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1.
Mol Metab ; 55: 101407, 2022 01.
Article in English | MEDLINE | ID: mdl-34844019

ABSTRACT

OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood. METHODS: We employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain. RESULTS: We found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs and for the induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance. CONCLUSIONS: In addition to disclosing a neuronal population required for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea - a major factor for withdrawal from treatment.


Subject(s)
Cholecystokinin/pharmacology , Gastric Inhibitory Polypeptide/metabolism , Glucagon-Like Peptide-1 Receptor/metabolism , Animals , Appetite/drug effects , Appetite Depressants/pharmacology , Blood Glucose/drug effects , Exenatide/pharmacology , Female , Glucagon/metabolism , Glucagon-Like Peptide 1/pharmacology , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/physiology , Hypoglycemic Agents/pharmacology , Insulin/pharmacology , Liraglutide/pharmacology , Male , Mice , Mice, Inbred C57BL , Neurons/metabolism , Receptors, Gastrointestinal Hormone/metabolism
2.
Cells ; 10(9)2021 09 21.
Article in English | MEDLINE | ID: mdl-34572144

ABSTRACT

Incretin-potentiated glucose-stimulated insulin secretion (GSIS) is critical to maintaining euglycemia, of which GLP-1 receptor (GLP-1R) on ß-cells plays an indispensable role. Recently, α-cell-derived glucagon but not intestine-derived GLP-1 has been proposed as the critical hormone that potentiates GSIS via GLP-1R. However, the function of glucagon receptors (GCGR) on ß-cells remains elusive. Here, using GCGR or GLP-1R antagonists, in combination with glucagon, to treat single ß-cells, α-ß cell clusters and isolated islets, we found that glucagon potentiates insulin secretion via ß-cell GCGR at physiological but not high concentrations of glucose. Furthermore, we transfected primary mouse ß-cells with RAB-ICUE (a genetically encoded cAMP fluorescence indicator) to monitor cAMP level after glucose stimulation and GCGR activation. Using specific inhibitors of different adenylyl cyclase (AC) family members, we revealed that high glucose concentration or GCGR activation independently evoked cAMP elevation via AC5 in ß-cells, thus high glucose stimulation bypassed GCGR in promoting insulin secretion. Additionally, we generated ß-cell-specific GCGR knockout mice which glucose intolerance was more severe when fed a high-fat diet (HFD). We further found that ß-cell GCGR activation promoted GSIS more than GLP-1R in HFD, indicating the critical role of GCGR in maintaining glucose homeostasis during nutrient overload.


Subject(s)
Glucagon/pharmacology , Insulin Secretion/physiology , Receptors, Glucagon/physiology , Animals , Glucagon/metabolism , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors , Glucagon-Like Peptide-1 Receptor/metabolism , Glucagon-Like Peptide-1 Receptor/physiology , Glucose/metabolism , Glucose Intolerance/metabolism , Insulin/metabolism , Insulin Secretion/drug effects , Insulin-Secreting Cells/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Glucagon/antagonists & inhibitors , Signal Transduction
4.
Front Endocrinol (Lausanne) ; 12: 665537, 2021.
Article in English | MEDLINE | ID: mdl-34122340

ABSTRACT

A key factor for the insulin response to oral glucose is the pro-glucagon derived incretin hormone glucagon-like peptide-1 (GLP-1), together with the companion incretin hormone, glucose-dependent insulinotropic polypeptide (GIP). Studies in GIP and GLP-1 receptor knockout (KO) mice have been undertaken in several studies to examine this role of the incretin hormones. In the present study, we reviewed the literature on glucose and insulin responses to oral glucose in these mice. We found six publications with such studies reporting results of thirteen separate study arms. The results were not straightforward, since glucose intolerance in GIP or GLP-1 receptor KO mice were reported only in eight of the arms, whereas normal glucose tolerance was reported in five arms. A general potential weakness of the published study is that each of them have examined effects of only one single dose of glucose. In a previous study in mice with genetic deletion of both GLP-1 and GIP receptors we showed that these mice have impaired insulin response to oral glucose after large but not small glucose loads, suggesting that the relevance of the incretin hormones may be dependent on the glucose load. To further test this hypothesis, we have now performed a stepwise glucose administration through a gastric tube (from zero to 125mg) in model experiments in anesthetized female wildtype, GLP-1 receptor KO and GIP receptor KO mice. We show that GIP receptor KO mice exhibit glucose intolerance in the presence of impaired insulin response after 100 and 125 mg glucose, but not after lower doses of glucose. In contrast, GLP-1 receptor KO mice have normal glucose tolerance after all glucose loads, in the presence of a compensatory increase in the insulin response. Therefore, based on these results and the literature survey, we suggest that GIP and GLP-1 receptor KO mice retain normal glucose tolerance after oral glucose, except after large glucose loads in GIP receptor KO mice, and we also show an adaptive mechanism in GLP-1 receptor KO mice, which needs to be further examined.


