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Miguel López,
Luis Varela,
María J Vázquez, Sergio Rodríguez-Cuenca,
Carmen R González,
Vidya R Velagapudi,
Donald A Morgan,
Erik Schoenmakers,
Khristofor Agassandian,
Ricardo Lage, [......],
Rubén Nogueiras,
David Carling,
Christopher Lelliott,
Rosalía Gallego,
Matej Oresic,
Krishna Chatterjee,
Asish K Saha,
Kamal Rahmouni,
Carlos Diéguez,
Antonio Vidal-Puig
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ABSTRACT: Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.
Nature medicine 09/2010; 16(9):1001-8. · 27.14 Impact Factor
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Miguel López,
Ricardo Lage,
Asish K Saha,
Diego Pérez-Tilve,
María J Vázquez,
Luis Varela,
Susana Sangiao-Alvarellos,
Sulay Tovar,
Kawtar Raghay, Sergio Rodríguez-Cuenca, [......],
Jesse Z Dong,
Michael Culler,
Mark W Sleeman,
Clara V Alvarez,
Rosalía Gallego,
Christopher J Lelliott,
David Carling,
Matthias H Tschöp,
Carlos Diéguez,
Antonio Vidal-Puig
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ABSTRACT: Current evidence suggests that hypothalamic fatty acid metabolism may play a role in regulating food intake; however, confirmation that it is a physiologically relevant regulatory system of feeding is still incomplete. Here, we use pharmacological and genetic approaches to demonstrate that the physiological orexigenic response to ghrelin involves specific inhibition of fatty acid biosynthesis induced by AMP-activated protein kinase (AMPK) resulting in decreased hypothalamic levels of malonyl-CoA and increased carnitine palmitoyltransferase 1 (CPT1) activity. In addition, we also demonstrate that fasting downregulates fatty acid synthase (FAS) in a region-specific manner and that this effect is mediated by an AMPK and ghrelin-dependent mechanisms. Thus, decreasing AMPK activity in the ventromedial nucleus of the hypothalamus (VMH) is sufficient to inhibit ghrelin's effects on FAS expression and feeding. Overall, our results indicate that modulation of hypothalamic fatty acid metabolism specifically in the VMH in response to ghrelin is a physiological mechanism that controls feeding.
Cell metabolism 06/2008; 7(5):389-99. · 17.35 Impact Factor
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ABSTRACT: Brown adipose tissue (BAT) thermogenesis is inhibited during late-pregnancy and lactation in the rat. However, scarce information concerning BAT functionality during mid-pregnancy is available. The aim of this work was to investigate uncoupling proteins and leptin expression during placentation in rat BAT as well as other key parameters in the thermogenic function of the tissue. BAT mitochondrial content was found to be reduced 50% in 11 and 13 day pregnant rats as compared to nonpregnant controls, although uncoupling protein 1 (UCP1) content was not modified. Furthermore, UCP3 mRNA levels were found to be highly increased during this period. beta3-adrenergic receptor (beta3-AR) decreased expression resulted in a higher alpha2/beta3 ratio. Finally, leptin mRNA levels in BAT were found to be 3-fold up-regulated in pregnant animals. In conclusion, we show the existence of profound changes in thermogenic features in BAT during gestational days 11 and 13, pointing to the importance of this tissue during mid-pregnancy.
Cellular Physiology and Biochemistry 02/2005; 15(5):203-10. · 2.86 Impact Factor
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ABSTRACT: To investigate the possible existence of a gender dimorphism in the morphology and functionality of brown adipose tissue (BAT) mitochondrial subpopulations, we obtained three mitochondrial fractions - heavy, medium and light - by differential centrifugation. Electron microscopic analysis was carried out and mitochondrial protein content, cytochrome c oxidase and ATP synthase activities, mitochondrial DNA content and UCP1 protein levels were measured in each mitochondrial fraction. Female rats showed a greater mitochondrial size than males, with a different distribution pattern of the subpopulations. These differences were accompanied by higher oxidative and thermogenic capacities and a higher protein content in female rat BAT. This tissue also showed a greater tendency to respiratory chain uncoupling, as well as a close coordination between the oxidative, phosphorylative and thermogenic processes. These differences were found in the heavy subpopulation but not in the light one. Our results demonstrate that female rat BAT shows a highly differentiated mitochondrial pool, with the heavy mitochondrial subpopulation as the main responsible for the greater thermogenic activity of this tissue. In addition, it seems that there is a differential regulation of the mitochondrial growth cycle between genders in BAT, which leads to enhanced thermogenic capacity in female rat mitochondria.
Life Sciences 02/2005; 76(10):1147-58. · 2.53 Impact Factor
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ABSTRACT: To investigate the effects of short-term (15 days) cafeteria-diet feeding on the expression of alpha- and beta-adrenergic receptors (AR) and its association with lipolytic stimulation in isolated retroperitoneal white adipocytes.
Six female and 6 male Wistar rats (4 weeks old) were fed a cafeteria diet plus standard diet for 15 days. The remaining 12 age- and sex-matched rats received a standard diet only. White retroperitoneal adipose tissue was isolated and used for the determination of both alpha(2) and beta-AR expression and for in vitro studies of lipolytic activity.
In female control rats, we found higher lipolytic capacities located at the postreceptor level and a lower alpha(2)/beta(3)-AR ratio than male rats. Cafeteria-diet feeding for 15 days decreased lipolytic activity in both male and female rats and altered the alpha(2A)- and beta(3)-AR protein levels with an increase of alpha(2A)-AR in males and a beta(3)-AR decrease in females.
Our results indicate that a 15-day cafeteria-diet feeding induced an increase in the alpha(2)/beta(3)-AR balance and impaired adipose tissue lipolytic activity, which was higher in males and may contribute to the development of increased fat mass. The higher functionality of alpha(2)-AR, together with the minor role developed by beta(3)-AR and lower lipolytic capacities located at the postreceptor level in cafeteria-diet-fed male rats compared with female rats, may be responsible for the gender-dependent differences observed in this study.
Obesity research 05/2002; 10(4):296-305. · 4.95 Impact Factor
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ABSTRACT: Gender-related differences in the brown adipose tissue (BAT) response to overfeeding rats on a cafeteria diet were studied by assessing the balance between the expression of #-adrenoceptors (ş-, Š-, š-AR) and ŌA-AR and their relation to the expression of uncoupling proteins (UCP1, UCP2, UCP3). Cafeteria diet feeding for 15 days, which involved a similar degree of hyperphagia in both sexes, led to a greater body weight excess in females than in males and a lower activation of thermogenesis. Gender-related differences were found for different adrenoceptor expression and protein levels, which might explain, in part, sex differences in the thermogenic parameters. The lower expression of ŌA-AR in females than in males could be responsible for the higher expression of UCP1 and thermogenic capacity under non-hyperphagic conditions. However, in a situation of high adrenergic stimulation - as occurs with overfeeding - as there is a preferential recruitment of the š-AR by noradrenaline compared with other adrenergic receptors, the higher levels of š-AR in males rats than in females could be responsible for the greater thermogenic capacity and the lesser weight gain in males. Thus, the Ō/š balance in BAT could be a key in the thermogenic control.
Pflügers Archiv - European Journal of Physiology 05/2001; 442(3):396-403. · 4.46 Impact Factor
