scholarly journals Orphan Receptor GPR50 Improves Inflammation and Insulin Signaling in 3T3-L1 Preadipocyte

2021 ◽  
Author(s):  
Zhenyu Yao ◽  
Chang Liu ◽  
Jun Meng ◽  
Jing Long ◽  
Long Li ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cell Line ◽  
Insulin Signaling ◽  
Polymerase Chain Reaction Analysis ◽  
Orphan Receptor ◽  
Ppar Γ ◽  
Cytokine Levels ◽  
Novel Target ◽  
G Protein Coupled

Abstract Purpose: The goal of this study was to investigate the effect of orphan G Protein-Coupled Receptor 50 (GPR50) receptor on inflammation and insulin signaling in 3T3-L1 preadipocyte.Subjects and Methods: A high-fat diet (HFD)-induced obesity-T2DM (Type 2 Diabetes Mellitus) mouse model was used in this research, and high expression of GPR50 in mouse adipose tissue was screened by microarray technology. Expression of GPR50 in 3T3-L1 cell line and obesity-T2DM mouse adipose tissue was confirmed. To gain more insight into the potential role of this new target in obesity-associated IR development, a GPR50 knockout cell line was constructed in 3T3-L1 cell line. Inflammatory cytokine levels and insulin signaling pathways in the GPR50 knockout 3T3-L1 cell line were determined by quantitative real-time polymerase chain reaction analysis and western blot.Results: GPR50 expression was significantly increased in adipose tissue of obesity-T2DM mice. GPR50 deficiency increased inflammation in 3T3-L1 cells. In addition, GPR50 deficiency induced the phosphorylation of AKT and insulin receptor substrate (IRS)1. Furthermore, GPR50 knockout 3T3-L1 cell line had suppressed PPAR-γ expression.Conclusions: These data demonstrated a novel target GPR50 can affect inflammation and insulin signaling in adipocytes. Furthermore, the effects are mediated through the regulation of insulin signaling and PPAR-γ expression.

scholarly journals Insulin sensing by astrocytes is critical for normal thermogenesis and body temperature regulation

2020 ◽  
Vol 247 (1) ◽  
pp. 39-52
Author(s):  
Iyad H Manaserh ◽  
Emily Maly ◽  
Marziyeh Jahromi ◽  
Lakshmikanth Chikkamenahalli ◽  
Joshua Park ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Body Temperature ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Insulin Signaling ◽  
Insulin Receptors ◽  
Metabolic Dysregulation ◽  
Brown Adipose ◽  
Novel Target

The important role of astrocytes in the central control of energy balance and glucose homeostasis has recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (Ir) in astrocytes (IrKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IrKOGFAP mice displayed significantly lower energy expenditure and a strikingly lower basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. IrKOGFAP mice displayed sex differences in metabolic function and thermogenesis that may contribute to the development of obesity and type II diabetes as early as 2 months of age. While brown adipose tissue exhibited higher adipocyte size in both sexes, more apoptosis was seen in IrKOGFAP males. Less innervation and lower BAR3 expression levels were also observed in IrKOGFAP brown adipose tissue. These effects have not been reported in models of astrocyte Ir deletion in adulthood. In contrast, body weight and glucose regulatory defects phenocopied such models. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

scholarly journals The role of miR‐146a‐5p on insulin signaling and inflammation in adipose tissue of longliving Ames dwarf mice.

