Ghrelin plays a pivotal role in the regulation of food intake, body weight and energy metabolism. However, these effects of ghrelin in the lateral parabrachial nucleus (LPBN) are unexplored. C57BL/6J mice and GHSR−/− mice were implanted with cannula above the right LPBN and ghrelin was microinjected via the cannula to investigate effect of ghrelin in the LPBN. In vivo electrophysiological technique was used to record LPBN glucose-sensitive neurons to explore potential udnderlying mechanisms. Microinjection of ghrelin in LPBN significantly increased food intake in the first 3 h, while such effect was blocked by [D-Lys3]-GHRP-6 and abolished in GHSR−/− mice. LPBN ghrelin microinjection also significantly increased the firing rate of glucose-excited (GE) neurons and decreased the firing rate of glucose-inhibited (GI) neurons. Additionally, LPBN ghrelin microinjection also significantly increased c-fos expression. Chronic ghrelin administration in the LPBN resulted in significantly increased body weight gain. Meanwhile, no significant changes were observed in both mRNA and protein expression levels of UCP-1 in BAT. These results demonstrated that microinjection of ghrelin in LPBN could increase food intake through the interaction with growth hormone secretagogue receptor (GHSR) in C57BL/6J mice, and its chronic administration could also increase body weight gain. These effects might be associated with altered firing rate in the GE and GI neurons.
Caishun Zhang, Junhua Yuan, Qian Lin, Manwen Li, Liuxin Wang, Rui Wang, Xi Chen, Zhengyao Jiang, Kun Zhu, Xiaoli Chang, Bin Wang, and Jing Dong
Alexander V. Amram, Stephen Cutie, and Guo N. Huang
Research conducted across phylogeny on cardiac regenerative responses following heart injury implicates endocrine signaling as a pivotal regulator of both cardiomyocyte proliferation and heart regeneration. Three prominently studied endocrine factors are thyroid hormone, vitamin D, and glucocorticoids, which canonically regulate gene expression through their respective nuclear receptors thyroid hormone receptor, vitamin D receptor, and glucocorticoid receptor. The main animal model systems of interest include humans, mice, and zebrafish, which vary in cardiac regenerative responses possibly due to the differential onsets and intensities of endocrine signaling levels throughout their embryonic to postnatal organismal development. Zebrafish and lower vertebrates tend to retain robust cardiac regenerative capacity into adulthood while mice and other higher vertebrates experience greatly diminished cardiac regenerative potential in their initial postnatal period that is sustained throughout adulthood. Here, we review recent progress in understanding how these three endocrine signaling pathways regulate cardiomyocyte proliferation and heart regeneration with a particular focus on the controversial findings that may arise from different assays, cellular-context, age, and species. Further investigating the role of each endocrine nuclear receptor in cardiac regeneration from an evolutionary perspective enables comparative studies between species in hopes of extrapolating the findings to novel therapies for human cardiovascular disease.
Xiuzhen Hou, Junfeng Zhang, Hehong Ma, Ming Li, and Pei Wang
Background: Oxidative stress leads to insulin resistance and gestational diabetes mellitus (GDM). The nuclear factor erythroid 2-related factor 2 (Nrf2) / heme oxygenase-1 (HO-1) signaling is an important anti-oxidative stress pathway, which can be activated by hypoxia‑reoxygenation (H/R) treatment. We aimed to demonstrate the effects of H/R treatment on GDM symptoms as well as reproductive outcomes.
Methods: Pregnant C57BL/KsJ db/+ mice were used as a genetic GDM model. Plasma insulin and other biochemical indexes of plasma, insulin sensitivity, glucose intolerance, blood glucose and liver biochemical indexes were evaluated. Protein abundance of HO-1 and Nrf2 were assessed with Western blot.
Results: H/R treatment markedly ameliorated β-cell insufficiency and glucose intolerance, suppressed oxidative stress in vivo, stimulated the activities of anti-oxidant enzymes, and led to improved reproductive outcomes. The beneficial effects of H/R treatment were mechanistically mediated via the restoration of Nrf2/HO-1 anti-oxidant signaling pathway in the liver of GDM mice.
Conclusion: Our study, for the first time, suggests that H/R treatment is a potentially novel therapeutic approach against GDM symptoms, by activating the Nrf2/HO-1 signaling pathway and inhibiting oxidative stress.
