Elena Roces de Álvarez-Buylla

Carotid Sinus Receptors Participate in Glucose Homeostasis

This paper describes (a) the influence of glucose on carotid chemoreceptor activity, and (b) the participation of carotid receptors in glucose homeostasis. After eliminating the carotid body baroreceptors in anesthetized cats, the injection of glucose to the vascularly isolated carotid sinus region reduced by 20% the electrical activity of carotid body chemoreceptors and increased their threshold to hypoxia. Mannitol in the same concentration did not change the chemoreceptor activity. A decrease in baroreceptor activity elicited by carotid occlusion, or carotid chemoreceptor stimulation with 50 micrograms/kg cyanide (NaCN), produced an immediate increase in the output of hepatic glucose, raising the hepatic venous-arterial glucose difference above basal levels. Bilateral adrenalectomy eliminated these reflex responses. Cyanide injected in the same conditions caused a sharp increase in glucose retention by the brain. In control experiments, after sectioning the carotid nerve, NaCN injections were ineffective. However, electrical stimulation of the central stump of carotid nerve elicited reflex effects similar to those obtained with NaCN stimulation.

GabaB receptors activation in the NTS blocks the glycemic responses induced by carotid body receptor stimulation

The carotid body receptors participate in glucose regulation sensing glucose levels in blood entering the cephalic circulation. The carotid body receptors information, is initially processed within the nucleus tractus solitarius (NTS) and elicits changes in circulating glucose and brain glucose uptake. Previous work has shown that gamma-aminobutyric acid (GABA) in NTS modulates respiratory reflexes, but the role of GABA within NTS in glucose regulation remains unknown. Here we show that GABA(B) receptor agonist (baclofen) or antagonists (phaclofen and CGP55845A) locally injected into NTS modified arterial glucose levels and brain glucose retention. Control injections outside NTS did not elicit these responses. In contrast, GABA(A) agonist and antagonist (muscimol or bicuculline) produced no significant changes in blood glucose levels. When these GABAergic drugs were applied before carotid body receptors stimulation, again, only GABA(B) agonist or antagonist significantly affected glycemic responses; baclofen microinjection significantly reduced the hyperglycemic response and brain glucose retention observed after carotid body receptors stimulation, while phaclofen produced the opposite effect, increasing significantly hyperglycemia and brain glucose retention. These results indicate that activation of GABA(B), but not GABA(A), receptors in the NTS modulates the glycemic responses after anoxic stimulation of the carotid body receptors, and suggest the presence of a tonic inhibitory mechanism in the NTS to avoid hyperglycemia.

Chronic Exercise Increases Plasma Brain-Derived Neurotrophic Factor Levels, Pancreatic Islet Size, and Insulin Tolerance in a TrkB-Dependent Manner

Background Physical exercise improves glucose metabolism and insulin sensitivity. Brain-derived neurotrophic factor (BDNF) enhances insulin activity in diabetic rodents. Because physical exercise modifies BDNF production, this study aimed to investigate the effects of chronic exercise on plasma BDNF levels and the possible effects on insulin tolerance modification in healthy rats. Methods Wistar rats were divided into five groups: control (sedentary, C); moderate- intensity training (MIT); MIT plus K252A TrkB blocker (MITK); high-intensity training (HIT); and HIT plus K252a (HITK). Training comprised 8 weeks of treadmill running. Plasma BDNF levels (ELISA assay), glucose tolerance, insulin tolerance, and immunohistochemistry for insulin and the pancreatic islet area were evaluated in all groups. In addition, Bdnf mRNA expression in the skeletal muscle was measured. Principal Findings Chronic treadmill exercise significantly increased plasma BDNF levels and insulin tolerance, and both effects were attenuated by TrkB blocking. In the MIT and HIT groups, a significant TrkB-dependent pancreatic islet enlargement was observed. MIT rats exhibited increased liver glycogen levels following insulin administration in a TrkB-independent manner. Conclusions/Significance Chronic physical exercise exerted remarkable effects on insulin regulation by inducing significant increases in the pancreatic islet size and insulin sensitivity in a TrkB-dependent manner. A threshold for the induction of BNDF in response to physical exercise exists in certain muscle groups. To the best of our knowledge, these are the first results to reveal a role for TrkB in the chronic exercise-mediated insulin regulation in healthy rats.

