Candido Celso Coimbra

The combination of high-fat diet-induced obesity and chronic ulcerative colitis reciprocally exacerbates adipose tissue and colon inflammation

BackgroundThis study evaluated the relationship between ulcerative colitis and obesity, which are both chronic diseases characterized by inflammation and increases in immune cells and pro-inflammatory cytokines.MethodsMice with chronic ulcerative colitis induced by 2 cycles of dextran sodium sulfate (DSS) in the first and fourth week of the experiment were fed a high-fat diet (HFD) to induce obesity by 8 weeks. The animals were divided into 4 \ groups (control, colitis, HFD and colitis + HFD).ResultsObesity alone did not raise histopathology scores, but the combination of obesity and colitis worsened the scores in the colon compared to colitis group. Despite the reduction in weight gain, there was increased inflammatory infiltrate in both the colon and visceral adipose tissue of colitis + HFD mice due to increased infiltration of macrophages, neutrophils and lymphocytes. Intravital microscopy of VAT microvasculature showed an increase in leukocyte adhesion and rolling and overexpression of adhesion molecules compared to other groups. Moreover, circulating lymphocytes, monocytes and neutrophils in the spleen and cecal lymph nodes were increased in the colitis + HFD group.ConclusionOur results demonstrated the relationship between ulcerative colitis and obesity as aggravating factors for each disease, with increased inflammation in the colon and adipose tissue and systemic alterations observed in the spleen, lymph nodes and bloodstream.

Cold-induced free fatty acid mobilization is impaired in rats with lesions in the preoptic area

The increase in plasma free fatty acids (FFA) induced by cold (2 h at 5 degrees C) in rats with bilateral electrolytic lesions in the preoptic area was reduced to 30% compared to sham-operated controls. Blood glucose of lesioned rats increased 35% over initial levels and remained elevated, whereas in controls it returned to initial levels after 2 h. Rectal temperature decreased 3 degrees C in lesioned rats but not in controls. These data demonstrate the participation of the preoptic area in cold-induced FFA mobilization and provide evidence for the role of this area in the integration of thermal inputs with energy-linked metabolic processes.

Effects of hyperprolactinemia on plasma glucose and prolactin in rats exposed to ether stress

The present study was designed to characterize the effect of chronic hyperprolactinemia on plasma glucose and prolactin (PRL) during ether stress in male and female rats. Wistar rats of both sexes were divided into a hyperprolactinemic group (bearing pituitary grafts) and a control group (sham operated). They were exposed to ether during 10 min and had blood samples taken immediately before, and 5, 15, 40, and 70 min after ether exposure and assayed for glucose and PRL concentrations. Ether stress induced significant increase in plasma PRL of control rats at 5 min (male 171%, female 161%; P < 0.01), but only a mild PRL increase occurred in grafted rats (male 66%, female 62%; P < 0.05). Control male rats sustained elevated plasma PRL longer than females. There was a marked elevation of glucose levels at 5 min (P < 0.01) which peaked at 15 min in all groups. Grafted rats had glucose levels significantly above control at baseline (female 15%, P < 0.05) and at 40 min (male 25%, female 29%; P < 0.05). It is concluded that ether-induced PRL release produced a rapid and transient response, more intense in males than in females and which was impaired by previous hyperprolactinemia (pituitary grafts). There was an acute hyperglycemic response, plasma glucose being increased in grafted rats, supporting the hypothesis of a hyperglycemic effect of PRL.

Hyperglycemic action of angiotensin II in freely moving rats

Angiotensin II has been implicated in the regulation of liver glycogen phosphorylase. Although it has been suggested that angiotensin II can raise blood glucose levels during hemorrhage, experimental data have not been presented. In the present study, the effect of angiotensin II on blood glucose levels was studied in freely moving rats, divided in three experimental groups: 1) intravenous administration of angiotensin II (0.48, 1.9, or 4.8 nmol) caused a dose-dependence response; 2) intracerebroventricular administration of angiotensin II (1.9 or 4.8 nmol) did not cause any significant change in glycemia compared with saline-treated controls; 3) intravenous administration of [Sar1,Thr8]angiotensin II, an antagonist of angiotensin II (750 ng/100 g b. wt. as a bolus plus a continuous injection of 25 ng/100 g b. wt./min over 30 min), greatly attenuated (39.2% lower than controls; p < 0.01) the hyperglycemic response to hemorrhage (1.2 ml/100 g b.wt.). These data indicate an in vivo involvement of angiotensin II in blood glucose regulation.

