Brain glucose sensing and body energy homeostasis: role in obesity and diabetes

1999 ◽  
Vol 276 (5) ◽  
pp. R1223-R1231 ◽  
Author(s):  
Barry E. Levin ◽  
Ambrose A. Dunn-Meynell ◽  
Vanessa H. Routh
Keyword(s):  
Firing Rate ◽  
Energy Homeostasis ◽  
Glucose Sensing ◽  
Diabetic Rats ◽  
Brain Glucose ◽  
Physiological Regulation ◽  
Glucose Levels ◽  
Obesity And Diabetes ◽  
Sympathoadrenal Activity ◽  
Insulin Dependent Diabetic

The brain has evolved mechanisms for sensing and regulating glucose metabolism. It receives neural inputs from glucosensors in the periphery but also contains neurons that directly sense changes in glucose levels by using glucose as a signal to alter their firing rate. Glucose-responsive (GR) neurons increase and glucose-sensitive (GS) decrease their firing rate when brain glucose levels rise. GR neurons use an ATP-sensitive K+ channel to regulate their firing. The mechanism regulating GS firing is less certain. Both GR and GS neurons respond to, and participate in, the changes in food intake, sympathoadrenal activity, and energy expenditure produced by extremes of hyper- and hypoglycemia. It is less certain that they respond to the small swings in plasma glucose required for the more physiological regulation of energy homeostasis. Both obesity and diabetes are associated with several alterations in brain glucose sensing. In rats with diet-induced obesity and hyperinsulinemia, GR neurons are hyporesponsive to glucose. Insulin-dependent diabetic rats also have abnormalities of GR neurons and neurotransmitter systems potentially involved in glucose sensing. Thus the challenge for the future is to define the role of brain glucose sensing in the physiological regulation of energy balance and in the pathophysiology of obesity and diabetes.

scholarly journals Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose

2009 ◽  
Vol 296 (5) ◽  
pp. E1101-E1109 ◽  
Author(s):  
Victoria E. Cotero ◽  
Vanessa H. Routh
Keyword(s):  
Energy Homeostasis ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Hypothalamic Nucleus ◽  
Compensatory Mechanisms ◽  
Glucose Levels ◽  
Compound C ◽  
Obesity And Diabetes ◽  
Extracellular Glucose ◽  
Pi3k Signaling Pathway

Insulin signaling is dysfunctional in obesity and diabetes. Moreover, central glucose-sensing mechanisms are impaired in these diseases. This is associated with abnormalities in hypothalamic glucose-sensing neurons. Glucose-sensing neurons reside in key areas of the brain involved in glucose and energy homeostasis, such as the ventromedial hypothalamus (VMH). Our results indicate that insulin opens the KATP channel on VMH GE neurons in 5, 2.5, and 0.1 mM glucose. Furthermore, insulin reduced the sensitivity of VMH GE neurons to a decrease in extracellular glucose level from 2.5 to 0.1 mM. This change in the glucose sensitivity in the presence of insulin was reversed by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (10 nM) but not by the mitogen-activated kinase (MAPK) inhibitor PD-98059 (PD; 50 μM). Finally, neither the AMPK inhibitor compound C nor the AMPK activator AICAR altered the activity of VMH GE neurons. These data suggest that insulin attenuates the ability of VMH GE neurons to sense decreased glucose via the PI3K signaling pathway. Furthermore, these data are consistent with the role of insulin as a satiety factor. That is, in the presence of insulin, glucose levels must decline further before GE neurons respond. Thus, the set point for detection of glucose deficit and initiation of compensatory mechanisms would be lowered.

Effect of chronic sulfonylurea treatment on the myocardium of insulin-dependent diabetic rats

1988 ◽  
Vol 66 (12) ◽  
pp. 1481-1486 ◽  
Author(s):  
Mahmood S. Mozaffari ◽  
Glenn L. Wilson ◽  
Stephen W. Schaffer
Keyword(s):  
Glucose Utilization ◽  
Fasting Blood Glucose ◽  
Active Form ◽  
Lactate Production ◽  
Diabetic Rats ◽  
Diabetic Heart ◽  
Adult Rats ◽  
Glucose Levels ◽  
Insulin Responsiveness ◽  
Insulin Dependent Diabetic

Adult rats treated with high doses of streptozocin became progressively more hyperglycemic during the first month of the diabetic condition. Treatment of these rats with the sulfonylurea glyburide halted, and in some cases, reversed this process in a high percentage of the diabetics. Associated with the glyburide-mediated improvement in fasting blood glucose levels was an increase in myocardial glucose utilization and lactate production. The stimulation of myocardial glucose utilization by insulin was greater in glyburide-treated hearts, indicating that the hyperglycemic agent increased insulin responsiveness. The sulfonylurea also partially restored insulin sensitivity to the normal range. In agreement with previous studies, myocardial mechanical function was significantly impaired in the diabetic heart. When treated with glyburide, the severity of the mechanical defect was significantly less. The sulfonylurea also promoted an increase in myosin ATPase activity and a shift in the myosin isozyme pattern in favour of the most active V1 form. These results imply that glyburide therapy can provide benefit to the diabetic heart by improving energy metabolism and promoting a shift in myosin towards the most active form.