Subject(s)
Glucagon-Like Peptide-1 Receptor/physiology , Glucose/administration & dosage , Insulin-Secreting Cells/drug effects , Insulin/pharmacology , Receptors, Gastrointestinal Hormone/physiology , Administration, Oral , Animals , Female , Gastric Inhibitory Polypeptide/metabolism , Glucagon/metabolism , Glucagon-Like Peptide 1/metabolism , Hypoglycemic Agents/pharmacology , Insulin Secretion , Insulin-Secreting Cells/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout
5.
Mediators Inflamm ; 2021: 5568159, 2021.
Article in English | MEDLINE | ID: mdl-33854404

ABSTRACT

AIMS: To investigate the effect of GLP-1/GLP-1R on the polarization of macrophages in the occurrence and development of atherosclerosis. METHODS: Totally, 49 patients with coronary heart disease (CHD) and 52 cases of health control (HC) were recruited, all subjects accept coronary angiography gold standard inspection. One or more major coronary arteries (LM, LAD, LCx, and RCA) stenosis degree in 50% of patients as CHD group; the rest of the stenosis less than 50% or not seen obvious stenosis are assigned to the HC group. Flow cytometry were used to detect the percentage of (CD14+) M macrophages, (CD14+CD80+) M1 macrophages, (CD14+CD206+) M2 macrophages, and their surface GLP-1R expression differences in the two groups, using BD cytokine kit to detect the levels of IL-8, IL-1ß, IL-6, IL-10, TNF, and IL-12p70. RESULTS: GLP-1R expression on the surface of total macrophages and M2 macrophages was different between the CHD group and the HC group (P < 0.05). There was no difference in the percentage of total, M1 or M2 macrophages (P > 0.05). Concentration of IL-8 in the HC group was higher than that in the CHD group (P < 0.05). There is no significant difference in the cytokine IL-1ß, IL-6, IL-10, TNF, and IL-12p70 in the two groups (P > 0.05). After controlling for potential confounders including age, gender, smoking status (S.S.), drinking status (D.S.), HR, SBP, DBP, PP, TC, TG, HDL-C, LDL-C, GHbA1c, M, M1, M2, GLP-1R_M, GLP-1R_M1, GLP-1R_M2, IL-8, IL-1ß, IL-6, IL-10, TNF, and IL-12p70 by multiple linear regression, decreasing Gensini Score was significantly associated with increased percentage of M1 macrophage. CONCLUSION: GLP-1R agonist is independent of the hypoglycemic effect of T2DM and has protective effect on cardiovascular system. GLP-1R may regulate the polarization of macrophages toward M2, thus playing a protective role in the progression of coronary atherosclerosis.


Subject(s)
Coronary Artery Disease/prevention & control , Glucagon-Like Peptide 1/physiology , Glucagon-Like Peptide-1 Receptor/physiology , Macrophages/physiology , Adult , Aged , Cell Polarity , Cytokines/blood , Cytokines/physiology , Diabetes Mellitus, Type 2/complications , Female , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/analysis , Humans , Lipids/blood , Male , Middle Aged
6.
Sci Rep ; 11(1): 8326, 2021 04 15.
Article in English | MEDLINE | ID: mdl-33859286

ABSTRACT

Metabolic syndrome, which increases the risk of obesity and type 2 diabetes has emerged as a significant issue worldwide. Recent studies have highlighted the relationship between metabolic imbalance and neurological pathologies such as memory loss. Glucagon-like peptide 1 (GLP-1) secreted from gut L-cells and specific brain nuclei plays multiple roles including regulation of insulin sensitivity, inflammation and synaptic plasticity. Although GLP-1 and GLP-1 receptor agonists appear to have neuroprotective function, the specific mechanism of their action in brain remains unclear. We investigated whether exendin-4, as a GLP-1RA, improves cognitive function and brain insulin resistance in metabolic-imbalanced mice fed a high-fat diet. Considering the result of electrophysiological experiments, exendin-4 inhibits the reduction of long term potentiation (LTP) in high fat diet mouse brain. Further, we identified the neuroprotective effect of exendin-4 in primary cultured hippocampal and cortical neurons in in vitro metabolic imbalanced condition. Our results showed the improvement of IRS-1 phosphorylation, neuronal complexity, and the mature of dendritic spine shape by exendin-4 treatment in metabolic imbalanced in vitro condition. Here, we provides significant evidences on the effect of exendin-4 on synaptic plasticity, long-term potentiation, and neural structure. We suggest that GLP-1 is important to treat neuropathology caused by metabolic syndrome.