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Allancer Divino De Carvalho Nunes ◽  
Lin Yu ◽  
Collin Lahde ◽  
Sarah Noureddine ◽  
Tatiana Saccon ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Signaling ◽  
Ames Dwarf Mice ◽  
Ames Dwarf ◽  
Dwarf Mice

scholarly journals Role of the G-Protein-Coupled Receptor Signaling Pathway in Insecticide Resistance

2019 ◽  
Vol 20 (17) ◽  
pp. 4300 ◽  
Author(s):  
Ting Li ◽  
Nannan Liu
Keyword(s):  
Insecticide Resistance ◽  
Cell Line ◽  
Signaling Pathway ◽  
G Protein ◽  
Cell Lines ◽  
Sf9 Cells ◽  
Camp Production ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

The G-protein-coupled receptor (GPCR) regulated intracellular signaling pathway is known to be involved in the development of insecticide resistance in the mosquito, Culex quinquefasciatus. To elucidate the specific role of each effector in the GPCR regulating pathway, we initially expressed a GPCR, G-protein alpha subunit (Gαs), adenylate cyclase (AC), and protein kinase A (PKA) in insect Spodoptera frugiperda (Sf9) cells and investigated their regulation function on cyclic AMP (cAMP) production and PKA activity. GPCR, Gαs, and AC individually expressed Sf9 cells showed higher cAMP production as the expression of each effector increased. All the effector-expressed cell lines showed increased PKA activity however. Moreover, Sf9 cytochrome P450 gene expression and cell tolerance to permethrin were examined. The relative expression of CYP9A32gene in Sf9 cells tested was significantly increased in all effector-expressed cell lines compared to a control cell line; these effector-expressed cell lines also showed significantly higher tolerance to permethrin. Inhibitor treatments on each effector-expressed cell line revealed that Bupivacaine HCl and H89 2HCl robustly inhibited cAMP production and PKA activity, respectively, resulting in decreased tolerance to permethrin in all cell lines. The synergistic functions of Bupivacaine HCl and H89 2HCl with permethrin were further examined in Culex mosquito larvae, providing a valuable new information for mosquito control strategies.

scholarly journals SAT-LB107 Insulin Sensing by Astrocytes Is Critical for Normal Thermogenesis and Body Temperature Regulation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jennifer Wootton Hill ◽  
Iyad H Manaserh
Keyword(s):  
Body Temperature ◽  
Energy Expenditure ◽  
Insulin Signaling ◽  
Insulin Receptors ◽  
Normal Body Temperature ◽  
Metabolic Dysregulation ◽  
Brown Adipose ◽  
Novel Target ◽  
Thermogenic Response

Abstract The important role of astrocytes in the central control of energy balance and glucose homeostasis has only recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (IR) in astrocytes (IRKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IRKOGFAP mice displayed a significant decrease in energy expenditure and a striking decrease in basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. Brown adipose tissue in IRKOGFAP mice exhibited increased adipocyte size, more apoptosis, loss of innervation, and decreased βAR3 expression levels. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

scholarly journals Potential Roles of Adipocyte Extracellular Vesicle–Derived miRNAs in Obesity-Mediated Insulin Resistance

2020 ◽  
Author(s):  
Yujeong Kim ◽  
Ok-Kyung Kim
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Metabolic Disorders ◽  
Extracellular Vesicle ◽  
Extracellular Mirnas

ABSTRACT Recently, extracellular microRNAs (miRNAs) from adipose tissue have been shown to be involved in the development of insulin resistance. Here, we summarize several mechanisms explaining the pathogenesis of obesity-induced insulin resistance and associated changes in the expression of obesity-associated extracellular miRNAs. We discuss how miRNAs, particularly miR-27a, miR-34a, miR-141-3p, miR-155, miR210, and miR-222, in extracellular vesicles secreted from the adipose tissue can affect the insulin signaling pathway in metabolic tissue. Understanding the role of these miRNAs will further support the development of therapeutics for obesity and metabolic disorders such as type 2 diabetes.

scholarly journals Deregulation of PP2A-Akt Interaction Contributes to Sucrose Non-Fermenting Related Kinase (SNRK) Deficiency Induced Insulin Resistance in Adipose Tissue (P21-071-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jie Li ◽  
Ran An ◽  
Simin Liu ◽  
Haiyan Xu
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Knockout Model ◽  
Potential Substrate

