Central regulation of sympathetic nerve activity by adipokines and insulin

Leptin, resistin and insulin are hormones that circulate in the blood and cross the blood brain barrier. In the brain, they are thought to activate specific regions, which play important roles in energy homeostasis and cardiovascular regulation. The plasma levels of these hormones have been shown to be elevated in overweight and obese conditions, and an increased sympathetic nerve activity (SNA) is also observed in these conditions. In addition, leptin, resistin and insulin plasma levels are strongly correlated with increases in blood pressure suggesting that these hormones may have cardiovascular effects. In high fat diet (HFD), the effects of leptin on renal sympathetic nerve activity (RSNA) are well known. However, the effects of insulin are little known, and the effects of resistin are not known. Since leptin, resistin and insulin levels are increased significantly in obesity and each of these hormones alone can increase RSNA, the question arises as to whether there is an interaction between these hormones on cardiovascular regulation. Thus, the general aim of this thesis was to compare the effects of leptin, resistin and insulin alone and in combination on RSNA, mean arterial pressure (MAP) and heart rate (HR) in rats fed a normal chow diet (ND) or HFD. Male Sprague-Dawley rats were fed a ND and HFD for approximately 8-10 weeks. Saline (5 µl), leptin (7 µg/5 µl), resistin (7 µg/5 µl) and insulin (500 mU/5 µl) were administered intracerebroventricularly (ICV) and RSNA, MAP and HR were monitored and recorded before and for 3 hours after the drug administration. We found that ICV administration of the interaction of (leptin + resistin) increases SNA to the kidney in ND and HFD animals. The effects of leptin and insulin in combination showed that HFD significantly reduced the RSNA responses induced by these hormones in contrast to the increases seen in ND. When resistin and insulin were combined, the response to RSNA was not increased in ND and this effect in HFD, RSNA fell markedly. Together, these data suggest that in HFD the presence of insulin with resistin or leptin may result in a negative interaction on RSNA. However, the positive interaction in HFD seen between resistin and leptin might overcome any negative interaction between insulin with resistin or leptin. Therefore, the interaction between leptin and resistin might be implicated in the abnormal elevation RSNA, seen in overweight /obese conditions

High fat diet decreases neuronal activation in the brain induced by resistin and leptin

Resistin and leptin are adipokines which act in the brain to regulate metabolic and cardiovascular functions which in some instances are similar, suggesting activation of some common brain pathways. High-fat feeding can reduce the number of activated neurons observed following the central administration of leptin in animals, but the effects on resistin are unknown. The present work compared the distribution of neurons in the brain that are activated by centrally administered resistin, or leptin alone, and, in combination, in rats fed a high fat (HFD) compared to a normal chow diet (ND). Immunohistochemistry for the protein, Fos, was used as a marker of activated neurons. The key findings are (i) following resistin or leptin, either alone or combined, in rats fed the HFD, there were no significant increases in the number of activated neurons in the paraventricular and arcuate nuclei, and in the lateral hypothalamic area (LHA). This contrasted with observations in rats fed a normal chow diet; (ii) in the OVLT and MnPO of HFD rats there were significantly less activated neurons compared to ND following the combined administration of resistin and leptin; (iii) In the PAG, RVMM, and NTS of HFD rats there were significantly less activated neurons compared to ND following resistin. The results suggest that the sensitivity to resistin in the brain was reduced in rats fed a HFD. This has similarities with leptin but there were instances where there was reduced sensitivity to resistin with no significant effects following leptin. This suggests diet influences neuronal effects of resistin

Effects of central administration of resistin on renal sympathetic nerve activity in rats fed a high-fat diet: a comparison with leptin

Similar to leptin, resistin acts centrally to increase renal sympathetic nerve activity (RSNA). In high-fat fed animals, the sympatho-excitatory effects of leptin are retained, in contrast to the reduced actions of leptin on dietary intake. In the present study, we investigated whether the sympatho-excitatory actions of resistin were influenced by a high-fat diet. Further, because resistin and leptin combined can induce a greater sympatho-excitatory response than each alone in rats fed a normal chow diet, we investigated whether a high-fat diet (22%) could influence this centrally-mediated interaction. Mean arterial pressure (MAP), heart rate (HR) and RSNA were recorded before and for 3 hours after i.c.v. saline (control; n=5), leptin (7 μg; n=4), resistin (7 μg; n=5) and leptin and resistin combined (n=6). Leptin alone and resistin alone significantly increased RSNA (71±16%, 62±4%, respectively). When leptin and resistin were combined, there was a significantly greater increase in RSNA (195±41%) compared to either hormone alone. MAP and HR responses were not significantly different between hormones. When the responses in high-fat fed rats were compared to normal chow fed rats, there were no significant differences in the maximum RSNA responses. The findings indicate that sympatho-excitatory effects of resistin on RSNA are not altered by high-fat feeding, including the greater increase in RSNA observed when resistin and leptin are combined. Our results suggest that diets rich in fat do not induce resistance to the increase in RSNA induced by resistin alone or in combination with leptin

Central Administration of Insulin Combined With Resistin Reduces Renal Sympathetic Nerve Activity in Rats Fed a High Fat Diet

