyperglycemia. To investigate the effects of placental 11beta-HSD2 inhibition on glucose metabolism and the 11beta-HSD system in adult offspring, pregnant rats were treated with daily injections of carbenoxolone (CBX), an inhibitor of 11beta-HSD. The offspring of the maternal CBX treatment group showed reduced birth weight (treated v control, 5.6 +/- 0.5 v 6.4 +/- 0.4 g, P < .0001). In adult offspring of the maternal CBX treatment group, plasma hemoglobin A1c was significantly increased (7.3% +/- 1.8% v 4.8% +/- 0.3%, P < .01) and glucose intolerance was shown on the oral glucose tolerance test. The gene expression of hepatic 11beta-HSD1 and renal 11beta-HSD2 was decreased 87.6% (P < .05) and 52.3% (P < .01) in adult offspring of the maternal CBX treatment group, whereas renal 11beta-HSD1 was not significantly altered. The change in 11beta-HSD activity corresponded to the change in the gene expression. These results suggest that inhibition of placental 11beta-HSD2 causes growth retardation, glucose intolerance, and partial suppression of the 11beta-HSD system in the offspring.
Assuntos
Envelhecimento/metabolismo , Glucose/metabolismo , Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Hidroxiesteroide Desidrogenases/metabolismo , Placenta/enzimologia , 11-beta-Hidroxiesteroide Desidrogenases , Animais , Carbenoxolona/farmacologia , Inibidores Enzimáticos/farmacologia , Feminino , Hidroxiesteroide Desidrogenases/genética , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
To investigate the effects of thyroid hormone and testosterone on 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), we measured changes in hepatic 11beta-dehydrogenase activity and its mRNA levels in pubertal methimazole (MMI)-induced hypothyroid male rats following treatment with thyroxine ([T4] 50 microg/kg/d) or testosterone (250 microg/d) for 14 days. Hypothyroidism in male rats markedly reduced hepatic 11beta-HSD1 mRNA levels and serum testosterone concentrations (P < .01). Subcutaneous injection of T4 in the hypothyroid rats significantly (P < .01) increased hepatic 11beta-HSD1 mRNA to approximately normal levels and simultaneously increased serum testosterone levels. However, the same daily dose of T4 administered to castrated male hypothyroid rats for 14 days did not elevate hepatic 11beta-HSD1 activity. Treatment with testosterone for 14 days in castrated hypothyroid male rats and rats without gonadectomy significantly (P < .01) increased the enzyme activity without administration of T4. Variations in hepatic 11beta-HSD1 activity were demonstrated to be accompanied by changes in serum testosterone levels in the rats following alteration of the thyroid hormone state. These results suggest that the effect of T4 in increasing the subnormal 11beta-HSD1 gene expression in hypothyroid male rats is mediated by its ability to increase testosterone production in these rats, because in castrated hypothyroid rats, T4 does not elevate 11beta-HSD1 gene expression.