Az ""alacsony T3 szindróma"" kialakulásáért felelős központi idegrendszeri szabályozó mechanizmusok tanulmányozása patkányban = Central regulatory mechanisms involved in the development of the 'low T3 syndrome'

A pályázat fő célja az éhezés és fertőzés hatására kialakuló centrális hipotiroidizmus kialakulásáért felelős központi idegrendszeri szabályozó mechanizmusok tanulmányozása volt. Kimutattuk, hogy a leptin, inzulin és glükóz eltérő hatást fejt ki az arcuatus idegmag sejtjeire és csak a leptin képes kivédeni az éhezés hatására kialakuló centrális hipotiroidizmust. Leírtuk, hogy az AGRP TRH idegsejtekre kifejtett gátló hatását elsősorban a 4-es típusú melanokortin receptor (MC4-R) közvetíti. Igazoltuk, hogy a PVN MC4-R tartalmú idegsejtjein a legtöbb AGRP tartalmú terminális közelében nem figyelhetők meg ?-MSH-tartalmú végződések, valószínűsítve, hogy az AGRP a PVN-ben inverz agonistaként hathat. Leírtuk, hogy LPS kezelés a pajzsmirigyhormonok szintjének változásától függetlenül D2 aktivitás fokozódást eredményez a mediobazális hipotalamuszban a tanycytákban. Továbbá azonosítottuk a D2 promoter NF-kB kötőhelyét. Ezek alapján feltételezzük, hogy LPS hatására a megemelkedett D2 aktivitás az eredményezett lokális hipertiroidizmus révén hozzájárul a TRH idegsejtek gátlásához. | The long term goal of the proposed studies was the examination of the hypothalamic regulatory systems involved in the development of the central hypothyroidism induced by fasting or infection. We have described that leptin, insulin and glucose have different effects on the neurons of the arcuate nucleus. In addition, only leptin is able to reverse the fasting induced changes of the hypothalamic-pituitary-thyroid axis. We have demonstrated that the effect of AGRP on the hypophysiotropic TRH neurons is primarily mediated by the melanocortin 4 receptor (MC4-R). In addition, we have provided evidence that ?-MSH-containing varicosities are not present in the proximity of the AGRP terminals on the surface of the MC4-R-producing cells in the PVN, suggesting that AGRP acts as an inverse agonist in the PVN. We have demonstrated that LPS induces an increase of D2 activity in the tanycytes of the mediobasal hypothalamus. These changes are independent from the changes of the peripheral thyroid hormone level. Furthermore, we have identified the NF-kB binding cite of the D2 promoter. Based on these data, we hypothesize that the LPS induced increase of D2 activity results in a local hyperthyroidism in the PVN that contribute to the LPS induced inhibition of the hypophysiotropic TRH neurons

A zsírszövet mint a 2-es típusú diabetest kísérő inzulinrezisztencia egyik célszerve.: Az antidiabetikumoktól a fejlesztés alatt álló „adipeutikumokig”

Az inzulinrezisztencia az a kóros állapot, amelyben az endogén vagy a kívülről adagolt (exogén) inzulin szöveti glükózfelvételt és -hasznosítást elősegítő hatása elmarad az anyagcseréjüket illetően egészséges személyeken megfigyelt- től. Az egész szervezetet érinti, kitüntetett célszövetei a máj-, az izom- és a zsírszövet, patogenetikai és az ezek hátterében álló molekuláris biológiai folyamatai azonban részben eltérnek egymástól. Az utóbbi időben jelentősen bővültek a zsírszövet szerepével kapcsolatos ismeretek, s egyre inkább úgy látszik, hogy a diszfunkcionális zsírszövet a kóroki történések központi szereplője. A kézirat áttekinti a zsírszövet szerkezetét, az adipogenezis és a lipolízis szabályozását, a mikrobiom és a zsírszövet kapcsolatára vonatkozó adatokat, az akut és a krónikus inzulinrezisztencia különbségeit, valamint a zsírszöveti inzulinrezisztencia mérséklésére ma rendelkezésre álló terápiás eszközöket. Jóllehet szelektív zsírszöveti támadáspontú, biztonságos, hosszú távú humán alkalmazást lehetővé tevő molekula ma még nincs a reménybeli közelségben, az első, fejlesztés alatt álló „adipeutikummal” kapcsolatos állatkísérletes megfigyelések új kezelési lehetőség ígéretét vázolják fel

Distribution of type 1 cannabinoid receptor expressing neurons in the septal-hypothalamic region of the mouse. Colocalization with GABAergic and glutamatergic markers.