Abstract Objectives Sucrose Non-Fermenting Related Kinase (SNRK), a serine/threonine kinase, is a novel member of the AMPK/SNF1 family. We previously reported that adipose specific SNRK deficiency induced systemic inflammation and insulin resistance. In this study, we aimed to dissect the role of SNRK in white versus brown adipose tissue in insulin signaling and glucose homeostasis. Methods The SNRKloxp/loxp mice were mated with adiponectin-Cre (A-Cre) transgenic mice to generate the adipose tissue specific knockout model (SNRK−/−, A-Cre), and with UCP1-Cre (U-Cre) mice to generate the brown adipose tissue (BAT) specific knockout model (SNRK−/−, U-Cre). RNA sequencing and phosphoproteomics analysis were applied to identify the signaling pathways affected by SNRK deficiency and the potential substrate of SNRK. Results SNRK deletion exclusively in BAT is sufficient to impair insulin signaling and glucose uptake without inducing local and systemic inflammation. Phosphoproteomic study identified PPP2R5D as the potential substrate of SNRK that regulates insulin signaling through controlling PP2A activity. Dephosphorylated PPP2R5D promotes constitutive assembly of PP2A-Akt complex in SNRK deficient primary brown adipocytes and BAT, therefore reduces insulin stimulated Akt phosphorylation and subsequent glucose uptake. RNA sequencing data provided further evidence to show that the PI3K/AKT signaling pathway is suppressed by SNRK deletion in primary brown adipocytes. Conclusions Insulin resistance in BAT alone is not sufficient to impact whole body glucose homeostasis, indicating that the role of SNRK in WAT and inflammation might be critical for observed systemic insulin resistance in SNRK−/−, A-Cre mice. Funding Sources National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK103699).

scholarly journals Obesity: The role of desynchronosis and genetic factors in mechanisms of its development

2017 ◽  
Vol 8 (1) ◽  
pp. 23-29
Author(s):  
M. O. Ryznychuk ◽  
V. P. Pishak
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Genetic Factors ◽  
Hormone Secretion ◽  
Insulin Receptors ◽  
Secretory Activity ◽  
Membrane Receptors ◽  
Brown Adipose

The article highlights the role of desynchronosis and certain genetic factors in the development of obesity. Some pathogenetic links of obesity and the influence of melatonin on them are analyzed.Desynchronosis is one of the causes of obesity as a result of dysregulatory changes in the chronoperiodic system – between suprachiasmatic nuclei of the hypothalamus and secretory activity of the pineal gland.In obesity there are some changes in circadian patterns of important physiological parameters. These include acrophases of blood pressure; rhythm of hormone secretion, including insulin; electrolytes; sleep-wake cycle displaced for a period of a day, which is a deviation from the normal course. Phase discrepancies of established circadian oscillations of physiological processes arise. Preconditions of fat metabolism imbalance, particularly visfatin, apelin and vaspin – components of atherosclerotic lesions, gradually emerge.There is abundant evidence for close relationships between metabolism and circadian mechanisms. It is proved, that there is a strong direct impact of endogenous circadian rhythms on the metabolic pathways that do not depend on food intake or sleep. A potential low molecular weight of biomarkers of human circadian phases has been identified. A number of key metabolic enzymes in tissues such as the liver, adipose tissue or the pancreas are chronodependent. Desynchronosis phenomena caused by genetic or environmental factors can lead to serious metabolic disorders, including obesity, insulin resistance and metabolic syndrome.Genesis of pineal removal-induced insulin resistance and reduced glucose tolerance in cells is related to the consequences of melatonin absence, which leads to abnormalities in insulin signaling pathways and reduced GLUT4 gene expression and protein content.Insulin-sensitive tissues (white and brown adipose tissue, skeletal and heart muscles) after pineal removal are characterized by a significant reduction of GLUT4 mRNA and the content of microsomal and membrane proteins, which are compensated during treatment by melatonin. Functional synergy exists between melatonin and insulin. Melatonin is able through the membrane receptors MT1 to cause rapid tyrosine phosphorylation, activate tyrosine kinase of beta subunits of insulin receptors and mobilize several intracellular stages of insulin-signaling pathway transduction.Thus, the protective effect of melatonin in cases of disturbance to the carbohydrate metabolism is manifested in the formation of circadian periodicity by modulating the expression of time genes.