Brain Glucose-Sensing Mechanism and Energy Homeostasis

2018 ◽  
Vol 56 (2) ◽  
pp. 769-796 ◽  
Author(s):  
A. J. López-Gambero ◽  
F. Martínez ◽  
K. Salazar ◽  
M. Cifuentes ◽  
F. Nualart
Keyword(s):  
Energy Homeostasis ◽  
Glucose Sensing ◽  
Brain Glucose ◽  
Sensing Mechanism

scholarly journals Remote control of glucose-sensing neurons to analyze glucose metabolism

2018 ◽  
Vol 315 (3) ◽  
pp. E327-E339 ◽  
Author(s):  
Alexandra Alvarsson ◽  
Sarah A. Stanley
Keyword(s):  
Firing Rate ◽  
Brain Regions ◽  
Glucose Sensing ◽  
Neural Stimulation ◽  
Neural Activation ◽  
Glucose Levels ◽  
Disease States ◽  
Neural Populations ◽  
Synthetic Ligand ◽  
The Central Nervous System

The central nervous system relies on a continual supply of glucose, and must be able to detect glucose levels and regulate peripheral organ functions to ensure that its energy requirements are met. Specialized glucose-sensing neurons, first described half a century ago, use glucose as a signal and modulate their firing rates as glucose levels change. Glucose-excited neurons are activated by increasing glucose concentrations, while glucose-inhibited neurons increase their firing rate as glucose concentrations fall and decrease their firing rate as glucose concentrations rise. Glucose-sensing neurons are present in multiple brain regions and are highly expressed in hypothalamic regions, where they are involved in functions related to glucose homeostasis. However, the roles of glucose-sensing neurons in healthy and disease states remain poorly understood. Technologies that can rapidly and reversibly activate or inhibit defined neural populations provide invaluable tools to investigate how specific neural populations regulate metabolism and other physiological roles. Optogenetics has high temporal and spatial resolutions, requires implants for neural stimulation, and is suitable for modulating local neural populations. Chemogenetics, which requires injection of a synthetic ligand, can target both local and widespread populations. Radio- and magnetogenetics offer rapid neural activation in localized or widespread neural populations without the need for implants or injections. These tools will allow us to better understand glucose-sensing neurons and their metabolism-regulating circuits.

Brain Glucose Sensing, Counterregulation, and Energy Homeostasis

Physiology ◽  
2007 ◽  
Vol 22 (4) ◽  
pp. 241-251 ◽  
Author(s):  
Nell Marty ◽  
Michel Dallaporta ◽  
Bernard Thorens
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Energy Homeostasis ◽  
Critical Role ◽  
Glucose Sensing ◽  
Neuronal Circuits ◽  
Brain Glucose ◽  
The Central Nervous System

Neuronal circuits in the central nervous system play a critical role in orchestrating the control of glucose and energy homeostasis. Glucose, beside being a nutrient, is also a signal detected by several glucose-sensing units that are located at different anatomical sites and converge to the hypothalamus to cooperate with leptin and insulin in controlling the melanocortin pathway.

Intestinal gluconeogenesis and protein diet: future directions

2020 ◽  
pp. 1-8
Author(s):  
Amandine Gautier-Stein ◽  
Fabienne Rajas ◽  
Gilles Mithieux
Keyword(s):  
Portal Vein ◽  
Energy Homeostasis ◽  
Glucose Sensing ◽  
Endogenous Glucose Production ◽  
Nutrient Sensing ◽  
Whole Body ◽  
Beneficial Effects ◽  
Obesity And Diabetes ◽  
Intestinal Gluconeogenesis ◽  
Protein Diets

High-protein meals and foods are promoted for their beneficial effects on satiety, weight loss and glucose homeostasis. However, the mechanisms involved and the long-term benefits of such diets are still debated. We here review how the characterisation of intestinal gluconeogenesis (IGN) sheds new light on the mechanisms by which protein diets exert their beneficial effects on health. The small intestine is the third organ (in addition to the liver and kidney) contributing to endogenous glucose production via gluconeogenesis. The particularity of glucose produced by the intestine is that it is detected in the portal vein and initiates a nervous signal to the hypothalamic nuclei regulating energy homeostasis. In this context, we demonstrated that protein diets initiate their satiety effects indirectly via IGN and portal glucose sensing. This induction results in the activation of brain areas involved in the regulation of food intake. The μ-opioid-antagonistic properties of protein digests, exerted in the portal vein, are a key link between IGN induction and protein-enriched diet in the control of satiety. From our results, IGN can be proposed as a mandatory link between nutrient sensing and the regulation of whole-body homeostasis. The use of specific mouse models targeting IGN should allow us to identify several metabolic functions that could be controlled by protein diets. This will lead to the characterisation of the mechanisms by which protein diets improve whole-body homeostasis. These data could be the basis of novel nutritional strategies targeting the serious metabolic consequences of both obesity and diabetes.