Subject(s)
Dendrites/pathology , Exenatide/pharmacology , Glucagon-Like Peptide-1 Receptor/agonists , Long-Term Potentiation/drug effects , Neurons/cytology , Obesity/pathology , Obesity/physiopathology , Animals , Cells, Cultured , Cerebral Cortex/cytology , Cognition/drug effects , Diet, High-Fat/adverse effects , Glucagon-Like Peptide-1 Receptor/physiology , Hippocampus/cytology , Insulin Resistance , Mice , Neuronal Plasticity/drug effects , Obesity/etiology , Obesity/psychology
7.
Diabetologia ; 64(1): 142-151, 2021 01.
Article in English | MEDLINE | ID: mdl-33043402

ABSTRACT

AIMS/HYPOTHESIS: The endocrine pancreas comprises the islets of Langerhans, primarily consisting of beta cells, alpha cells and delta cells responsible for secretion of insulin, glucagon and somatostatin, respectively. A certain level of intra-islet communication is thought to exist, where the individual hormones may reach the other islet cells and regulate their secretion. Glucagon has been demonstrated to importantly regulate insulin secretion, while somatostatin powerfully inhibits both insulin and glucagon secretion. In this study we investigated how secretion of somatostatin is regulated by paracrine signalling from glucagon and insulin. METHODS: Somatostatin secretion was measured from perfused mouse pancreases isolated from wild-type as well as diphtheria toxin-induced alpha cell knockdown, and global glucagon receptor knockout (Gcgr-/-) mice. We studied the effects of varying glucose concentrations together with infusions of arginine, glucagon, insulin and somatostatin, as well as infusions of antagonists of insulin, somatostatin and glucagon-like peptide 1 (GLP-1) receptors. RESULTS: A tonic inhibitory role of somatostatin was demonstrated with infusion of somatostatin receptor antagonists, which significantly increased glucagon secretion at low and high glucose, whereas insulin secretion was only increased at high glucose levels. Infusion of glucagon dose-dependently increased somatostatin secretion approximately twofold in control mice. Exogenous glucagon had no effect on somatostatin secretion in Gcgr-/- mice, and a reduced effect when combined with the GLP-1 receptor antagonist exendin 9-39. Diphtheria toxin-induced knockdown of glucagon producing cells led to reduced somatostatin secretion in response to 12 mmol/l glucose and arginine infusions. In Gcgr-/- mice (where glucagon levels are dramatically increased) overall somatostatin secretion was increased. However, infusion of exendin 9-39 in Gcgr-/- mice completely abolished somatostatin secretion in response to glucose and arginine. Neither insulin nor an insulin receptor antagonist (S961) had any effect on somatostatin secretion. CONCLUSIONS/INTERPRETATION: Our findings demonstrate that somatostatin and glucagon secretion are linked in a reciprocal feedback cycle with somatostatin inhibiting glucagon secretion at low and high glucose levels, and glucagon stimulating somatostatin secretion via the glucagon and GLP-1 receptors. Graphical abstract.


Subject(s)
Glucagon/physiology , Insulin/physiology , Somatostatin/metabolism , Animals , Arginine/administration & dosage , Cell Communication , Diphtheria Toxin/pharmacology , Gene Knockdown Techniques , Glucagon/administration & dosage , Glucagon-Like Peptide-1 Receptor/drug effects , Glucagon-Like Peptide-1 Receptor/physiology , Glucagon-Secreting Cells/drug effects , Glucagon-Secreting Cells/physiology , Glucose/administration & dosage , Insulin/administration & dosage , Insulin Secretion/drug effects , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Glucagon/deficiency , Receptors, Glucagon/genetics , Receptors, Glucagon/physiology , Receptors, Somatostatin/antagonists & inhibitors , Signal Transduction/physiology , Somatostatin/administration & dosage
8.
Neuroreport ; 31(18): 1283-1288, 2020 12 16.
Article in English | MEDLINE | ID: mdl-33165198

ABSTRACT

Neuropeptides and peptide hormones affect food-directed motivation, in part, through actions on brain regions associated with reward processing. For instance, previous reports have shown that stimulating glucagon-like peptide-1 (GLP-1) receptors in the nucleus accumbens (NAc), an area that directs motivational processes towards food and drugs of abuse, has an anorectic effect. In contrast, µ-opioid receptor activation of the NAc increases feeding, particularly on highly palatable diets. While both neurotransmitters act within the NAc to impact food intake, it is not clear if and how they might interact to affect feeding. Therefore, these experiments tested the effects of NAc injections of the GLP-1 receptor agonist Exendin 4 (EX4) or antagonist Exendin 9 (EX9) on the consumption of a sweetened fat diet, with and without simultaneous µ-opioid receptor stimulation. Male Sprague-Dawley rats (n = 8/group, EX4 or EX9) underwent surgery to place bilateral cannula above the NAc core. After recovery, animals were tested following NAc injections of saline or the µ-opioid agonist [D-Ala, N-MePhe, Gly-ol]-enkephalin (DAMGO) (0.025 µg/side), combined with varying doses of EX4 (0, 0.05, or 0.10 µg/side) or EX9 (0, 2.5, 5.0 µg/side), counterbalanced across 6 testing days. Food and water intake, along with locomotor activity, was monitored for 2 h. Mu-opioid receptor stimulation significantly increased feeding, and this effect was reduced by GLP-1 receptor stimulation. In contrast, GLP-1 antagonism with EX9 altered the dynamics of DAMGO-induced binge-like feeding, extending µ-opioid-induced binging, and increasing food consumption. These findings are the first to demonstrate an interaction between NAc µ-opioid and GLP-1 receptors on palatable food intake.