Modulation of plasma glucose by the medial preoptic area in freely moving rats

The effect of norepinephrine (NE) injection into the medial preoptic area (MPOA) on plasma glucose was studied in freely moving male rats. The rats were implanted with chronic jugular catheters for blood sampling and with unilateral intracerebral cannulas placed just above the MPOA. Blood samples were taken immediately before and 5, 10, 15, and 30 min after NE injection. As early as 5 min after NE injection, plasma glucose levels rose rapidly, reaching a peak at 15 min poststimulus. The hyperglycemic response to NE injection into the MPOA was dose-related within the range of doses tested (10, 20, and 40 nmol). Previous administration of phentolamine (50 nmol), but not propranolol (100 nmol), into the MPOA blocked the hyperglycemic response to NE injection into the MPOA. The increase of plasma glucose induced by NE into the MPOA and the blockade of the hyperglycemic response to NE by phentolamine suggest the involvement of an alpha-adrenergic mechanism in MPOA-mediated hyperglycemia. On the basis of these and previous results, we propose that MPOA alpha-adrenergic synapses relay impulses activating the sympathetic outflow expressed by neurally mediated hyperglycemia.

α-Estrogen and Progesterone Receptors Modulate Kisspeptin Effects on Prolactin: Role in Estradiol-Induced Prolactin Surge in Female Rats

Kisspeptin (Kp) regulates prolactin (PRL) in an estradiol-dependent manner. We investigated the interaction between ovarian steroid receptors and Kp in the control of PRL secretion. Intracerebroventricular injections of Kp-10 or Kp-234 were performed in ovariectomized (OVX) rats under different hormonal treatments. Kp-10 increased PRL release and decreased 3,4-dihydroxyphenylacetic acid levels in the median eminence (ME) of OVX rats treated with estradiol (OVX+E), which was prevented by tamoxifen. Whereas these effects of Kp-10 were absent in OVX rats, they were replicated in OVX rats treated with selective agonist of estrogen receptor (ER)α, propylpyrazole triol, but not of ERβ, diarylpropionitrile. Furthermore, the Kp-10-induced increase in PRL was two times higher in OVX+E rats also treated with progesterone (OVX+EP), which was associated with a reduced expression of both tyrosine hydroxylase (TH) and Ser40-phosphorylated TH in the ME. Kp-10 also reduced dopamine levels in the ME of OVX+EP rats, an effect blocked by the progesterone receptor (PR) antagonist RU486. We also determined the effect of Kp antagonism with Kp-234 on the estradiol-induced surges of PRL and luteinizing hormone (LH), using tail-tip blood sampling combined with ultrasensitive enzyme-linked immunosorbent assay. Kp-234 impaired the early phase of the PRL surge and prevented the LH surge in OVX+E rats. Thus, we provide evidence that Kp stimulation of PRL release requires ERα and is potentiated by progesterone via PR activation. Moreover, alongside its essential role in the LH surge, Kp seems to play a role in the peak phase of the estradiol-induced PRL surge.

Angiotensin-converting enzyme inhibition changes the metabolic response to neuroglucopenic stress

Neuroglucopenia induced by 2-deoxy-D-glucose (2DG) activates hypothalamic glucoreceptors leading to increased hepatic glucose production and insulin inhibition. This response is similar to what is observed with intravenous injection of angiotensin II (Ang II). However, the involvement of an angiotensin-converting enzyme inhibitor on neuroglucopenia has not been investigated. The aim of this study was to determine the effects of chronic enalapril treatment on plasma glucose, insulin and lipid levels in response to neuroglucopenia. Male Holtzman rats (120—170 g) were chronically treated with enalapril (10 mg/kg per day) in the drinking water for two weeks. On the day of experiment the animals received an i.v. enalapril final dose one hour before the neuroglucopenic stress by 2DG infusion (500 mg/kg), and blood samples were drawn before and 5, 10, 20, 30 and 60 minutes following infusion. The hyperglycaemic response to 2DG was not significantly changed by enalapril treatment. The enalapril-treated group exhibited a peak of plasma insulin higher than controls. Plasma triglyceride showed a significant increase only in the enalapril group after neuroglucopenic stress (p < 0.05).These data show that chronic enalapril treatment changes insulin and triglyceride responses to neuroglucopenia, suggesting an effect on glucose-induced insulin secretion and the storage of triglycerides.

