Chronic Antidiabetic Actions of Leptin: Evidence from Parabiosis Studies for a CNS-Derived Circulating Antidiabetic Factor

We used parabiosis to determine whether the central nervous system (CNS)-mediated antidiabetic effects of leptin are mediated by release of a brain-derived circulating factor(s). Parabiosis was surgically induced at 4 weeks of age and an intracerebroventricular (ICV) cannula was placed in the lateral cerebral ventricles at 12 weeks of age for ICV infusion of leptin or saline vehicle. Ten days after surgery, food intake, body weight and blood glucose were measured for 5 consecutive days and insulin-deficiency diabetes was induced in all rats by a single streptozotocin (STZ) injection (40 mg/kg). Five days after STZ injection, leptin or vehicle was infused ICV for 7 days, followed by 5-day recovery period. STZ increased blood glucose and food intake. Chronic ICV leptin infusion restored normoglycemia in leptin-infused rats while reducing blood glucose by ~27% in conjoined vehicle-infused rats. This glucose reduction was caused mainly by decreased hepatic gluconeogenesis. Chronic ICV leptin infusion also reduced net cumulative food intake and increased GLUT4 expression in skeletal muscle in leptin/vehicle compared to vehicle/vehicle conjoined rats. These results indicate that leptin’s CNS-mediated antidiabetic effects are mediated, in part, by release into the systemic circulation of a leptin-stimulated factor(s) that enhances glucose utilization and reduces liver gluconeogenesis.

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Chronic Antidiabetic Actions of Leptin: Evidence from Parabiosis Studies for a CNS-Derived Circulating Antidiabetic Factor

10.2337/figshare.15067695 ◽

2021 ◽

Author(s):

Alexandre A. da Silva ◽

John E. Hall ◽

Xuemei Dai ◽

Zhen Wang ◽

Mateus C. Salgado ◽

...

Keyword(s):

Blood Glucose ◽

Food Intake ◽

Recovery Period ◽

Systemic Circulation ◽

Glut4 Expression ◽

The Central Nervous System ◽

Glucose Reduction ◽

Surgically Induced ◽

Saline Vehicle ◽

Antidiabetic Effects

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Control of appetite, blood glucose, and blood pressure during melanocortin-4 receptor activation in normoglycemic and diabetic NPY-deficient mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00293.2017 ◽

2018 ◽

Vol 314 (4) ◽

pp. R533-R539 ◽

Cited By ~ 5

Author(s):

Alexandre A. da Silva ◽

J. Nathan Freeman ◽

John E. Hall ◽

Jussara M. do Carmo

Keyword(s):

Food Intake ◽

Recovery Period ◽

Receptor Activation ◽

Metabolic Functions ◽

Melanocortin 4 Receptor ◽

The Central Nervous System ◽

Deficient Mice ◽

Antidiabetic Effects

Although central melanocortin 4 receptor (MC4R) blockade abolishes the central nervous system (CNS)-mediated anorexogenic, antidiabetic, and cardiovascular actions of leptin, chronic MC4R stimulation fails to completely mimic the effects of leptin. Because neuropeptide Y (NPY) and MC4R exert opposite effects on cardiovascular and metabolic functions, we tested the role of NPY in offsetting the long-term actions of MC4R activation. Wild-type (WT) and NPY-deficient (NPY−/−) mice were implanted with telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR) 24 h/day. After the mice recovered from surgery and stable baseline measurements, the MC3/4R agonist melanotan II (MTII, 120 μg·kg−1·day−1 iv) was infused for 7 days followed by a recovery period. No major differences between groups were observed at baseline except for slightly higher food intake and HR in NPY−/− mice (4.3 ± 0.2 vs. 3.4 ± 0.2 g/day and 567 ± 14 vs. 522 ± 13 beats/min). Chronic MTII infusion reduced food intake in both groups while causing transient increases in MAP and HR only in WT mice (peaks of 11 ± 3 mmHg and 126 ± 13 beats/min). To examine whether NPY deficiency would amplify the antidiabetic effects of MC4R activation, diabetes was induced with streptozotocin (STZ) 1 wk before baseline measurements were taken, and the same experimental protocol was followed. In WT and NPY−/− mice, STZ-induced diabetes led to similar hyperphagia, hyperglycemia, and weight loss, which were not reversed by chronic MTII treatment. Our results demonstrate that chronic MC4R activation, even in NPY-deficient mice, does not mimic chronic antidiabetic, cardiovascular, or metabolic actions of leptin, and that NPY is not essential for hyperphagia or cardiovascular changes associated with diabetes.