Subject(s)
Bulimia/physiopathology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Feeding Behavior/physiology , Glucagon-Like Peptide-1 Receptor/physiology , Neurotransmitter Agents/pharmacology , Nucleus Accumbens/drug effects , Receptors, Opioid, mu/agonists , Animals , Bulimia/metabolism , Exenatide/pharmacology , Feeding Behavior/drug effects , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors , Male , Nucleus Accumbens/metabolism , Peptide Fragments/pharmacology , Rats , Receptors, Opioid, mu/metabolism
9.
Sci Rep ; 10(1): 18415, 2020 10 28.
Article in English | MEDLINE | ID: mdl-33116243

ABSTRACT

The gastrointestinal tract transmits feeding-regulatory signals to the brain via neuronal and hormonal pathways. Here we studied the interaction between the orexigenic gastric peptide, ghrelin, and the anorectic intestinal peptide, glucagon-like peptide 1 (GLP-1), in terms of feeding regulation via the vagal afferents. GLP-1 preadministration 30 min before ghrelin administration to rats and mice abolished ghrelin-induced food intake, while ghrelin preadministration abolished the anorectic effect of GLP-1. Ghrelin preadministration suppressed GLP-1-induced Fos expression in the nodose ganglia (NG). Electrophysiological assessment confirmed that the initially administered peptide abolished the vagal afferent electrical alteration induced by the subsequently administered peptide. Both the growth hormone secretagogue receptor (GHSR) and the GLP-1 receptor (GLP-1R) are co-localised in a major proportion of NG neurons that innervate the stomach. In these Ghsr+Glp1r+ neurons, ghrelin preadministration abolished the GLP-1-induced calcium response. Ghrelin generated a hyperpolarising current and GLP-1 generated a depolarising current in isolated NG neurons in a patch-clamp experiment. Ghrelin and GLP-1 potently influenced each other in terms of vagally mediated feeding regulation. This peptidergic interaction allows for fine control of the electrophysiological properties of NG neurons.


Subject(s)
Afferent Pathways/physiology , Appetite Regulation , Ghrelin/physiology , Glucagon-Like Peptide 1/physiology , Nodose Ganglion/physiology , Animals , Calcium/metabolism , Glucagon-Like Peptide-1 Receptor/physiology , Male , Mice, Inbred C57BL , Rats, Wistar , Receptors, Ghrelin/metabolism
10.
Alcohol Clin Exp Res ; 44(10): 2118-2129, 2020 10.
Article in English | MEDLINE | ID: mdl-33043520

ABSTRACT

BACKGROUND: The misuse and abuse of alcohol is a major public health issue. However, available treatments are limited with variable efficacy. Recently, preclinical studies show that glucagon-like-peptide-1 (GLP-1) and its analogue Exendin-4 (Ex4) potently reduce a range of alcohol intake behaviors, thus highlighting its potential as a treatment for alcohol use disorders. However, the neural mechanisms and sites of action mediating the effects of Ex4 on alcohol intake behaviors remain to be characterized. This study examined the ventral tegmental area (VTA) as a site of action for the effects of GLP-1 on alcohol intake. METHODS: Male Long-Evans rats were given intermittent access to 20% alcohol and trained to nose poke for 20% alcohol. Rats received intra-VTA injections of Ex4 (vehicle, 0.01, 0.05 µg), and the effects of VTA Ex4 on alcohol self-administration, motivation, and relapse were assessed. RESULTS: When compared to vehicle treatment, intra-VTA Ex4 (0.01, 0.05 µg) delivery significantly reduced alcohol self-administration, an effect that was particularly prominent in high alcohol drinkers. However, VTA Ex4 did not reduce reacquisition of alcohol self-administration after extinction nor the motivation to obtain alcohol. Importantly, the lower dose of Ex4 (0.01 µg) used had no effect on food intake or locomotor activity, suggesting that the reduction in alcohol self-administration observed was not secondary to caloric intake or motor deficits. CONCLUSIONS: Together, these findings provide support for the VTA as a key site of action for GLP-1 on alcohol self-administration but not the reacquisition of alcohol self-administration or motivation to work for alcohol.


