scholarly journals The Role of Hypothalamic Tri-Iodothyronine Availability in Seasonal Regulation of Energy Balance and Body Weight

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Michelle Murphy ◽  
Francis J. P. Ebling
Keyword(s):  
Body Weight ◽  
Thyroid Hormone ◽  
Energy Balance ◽  
Third Ventricle ◽  
Peripheral Circulation ◽  
Brain Cell ◽  
Monocarboxylate Transporter ◽  
Type Iii ◽  
Seasonal Regulation ◽  
The Brain

Seasonal cycles of body weight provide a natural model system to understand the central control of energy balance. Studies of such cycles in Siberian hamsters suggest that a change in the hypothalamic availability of thyroid hormone is the key determinant of annual weight regulation. Uptake of thyroid hormone into the hypothalamus from the peripheral circulation occurs largely through a specific monocarboxylate transporter expressed by tanycyte cells lining the third ventricle. Tanycytes are the principal brain cell type expressing type II and type III deiodinases, so they control the local concentrations of T4, T3, and inactive metabolites. Type III deiodinase mRNA in tanycytes is photoperiodically upregulated in short photoperiod. This would be expected to reduce the availability of T3 in the hypothalamus by promoting the production of inactive metabolites such as rT3. Experimental microimplantation of T3 directly into the hypothalamus during short-days promotes a long-day phenotype by increasing food intake and body weight without affecting the peripheral thyroid axis. Thus, thyroid hormone exerts anabolic actions within the brain that play a key role in the seasonal regulation of body weight. Understanding the precise actions of thyroid hormone in the brain may identify novel targets for long-term pharmacological manipulation of body weight.

scholarly journals Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance

2016 ◽  
Vol 48 (7) ◽  
pp. 491-501 ◽  
Author(s):  
Madeliene Stump ◽  
Deng-Fu Guo ◽  
Ko-Ting Lu ◽  
Masashi Mukohda ◽  
Xuebo Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Energy Balance ◽  
High Fat Diet ◽  
Control Diet ◽  
Cre Recombinase ◽  
Dominant Negative ◽  
High Fat ◽  
Pparγ Agonist ◽  
The Brain

Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NESCre/PPARγ-P467L) or selectively in POMC neurons (POMCCre/PPARγ-P467L). Whereas POMCCre/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMCCre/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMCCre/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMCCre/PPARγ-WT, but not POMCCre/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.

Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase

2013 ◽  
Vol 305 (5) ◽  
pp. R499-R505 ◽  
Author(s):  
Hyun-Ju Kim ◽  
Eun-Young Park ◽  
Mi-Jeong Oh ◽  
Sung-Soo Park ◽  
Kyung-Ho Shin ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Third Ventricle ◽  
Meal Size ◽  
Dependent Manner ◽  
Central Administration ◽  
Mediobasal Hypothalamus ◽  
S6 Kinase ◽  
The Third

Administration of metformin is known to reduce both body weight and food intake. Although the hypothalamus is recognized as a critical regulator of energy balance and body weight, there is currently no evidence for an effect of metformin in the hypothalamus. Therefore, we sought to determine the central action of metformin on energy balance and body weight, as well as its potential involvement with key hypothalamic energy sensors, including adenosine monophosphate-activated protein kinase (AMPK) and S6 kinase (S6K). We used meal pattern analysis and a conditioned taste aversion (CTA) test and measured energy expenditure in C56BL/6 mice administered metformin (0, 7.5, 15, or 30 μg) into the third ventricle (I3V). Furthermore, we I3V-administered either control or metformin (30 μg) and compared the phosphorylation of AMPK and S6K in the mouse mediobasal hypothalamus. Compared with the control, I3V administration of metformin decreased body weight and food intake in a dose-dependent manner and did not result in CTA. Furthermore, the reduction in food intake induced by I3V administration of metformin was accomplished by decreases in both nocturnal meal size and number. Compared with the control, I3V administration of metformin significantly increased phosphorylation of S6K at Thr389 and AMPK at Ser485/491 in the mediobasal hypothalamus, while AMPK phosphorylation at Thr172 was not significantly altered. Moreover, I3V rapamycin pretreatment restored the metformin-induced anorexia and weight loss. These results suggest that the reduction in food intake induced by the central administration of metformin in the mice may be mediated by activation of S6K pathway.

scholarly journals Adeno Associated Virus 9–Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice

Thyroid ◽  
2016 ◽  
Vol 26 (9) ◽  
pp. 1311-1319 ◽  
Author(s):  
Hideyuki Iwayama ◽  
Xiao-Hui Liao ◽  
Lyndsey Braun ◽  
Soledad Bárez-López ◽  
Brian Kaspar ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Thyroid Hormone ◽  
Monocarboxylate Transporter ◽  
Adeno Associated Virus ◽  
The Brain ◽  
Deficient Mice

scholarly journals Leptin-Mediated Hypothalamic Pathway of Cholecystokinin (CCK-8) to Regulate Body Weight in Free-Feeding Rats