Type 1 cannabinoid receptor (CB1) is the principal mediator of retrograde endocannabinoid signaling in the brain. In this study, we addressed the topographic distribution and amino acid neurotransmitter phenotype of endocannabinoid-sensitive hypothalamic neurons in mice. The in situ hybridization detection of CB1 mRNA revealed high levels of expression in the medial septum (MS) and the diagonal band of Broca (DBB), moderate levels in the preoptic area and the hypothalamic lateroanterior (LA), paraventricular (Pa), ventromedial (VMH), lateral mammillary (LM) and ventral premammillary (PMV) nuclei, and low levels in many other hypothalamic regions including the suprachiasmatic (SCh) and arcuate (Arc) nuclei. This regional distribution pattern was compared to location of GABAergic and glutamatergic cell groups, as identified by the expression of glutamic acid decarboxylase 65 (GAD65) and type 2 vesicular glutamate transporter (VGLUT2) mRNAs, respectively. The MS, DBB and preoptic area showed overlaps between GABAergic and CB1-expressing neurons, whereas hypothalamic sites with moderate CB1 signals, including the LA, Pa, VMH, LM and PMV, were dominated by glutamatergic neurons. Low CB1 mRNA levels were also present in other glutamatergic and GABAergic regions. Dual-label in situ hybridization experiments confirmed the cellular co-expression of CB1 with both glutamatergic and GABAergic markers. In this report we provide a detailed anatomical map of hypothalamic glutamatergic and GABAergic systems whose neurotransmitter release is controlled by retrograde endocannabinoid signaling from hypothalamic and extrahypothalamic target neurons. This neuroanatomical information contributes to the understanding of the role that the endocannabinoid system plays in the regulation of endocrine and metabolic functions. J. Comp. Neurol., 2011. (c) 2011 Wiley-Liss, Inc

Az elhízás modern szemlélete és korszerű kezelése = Modern approach and advanced treatment of obesity

Az elhízás a szervezet zsírfelhalmozódásával járó recidiváló, progresszív krónikus betegség. Jellege miatt kezelésének, gondozásának élethosszig kell tartania. A terápia elemei: az életmód (diéta és mozgás), a pszichés vezetés, a gyógyszeres, és szükség esetén a sebészi kezelés. A Magyar Obezitológiai és Mozgásterápiás Társaság a testtömegcsökkentô program elsô félévében csökkentett szénhidrát- és fokozott fehérjetartalmú diétát javasol. Fizikai aktivitás során elônyösek a dinamikus, aerob jellegû (például séta, gyaloglás, kocogás, úszás, kerékpározás stb.) mozgásformák. A gyógyszeres kezelés lehetôségei hazánkban az orlistat, a naltrexon/bupropion fix kombináció, a subcutan liraglutid (3,0 mg), és a sebészeti kezelés, amelyek sikeres kiegészítôi lehetnek a testtömegcsökkentô programnak. = Obesity is a recurrent, progressive chronic disease associated with body fat accumula - tion the body. Due to the nature of the dis - ease, its treatment and care is a life-long program. Elements of therapy: lifestyle modification (diet and exercise), psychological treatment, medication and if necessary, surgery. The Hungarian Society of Obesity and Exercise, recommends a low-carbohydrate and high-protein diet in the first half year of the weight loss program. During physical activity, dynamic, aerobic forms of movement (e.g. walking, jogging, swimming, cycling, etc.) are preferred. The options of drug treatment in Hungary are orlistat, naltrexone/bupropion fixed dose combination and liraglutide sc (3.0 mg) and bariatric surgery, which all can contribute successfully to the weight loss program

Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents

There is increasing evidence that local thyroid hormone (TH) availability changes profoundly in inflammatory conditions due to altered expression of deiodinases that metabolize TH. It is largely unknown, however, how inflammation affects TH availability via the expression of TH transporters. In this study we examined the effect of bacterial lipopolysaccharide (LPS) administration on two TH transporters that are critically important for brain TH homeostasis, organic anion-transporting polypeptide 1c1 (OATP1c1) and monocarboxylate transporter 8 (MCT8). Messenger RNA levels were studied by in situ hybridization and quantitative PCR, and protein levels by immunofluorescence in both the rat and mouse forebrain. The mRNA of both transporters decreased robustly in the first 9h after LPS injection, selectively in brain blood vessels; OATP1c1 mRNA in astrocytes and MCT8 mRNA in neurons remained unchanged. At 24 and/or 48h after LPS administration, OATP1c1 and MCT8 mRNAs increased markedly above control levels in brain vessels. OATP1c1 protein decreased markedly in vessels by 24h, whereas MCT8 protein levels did not decrease significantly. These changes were highly similar in mice and rats. The data demonstrate that OATP1c1 and MCT8 expression are regulated in a parallel manner during inflammation at the blood-brain barrier of rodents. Given the indispensable role of both transporters in allowing TH access to the brain, the results suggest reduced brain TH uptake during systemic inflammation

Elevated miR-33a and miR-224 in steatotic chronic hepatitis C liver biopsies

AIM: To assess the expression of selected microRNAs (miRNA) in hepatitis C, steatotic hepatitis C, noninfected steatotic and normal liver tissues. METHODS: The relative expression levels of miR-21, miR-33a, miR-96, miR-122, miR-125b, miR-221 and miR-224 were determined in 76 RNA samples isolated from 18 non-steatotic and 28 steatotic chronic hepatitis C (CHC and CHC-Steatosis, respectively) cases, 18 non-infected, steatotic liver biopsies of metabolic origin (Steatosis) and 12 normal formalin-fixed paraffin-embedded liver tissues using TaqMan MicroRNA Assays. All CHC biopsy samples were obtained prior to initiating therapy. Patients’ serum biochemical values, which included glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl-transferase (GGT), alkaline phosphatase (AP), were obtained and correlated with relative miRNA expression. RESULTS: When compared with control non-infected liver samples, miR-122 and miR-221 levels were reduced in CHC-Steatosis (P < 0.03) and in CHC, CHC-Steatosis and Steatosis (P < 0.01). Alternatively, the expression of miR-33a and miR-224 were elevated in CHC-Steatosis and Steatosis in comparison to control tissue (P < 0.01). The levels of miR-33a and miR-224 in CHC-Steatosis (P < 0.02) and miR-224 in Steatosis (P < 0.001) were increased in comparison to CHC samples. By contrast, the expression of miR-21 did not differ statistically between diseased and normal liver samples. Levels of miR-33a correlated negatively with serum AST and AP levels in Steatosis as well as with necroinflammatory grade in CHC, whereas miR-21 correlated positively with AST in Steatosis and displayed negative correlation with triglyceride level in CHC-Steatosis. In contrast, miRNA levels were not correlated with ALT, GGT, cholesterol levels or fibrosis stage. CONCLUSION: Differences in miRNA expression were observed between CHC and steatotic CHC, CHC and steatotic liver, but not between steatotic CHC and steatotic liver of metabolic origin

Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats.

OBJECTIVE Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats. RESEARCH DESIGN AND METHODS Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies. RESULTS Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonist-elicited reduction of food intake. CONCLUSIONS Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight

Elevated miR-33a and miR-224 in steatotic chronic hepatitis C liver biopsies.