Subject(s)
Alcohol Deterrents/pharmacology , Alcohol Drinking/drug therapy , Exenatide/pharmacology , Glucagon-Like Peptide 1/pharmacology , Glucagon-Like Peptide-1 Receptor/drug effects , Signal Transduction/drug effects , Ventral Tegmental Area/drug effects , Alcohol Deterrents/metabolism , Alcohol Deterrents/therapeutic use , Alcohol Drinking/metabolism , Alcohol Drinking/physiopathology , Animals , Exenatide/metabolism , Exenatide/therapeutic use , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide 1/therapeutic use , Glucagon-Like Peptide-1 Receptor/metabolism , Glucagon-Like Peptide-1 Receptor/physiology , Male , Motor Activity/drug effects , Rats , Rats, Long-Evans , Ventral Tegmental Area/metabolism , Ventral Tegmental Area/physiopathology
11.
Life Sci ; 260: 118339, 2020 Nov 01.
Article in English | MEDLINE | ID: mdl-32841660

ABSTRACT

AIMS: To design and screen a potent GLP-1/GIP/Gcg receptors triagonist with therapeutic potential in rodent animals with diabetes and obesity. MAIN METHODS: First, we obtained a 12-mer dual GIP/Gcg receptor agonist from a large combinatorial peptide library via high-throughput screening technique and then fused to the Exendin (9-39) to generate a potent GLP-1/GIP/Gcg triagonist. Further site fatty chain modification was performed to improve the druggability via enhancing in vivo stability and cyclic half-life. In vitro signaling and functional assays in cell lines expressing each receptor and in vivo efficacy evaluation in rodent model animals with hyperglycemia and obesity were all carefully performed. KEY FINDINGS: We screened and obtained a potent GLP-1/GIP/Gcg triagonist, termed XFL0, which promotes in vitro GLP-1, GIP, Gcg receptor activation comparable to native GLP-1, GIP and glucagon, respectively. Site-specific fatty acid modification significantly enhanced plasma stability of XFL0 and exhibited no obvious impact on receptor activation. The selected XFL0 conjugates termed XFL6, showed glucose-dependent insulin secretion and improved glucose tolerance by acting on all GLP-1, GIP and Gcg receptors in gene-deficient mice of which the effects were all significantly greater than any single receptor agonist. After chronic treatment in rodent animals with diabetes and obesity, XFL6 potently decreased body weight and food intake, ameliorated the hyperglycemia and hemoglobin A1c levels as well as the lipid metabolism and diabetic nephropathy related disorders. SIGNIFICANCE: XFL6, as a novel GLP-1/GIP/Gcg receptor triagonist, held potential to deliver outstanding improvement in correcting hyperglycemia, obesity and diabetic nephropathy.


Subject(s)
Diabetic Nephropathies/prevention & control , Drug Design , Gastric Inhibitory Polypeptide/agonists , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon/agonists , Hyperglycemia/prevention & control , Obesity/prevention & control , Animals , Diabetes Mellitus, Experimental/physiopathology , Diabetic Nephropathies/etiology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Gastric Inhibitory Polypeptide/physiology , Glucagon/physiology , Glucagon-Like Peptide-1 Receptor/physiology , Hyperglycemia/etiology , Hyperglycemia/metabolism , Hyperglycemia/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Obesity/etiology , Obesity/metabolism , Obesity/pathology
12.
Psychoneuroendocrinology ; 119: 104720, 2020 09.
Article in English | MEDLINE | ID: mdl-32563174

ABSTRACT

Anxiety disorders are among the most prevalent categories of mental illnesses. The gut-brain axis, along with gastrointestinally-derived neuropeptides, like glucagon-like peptide-1 (GLP-1), are emerging as potential key regulators of emotionality, including anxiety behavior. However, the neuroanatomical substrates from which GLP-1 exerts its anxiogenic effect remain poorly characterized. Here we focus on a relatively new candidate nucleus, the supramammillary nucleus (SuM), located just caudal to the lateral hypothalamus and ventral to the ventral tegmental area. Our focus on the SuM is supported by previous data showing expression of GLP-1R mRNA throughout the SuM and activation of the SuM during anxiety-inducing behaviors in rodents. Data show that chemogenetic activation of neurons in the SuM results in an anxiolytic response in male and female rats. In contrast, selective activation of SuM GLP-1R, by microinjection of a GLP-1R agonist exendin-4 into the SuM resulted in potent anxiety-like behavior, measured in both open field and elevated plus maze tests in male and female rats. This anxiogenic effect of GLP-1R activation persisted after high-fat diet exposure. Importantly, reduction of GLP-1R expression in the SuM, by AAV-shRNA GLP-1R knockdown, resulted in a clear anxiolytic response; an effect only observed in female rats. Our data identify a new neural substrate for GLP-1 control of anxiety-like behavior and indicate that the SuM GLP-1R are sufficient for anxiogenesis in both sexes, but necessary only in females.