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1994-2000 ◽  
Author(s):  
Beatriz Merino ◽  
Victoria Cano ◽  
Rocío Guzmán ◽  
Beatriz Somoza ◽  
Mariano Ruiz-Gayo
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Energy Balance ◽  
Negative Impact ◽  
Muscle Metabolism ◽  
Peripheral Circulation ◽  
Leptin Signaling ◽  
Leptin Receptors ◽  
Free Feeding ◽  
Amp Activated Protein Kinase

Regulation of body weight (BW) results from the interplay between different hormonal systems acting at central and peripheral level. This study aims at characterizing the involvement of cholecystokinin (CCK) in BW and energy balance regulation. We have characterized, in free-feeding rats, the effect of CCK-8 on 1) food intake, BW, and adiposity; 2) skeletal muscle metabolism; 3) leptin signaling pathway within the arcuate nucleus of the hypothalamus; and 4) the permeability of brain barriers to leptin. We demonstrate here that CCK-8 acutely decreases BW by a mechanism partially dependent on central leptin pathways, based on the following results: 1) the effect of CCK was less intense in rats lacking functional leptin receptors (Zucker fa/fa), 2) CCK-8 facilitated the uptake of leptin from peripheral circulation to cerebrospinal fluid (CSF), 3) the concentration of leptin in CSF of rats receiving CCK was more elevated in those animals showing higher loss of BW, and 4) CCK activated leptin signaling pathways within the hypothalamus as well as phosphorylation of AMP-activated protein kinase in skeletal muscle. We also suggest that gain of BW may be linked to individual susceptibility to the effect of CCK, because we observed that in animals treated with this hormone, the increase of BW negatively correlated with leptin concentration within the CSF. Our data show that CCK has a negative impact on energy balance and suggest that CCK facilitates the access of leptin to hypothalamic areas, thus allowing leptin to act on hypothalamic targets involved in BW control.

Effects of intracerebroventricular and intra-accumbens melanin-concentrating hormone agonism on food intake and energy expenditure

2009 ◽  
Vol 296 (3) ◽  
pp. R469-R475 ◽  
Author(s):  
Benjamin Guesdon ◽  
Éric Paradis ◽  
Pierre Samson ◽  
Denis Richard
Keyword(s):  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Third Ventricle ◽  
Substrate Oxidation ◽  
Nucleus Accumbens Shell ◽  
Experimental Conditions ◽  
Male Wistar Rats ◽  
Melanin Concentrating Hormone ◽  
The Brain

The brain melanin-concentrating hormone (MCH) system represents an anabolic system involved in energy balance regulation through influences exerted on the homeostatic and nonhomeostatic controls of food intake and energy expenditure. The present study was designed to further delineate the effect of the MCH system on energy balance regulation by assessing the actions of the MCH receptor 1 (MCHR1) agonism on both food intake and energy expenditure after intracerebroventricular (third ventricle) and intra-nucleus-accumbens-shell (intraNAcSH) injections of a MCHR1 agonist. Total energy expenditure and substrate oxidation were assessed following injections in male Wistar rats using indirect calorimetry. Food intake was also measured. Pair-fed groups were added to evaluate changes in thermogenesis that would occur regardless of the meal size and its thermogenic response. Using such experimental conditions, we were able to demonstrate that acute MCH agonism in the brain, besides its orexigenic effect, induced a noticeable change in the utilization of the main metabolic fuels. In pair-fed animals, MCH significantly reduced lipid oxidation when it was injected in the third ventricle. Such an effect was not observed following the injection of MCH in the NAcSH, where MCH nonetheless strongly stimulated appetite. The present results further delineate the influence of MCH on energy expenditure and substrate oxidation while confirming the key role of the NAcSH in the effects of the MCH system on food intake.

scholarly journals Diagnostic and Therapeutic Challenges in the Allan—Herndon—Dudley Syndrome

2016 ◽  
Vol 12 (02) ◽  
pp. 90 ◽  
Author(s):  
Stefan Groeneweg ◽  
Robin P Peeters ◽  
Theo J Visser ◽  
W Edward Visser ◽  
◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Serum Levels ◽  
Monocarboxylate Transporter ◽  
Normal Brain ◽  
Thyroid Function Tests ◽  
Neurocognitive Development ◽  
Transporter Protein ◽  
Male Patients ◽  
The Brain ◽  
Normal Brain Development

