Role of neuropeptides in various adaptive processes of energy balance

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Intranasal Delivery of a Methyllanthionine-Stabilized Galanin Receptor-2-Selective Agonist Reduces Acute Food Intake

The regulatory (neuro)peptide galanin is widely distributed in the central and peripheral nervous systems, where it mediates its effects via three G protein-coupled receptors (GAL(1-3)R). Galanin has a vast diversity of biological functions, including modulation of feeding behavior. However, the clinical application of natural galanin is not practicable due to its rapid in vivo breakdown by peptidases and lack of receptor subtype specificity. Much effort has been put into the development of receptor-selective agonists and antagonists, and while receptor selectivity has been attained to some degree, most ligands show overlapping affinity. Therefore, we aimed to develop a novel ligand with specificity to a single galanin receptor subtype and increased stability. To achieve this, a lanthionine amino acid was enzymatically introduced into a galanin-related peptide. The residue’s subsequent cyclization created a conformational constraint which increased the peptide’s receptor specificity and proteolytic resistance. Further exchange of certain other amino acids resulted in a novel methyllanthionine-stabilized galanin receptor agonist, a G1pE-T3N-S6A-G12A-methyllanthionine[13–16]-galanin-(1–17) variant, termed M89b. M89b has exclusive specificity for GAL(2)R and a prolonged half-life in serum. Intranasal application of M89b to unfasted rats significantly reduced acute 24 h food intake inducing a drop in body weight. Combined administration of M89b and M871, a selective GAL(2)R antagonist, abolished the anorexigenic effect of M89b, indicating that the effect of M89b on food intake is indeed mediated by GAL(2)R. This is the first demonstration of in vivo activity of an intranasally administered lanthipeptide. Consequently, M89b is a promising candidate for clinical application as a galanin-related peptide-based therapeutic. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01155-x

Időskori anorexia, sarcopenia: orexigén és anorexigén peptidek energetikai hatásainak változása az életkorral rágcsálókban = Anorexia of aging, sarcopenia: age-dependent changes in the effects of orexigenic and anorexigenic peptides on energy homeostasis in rodents

Az alpha-MSH, a melanocortin rendszer endogén agonistája intracerebroventricularisan (ICV) adva katabolikus hatású: gátolja a spontán és a 24-h éheztetéssel kiváltott táplálékfelvételt (FI-t) (anorexigén) és biotelemetriás mérések szerint fokozza az anyagcserét és a testhőmérsékletet (Tc-t). Hőszabályozási hatásai nem koordináltak, mert az anyagcserével együtt a hőleadást is fokozza, ami a Tc emelkedését limitálja, ill. az LPS-lázat csökkenti. Anorexigén hatása korfüggő: a fiatal felnőtt (3-4 hó) patkányban kimutatott erős hatás 6-12-hónapos (középkorú) állatokban fokozatosan gyengül, majd öregekben (18-24 hó) maximális lesz. A 7-napos ICV infúzió eredményei ezt megerősítik, viszont azt is igazolják, hogy a peptid metabolikus hatásai nem párhuzamosan változnak az anorexigén hatásokkal. Kimutattuk, hogy az alpha-MSH anorexigén hatása normálisan táplált, kalóriarestrikciós és high-fat-diet által elhizlalt 6-hónapos állatokban hasonló volt, tehát az előzőekben leírt érzékenység-változások valóban a kortól és nem a testösszetételtől függtek. A CRF-el eddig elért eredményeink nagymértékben hasonlítanak az alpha-MSH-val elértekhez. Az orexigén NPY 12-hónapos állatokban hatásosabb, mint a 3 hónaposakban, viszont a 24 hónaposakban sokkal kisebb FI-t indukál. Mindezek elősegíthetik a középkorúak elhízását és az öregek anorexiáját és sarcopeniáját. | The intracerebroventricular (ICV) injection of alpha-MSH, the endogenous agonist of the melanocortin system has catabolic effects: it inhibits the spontaneous and fasting-induced food intake (anorexic) and elevates metabolic rate and body temperature (Tc). Its thermoregulatory effects are uncoordinated: heat loss is enhanced together with the rise in metabolic rate, thereby limiting the rise in Tc or inhibiting LPS-fever. The anorexic effects are age-dependent: the strong effect seen in young adult (3-4 months) rats gradually decreases by the age of 6-12 months ('middle-age'), then it becomes very pronounced in old (18-24 months) rats. Results of a 7 day-long ICV infusion confirm these data, but also demonstrate that the changes in metabolic and anorexic effects are not parallel. The anorexic effect was similar in normally fed, calorie-restricted and high fat diet-induced obese 6 month-old rats, proving that the previously seen changes in the anorexic effects of the peptide are due to aging and not to body composition. Results of studies with CRF greatly resemble those gained with alpha-MSH. The orexigenic NPY is more effective in 12 than in 3 month-old rats, but its efficacy significantly decreases by the age of 24 months. All these may contribute to the development of obesity in middle-aged and anorexia/sarcopenia in old rats