AIM: To assess the expression of selected microRNAs (miRNA) in hepatitis C, steatotic hepatitis C, noninfected steatotic and normal liver tissues. METHODS: The relative expression levels of miR-21, miR-33a, miR-96, miR-122, miR-125b, miR-221 and miR-224 were determined in 76 RNA samples isolated from 18 non-steatotic and 28 steatotic chronic hepatitis C (CHC and CHC-Steatosis, respectively) cases, 18 non-infected, steatotic liver biopsies of metabolic origin (Steatosis) and 12 normal formalin-fixed paraffin-embedded liver tissues using TaqMan MicroRNA Assays. All CHC biopsy samples were obtained prior to initiating therapy. Patients' serum biochemical values, which included glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl-transferase (GGT), alkaline phosphatase (AP), were obtained and correlated with relative miRNA expression. RESULTS: When compared with control non-infected liver samples, miR-122 and miR-221 levels were reduced in CHC-Steatosis (P < 0.03) and in CHC, CHC-Steatosis and Steatosis (P < 0.01). Alternatively, the expression of miR-33a and miR-224 were elevated in CHC-Steatosis and Steatosis in comparison to control tissue (P < 0.01). The levels of miR-33a and miR-224 in CHC-Steatosis (P < 0.02) and miR-224 in Steatosis (P < 0.001) were increased in comparison to CHC samples. By contrast, the expression of miR-21 did not differ statistically between diseased and normal liver samples. Levels of miR-33a correlated negatively with serum AST and AP levels in Steatosis as well as with necroinflammatory grade in CHC, whereas miR-21 correlated positively with AST in Steatosis and displayed negative correlation with triglyceride level in CHC-Steatosis. In contrast, miRNA levels were not correlated with ALT, GGT, cholesterol levels or fibrosis stage. CONCLUSION: Differences in miRNA expression were observed between CHC and steatotic CHC, CHC and steatotic liver, but not between steatotic CHC and steatotic liver of metabolic origin

Elevated miR-33a and miR-224 in steatotic chronic hepatitis C liver biopsies

AIM: To assess the expression of selected microRNAs (miRNA) in hepatitis C, steatotic hepatitis C, noninfected steatotic and normal liver tissues. METHODS: The relative expression levels of miR-21, miR-33a, miR-96, miR-122, miR-125b, miR-221 and miR-224 were determined in 76 RNA samples isolated from 18 non-steatotic and 28 steatotic chronic hepatitis C (CHC and CHC-Steatosis, respectively) cases, 18 non-infected, steatotic liver biopsies of metabolic origin (Steatosis) and 12 normal formalin-fixed paraffin-embedded liver tissues using TaqMan MicroRNA Assays. All CHC biopsy samples were obtained prior to initiating therapy. Patients' serum biochemical values, which included glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl-transferase (GGT), alkaline phosphatase (AP), were obtained and correlated with relative miRNA expression. RESULTS: When compared with control non-infected liver samples, miR-122 and miR-221 levels were reduced in CHC-Steatosis (P < 0.03) and in CHC, CHC-Steatosis and Steatosis (P < 0.01). Alternatively, the expression of miR-33a and miR-224 were elevated in CHC-Steatosis and Steatosis in comparison to control tissue (P < 0.01). The levels of miR-33a and miR-224 in CHC-Steatosis (P < 0.02) and miR-224 in Steatosis (P < 0.001) were increased in comparison to CHC samples. By contrast, the expression of miR-21 did not differ statistically between diseased and normal liver samples. Levels of miR-33a correlated negatively with serum AST and AP levels in Steatosis as well as with necroinflammatory grade in CHC, whereas miR-21 correlated positively with AST in Steatosis and displayed negative correlation with triglyceride level in CHC-Steatosis. In contrast, miRNA levels were not correlated with ALT, GGT, cholesterol levels or fibrosis stage. CONCLUSION: Differences in miRNA expression were observed between CHC and steatotic CHC, CHC and steatotic liver, but not between steatotic CHC and steatotic liver of metabolic origin