Subject(s)
Anxiety/psychology , Glucagon-Like Peptide-1 Receptor/physiology , Hypothalamus, Posterior/physiology , Animals , Anxiety/genetics , Anxiety/physiopathology , Avoidance Learning/drug effects , Avoidance Learning/physiology , Behavior, Animal/drug effects , Behavior, Animal/physiology , Exenatide/pharmacology , Female , Gene Knockdown Techniques , Glucagon-Like Peptide 1/pharmacology , Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors , Glucagon-Like Peptide-1 Receptor/genetics , Hypothalamus, Posterior/drug effects , Male , RNA, Small Interfering/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Transgenic
13.
Pharmacol Ther ; 212: 107559, 2020 08.
Article in English | MEDLINE | ID: mdl-32380197

ABSTRACT

The linkage of neurodegenerative diseases with insulin resistance (IR) and type 2 diabetes mellitus (T2DM), including oxidative stress, mitochondrial dysfunction, excessive inflammatory responses and abnormal protein processing, and the correlation between cerebrovascular diseases and hyperglycemia has opened a new window for novel therapeutics for these cognitive disorders. Various antidiabetic agents have been studied for their potential treatment of cognitive disorders, among which the dipeptidyl peptidase-4 (DPP-4) inhibitors have been investigated more recently. So far, DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models, and cognitive benefits in diabetic patients with or without cognitive impairments. This review aims to summarize the potential mechanisms, advantages and limitations, and currently available evidence for developing DPP-4 inhibitors as a treatment of cognitive disorders.


Subject(s)
Cognitive Dysfunction/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Animals , Diabetes Mellitus, Type 2/complications , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Gastric Inhibitory Polypeptide/physiology , Gastrointestinal Microbiome/drug effects , Glucagon-Like Peptide 1/physiology , Glucagon-Like Peptide-1 Receptor/physiology , Humans , Insulin Resistance
14.
Neuropharmacology ; 170: 108042, 2020 06 15.
Article in English | MEDLINE | ID: mdl-32147454

ABSTRACT

Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health and cannot be stopped by current treatments. Type 2 diabetes mellitus (T2DM) is a risk factor for AD. Our recent studies reported the neuroprotective effects of a GLP-1/GIP/Glucagon receptor triagonist (Triagonist), a novel unimolecular anti-diabetic drug, in cognitive and pathological improvements of 3xTg-AD mice. However, the detailed electrophysiological and molecular mechanisms underlying neuroprotection remain unexplored. The present study investigated the underlying electrophysiological and molecular mechanisms further by using whole-cell patch clamp techniques. Our results revealed that chronic Triagonist treatment effectively reduced working memory and reference memory errors of 3xTg-AD mice in a radial maze test. In addition, the Triagonist increased spontaneous excitatory synaptic activities, differentially modulated voltage- and chemically-gated Ca2+ flux, and reduced the over-excitation of pyramidal neurons in hippocampal slices of 3xTg-AD mice. In addition, chronic Triagonist treatment also up-regulated the expression levels of synaptophysin and PSD-95 in the hippocampus of 3xTg-AD mice. These results indicate that the Triagonist could improve memory formation, as well as synaptic transmission, Ca2+ balance, and neuronal excitability in 3xTg-AD mice. These neuroprotective effects of Triagonist may be involved in the up-regulation of synaptophysin and PSD-95. Therefore, the study suggests that multi-receptor agonists might be a novel therapeutic strategy for the treatment of AD.


Subject(s)
Calcium Signaling/drug effects , Glucagon-Like Peptide-1 Receptor/agonists , Memory, Short-Term/drug effects , Receptors, Gastrointestinal Hormone/agonists , Receptors, Glucagon/agonists , Synaptic Transmission/drug effects , Amyloid beta-Protein Precursor/genetics , Animals , Calcium Signaling/physiology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Female , Glucagon-Like Peptide-1 Receptor/physiology , Hippocampus/drug effects , Hippocampus/physiology , Homeostasis/drug effects , Homeostasis/physiology , Humans , Hypoglycemic Agents/administration & dosage , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory, Short-Term/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/drug effects , Neurons/physiology , Organ Culture Techniques , Presenilin-1/genetics , Receptors, Gastrointestinal Hormone/physiology , Receptors, Glucagon/physiology , Synaptic Transmission/physiology , tau Proteins/genetics
15.
Am J Pathol ; 190(2): 400-411, 2020 02.
Article in English | MEDLINE | ID: mdl-31759969

ABSTRACT

Glucagon-like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, the anti-inflammatory action of Glp1r agonism was tested in a nondiabetic, T-cell-mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r-/- mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r-/- mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r-/- mice. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1 mRNA expression. Together, Glp1r agonism protects mice from a T-cell-dependent glomerulonephritis model by inhibition of T-cell proliferation, possibly by interacting with their metabolic program. This mechanism may explain in part the renoprotective effects of Glp1r agonism in diabetic nephropathy.