Raluca Maria Furnica, Muhammad Muddaththir Dusoruth, Alexandre Persu, Damien Gruson, Michel Mourad, and Dominique Maiter
Objectives: Surgery of pheochromocytomas (PCs) still carries a high risk of hemodynamic complications during the perioperative period. We aimed to evaluate the influence of their secretory phenotype and preoperative alpha-blocker treatment on surgical outcome.
Design: a retrospective monocentric study at a tertiary medical centre.
Patients: 80 consecutive patients operated by the same team for a PC between 1988 and 2018.
Results: Diagnosis was based on typical symptoms and signs in 58 patients, genetic testing in 12 and work-up of an adrenal incidentaloma in 9. It was made during surgery in one patient. A genetic predisposition was found in one third of index cases (21/62). The majority of the patients (73/79) had a secreting PC; more than 2/3 had an adrenergic phenotype and less than 1/3 a noradrenergic phenotype. The rate of perioperative hemodynamic complications was not influenced by the secretory phenotype, but persistent hypertension after surgery, recurrence and malignancy were more frequently observed in patients with a noradrenergic tumour. Preoperative alpha-blocker treatment was given for ≥ 14 days in 29 patients and, although being more symptomatic at diagnosis, these patients had less hemodynamic complications (3/29 vs. 12/51 non-treated patients, p=0.05).
Conclusions: The occurrence of hemodynamic complications during surgery was not significantly affected by the secretory phenotype in our study, but noradrenergic tumours show a worse post-surgical outcome. Our data also provide additional support in favor of a sufficient preoperative alpha-blockade in patients with pheochromocytoma.
Qinglei Yin, Zhou Jin, Yulin Zhou, Dalong Song, Chenyang Fu, FengJiao Huang, and Shu Wang
Graves’ disease (GD) is a common autoimmune disease that affects the thyroid gland. As a new class of modulators of gene expression, long noncoding RNAs (lncRNAs) have been reported to play a vital role in immune functions and in the development of autoimmunity and autoimmune disease. The aim of this study is to identify lncRNAs in CD4+ T cells as potential biomarkers of GD. lncRNA and mRNA microarrays were performed to identify differentially expressed lncRNAs and mRNAs in GD CD4+ T cells compared with healthy control CD4+ T cells. Quantitative PCR (qPCR) was used to validate the results, and correlation analysis was used to analyze the relationship between these aberrantly expressed lncRNAs and clinical parameters. The microarray identified 164 lncRNAs and 93 mRNAs in GD CD4+ T cells differentially expressed compared to healthy control CD4+ T cells (fold change >2.0 and a P < 0.05). Further analysis consistently showed that the expression of HMlincRNA1474 (P < 0.01) and TCONS_00012608 (P < 0.01) was suppressed, while the expression of AK021954 (P < 0.01) and AB075506 (P < 0.01) was upregulated from initial GD patients. In addition, their expression levels were recovered in euthyroid GD patients and GD patients in remission. Moreover, these four aberrantly expressed lncRNAs were correlated with GD clinical parameters. Moreover, the areas under the ROC curve were 0.8046, 0.7579, 0.8115 for AK021954, AB075506, HMlincRNA1474, respectively. The present work revealed that differentially expressed lncRNAs were associated with GD, which might serve as novel biomarkers of GD and potential targets for GD treatment.
Anna Malczewska, Kjell E Oberg, and Beata Kos-Kudła
Introduction: The absence of a reliable, universal biomarker is a significant limitation in neuroendocrine neoplasia (NEN) management. We prospectively evaluated two CgA assays, (NEOLISA, EuroDiagnostica,) and (CgA ELISA, Demeditec Diagnostics (DD)) and compared the results to the NETest.
Methods: NEN cohort (n=258): pancreatic, n=67; small intestine, n=40; appendiceal, n=10; rectal, n=45; duodenal, n=9; gastric, n=44; lung, n=43. Image-positive disease (IPD) (n=123), image and histology negative (IND) (n=106), and image negative and histology positive (n=29). CgA metrics: NEOLISA, ULN: 108ng/mL, DD: ULN: 99ng/mL. Data: mean ±SEM. NETest: qRT-PCR - multianalyte analyses, ULN: 20. All samples de-identified and assessed blinded. Statistics: Mann-Whitney U-test, Pearson correlation and McNemar-test.
