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Cell Metabolism Aug 2020Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting...
Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β-adrenergic receptor (β-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of β-AR. Oral administration of the β-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to β-AR and β-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the β-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through β-AR signaling in humans (ClinicalTrials.govNCT02811289).
Topics: Adipocytes, Brown; Adolescent; Adult; Animals; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Receptors, Adrenergic, beta-2; Thermogenesis; Young Adult
PubMed: 32755608
DOI: 10.1016/j.cmet.2020.07.005 -
The Journal of Clinical Investigation Jan 2022The dysregulation of energy homeostasis in obesity involves multihormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine...
The dysregulation of energy homeostasis in obesity involves multihormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine resistance remains largely unexplored. Murine β3-adrenergic receptor expression in adipocytes is orders of magnitude higher compared with that of other isoforms. While resistant to classical desensitization pathways, its mRNA (Adrb3) and protein expression are dramatically downregulated after ligand exposure (homologous desensitization). β3-Adrenergic receptor downregulation also occurs after high-fat diet feeding, concurrent with catecholamine resistance and elevated inflammation. This downregulation is recapitulated in vitro by TNF-α treatment (heterologous desensitization). Both homologous and heterologous desensitization of Adrb3 were triggered by induction of the pseudokinase TRIB1 downstream of the EPAC/RAP2A/PI-PLC pathway. TRIB1 in turn degraded the primary transcriptional activator of Adrb3, CEBPα. EPAC/RAP inhibition enhanced catecholamine-stimulated lipolysis and energy expenditure in obese mice. Moreover, adipose tissue expression of genes in this pathway correlated with body weight extremes in a cohort of genetically diverse mice and with BMI in 2 independent cohorts of humans. These data implicate a signaling axis that may explain reduced hormone-stimulated lipolysis in obesity and resistance to therapeutic interventions with β3-adrenergic receptor agonists.
Topics: 3T3-L1 Cells; Adipocytes; Animals; Catecholamines; Down-Regulation; Drug Resistance; Energy Metabolism; Lipolysis; Male; Mice; Obesity; Receptors, Adrenergic, beta-3; Signal Transduction
PubMed: 34847077
DOI: 10.1172/JCI153357 -
Science (New York, N.Y.) Dec 2023Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) bind to extracellular ligands and drugs and modulate intracellular responses...
Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) bind to extracellular ligands and drugs and modulate intracellular responses through conformational changes. Despite their importance as drug targets, the molecular origins of pharmacological properties such as efficacy (maximum signaling response) and potency (the ligand concentration at half-maximal response) remain poorly understood for any ligand-receptor-signaling system. We used the prototypical adrenaline-β2 adrenergic receptor-G protein system to reveal how specific receptor residues decode and translate the information encoded in a ligand to mediate a signaling response. We present a data science framework to integrate pharmacological and structural data to uncover structural changes and allosteric networks relevant for ligand pharmacology. These methods can be tailored to study any ligand-receptor-signaling system, and the principles open possibilities for designing orthosteric and allosteric compounds with defined signaling properties.
Topics: Humans; Adrenergic beta-2 Receptor Agonists; Allosteric Regulation; Biosensing Techniques; Ligands; Protein Conformation; Receptors, Adrenergic, beta-2; Signal Transduction; Bioluminescence Resonance Energy Transfer Techniques
PubMed: 38127743
DOI: 10.1126/science.adh1859 -
Cell Death & Disease Oct 2019An increasing number of studies indicate that adrenergic signalling plays a fundamental role in chronic stress-induced tumour progression and metastasis. However, its...
An increasing number of studies indicate that adrenergic signalling plays a fundamental role in chronic stress-induced tumour progression and metastasis. However, its function in gastric cancer (GC) and its potential mechanisms remain unknown. The expression levels of β-adrenergic receptor (ADRB) in GC cell lines were examined by using real-time polymerase chain reaction (RT-PCR) and western blotting. The effects of β2 adrenergic receptor (ADRB2) activation and blockade were investigated in vitro in GC cells by using proliferation, migration, invasion, cell cycle and apoptosis assays. Chronic restraint stress (CRS) increased the plasma levels of catecholamines and cortisol and also induced progression and metastasis of GC in vivo. Furthermore, immunohistochemical staining and a TUNEL assay were employed to observe the regulation of cell viability in vivo. The expression levels of ADRB2 in 100 human GC samples were measured by RT-PCR and immunohistochemistry. The stress hormones epinephrine and norepinephrine significantly accelerated GC cell proliferation, invasion and viability in culture, as well as tumour growth in vivo. These effects were reversed by the ADRB antagonists propranolol and ICI118,551 (an ADRB2-specific antagonist). Moreover, the selective ADRB1 antagonist atenolol had almost no effect on tumour cell proliferation and invasion in vitro and in vivo. ADRB2 antagonists suppressed proliferation, invasion and metastasis by inhibiting the ERK1/2-JNK-MAPK pathway and transcription factors, such as NF-κB, AP-1, CREB and STAT3. Analysis of xenograft models using GC cells revealed that ADRB2 antagonists significantly inhibited tumour growth and metastasis, and chronic stress antagonized these inhibitory effects. In addition, chronic stress increased the expression of VEGF, MMP-2, MMP-7 and MMP-9 in transplanted tumour tissue, and catecholamine hormones enhanced the expression of metastasis-related proteins. The expression of ADRB2 was upregulated in tumour tissues and positively correlated with tumour size, histological grade, lymph node metastasis and clinical stage in human GC samples. Stress hormone-induced activation of the ADRB2 signalling pathway plays a crucial role in GC progression and metastasis. These findings indicate that ADRB2 signalling regulates GC progression and suggest β2 blockade as a novel strategy to complement existing therapies for GC.