Subject(s)
Glucagon-Like Peptide-1 Receptor/agonists , Hypoglycemic Agents/pharmacology , Liraglutide/pharmacology , Lymphocyte Activation/immunology , Nephritis/prevention & control , T-Lymphocytes/immunology , Animals , Glucagon-Like Peptide-1 Receptor/physiology , Lymphocyte Activation/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nephritis/immunology , Nephritis/metabolism , Nephritis/pathology , T-Lymphocytes/drug effects
16.
Biochem Pharmacol ; 169: 113630, 2019 11.
Article in English | MEDLINE | ID: mdl-31491414

ABSTRACT

Here, we described the effects of obesity induced by high-calorie diet and its treatment with exenatide, an anti-diabetogenic and potential anti-obesogenic drug derived from the venom of the Gila monster Heloderma suspectum, on the affinity, density, subtypes and intracellular signaling pathways linked to activation of muscarinic acetylcholine receptors (mAChRs) in rat hippocampus. Male Wistar rats were divided into three groups: control (CT), obese induced by high-calorie diet (DIO) and DIO treated with exenatide (DIO + E). [3H]Quinuclidinyl benzilate specific binding analysis showed that the equilibrium dissociation constant (KD) did not differ among CT, DIO and DIO + E, indicating that affinity is not affected by high-calorie diet or its treatment with exenatide. On the other hand, the density of mAChRs obtained in DIO animals was lower than that obtained from CT rats, and that DIO + E restored the density of mAChRs. Immunoprecipitation assays reveal a decrease in the expression of M1 and M3 subtypes of DIO animals when compared with CT. Treatment with exenatide (DIO + E) restored the expression of the two subtypes similar to obtained from CT. On the other hand, the M2, M4 and M5 mAChR subtypes expression did not differ among CT, DIO and DIO + E. Carbacol caused a concentration-dependent increase in the accumulation of total [3H] inositol phosphate in CT, DIO and DIO + E. However, the magnitude of the maximal response to carbachol was lower in DIO when compared with those obtained from CT and DIO + E animals, which did not differ from each other. Our results indicate that obesity induced by high-calorie diet strongly influences the expression and intracellular signaling coupled to M1-M3 mAChR subtypes. The exenatide ameliorated these effects, suggesting an important role on hippocampal muscarinic cholinergic system. This action of obesity induced by high-calorie diet and its treatment with exenatide might be a key step mediating cellular events important for learning and memory.


Subject(s)
Exenatide/therapeutic use , Hippocampus/drug effects , Obesity/drug therapy , Receptors, Muscarinic/drug effects , Animals , Carbachol/pharmacology , Energy Intake , Exenatide/pharmacology , Glucagon-Like Peptide-1 Receptor/physiology , Hippocampus/physiology , Male , Rats , Rats, Wistar , Receptors, Muscarinic/physiology
17.
PLoS Biol ; 17(8): e3000097, 2019 08.
Article in English | MEDLINE | ID: mdl-31430273

ABSTRACT

The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in fine-tuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquid-ordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.


Subject(s)
Glucagon-Like Peptide-1 Receptor/metabolism , Insulin-Secreting Cells/metabolism , Animals , CHO Cells , Cell Membrane/metabolism , Cluster Analysis , Cricetulus , Cyclic AMP/metabolism , Diabetes Mellitus, Type 2 , Endocytosis/drug effects , Glucagon-Like Peptide 1/agonists , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide-1 Receptor/physiology , HEK293 Cells , Humans , Insulin/metabolism , Insulin Secretion/physiology , Insulin-Secreting Cells/physiology , Lipoylation , Signal Transduction/drug effects
18.
Epilepsy Res ; 154: 97-106, 2019 08.
Article in English | MEDLINE | ID: mdl-31121474

ABSTRACT

AIMS: Glia-mediated neuro-inflammation and oxidative stress-induced neuronal apoptosis can contribute to epileptogenesis. We have demonstrated previously that mimetics of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and dual-GLP-1/GIP receptor agonists protect the brain from inflammation, oxidative stress, apoptosis and neuronal loss in animal models of central nervous system diseases. METHODS: This study investigated for the first time whether the novel dual GLP-1/GIP receptor agonist DA3-CH has neuroprotective effects in the pilocarpine-induced status epilepticus (SE) rat model and the studies the underlying mechanisms. DA3-CH was administered once daily at 10 nmol/kg ip. following SE induction. The effect of DA3-CH was evaluated by immunohistochemistry and western blot at 12 h, 1 d, 3 d, 7 d after kindling. RESULTS: Our findings show that DA3-CH reduced the chronic inflammation response (astrogliosis and microgliosis), and the associated release of the pro-inflammatory cytokines interleukin-1ß (IL-ß) and tumor necrosis factor-α (TNF-α) in the hippocampal CA1 area. Furthermore, DA3-CH reduced the expression of the mitochondrial pro-apoptotic protein Bax, while increasing the expression of the anti-apoptotic protein Bcl-2. Neuronal numbers in the CA1 area were much reduced by pilocarpine treatment, and DA3-CH protected neurons from neurotoxicity. CONCLUSION: These results demonstrated that DA3-CH could mitigate pilocarpine-induced neuro-inflammation, mitochondrial apoptosis and neuronal loss. The findings encourage the development of dual agonists as novel therapeutic interventions for epilepsy.