Az energetika biotelemetriás vizsgálata TRPV génhiányos és vad típusú egérben: testhőmérsékleti és aktivitási ritmusok változásai különböző tápláltsági és stressz állapotokban = Biotelemetric studies of energetics in TRPV knockout and wild type mice: modifications body temperature and activity rhythms under different feeding and stress situations

C57/BL egerek maghőmérsékletét és lokomotor aktivitását vizsgáltuk biotelemetriás módszerrel különböző környezeti hőmérsékleten. Normális és zsírdús táplálás hatásait követtük a napszaki hullámzásokra táplálás, több napos teljes éheztetés és újratáplálás ideje alatt, valamint ismételt laparotomiás beavatkozást követően is. Mindezen változások energetikai hátterének megismerése céljából releváns mediátorok, gátló anyagok centrális vagy perifériás infúzióját végeztük ALZET minipumpa segítségével. Szabadon mozgó egerek napszaki hőmérsékleti és aktivitási hullámzásának nagysága fokozódik teljes éhezés során és a maghőmérséklet 30 °C-ra való csökkenése jelzi a túlélhető éhezés végét az aktivitás fokozódása mellett. Újratápláláskor, hidegben, elhízásban, CNTF infúzió alatt és laparotomia után csökken a hullámzások amplitúdója. CNTF és CCK-8 icv infúziója lázat vált ki. Eredményeink több új információval szolgáltak a szabadon mozgó egerek normális és kóros energetikájának mechanizmusáról. | Changes of core temperature and locomotor activity were monitored in C57/BL mice under different thermal conditions by using a biotelemetric method. Effects of normal or fat-rich diet were observed on daily oscillatons during feeding, total fasting, re-feeding or on repeated laparotomy. To learn the energetic background of all these stimuli relevant meditors or blocker were infused either centrally or peripherally by using ALZET minipumps. Excursions of daily changes in core temperature and activity were found to be increased during total fasting with core temperature falling to about 30 °C as a sign of threshold of survivability with locomotor activity increasing progressively. Re-feeding, cold exposure, obesity, CNTF infusion or laparotomy led to reversible decreases of daily oscillations. Icv infusion of CNTF or CCK-8 induced fever. Our results furnished new information on the mechanisms of changes in energetics observed under normal and various types of pathological conditions in freely moving mice

Maternal overnutrition impairs offspring's insulin sensitivity: A systematic review and meta-analysis

This systematic review and meta-analysis aimed to investigate the association between maternal overnutrition and offspring's insulin sensitivity-following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Studies published in English before April 22, 2019, were identified through searches of four medical databases. After selection, 15 studies aiming to explore the association between prepregnancy body mass index (ppBMI) or gestational weight gain (GWG) of non-diabetic mothers and their offspring's insulin sensitivity (fasting insulin or glucose level and Homeostatic Measurement Assessment for Insulin Resistance [HOMA-IR]) were included in the meta-analysis. Associations of ppBMI and GWG with offspring's insulin sensitivity were analysed by pooling regression coefficients or standardized differences in means with 95% confidence intervals (CIs). Maternal ppBMI showed significant positive correlations with the level of both fasting insulin and HOMA-IR in offspring (standardized regression coefficient for fasting insulin: 0.107, CI [0.053, 0.160], p < 0.001 and that for HOMA-IR: 0.063, CI [0.006, 0.121], p = 0.031). However, the result of the analysis on coefficients adjusted for offspring's actual anthropometry (BMI and adiposity) was not significant. Independent from ppBMI, GWG tended to show a positive correlation with insulin level, but not after adjustment for offspring's anthropometry. Offspring of mothers with excessive GWG showed significantly higher HOMA-IR than those of mothers with optimal GWG (p = 0.004). Our results demonstrate that both higher ppBMI and GWG increase the risk of offspring's insulin resistance, but the effect of ppBMI on insulin sensitivity in offspring may develop as consequence of their adiposity