Insulin receptors are widely distributed in the central nervous system and their activation by insulin elicits renal sympatho-excitatory effects. Resistin, an adipokine, promotes resistance to the metabolic effects of insulin. Resistin also induces increases in renal sympathetic nerve activity (RSNA) by acting in the brain, but whether it can influence insulin's actions on RSNA is unknown. In the present study we investigated, in male Sprague-Dawley rats (7-8 weeks of age), the effects of central administration of insulin combined with resistin on RSNA following a normal diet (ND) and a high fat diet (HFD) (22% fat), since HFD can reportedly attenuate insulin's actions. RSNA, mean arterial pressure (MAP) and heart rate (HR) responses were monitored and recorded before and for 180 min after intracerebroventricular injection of saline (control) (n = 5 HFD and ND), resistin (7 mu g; n = 4 ND, n = 5 HFD), insulin (500 mU; n = 6 ND, n = 5 HFD), and the combination of both resistin and insulin (n = 7 ND, n = 5 HFD). The key finding of the present study was that when resistin and insulin were combined there was no increase in RSNA induced in rats fed a normal diet or the high fat diet. This contrasted with the sympatho-excitatory RSNA effects of the hormones when each was administered alone in rats fed the ND and the HFD

Central leptin and resistin combined elicits enhanced central effects on renal sympathetic nerve activity

Leptin and resistin act centrally to increase renal sympathetic nerve activity (RSNA). We investigated whether resistin and leptin combined could induce a greater response than each alone. MAP, HR and RSNA were recorded before and for 3 hours after intracerebroventricular saline (control) (n = 5), leptin (7 μg; n = 5), resistin (7 μg; n = 4) and leptin administered 15 min after resistin (n = 6). Leptin alone and resistin alone significantly increased RSNA (74±17%, 50±14% respectively) (P < 0.0001 compared to saline). When leptin and resistin were combined there was a significantly greater increase in RSNA (163±23%) compared to either drug alone (P < 0.0001). Maximum responses in MAP and HR were not significantly different between groups. We also used Fos protein to quantify the number of activated neurons in the brain. Compared to controls, there were significant increases in numbers of Fos-positive neurons (i) in the arcuate and hypothalamic paraventricular nuclei when leptin or resistin were administered alone, or combined, and (ii) in the lamina terminalis when leptin or resistin were combined. Only in the arcuate nucleus was the increase significantly greater compared to either drug alone. The findings show that leptin and resistin, combined, induces (i) a greater RSNA increase, and (ii) a greater number of activated neurons in the arcuate nucleus, than with either drug alone. Since leptin makes an important contribution to the elevated RSNA observed in obese/overweight conditions, the increased levels of leptin and resistin may mean the contribution of leptin to the elevated RSNA in those conditions is enhanced

Treatment of acute mesenteric ischemia between 2010 and 2020 – a German nation-wide study

Abstract Background Aim of this study was to analyze long-term trends of hospitalizations, treatment regimen and in-hospital mortality of in-patients with acute mesenteric ischemia (AMI) over the past decade and effects of the SARS-CoV2-pandemic. Methods We analyzed fully anonymized data from the German Federal Statistical Office of patients with AMI between 2010 and 2020. Besides descriptive analyses of age, gender, in-hospital mortality, comorbidity burden and treatment regimen, multivariable logistic regression analyses were performed to identify independent variables associated with in-hospital mortality and different treatment. Results A total of 278,121 hospitalizations (120,667 male [43.4%], mean age 72.1 years) with AMI were included in this study. The total number of hospitalizations increased from 2010 (n = 24,172) to 2019 (n = 26,684) (relative increase 10.4%). In-hospital mortality decreased over the past decade from 36.6% to 2010 to 31.1% in 2019 (rel. decrease 15.2%). Independent risk factors for in-hospital mortality were older age (OR = 1.03 per year), higher comorbidity burden (OR = 1.06 per point in van Walraven score [vWs]), male gender (OR = 1.07), AMI as a secondary diagnosis (OR = 1.44), and the need for surgical (visceral surgery: OR = 1.38, vascular surgery: OR = 3.33) and endovascular treatment (OR = 1.21). We report a decline in hospitalizations during the first wave of infection in spring 2020 (rel. decrease 9.7%). Conclusion In-hospital mortality rate has declined over the past decade, but remains high at above 30%. Older age, increased comorbidity and male gender are independent factors for in-hospital mortality. Hospitalizations requiring vascular surgery are associated with high in-hospital mortality, followed by visceral surgery and endovascular approaches. The first wave of the SARS-CoV2-pandemic in spring 2020 implied a decrease in hospital admissions

The Influence of Prenatal Exposure to Quetiapine Fumarate on the Development of Dopaminergic Neurons in the Ventral Midbrain of Mouse Embryos

The effects of second-generation antipsychotics on prenatal neurodevelopment, apoptotic neurodegeneration, and postnatal developmental delays have been poorly investigated. Even at standard doses, the use of quetiapine fumarate (QEPF) in pregnant women might be detrimental to fetal development. We used primary mouse embryonic neurons to evaluate the disruption of morphogenesis and differentiation of ventral midbrain (VM) neurons after exposure to QEPF. The dopaminergic VM neurons were deliberately targeted due to their roles in cognition, motor activity, and behavior. The results revealed that exposure to QEPF during early brain development decreased the effects of the dopaminergic lineage-related genes Tyrosine hydroxylase(Th), Dopamine receptor D1 (Drd1), Dopamine transporter (Dat), LIM homeobox transcription factor 1 alfa (Lmx1a), and Cell adhesion molecule L1 (Chl1), and the senescent dopaminergic gene Pituitary homeobox 3 (Pitx3). In contrast, Brain derived neurotrophic factor (Bdnf) and Nuclear receptor-related 1 (Nurr1) expressions were significantly upregulated. Interestingly, QEPF had variable effects on the development of non-dopaminergic neurons in VM. An optimal dose of QEPF (10 µM) was found to insignificantly affect the viability of neurons isolated from the VM. It also instigated a non-significant reduction in adenosine triphosphate formation in these neuronal populations. Exposure to QEPF during the early stages of brain development could also hinder the formation of VM and their structural phenotypes. These findings could aid therapeutic decision-making when prescribing 2nd generation antipsychotics in pregnant populations