Chronic hypoglycemia increases brain glucose transport

1986 ◽  
Vol 251 (4) ◽  
pp. E442-E447 ◽  
Author(s):  
A. L. McCall ◽  
L. B. Fixman ◽  
N. Fleming ◽  
K. Tornheim ◽  
W. Chick ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Creatine Phosphate ◽  
Regular Insulin ◽  
Diabetic Rats ◽  
Repeated Injection ◽  
Brain Glucose ◽  
Glucose Levels ◽  
Brain Uptake Index ◽  
Acute Hypoglycemia ◽  
The Brain

Glucose transport into the brain is depressed in chronically hyperglycemic (diabetic) rats. To determine whether hypoglycemia has the opposite effect, brain transport of hexoses and other substrates was examined in chronically and acutely hypoglycemic rats. We produced chronic hypoglycemia by implanting insulin-secreting tumors or insulin-releasing osmotic mini-pumps or by repeated injection of protamine zinc insulin (PZI) and acute hypoglycemia by intravascular injection of regular insulin. Blood-brain barrier (BBB) transport was measured using the brain uptake index (BUI) method. In the three models of chronic hypoglycemia, brain glucose extraction was increased compared with controls. The extraction of deoxyglucose and several other hexoses was also increased by chronic hypoglycemia. Acute hypoglycemia had no effect on brain transport. The transport of other substrates was either not affected or depressed, suggesting increased brain hexose transport is specific. Studies of freeze-blown brain in insulinoma-engrafted rats showed that brain glucose levels were depressed while creatine phosphate, ATP, and glucose 6-phosphate were maintained. Tumor removal led to a reversion of brain glucose transport to control rates but only after 5-25 days. These findings support the view that glucose transport across the BBB is modulated by chronic alterations in the ambient glucose concentration. They also may explain why some patients with chronic hypoglycemia tolerate low blood glucose concentrations.

scholarly journals Chronic CNS-mediated cardiometabolic actions of leptin: potential role of sex differences

2020 ◽  
Author(s):  
Alexandre A. da Silva ◽  
Mark A. Pinkerton ◽  
Frank T. Spradley ◽  
Ana C. Palei ◽  
John E. Hall ◽  
...  
Keyword(s):  
Sex Differences ◽  
Glucose Homeostasis ◽  
Energy Homeostasis ◽  
Caloric Intake ◽  
Diabetic Rats ◽  
Female Rats ◽  
Male Rats ◽  
Sprague Dawley ◽  
Glucose Levels ◽  
Male And Female Rats

Previous studies using male rodents showed the adipocyte-derived hormone leptin acts in the brain to regulate cardiovascular function, energy balance and glucose homeostasis. The importance of sex differences in cardiometabolic responses to leptin, however, is still unclear. We examined potential sex differences in leptin's chronic central nervous system (CNS)-mediated actions on blood pressure (BP), heart rate (HR), appetite, and glucose homeostasis in normal and type 1 diabetic rats. Female (n=6) and male (n=5) Sprague-Dawley rats were instrumented with intracerebroventricular (ICV) cannulas for continuous 7-day leptin infusion (15 mg/day) and BP and HR were measured by telemetry 24-hrs/day. At baseline, females had lower MAP (96±3 vs. 104±4 mmHg, p<0.05) but higher HR (375±5 vs. 335±5 bpm, p<0.05) compared to males. Following leptin treatment, we observed similar changes in BP (~3 mmHg) and HR (~25 bpm) in both sexes. Females had significantly reduced body weight (BW, 283±2 vs. 417±7 g, p<0.05) and lower caloric intake (162±20 vs. 192±9 kcal/kg of BW, p<0.05) compared to males, and leptin infusion reduced BW (-10%) and caloric intake (-62%) similarly in both sexes. Leptin infusion also caused similar reductions in fasting insulin and blood glucose levels in both sexes. In female and male rats with streptozotocin-induced diabetes (n=5/sex), ICV leptin treatment for 7 days completely normalized glucose levels. These results show that leptin's CNS effects on BP, HR, glucose regulation and energy homeostasis are similar in male and female rats. Therefore, our results provide no evidence for sex differences in leptin's brain-mediated cardiovascular or metabolic actions.

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