Brain-Derived Neurotrophic Factor in the Nucleus Tractus Solitarii Modulates Glucose Homeostasis After Carotid Chemoreceptor Stimulation in Rats

Neuronal systems, which regulate energy intake, energy expenditure and endogenous glucose production, sense and respond to input from hormonal related signals that convey information from body energy availability. Carotid chemoreceptors (CChr) function as sensors for circulating glucose levels and contribute to glycemic counterregulatory responses. Brain-derived neurotrophic factor (BDNF) that plays an important role in the endocrine system to regulate glucose metabolism could play a role in hyperglycemic glucose reflex with brain glucose retention (BGR) evoked by anoxic CChr stimulation. Infusing BDNF into the nucleus tractus solitarii (NTS) before CChr stimulation, showed that this neurotrophin increased arterial glucose and BGR. In contrast, BDNF receptor (TrkB) antagonist (K252a) infusions in NTS resulted in a decrease in both glucose variables.

Nitric oxide in the commissural nucleus tractus solitarii regulates carotid chemoreception hyperglycemic reflex and c-Fos expression

Carotid body chemoreceptors function as glucose sensors and contribute to glucose homeostasis. The nucleus tractus solitarii (NTS) is the first central nervous system (CNS) nuclei for processing of information arising in the carotid body. Here, we microinjected a nitric oxide (NO) donor sodium nitroprusside (SNP), an NO-independent activator of the soluble guanylyl cyclase (sGC) (YC₁) or an NO-synthase (NOS) inhibitor Nω-nitro-l-arginine methyl ester (L-NAME) into the commissural NTS (cNTS) before carotid chemoreceptor anoxic stimulation and measured arterial glucose and the expression of Fos-like immunoreactivity (Fos-ir). Male Wistar rats (250-300 g) were anesthetized, and the carotid sinus was vascularly isolated. Either artificial cerebrospinal fluid (aCSF), SNP, YC₁ or L-NAME were stereotaxically injected into the cNTS. The SNP and YC₁ infused into the cNTS before carotid chemoreceptor stimulation (SNP-2 and YC₁-2 groups) similarly increased arterial glucose compared to the aCSF-2 group. By contrast, infusion of L-NAME into the cNTS before carotid chemoreceptor stimulation (L-NAME-2 group) decreased arterial glucose concentration. The number of cNTS Fos-ir neurons, determined in all the groups studied except for YC₁ groups, significantly increased in SNP-2 rat when compared to the aCSF-2 or SNP-2 groups. Our findings demonstrate that NO signaling, and the correlative activation of groups of cNTS neurons, plays key roles in the hyperglycemic reflex initiated by carotid chemoreceptor stimulation.

Effects of moderate- and high-intensity chronic exercise on brain-derived neurotrophic factor expression in fast and slow muscles

Introduction: Brain‐derived neurotrophic factor (BDNF) protein expression is sensitive to cellular activity. In the sedentary state, BDNF expression is affected by the muscle phenotype. Methods: Eighteen Wistar rats were divided into the following 3 groups: sedentary (S); moderate‐intensity training (MIT); and high‐intensity training (HIT). The training protocol lasted 8 weeks. Forty‐eight hours after training, total RNA and protein levels in the soleus and plantaris muscles were obtained. Results: In the plantaris, the BDNF protein level was lower in the HIT than in the S group (P < 0.05). A similar effect was found in the soleus (without significant difference). In the soleus, higher Bdnf mRNA levels were found in the HIT group (P < 0.001 vs. S and MIT groups). In the plantaris muscle, similar Bdnf mRNA levels were found in all groups. Conclusions: These results indicate that high‐intensity chronic exercise reduces BDNF protein level in fast muscles and increases Bdnf mRNA levels in slow muscles. Muscle Nerve 53: 446–451, 2016

Effects of moderate‐ and high‐intensity chronic exercise on bdnf expression in fast and slow muscles

Introduction: Brain‐derived neurotrophic factor (BDNF) protein expression is sensitive to cellular activity. In the sedentary state, BDNF expression is affected by the muscle phenotype. Methods: Eighteen Wistar rats were divided into the following 3 groups: sedentary (S); moderate‐intensity training (MIT); and high‐intensity training (HIT). The training protocol lasted 8 weeks. Forty‐eight hours after training, total RNA and protein levels in the soleus and plantaris muscles were obtained. Results: In the plantaris, the BDNF protein level was lower in the HIT than in the S group (P < 0.05). A similar effect was found in the soleus (without significant difference). In the soleus, higher Bdnf mRNA levels were found in the HIT group (P < 0.001 vs. S and MIT groups). In the plantaris muscle, similar Bdnf mRNA levels were found in all groups. Conclusions: These results indicate that high‐intensity chronic exercise reduces BDNF protein level in fast muscles and increases Bdnf mRNA levels in slow muscles. Muscle Nerve 53: 446–451, 2016