Results: CgA positive in 53/258 (NEOLISA), 32 (DD) and NETest-positive in 157/258. In image positive disease (IPD, n=123), NEOLISA-positive: 33% and DD: 19%. NETest-positive: 122/123 (99%; McNemar’s Chi2=79-97, p<0.0001). NEOLISA was more accurate than DD (p=0.0003). In image negative disease (IND), CgA was NEOLISA-positive (11%), DD (8%), p=NS, and NETest (33%). CgA assays could not distinguish progressive (PD) from stable disease (SD) or localized from metastatic disease (MD). NETest was significantly higher in PD (47±5) than SD (29±1, p=0.0009). NETest levels in MD (35±2) were elevated versus localized disease (24±1.3, p=0.008).
Conclusions: NETest, a multigenomic mRNA biomarker, was ~99% accurate in the identification of NEN disease. The CgA assays detected NEN disease in 19-33%. Multigenomic blood analysis using NETest is more accurate than CgA and should be considered the biomarker standard of care.
Ruixin Hu, Yanting Yuan, Chaolong Liu, Ji Zhou, Lixia Ji, and Guohui Jiang
In patients with type 2 diabetes mellitus (T2DM), the intestinal flora is out of balance and accompanied by leaky gut. The flora is characterized by an increase in mucus-degrading bacteria and a decrease in fiber-degrading bacteria. Short-chain fatty acids (SCFAs), as the major fiber-degrading bacteria fermentation, not only ameliorate the leaky gut, but also activate GPR43 to increase the mass of functional pancreatic β-cells and exert anti-inflammation effect. At present, the gut microbiota is considered as the potential target for anti-diabetes drugs, and how to reverse the imbalance of gut microbiota has become a therapeutic strategy for T2DM. This review briefly summarizes the drugs or compounds that have direct or potential therapeutic effects on T2DM by modulating the gut microbiota, including biguanides, isoquinoline alkaloids, stilbene and C7N-aminocyclic alcohols.
David S Mathiesen, Jonatan I Bagger, Katrine B Hansen, Anders E Junker, Astrid Plamboeck, Signe Harring, Thomas Idorn, Mads Hornum, Jens J Holst, Anna E Jonsson, Torben Hansen, Tina Vilsbøll, Asger Lund, and Filip K Knop
The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.
Jeyanthini Risikesan, Birgitte Nellemann, Britt Christensen, Jens Otto Lunde Jørgensen, and Søren Nielsen
Studies indicate that erythropoietin (EPO) has effect on lipid and energy metabolism; however, the impact of EPO on lipid oxidation in vivo has not been well documented. Here, we evaluate whether long-term erythropoiesis-stimulating agent (ESA) treatment affects the oxidation of plasma very low-density lipoprotein triglycerides (VLDL-TG) fatty acids (FA), plasma free fatty acids (FFA) and non-plasma (residual) FA in healthy, young, sedentary men. Infusion of [1-14C]VLDL-TG and [9,10-3H]palmitate was used in combination with indirect calorimetry to assess resting lipid fuel utilization and kinetics, and resting energy expenditure (REE) before and after 10 weeks of ESA exposure compared with placebo. REE increased significantly during ESA compared with placebo (P = 0.023, RM-ANOVA). Oxidation rates of VLDL-TG FA, FFA, and residual FA remained unchanged during ESA compared with placebo. The relative contribution of the lipid stores was greatest for FFA (47.1%) and the total lipid oxidation rate and was not significantly different between ESA and placebo-treated subjects. We conclude that long-term ESA treatment of healthy young men increases REE but does not alter the oxidation rates of plasma and non-plasma FA sources.
Bernardo Maia, Leandro Kasuki, and Mônica R Gadelha
Acromegaly is a systemic disease associated with increased morbidity and mortality. Most of these comorbidities can be prevented or delayed with adequate disease treatment. Although three modalities of treatment (surgery, medical treatment, and radiotherapy) are available and new drugs were approved in the last decades, there are still some patients that maintain disease activity despite treatment. Therefore, there is a need for novel therapies for acromegaly and for that purpose new formulations of currently used drugs and also new drugs are currently under study. In this review, we summarize the novel therapies for acromegaly.