Subject(s)
Epilepsy/chemically induced , Epilepsy/drug therapy , Glucagon-Like Peptide-1 Receptor/agonists , Neuroprotective Agents/therapeutic use , Pilocarpine/toxicity , Receptors, Gastrointestinal Hormone/agonists , Animals , Disease Models, Animal , Epilepsy/physiopathology , Glucagon-Like Peptide-1 Receptor/physiology , Male , Neuroprotective Agents/pharmacology , Random Allocation , Rats , Rats, Sprague-Dawley , Receptors, Gastrointestinal Hormone/physiology
19.
Naunyn Schmiedebergs Arch Pharmacol ; 392(6): 715-722, 2019 06.
Article in English | MEDLINE | ID: mdl-30762075

ABSTRACT

Endoplasmic reticulum (ER) stress-induced apoptosis is a major cause of myocardial ischemia/reperfusion (I/R) injury. Emerging evidence indicates that glucagon-like peptide-1 (GLP-1) has potential cardioprotective effects. However, the precise mechanisms underlying the involvement of GLP-1 in I/R injury remain largely unknown. In the present study, we aimed to determine whether GLP-1 attenuates hypoxia/reoxygenation (H/R) injury in cardiomyocytes and to further elucidate the underlying signaling pathway. The results indicate that GLP-1 reversed the increased apoptotic ratio, the increased lactate dehydrogenase (LDH) levels, the reduced cell viability, the increased Caspase-3 activity, and the increased Bax/Bcl-2 ratio caused by H/R. Importantly, GLP-1 significantly decreased the expression of H/R-induced ER stress proteins (GRP78, CHOP) and Caspase-12. In addition, we found that GLP-1 increased the expression of p-Akt in H9c2 cells with H/R injuries, and that the protective action of GLP-1 against H/R-induced injury was blocked by the GLP-1 receptor (GLP-1R) inhibitor Exendin9-39 and the PI3K inhibitor LY294002. Exendin9-39 and LY294002 also blocked the downregulation of ER stress protein expression by GLP-1, after H/R injury. Therefore, we have shown that GLP-1 exerts its cardioprotective effects by alleviating ER stress-induced apoptosis due to H/R injury and that these effects are most likely associated with the activation of GLP-1R/PI3K/Akt signaling pathway.


Subject(s)
Apoptosis/drug effects , Endoplasmic Reticulum Stress/drug effects , Glucagon-Like Peptide 1/pharmacology , Glucagon-Like Peptide-1 Receptor/physiology , Myocardial Reperfusion Injury/prevention & control , Myocytes, Cardiac/drug effects , Phosphatidylinositol 3-Kinases/physiology , Proto-Oncogene Proteins c-akt/physiology , Animals , Cells, Cultured , Endoplasmic Reticulum Stress/physiology , Myocytes, Cardiac/physiology , Rats , Signal Transduction/drug effects , Signal Transduction/physiology
20.
Psychoneuroendocrinology ; 103: 284-295, 2019 05.
Article in English | MEDLINE | ID: mdl-30771711

ABSTRACT

Glucagon-like peptide 1 (GLP-1), an incretin hormone that reduces food intake, was recently established as a novel regulator of alcohol-mediated behaviors. Clinically available analogues pass freely into the brain, but the mechanisms underlying GLP-1-modulated alcohol reward remains largely unclear. GLP-1 receptors (GLP-1R) are expressed throughout the nuclei of importance for acute and chronic effects of alcohol, such as the laterodorsal tegmental area (LDTg), the ventral tegmental area (VTA) and the nucleus accumbens (NAc). We therefore evaluated the effects of bilateral infusion of the GLP-1R agonist exendin-4 (Ex4) into NAc shell, anterior (aVTA), posterior (pVTA) or LDTg on the acute alcohol-induced locomotor stimulation and memory of alcohol reward in the conditioned place preference (CPP) model in mice, as well as on alcohol intake in rats consuming high amounts of alcohol for 12 weeks. Ex4 into the NAc shell blocks alcohol-induced locomotor stimulation and memory of alcohol reward as well as decreases alcohol intake. The GLP-1R expression in NAc is elevated in high compared to low alcohol-consuming rats. On the contrary, GLP-1R activation in the aVTA does not modulate alcohol-induced behaviors. Ex4 into the pVTA prevents alcohol-induced locomotor simulation, but does neither modulate CPP-dependent alcohol memory nor alcohol intake. Intra-LDTg-Ex4 attenuates alcohol-induced locomotor stimulation and reduces alcohol intake, but does not affect memory of alcohol reward. Collectively, these data provide additional knowledge of the functional role of GLP-1R in reward-related areas for alcohol-mediated behaviors and further support GLP-1R as a potential treatment target for alcohol use disorder.


Subject(s)
Alcohol Drinking/drug therapy , Ethanol/metabolism , Glucagon-Like Peptide-1 Receptor/metabolism , Alcohol Drinking/metabolism , Alcoholism/metabolism , Animals , Conditioning, Operant/drug effects , Conditioning, Psychological/drug effects , Ethanol/pharmacology , Exenatide/metabolism , Exenatide/pharmacology , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide-1 Receptor/physiology , Male , Mice , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Peptides/pharmacology , Rats , Rats, Wistar , Receptors, Glucagon/metabolism , Reward , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/metabolism
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