Noninvasive ventilation improves the outcome in patients with pneumonia-associated respiratory failure: Systematic review and meta-analysis

Noninvasive ventilation (NIV) is beneficial in exacerbations of chronic obstructive pulmonary disease (COPD), but its effectiveness in pneumonia-associated respiratory failure is still controversial. In the current meta-analysis, we aimed to investigate whether the use of NIV before intubation in pneumonia improves the mortality and intubation rates of respiratory failure as compared to no use of NIV in adults.We searched three databases from inception to December 2019. We included studies, in which pneumonia patients were randomized initially into either NIV-treated or non-NIV-treated groups. Five full-text publications, including 121 patients, reported eligible data for statistical analysis.With NIV the overall hospital mortality rate seemed lower in patients with pneumonia-associated respiratory failure, but this was not significant [odds ratio (OR) = 0.39; 95% confidence interval (CI): 0.13-1.14; P = 0.085]. In the intensive care unit, the mortality was significantly lower when NIV was applied compared to no NIV treatment (OR = 0.22; 95% CI: 0.07-0.75; P = 0.015). NIV also decreased mortality compared to no NIV in patient groups, which did not exclude patients with COPD (OR = 0.25; 95% CI: 0.08-0.74; P = 0.013). The need for intubation was significantly reduced in NIV-treated patients (OR = 0.22; 95% CI: 0.09-0.53; P = 0.001), which effect was more prominent in pneumonia patient groups not excluding patients with pre-existing COPD (OR = 0.13; 95% CI: 0.03-0.46; P = 0.002).NIV markedly decreases the death rate in the intensive care unit and reduces the need for intubation in patients with pneumonia-associated respiratory failure. The beneficial effects of NIV seem more pronounced in populations that include patients with COPD. Our findings suggest that NIV should be considered in the therapeutic guidelines of pneumonia, given that future clinical trials confirm the results of our meta-analysis.All data and materials generated during the current study are available from the corresponding author on reasonable request

Meta-Analysis of the Long Term Success Rate of Different Interventions in Benign Biliary Strictures.

BACKGROUND: Benign biliary stricture is a rare condition and the majority of the cases are caused by operative trauma or chronic inflammation based on various etiology. Although the initial results of endoscopic, percutaneous and surgical treatment are impressive, no comparison about long term stricture resolution is available. AIMS: The goal of this study was to compare the long term disease free survival in benign biliary strictures with various etiology after surgery, percutaneous transhepatic-and endoscopic treatment. METHODS: PubMed, Embase, and Cochrane Library were searched by computer and manually for published studies. The investigators selected the publications according to the inclusion and exclusion criteria, processed the data and assessed the quality of the selected studies. Meta-analysis of data of 24 publications was performed to compare long term disease free survival of different treatment groups. RESULTS: Compared the subgroups surgery resulted in the highest long term stricture resolution rate, followed by the percutaneous transhepatic treatment, the multiple plastic stent insertion and covered self-expanding metal stents (SEMS), however the difference was not significant. All compared methods are significantly superior to the single plastic stent placement. Long term stricture resolution rate irrespectively of any therapy is still not more than 84%. CONCLUSIONS: In summary, the use of single plastic stent is not recommended. Further randomized studies and innovative technical development are required for improving the treatment of benign biliary strictures

Gender difference in the effects of interleukin-6 on grip strength - a systematic review and meta-analysis