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Insulin secretion: mechanism of the stimulation by glucose

Quarterly Reviews of Biophysics ◽

10.1017/s0033583500001281 ◽

1975 ◽

Vol 8 (1) ◽

pp. 1-41 ◽

Cited By ~ 20

Author(s):

Erol Cerasi

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Insulin Secretion ◽

Blood Glucose ◽

Food Intake ◽

Blood Glucose Level ◽

Glucose Level ◽

Glucose Concentration ◽

The Central Nervous System ◽

The Stability

Glucose is one of the substrates that is controlled with the most efficient hormonal mechanisms in higher organisms. The presence of tissues such as the central nervous system which, under normal conditions, depend solely on glucose as substrate, and the sporadic type of food intake with periods of fasting of various lengths in the mammalians necessitate that the distribution of energy-rich substrates among various tissues be continuously adjusted by changes in the secretion of a number of hormones. The efficiency of this system is evidenced by the stability of the blood glucose level in man, in whom after a carbohydrate-rich meal more than 70% of the glucose that has been ingested will be retained in the liver during a single passage of portal blood, resulting in only small changes of the glucose concentration in peripheral blood. Likewise, periods of fasting up to24–36 h are followed by modest to minimal reductions of the blood glucose level, the liver now supplying the circulation with the hexose.

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The contribution of afferent signals from the liver to metabolic regulation during exercise

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-137 ◽

2002 ◽

Vol 80 (11) ◽

pp. 1035-1044 ◽

Cited By ~ 8

Author(s):

Jean-Marc Lavoie

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Blood Glucose ◽

Food Intake ◽

Vagus Nerve ◽

Metabolic Regulation ◽

Vagal Activity ◽

The Central Nervous System ◽

Response To Exercise

The crucial role of the liver as the only organ to produce glucose used by skeletal muscle during exercise is well known. Since hepatic glucose production is central to blood glucose homeostasis during exercise, it has been postulated that the liver may inform the central nervous system and other organs of its diminishing capacity to produce glucose from glycogen, before blood glucose falls. The sensory role of the liver during exercise would be similar to its role in the control of food intake. As a consequence, the experimental approaches used to test the hypothesis that afferent signals from the liver contribute to metabolic regulation during exercise are inspired by those used to test the same hypothesis in the regulation of food intake. In the present review, two questions are addressed. The existing evidence for the liver's sensory influence on metabolic adjustments to exercise is first reviewed; the nature of the initiating stimuli for the afferent contribution of the liver to physical exercise is discussed thereafter. The hypothetical construct upon which rests the contribution of the liver's afferent signals to metabolic regulation during exercise is that a decrease in liver glycogen or a related metabolic intermediate is sensed by the liver, and the signal is transduced to the central nervous system, most likely through the afferent activity of the hepatic vagus nerve, where it contributes to the orchestration of the metabolic and hormonal responses to exercise. Support in favour of this construct comes mainly from the demonstration that sectioning of the hepatic vagus nerve attenuates the normal hormonal response to exercise. It seems that the liverglucagon axis is particularly responsive to this reflex activation. In other respects, the hepatic mechanism responsible for linking the metabolic activity in the liver to an afferent signal capable of regulating the metabolic response to exercise remains speculative. Substrates or derivatives of substrate oxidation, energy-related compounds (ATP and Pi), or changes in cell volume may all be related to changes in transmembrane potential in the liver cell, which according to the "potentiostatic" theory would determine the afferent vagal activity. Key words: hepatic vagotomy, insulin, glucagon, portal infusion, metabolic regulation.

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Development of a Fish Paste with Oreochromis mossambicus and Coccina grandis as a Natural Blood Glucose Reduction Food

International Conference on Agricultural, Ecological and Medical Sciences (AEMS-2015) Feb. 10-11, 2015 Penang (Malaysia) ◽

10.15242/iicbe.c0215114 ◽

2015 ◽

Keyword(s):

Blood Glucose ◽

Oreochromis Mossambicus ◽

Glucose Reduction

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Pharmacological effects of secondary bile acid microparticles in diabetic murine model

Current Diabetes Reviews ◽

10.2174/1573399816666200626213735 ◽

2020 ◽

Vol 16 ◽

Author(s):

Armin Mooranian ◽

Nassim Zamani ◽

Bozica Kovacevic ◽

Corina Mihaela Ionescu ◽

Giuseppe Luna ◽

...