scholarly journals Role of Gut Microbiome on Metabolic Disorders

2020 ◽  
pp. 21-35
Author(s):  
Ifeanyi O. Oshim ◽  
Nneka R. Agbakoba ◽  
Evelyn U. Urama ◽  
Oluwayemisi Odeyemi ◽  
Nkechi A. Olise ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Intestinal Permeability ◽  
Visceral Adipose Tissue ◽  
Gut Microbiome ◽  
Metabolic Disorders ◽  
Ppar Γ ◽  
Visceral Adipose

Microbiome that reside in the human gut are key contributors to host metabolism and are considered potential sources of novel therapeutics in metabolic disorders. This review discusses the role of gut microbiome in the pathogenesis of obesity, type 2 diabetes mellitus (T2DM), chronic kidney disease and cardiovascular disease. Gut microbiome remains quite stable, although changes take place between birth and adulthood due to external influences, such as diet, disease and environment. Understanding these changes is important to predict diseases and develop therapies. In gut heamostasis, Gut microbiome converts high fibres intake into short-chain fatty acids like butyrate, propionate and acetate which normalize intestinal permeability and alter de novo lipogenesis and gluconeogenesis through reduction of free fatty acid production by visceral adipose tissue. This effect contributes to reduce food intake and to improve glucose metabolism. Propionate can also bind to G protein coupled receptors (GPR)-43 expressed on lymphocytes in order to maintain appropriate immune defence. Butyrate activates peroxisome proliferator-activated receptor-γ (PPAR-γ) leading to beta-oxidation and oxygen consumption, a phenomenon contributing to maintain anaerobic condition in the gut lumen. In contrast, diets most especially western diet consisting among others of high fat and high salt content has been reported to cause gut dysbiosis. This alteration of gut microbiome result to chronic bacterial translocation and increased intestinal permeability that can drive a systemic inflammation leading to macrophage influx into visceral adipose tissue, activation of hepatic kuffer cells and insulin resistance in type 2 diabetes. This effect contributes to lower mucus thickness, decrease butyrate and propionate producing bacteria, L-cells secrete less gut peptides, lack of PPAR-γ activation lead to higher oxygen available for the microbiome at the proximity of the mucosa and increases the proliferation of Enterobacteriaceae with commensurate increase in opportunistic pathogens. However, Gut microbiome are major biomarker for early prognosis of diabetes and other metabolic disorders.

scholarly journals The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Thibaut Laboute ◽  
Jorge Gandía ◽  
Lucie P Pellissier ◽  
Yannick Corde ◽  
Florian Rebeillard ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptors ◽  
Orphan Receptor ◽  
Locomotor Sensitization ◽  
Promising Therapeutic Target ◽  
Close Proximity ◽  
The Impact ◽  
G Protein Coupled

GPR88 is an orphan G protein-coupled receptor (GPCR) considered as a promising therapeutic target for neuropsychiatric disorders; its pharmacology, however, remains scarcely understood. Based on our previous report of increased delta opioid receptor activity in Gpr88 null mice, we investigated the impact of GPR88 co-expression on the signaling of opioid receptors in vitro and revealed that GPR88 inhibits the activation of both their G protein- and β-arrestin-dependent signaling pathways. In Gpr88 knockout mice, morphine-induced locomotor sensitization, withdrawal and supra-spinal analgesia were facilitated, consistent with a tonic inhibitory action of GPR88 on µOR signaling. We then explored GPR88 interactions with more striatal versus non-neuronal GPCRs, and revealed that GPR88 can decrease the G protein-dependent signaling of most receptors in close proximity, but impedes β-arrestin recruitment by all receptors tested. Our study unravels an unsuspected buffering role of GPR88 expression on GPCR signaling, with intriguing consequences for opioid and striatal functions.

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