BACKGROUND: Aging sarcopenia characterized by low muscle mass with low muscle strength affects men and women differently. The contribution of interleukin-6 (IL-6) to sarcopenia has been suggested based on a negative correlation between plasma IL-6 and muscle function described by some studies. However, no consensus regarding clinically relevant cut-off criteria has been reached. Another question arises whether pooling male and female data is an accurate way to determine the predictive value of IL-6 in sarcopenia. The present meta-analysis was designed to assess: (1) whether plasma IL-6 in aged populations in fact correlates negatively to muscle strength; (2) whether such a correlation exists both in men and in women; and (3) whether plasma IL-6 shows a gender difference in old age. METHODS: We applied the preferred reporting items for systematic review and meta-analysis protocols (PRISMA). We searched PubMed and Embase for papers that reported data on individuals over 65 without inflammatory diseases. We extracted either separate male and female data on plasma IL-6 along with at least one muscle parameter or correlation coefficient between plasma IL-6 and these parameters. Random effect models calculated with DerSimonian and Laird weighting methods were applied to analyze correlation coefficients and gender difference in plasma IL-6. Egger's test was used to assess the small study effect. RESULTS: Twenty articles out of 468 records identified were suitable for analyses. Plasma IL-6 correlates negatively with grip strength in mixed populations and also separately in men [- 0.25 with 95% confidence interval (CI): - 0.48, - 0.02] and in women (- 0.14 with 95% CI: - 0.24, - 0.03). However, contrary to expectations, men with better muscle condition have higher plasma IL-6 than women of similar age with worse muscle condition (plasma IL-6 male-female difference: 0.25 pg/mL with 95% CI: 0.15, 0.35). CONCLUSION: This is the first study to demonstrate that a higher predictive IL-6 cut-off level should be determined for aging sarcopenia in men than in women

Compared efficacy of preservation solutions on the outcome of liver transplantation: Meta-analysis

AIM: To compare the effects of the four most commonly used preservation solutions on the outcome of liver transplantations. METHODS: A systematic literature search was performed using MEDLINE, Scopus, EMBASE and the Cochrane Library databases up to January 31(st), 2017. The inclusion criteria were comparative, randomized controlled trials (RCTs) for deceased donor liver (DDL) allografts with adult and pediatric donors using the gold standard University of Wisconsin (UW) solution or histidine-tryptophan-ketoglutarate (HTK), Celsior (CS) and Institut Georges Lopez (IGL-1) solutions. Fifteen RCTs (1830 livers) were included; the primary outcomes were primary non-function (PNF) and one-year post-transplant graft survival (OGS-1). RESULTS: All trials were homogenous with respect to donor and recipient characteristics. There was no statistical difference in the incidence of PNF with the use of UW, HTK, CS and IGL-1 (RR = 0.02, 95%CI: 0.01-0.03, P = 0.356). Comparing OGS-1 also failed to reveal any difference between UW, HTK, CS and IGL-1 (RR = 0.80, 95%CI: 0.80-0.80, P = 0.369). Two trials demonstrated higher PNF levels for UW in comparison with the HTK group, and individual studies described higher rates of biliary complications where HTK and CS were used compared to the UW and IGL-1 solutions. However, the meta-analysis of the data did not prove a statistically significant difference: the UW, CS, HTK and IGL-1 solutions were associated with nearly equivalent outcomes. CONCLUSION: Alternative solutions for UW yield the same degree of safety and effectiveness for the preservation of DDLs, but further well-designed clinical trials are warranted

Metformin induces significant reduction of body weight, total cholesterol and LDL levels in the elderly - A meta-analysis

Metformin is the first-choice drug for patients with Type 2 diabetes, and this therapy is characterized by being weight neutral. However, in the elderly an additional unintentional weight loss could be considered as an adverse effect of the treatment.We aimed to perform a meta-analysis of placebo-controlled studies investigating the body weight changes upon metformin treatment in participants older than 60 years.PubMed, EMBASE and the Cochrane Library were searched. We included at least 12 week-long studies with placebo control where the mean age of the metformin-treated patients was 60 years or older and the body weight changes of the patients were reported. We registered our protocol on PROSPERO (CRD42017055287).From the 971 articles identified by the search, 6 randomized placebo-controlled studies (RCTs) were included in the meta-analysis (n = 1541 participants). A raw difference of -2.23 kg (95% CI: -2.84 --1.62 kg) body weight change was detected in the metformin-treated groups as compared with that of the placebo groups (p<0.001). Both total cholesterol (-0.184 mmol/L, p<0.001) and LDL cholesterol levels (-0.182 mmol/L, p<0.001) decreased upon metformin-treatment.Our meta-analysis of RCTs showed a small reduction of body weight together with slight improvement of the blood lipid profile in patients over 60 years. With regard to the risk of unintentional weight loss, metformin seems to be a safe agent in the population of over 60 years. Our results also suggest that metformin treatment may reduce the risk of major coronary events (-4-5%) and all-cause mortality (-2%) in elderly diabetic populations