Keyword(s):

Bile Acid ◽

Blood Glucose ◽

Bile Acids ◽

Lithocholic Acid ◽

Diabetes Treatment ◽

Secondary Bile Acid ◽

Glucose Levels ◽

Anti Inflammatory ◽

Antidiabetic Effects

Aim: Examine bile acids effects in Type 2 diabetes. Background: In recent studies, the bile acid ursodeoxycholic acid (UDCA) has shown potent anti-inflammatory effects in obese patients while in type 2 diabetics (T2D) levels of the pro-inflammatory bile acid lithocholic acid were increased, and levels of the anti-inflammatory bile acid chenodeoxycholic acid were decreased, in plasma. Objective: Hence, this study aimed to examine applications of novel UDCA nanoparticles in diabetes. Methods: Diabetic balb/c adult mice were divided into three equal groups and gavaged daily with either empty microcapsules, free UDCA, or microencapsulated UDCA over two weeks. Their blood, tissues, urine, and faeces were collected for blood glucose, inflammation, and bile acid analyses. UDCA resulted in modulatory effects on bile acids profile without antidiabetic effects suggesting that bile acid modulation was not directly linked to diabetes treatment. Results: UDCA resulted in modulatory effects on bile acids profile without antidiabetic effects suggesting that bile acid modulation was not directly linked to diabetes treatment. Conclusion: Bile acids modulated the bile profile without affecting blood glucose levels.

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Central Histamine, the H3-Receptor and Obesity Therapy

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190703094846 ◽

2019 ◽

Vol 18 (7) ◽

pp. 516-522

Author(s):

Néstor F. Díaz ◽

Héctor Flores-Herrera ◽

Guadalupe García-López ◽

Anayansi Molina-Hernández

Keyword(s):

Body Weight ◽

Food Intake ◽

Animal Studies ◽

Energy Homeostasis ◽

Receptor Activation ◽

Receptor Ligands ◽

Histaminergic System ◽

H3 Receptor ◽

Weight One ◽

The Central Nervous System

The brain histaminergic system plays a pivotal role in energy homeostasis, through H1- receptor activation, it increases the hypothalamic release of histamine that decreases food intake and reduces body weight. One way to increase the release of hypothalamic histamine is through the use of antagonist/inverse agonist for the H3-receptor. Histamine H3-receptors are auto-receptors and heteroreceptors located on the presynaptic membranes and cell soma of neurons, where they negatively regulate the synthesis and release of histamine and other neurotransmitters in the central nervous system. Although several compounds acting as H3-receptor antagonist/inverse agonists have been developed, conflicting results have been reported and only one has been tested as anti-obesity in humans. Animal studies revealed the opposite effect in food intake, energy expeditor, and body weight, depending on the drug, spice, and route of administration, among others. The present review will explore the state of art on the effects of H3-receptor ligands on appetite and body-weight, going through the following: a brief overview of the circuit involved in the control of food intake and energy homeostasis, the participation of the histaminergic system in food intake and body weight, and the H3-receptor as a potential therapeutic target for obesity.

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Anti-Diabetic and Angio-Protective Effect of Guluronic Acid (G2013) as a New Nonsteroidal Anti-Inflammatory Drug in the Experimental Model of Diabetes

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666191016103918 ◽

2020 ◽

Vol 20 (3) ◽

pp. 446-452

Author(s):

Seyed S. Mortazavi-Jahromi ◽

Shahab Alizadeh ◽

Mohammad H. Javanbakht ◽

Abbas Mirshafiey

Keyword(s):

Gene Expression ◽

Blood Glucose ◽

Food Intake ◽

Experimental Model ◽

Serum Insulin ◽

Fasting Blood Glucose ◽

Diabetic Control ◽

The Body ◽

Sprague Dawley ◽

Guluronic Acid

Background: This study aimed to investigate the effects of guluronic acid (G2013) on blood sugar, insulin, and gene expression profile of oxLDL receptors (SR-A, CD36, LOX-1, and CD68) in the experimental model of diabetes. Methods: 18 Sprague Dawley rats were randomly assigned to three groups of healthy control, diabetic control, and G2013 group. Diabetes was induced through intraperitoneal (IP) injection of 60 mg/kg streptozotocin. The subjects were IP treated with 25 mg/kg of G2013 per day for 28 days. The body weight, food intake, fasting blood glucose and insulin were measured. In addition, the expression of mentioned genes was investigated through quantitative real-time PCR. Results: The data showed that the final weight increased significantly in the G2013-treated subjects compared to the diabetic control (p < 0.05). The results indicated that final food intake significantly reduced in the G2013-treated subjects compared to the diabetic control (p < 0.05). The study findings also suggested that the final fasting blood glucose significantly reduced in the G2013-treated group, whereas the final fasting serum insulin level significantly increased in this group compared to the diabetic control (p < 0.05). Moreover, the gene expression levels of SR-A, CD36, LOX-1, and CD68 in the G2013 group significantly reduced compared to the diabetic control (p < 0.05). Conclusion: This study showed that G2013, could reduce blood glucose and increase insulin levels and reduce the gene expression level of oxLDL receptors. In addition, it may probably play an important role in reducing the severity of diabetes-induced inflammatory symptoms.

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