Fast and slow-twitching muscles are differentially affected by reduced cholinergic transmission in mice deficient for VAChT: A mouse model for congenital myasthenia

&NA; Congenital myasthenic syndromes (CMS) result from reduced cholinergic transmission at neuromuscular junctions (NMJs). While the etiology of CMS varies, the disease is characterized by muscle weakness. To date, it remains unknown if CMS causes long‐term and irreversible changes to skeletal muscles. In this study, we examined skeletal muscles in a mouse line with reduced expression of Vesicular Acetylcholine Transporter (VAChT, mouse line herein called VAChT‐KDHOM). We examined this mouse line for several reasons. First, VAChT plays a central function in loading acetylcholine (ACh) into synaptic vesicles and releasing it at NMJs, in addition to other cholinergic nerve endings. Second, loss of function mutations in VAChT causes myasthenia in humans. Importantly, VAChT‐KDHOM present with reduced ACh and muscle weakness, resembling CMS. We evaluated the morphology, fiber type (myosin heavy chain isoforms), and expression of muscle‐related genes in the extensor digitorum longus (EDL) and soleus muscles. This analysis revealed that while muscle fibers atrophy in the EDL, they hypertrophy in the soleus muscle of VAChT‐KDHOM mice. Along with these cellular changes, skeletal muscles exhibit altered levels of markers for myogenesis (Pax‐7, Myogenin, and MyoD), oxidative metabolism (PGC1‐&agr; and MTND1), and protein degradation (Atrogin1 and MuRF1) in VAChT‐KDHOM mice. Importantly, we demonstrate that deleterious changes in skeletal muscles and motor deficits can be partially reversed following the administration of the cholinesterase inhibitor, pyridostigmine in VAChT‐KDHOM mice. These findings reveal that fast and slow type muscles differentially respond to cholinergic deficits. Additionally, this study shows that the adverse effects of cholinergic transmission, as in the case of CMS, on fast and slow type skeletal muscles are reversible. Graphical abstract Figure. No caption available. HighlightsAtrophy of the fast‐EDL and hypertrophy of the slow‐Soleus muscles from a VAChT Knockdown, homozygous mice (VAChT KDHOM).Cholinergic dysfunction induces fiber type switching in EDL and Soleus and causes myofibrils ultrastructure abnormalities.VAChT KDHOM mice presented altered levels of markers for myogenesis, oxidative metabolism and protein degradation.The muscle waste in this type of congenital myasthenia may be rescuable following pyridostigmine treatment.

Angiotensin-converting enzyme inhibition increases glucose-induced insulin secretion in response to acute restraint.

There is increasing evidence suggesting involvement of the renin–angiotensin system (RAS) in carbohydrate metabolism and its response to stress. Thus, the aim of the present study was to evaluate the effects of chronic inhibition of the RAS on glucose and insulin levels during acute restraint stress. Male Holtzman rats were treated with 10 mg/kg per day enalapril solution or vehicle for 14 days. After 14 days, rats were divided into three experimental groups: enalapril + restraint (ER), vehicle + restraint (VR) and enalapril + saline (ES). Rats in the restraint groups were subjected to 30 min restraint stress, whereas rats in the ES groups were given saline infusion instead. Blood samples were collected at baseline and after 5, 10, 20 and 30 min restraint stress or saline infusion. After restraint, a hyperglycaemic response was observed in the ER and VR groups that peaked at 20 and 10 min, respectively (P < 0.05 compared with baseline). The area under the glucose curve was markedly increased in the ER and VR groups compared with that in the ES group (P < 0.05 for both). Importantly, restraint induced a marked increase in insulin secretion in the ER group compared with only a mild elevation in the VR group; insulin secretion in both groups peaked at 20 min (P < 0.05 compared with baseline). Analysis of the area under the insulin curve confirmed an increase in insulin secretion in the ER compared with the VR and ES groups (P < 0.05 for both). The results of the present study reinforce that the RAS is involved in modulating responses to stress and suggest that RAS inhibition with enalapril may increase glucose‐induced insulin secretion in response to acute restraint.