Thyroid hormone (TH) is important for normal brain development. The TH transporter protein monocarboxylate transporter 8 (MCT8) is crucial to maintain adequate TH levels in the brain during development and throughout life. Mutations in MCT8 result in the Allan–Herndon–Dudley syndrome (AHDS), which is characterized by a severe delay in neurocognitive development, combined with abnormal serum thyroid function tests (TFTs). The combination of an increased (F)T3 and decreased (F)T4 and rT3 serum levels are characteristic for the presence of AHDS in male patients with moderate to severe delay in neurocognitive development. Here, we provide an overview of current insights, challenges and pitfalls in the diagnosis and management of patients with AHDS.

scholarly journals A Thyroid Hormone Analog with Reduced Dependence on the Monocarboxylate Transporter 8 for Tissue Transport

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4450-4458 ◽  
Author(s):  
Caterina Di Cosmo ◽  
Xiao-Hui Liao ◽  
Alexandra M. Dumitrescu ◽  
Roy E. Weiss ◽  
Samuel Refetoff
Keyword(s):  
Thyroid Hormone ◽  
Neurological Impairment ◽  
Monocarboxylate Transporter ◽  
Human Thyroid ◽  
Th Cell ◽  
Hormone Analog ◽  
Potential Clinical Utility ◽  
The Brain ◽  
Serum Tsh ◽  
Different Doses

Abstract Mutations of the thyroid hormone (TH) cell membrane transporter MCT8, on chromosome-X, produce severe mental and neurological impairment in men. We generated a Mct8-deficient mouse (Mct8KO) manifesting the human thyroid phenotype. Although these mice have no neurological manifestations, they have decreased brain T3 content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T3 content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent. We tested the effect of 3,5-diiodothyropropionic acid (DITPA), a TH receptor agonist, for its dependence on Mct8 in Mct8KO and wild-type (Wt) mice tissues. After depletion of endogenous TH, mice were given three different doses of DITPA. Effects were compared with treatment with two doses of l-T4. As expected, physiological doses of l-T4 normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice. The higher dose of T4 suppressed TSH in the Wt mice, normalized TSH and brain D2 in Mct8KO mice, but produced a thyrotoxic effect on liver D1 in both genotypes. In contrast DITPA produced similar effects on TSH, D2, and D1 in both Wt and Mct8KO mice. The higher dose fully normalized all measurements and other parameters of TH action. Thus, DITPA is relatively MCT8 independent for entry into the brain and corrects the TH deficit in Mct8KO mice without causing thyrotoxic effect in liver. The potential clinical utility of this analog to patients with MCT8 mutations requires further studies.

scholarly journals The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 3889-3894 ◽  
Author(s):  
Alfonso Massimiliano Ferrara ◽  
Xiao-Hui Liao ◽  
Honggang Ye ◽  
Roy E. Weiss ◽  
Alexandra M. Dumitrescu ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Energy Expenditure ◽  
Target Genes ◽  
High Serum ◽  
Metabolic Parameters ◽  
Monocarboxylate Transporter ◽  
Hormone Analog ◽  
Serum T3 ◽  
Mct8 Deficiency ◽  
The Brain

Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.

scholarly journals Ontogenic Redistribution of Type 2 Deiodinase Messenger Ribonucleic Acid in the Brain of Chicken

Endocrinology ◽  
2004 ◽  
Vol 145 (8) ◽  
pp. 3619-3625 ◽  
Author(s):  
Balázs Gereben ◽  
Janusz Pachucki ◽  
Anna Kollár ◽  
Zsolt Liposits ◽  
Csaba Fekete
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Function ◽  
Hormone Receptors ◽  
Third Ventricle ◽  
Hybridization Signal ◽  
Adult Chicken ◽  
Chicken Brain ◽  
Messenger Ribonucleic Acid ◽  
The Brain

Abstract Thyroid hormone is essential for brain development. T4 has to be converted to T3 for efficient binding to thyroid hormone receptors. Type 2 deiodinase (D2) is the key enzyme that allows T3 generation in the brain. To elucidate the onset and localization of T3 production in the brain, we studied the changes of D2 activity, mRNA content, and the distribution of D2 mRNA in the brain of chicken embryos before and after the onset of thyroid function. D2 activity was detectable in the brain at all stages studied from embryonic day (E)7 to E15 and increased significantly with time. The wild-type chicken D2 transcript was detectable at all those stages by RT-PCR. The amount of D2 mRNA in the brain increased approximately 14-fold from E10 to E17 as assessed by Northern blot. Week D2 hybridization signal could be detected by in situ hybridization at E8 in cell clusters throughout the brain, and its intensity markedly increased to E15. Interestingly, no D2 expression was detected in hypothalamic tanycytes at these embryonic stages. However, D2 hybridization signal was observed in the wall of the third ventricle of adult chicken posterior to the rostral pole of the median eminence in the location typical for tanycytes, whereas D2 signal in other localizations was decreased throughout the brain. Our data suggest that D2 contributes to T3 content of the developing chicken brain even before the onset of thyroid function. Furthermore, redistribution of D2 mRNA expression was observed during the development of the chicken brain.

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