A5011009221- Receptor Mechanisms and Signaling
- Pancreatic function and diabetes
- Adipose Tissue and Metabolism
- Diabetes Treatment and Management
- Neuroscience and Neuropharmacology Research
- Neuropeptides and Animal Physiology
- Regulation of Appetite and Obesity
- Metabolism, Diabetes, and Cancer
- Adipokines, Inflammation, and Metabolic Diseases
- Growth Hormone and Insulin-like Growth Factors
- Nicotinic Acetylcholine Receptors Study
- Diabetes and associated disorders
- Biochemical Analysis and Sensing Techniques
- Neurotransmitter Receptor Influence on Behavior
- FOXO transcription factor regulation
- Cytokine Signaling Pathways and Interactions
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Protein Kinase Regulation and GTPase Signaling
- Telomeres, Telomerase, and Senescence
- Sphingolipid Metabolism and Signaling
- Memory and Neural Mechanisms
- Cannabis and Cannabinoid Research
- Nitric Oxide and Endothelin Effects
- Ion channel regulation and function
- Vagus Nerve Stimulation Research
National Institute of Diabetes and Digestive and Kidney Diseases
2014-2024
Hunan Normal University
2020-2024
National Institutes of Health
2001-2019
Sichuan University
2017
Toxicologie, Pharmacologie et Signalisation Cellulaire
2010
Leo Baeck College
2008
University of Iowa
2001-2004
Eli Lilly (United States)
2001
The M 5 muscarinic receptor is the most recent member of acetylcholine family (M 1 -M ) to be cloned. At present, physiological relevance this subtype remains unknown, primarily because its low expression levels and lack receptor-selective ligands. To circumvent these difficulties, we used gene targeting technology generate receptor-deficient mice ( M5R −/− mice). did not differ from their wild-type littermates in various behavioral pharmacologic tests. However, vitro neurotransmitter...
Pancreatic muscarinic acetylcholine receptors play an important role in stimulating insulin and glucagon secretion from islet cells. To study the potential of M3 receptor subtype cholinergic stimulation release, we initially examined effect agonist, oxotremorine-M (Oxo-M), on isolated pancreatic islets prepared wild-type (WT) receptor–deficient mice (M3+/− M3−/− mice). At a stimulatory glucose level (16.7 mmol/l), Oxo-M strongly potentiated output WT mice. Strikingly, this was completely...
Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh (M 1 –M 5 mAChRs). Like other mAChR subtypes, M 4 is widely expressed in different regions forebrain. Interestingly, mAChRs are coexpressed with D dopamine a specific subset striatal projection neurons. To investigate physiological relevance this subpopulation modulating dopamine-dependent behaviors, we used Cre/loxP technology generate mutant mice that lack only...
Glucagon, a hormone released from pancreatic α cells, plays key role in maintaining proper glucose homeostasis and has been implicated the pathophysiology of diabetes. In vitro studies suggest that intraislet glucagon can modulate function β cells. However, because lack suitable experimental tools, vivo physiological this cross-talk remained elusive. To address issue, we generated mouse model selectively expressed an inhibitory designer GPCR (Gi DREADD) cells only. Drug-induced activation...
Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; neuropeptide Y. AgRP express various G protein-coupled receptors (GPCRs) with coupling properties, including Gs-linked GPCRs. At present, potential Gs-coupled GPCRs activity remains unknown. Here we show that activation expressed leads to robust sustained increase intake. We also provide detailed mechanistic data...
Identification of the specific muscarinic acetylcholine receptor (mAChR) subtypes mediating stimulation salivary secretion is considerable clinical interest. Recent pharmacological and molecular genetic studies have yielded somewhat confusing partially contradictory results regarding involvement individual mAChRs in this activity. In present study, we re-examined roles M(1) M(3) agonist-mediated by using single-knockout (KO) mice newly generated M(1)/M(3) double-KO mice. When applied at a...
β-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show inactivation β-arrestin-2 gene, barr2, in β-cells adult mice greatly impairs release glucose tolerance fed with a calorie-rich diet. Both KCl-induced secretion calcium responses were profoundly reduced (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced secretion. We...
A large body of evidence indicates that muscarinic acetylcholine receptors (mAChRs) play critical roles in regulating the activity many important functions central and peripheral nervous systems. However, identification physiological pathophysiological individual mAChR subtypes (M(1)-M(5)) has proven a difficult task, primarily due to lack ligands endowed with high degree receptor subtype selectivity fact most tissues organs express multiple mAChRs. To circumvent these difficulties, we used...
Increased hepatic glucose production is a key pathophysiological feature of type 2 diabetes. Like all other cell types, hepatocytes express many G protein-coupled receptors (GPCRs) that are linked to different functional classes heterotrimeric proteins. The important physiological functions mediated by G(s)-coupled glucagon well-documented. In contrast, little known about the in vivo roles hepatocyte GPCRs proteins G(q) family. To address this issue, we established transgenic mouse line...