Nitric oxide infused in the solitary tract nucleus blocks brain glucose retention induced by carotid chemoreceptor stimulation

Previous work has shown that the carotid body glomus cells can function as glucose sensors. The activation of these chemoreceptors, and of its afferent nucleus in the brainstem (solitary tract nucleus - STn), induces rapid changes in blood glucose levels and brain glucose retention. Nitric oxide (NO) in STn has been suggested to play a key role in the processing of baroreceptor signaling initiated in the carotid sinus. However, the relationship between changes in NO in STn and carotid body induced glycemic changes has not been studied. Here we investigated in anesthetized rats how changes in brain glucose retention, induced by the local stimulation of carotid body chemoreceptors with sodium cyanide (NaCN), were affected by modulation of NO levels in STn. We found that NO donor sodium nitroprusside (SNP) micro-injected into STn completely blocked the brain glucose retention reflex induced by NaCN chemoreceptor stimulation. In contrast, NOS inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) increased brain glucose retention reflex compared to controls or to SNP rats. Interestingly, carotid body stimulation doubled the expression of nNOS in STn, but had no effect in iNOS. NO in STn could function to terminate brain glucose retention induced by carotid body stimulation. The work indicates that NO and STn play key roles in the regulation of brain glucose retention.

Effect of moderate and high intensity chronic exercise on the pancreatic islet morphometry in healthy rats: BDNF receptor participation

ABSTRACT The function and morphology of β-cells is largely dependent on insulin demand. As β-cells cover a bigger cell proportion in pancreas islets, changes of insulin producer cells affect the whole pancreatic islet morphology. Growth factors as the neurotrophins regulate the pancreas physiology, besides; physical exercise increases insulin sensitivity, and further modifies brain derived neurotrophic factor (BDNF) concentration in plasma. The aim of this study was to investigate the effects of chronic exercise (running in a treadmill for 8 weeks) intensity on pancreatic islet morphometry in healthy state. The BDNF receptor effect on the pancreatic islet morphometry was also evaluated. Adult male Wistar rats were divided in 6 groups: Control (C); moderate intensity training (MIT); high intensity training (HIT) did not treat with BDNF receptor inhibitor (K252a), and C, MIT and HIT treated with K252a. The results shown that chronic exercise induces β-cells hypertrophy without BDNF receptor participation. On the other hand, the moderate exercise increases the number of β cells per islet; the last effect does not require TrkB participation. In sedentary conditions, the K252a treatment reduced the β-cell density. Exercise intensity has differential effects on pancreas islet morphometry in healthy model; furthermore, BDNF receptor plays a role to maintain the amount of β-cells in sedentary state.

Concomitant Effects of Nitric Oxide and Carotid Chemoreceptor Stimulation on Brain Glucose in Normoglycemic and Hyperglycemic Rats

BACKGROUND AND AIMS Carotid body (CB) sinus perfusion with different glucose concentrations modifies arterial glucose concentration and brain glucose retention, thereby changing the brains threshold to hypoxia. Because nitric oxide (NO) modulates hypoxic chemoreception, we investigated the relationship between NO- and CB-receptor pathways on arterial glucose and brain arteriovenous (a-v) glucose difference after hypoxic stimulation under hyperglycemic conditions. METHODS Normoglycemic and streptozotocin (STZ, 50 mg/kg i.p.)-induced hyperglycemic Sprague Dawley rats were infused with the NO donor, sodium nitroprusside (SNP), or the NOS inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME) into the circulatory isolated carotid sinus after (30 sec) local anoxic CB chemoreceptor stimulation with sodium cyanide (NaCN). RESULTS L-NAME abolished the hyperglycemia and the increase in brain a-v glucose concentration difference induced by CB chemoreceptor stimulation in normoglycemic rats, whereas the same treatment in hyperglycemic rats did not change the glucose variables studied. However, SNP infused under the same conditions induced a bigger rise in arterial glucose and brain a-v glucose concentration difference only in normoglycemic rats, when compared with the results obtained in sham-2-control rats. CB stimulation plus SNP treatment also resulted in an increase in nitrite levels in cephalic venous blood in normoglycemic, but not in hyperglycemic, rats. CONCLUSIONS We showed a clear concomitant effect of SNP infusion into local CB circulation and anoxic cyanide stimulation, enhancing hyperglycemia and brain a-v glucose concentration difference. Importantly, at high glucose levels, nitrergic drugs did not modify glucose variables when compared with the corresponding sham controls.