Abstract β-Arrestins are major regulators of G protein-coupled receptor-mediated signaling processes. Their potential roles in regulating adipocyte function vivo remain unexplored. Here we report the novel finding that mice lacking β-arrestin-2 (barr2) selectively adipocytes show significantly reduced adiposity and striking metabolic improvements when consuming excess calories. We demonstrate these beneficial effects due to enhanced through β3-adrenergic receptors (β3-ARs), indicating barr2...
Abstract Activation of the sympathetic nervous system causes pronounced metabolic changes that are mediated by multiple adrenergic receptor subtypes. Systemic treatment with β 2- agonists results in beneficial effects, including improved glucose homeostasis. To elucidate underlying cellular and molecular mechanisms, we chronically treated wild-type mice several newly developed mutant mouse strains clenbuterol, a selective 2 -adrenergic agonist. Clenbuterol administration caused improvements...
The release of insufficient amounts insulin in the presence elevated blood glucose levels is one key features type 2 diabetes. Various lines evidence indicate that acetylcholine (ACh), major neurotransmitter parasympathetic nervous system, can enhance glucose-stimulated secretion from pancreatic beta-cells. Studies with isolated islets prepared whole body M(3) muscarinic ACh receptor knockout mice showed cholinergic amplification glucose-dependent exclusively mediated by subtype. To...
The neurotransmitter dopamine plays important roles in modulating cognitive, affective, and motor functions. Dysregulation of dopaminergic neurotransmission is thought to be involved the pathophysiology several psychiatric neurological disorders, including schizophrenia, Parkinson's disease drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input. Not surprisingly, increasing evidence implicates muscarinic acetylcholine receptor-mediated pathways as...
An increase in hepatic glucose production (HGP) represents a key feature of type 2 diabetes. This deficiency metabolic control critically depends on enhanced signaling through glucagon receptors (GCGRs). Here, we have demonstrated that selective inactivation the GPCR-associated protein β-arrestin hepatocytes adult mice results greatly increased GCGR signaling, leading to striking deficits homeostasis. However, hepatocyte-specific did not affect insulin sensitivity or β-adrenergic signaling....
An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through Gs-linked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing Gi signaling. Specifically, used chemogenetic approach selectively activate Gi-type G proteins mouse hepatocytes vivo. Unexpectedly, activation triggered pronounced HGP and severely impaired homeostasis....
β-Arrestin 1 and 2 (Barr1 Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated mice lacking Barr2 selectively in pancreatic β cells showed pronounced impairments. Here we investigated whether Barr1 plays a similar role regulating cell function whole-body glucose homeostasis. Initially, inactivated the gene of adult (β-barr1-KO mice). β-barr1-KO did not display any obvious phenotypes series vivo vitro tests....
Abstract Adipocyte dysfunction links obesity to insulin resistance and type 2 diabetes. function is regulated by receptor-mediated activation of heterotrimeric G proteins. Little known about the potential in vivo metabolic roles i -type proteins expressed adipocytes, primarily due lack suitable animal models. To address this question, we generated mice lacking functional selectively adipocytes. Here report that these mutant displayed significantly impaired glucose tolerance reduced...
Obesity is the major driver of global epidemic in type 2 diabetes (T2D). In individuals with obesity, impaired insulin action leads to increased lipolysis adipocytes, resulting elevated plasma free fatty acid (FFA) levels that promote peripheral resistance, a hallmark T2D. Here we show, by using combined genetic/biochemical/pharmacologic approach, adipocyte can be prevented selective activation Gq signaling vitro and vivo (in mice). Activation this pathway Gq-coupled designer receptor or an...
Stem Leydig cells (SLCs) are essential for maintaining normal spermatogenesis as the significant component of testis microenvironment and gonadal aging. Although progress has been achieved in regulation male germ mammals humans, it remains unknown about genes signaling pathways human SLCs. Here we have demonstrated, first time, that WNT5A (Wnt family member 5a) mediates proliferation, apoptosis, stemness SLCs, namely NGFR+ cells. We revealed expressed NGFR, PDGFRA, NES, NR2F2, THY1,...
Determining the role of specific muscarinic (M) receptor subtypes mediating responses to acetylcholine (ACh) has been limited by specificity pharmacological agents. Deletion gene for M5 receptors abolished response ACh in cerebral blood vessels but did not affect dilation coronary arteries. The goal this study was determine M circulation using mice deficient M2 or M3 (M2-/-, M3-/-, respectively).Coronary arteries from respective wild-type, M2-/-, M3-/- were isolated, cannulated, and...