Topics: Animals; Cell Movement; Cell Proliferation; Disease Progression; Female; Heterografts; Humans; MAP Kinase Signaling System; Male; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Neoplasm Metastasis; RNA, Messenger; Receptors, Adrenergic, beta-2; STAT3 Transcription Factor; Signal Transduction; Stomach Neoplasms; Stress, Physiological
PubMed: 31624248
DOI: 10.1038/s41419-019-2030-2 -
Circulation Research Nov 2018The actions and regulation of cardiomyocyte βARs differ in several respects from the properties described for the prototypical βAR subtype; a mechanism to explain the... (Review)
Review
The actions and regulation of cardiomyocyte βARs differ in several respects from the properties described for the prototypical βAR subtype; a mechanism to explain the unique properties of the βAR subtype has never been obvious. This viewpoint summarizes recent studies that identify a novel signaling paradigm for the βAR, implicating the N-terminus as a molecular determinant of βAR responsiveness.
Topics: Adrenergic beta-Antagonists; Animals; Heart Diseases; Humans; Myocytes, Cardiac; Receptors, Adrenergic, beta
PubMed: 30571467
DOI: 10.1161/CIRCRESAHA.118.313884 -
Thorax Oct 2019
Topics: Adrenergic Agents; Bronchodilator Agents; Genotype; Humans; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Receptors, Adrenergic, beta-2
PubMed: 31481632
DOI: 10.1136/thoraxjnl-2019-213697 -
Scientific Reports Nov 2021Interactions between the endoplasmic reticulum (ER) and mitochondria (Mito) are crucial for many cellular functions, and their interaction levels change dynamically...
Interactions between the endoplasmic reticulum (ER) and mitochondria (Mito) are crucial for many cellular functions, and their interaction levels change dynamically depending on the cellular environment. Little is known about how the interactions between these organelles are regulated within the cell. Here we screened a compound library to identify chemical modulators for ER-Mito contacts in HEK293T cells. Multiple agonists of G-protein coupled receptors (GPCRs), beta-adrenergic receptors (β-ARs) in particular, scored in this screen. Analyses in multiple orthogonal assays validated that β2-AR activation promotes physical and functional interactions between the two organelles. Furthermore, we have elucidated potential downstream effectors mediating β2-AR-induced ER-Mito contacts. Together our study identifies β2-AR signaling as an important regulatory pathway for ER-Mito coupling and highlights the role of these contacts in responding to physiological demands or stresses.
Topics: Adrenergic beta-2 Receptor Agonists; Endoplasmic Reticulum; HEK293 Cells; Humans; Mitochondria; Receptors, Adrenergic, beta-2; Receptors, Androgen; Signal Transduction
PubMed: 34728663
DOI: 10.1038/s41598-021-00801-w -
Cells Dec 2020The third isotype of beta-adrenoreceptors (β3-AR) has recently come (back) into focus after the observation of its expression in white and beige human adipocytes and... (Review)
Review
The third isotype of beta-adrenoreceptors (β3-AR) has recently come (back) into focus after the observation of its expression in white and beige human adipocytes and its implication in metabolic regulation. This coincides with the recent development and marketing of agonists at the human receptor with superior specificity. Twenty years ago, however, we and others described the expression of β3-AR in human myocardium and its regulation of contractility and cardiac remodeling. Subsequent work from many laboratories has since expanded the characterization of β3-AR involvement in many aspects of cardiovascular physio(patho)logy, justifying the present effort to update current paradigms under the light of the most recent evidence.
Topics: Adipocytes, Beige; Animals; Antioxidants; Cardiovascular Diseases; Cardiovascular System; Catecholamines; Gene Expression Profiling; Gene Expression Regulation; Heart Failure; Humans; Myocardium; Protein Isoforms; Receptors, Adrenergic, beta-3; Signal Transduction
PubMed: 33276630
DOI: 10.3390/cells9122584 -
Trends in Endocrinology and Metabolism:... Jun 2017Recent advances show that insulin may affect β adrenergic receptor (βAR) signaling in the heart to modulate cardiac function in clinically relevant states, such as... (Review)
Review
Recent advances show that insulin may affect β adrenergic receptor (βAR) signaling in the heart to modulate cardiac function in clinically relevant states, such as diabetes mellitus (DM) and heart failure (HF). Conversely, activation of βAR regulates cardiac glucose uptake and promotes insulin resistance (IR) in HF. Here, we discuss the recent characterization of the interaction between the cardiac insulin receptor (InsR) and βAR in the myocardium, in which insulin stimulation crosstalks with cardiac βAR via InsR substrate (IRS)-dependent and G-protein receptor kinase 2 (GRK2)-mediated phosphorylation of βAR. The insulin-induced phosphorylation promotes βAR coupling to G and expression of phosphodiesterase 4D, which both inhibit cardiac adrenergic signaling and compromise cardiac contractile function. These recent developments could support new approaches for the effective prevention or treatment of obesity- or DM-related HF.
Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Humans; Insulin; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 28256297
DOI: 10.1016/j.tem.2017.02.002 -
Nature Communications Jun 2023The αadrenergic receptor (αAR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. αAR is involved in smooth muscle...
The αadrenergic receptor (αAR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. αAR is involved in smooth muscle contraction and cognitive function. Here, we present three cryo-electron microscopy structures of human αAR bound to the endogenous agonist noradrenaline, its selective agonist oxymetazoline, and the antagonist tamsulosin, with resolutions range from 2.9 Å to 3.5 Å. Our active and inactive αAR structures reveal the activation mechanism and distinct ligand binding modes for noradrenaline compared with other adrenergic receptor subtypes. In addition, we identified a nanobody that preferentially binds to the extracellular vestibule of αAR when bound to the selective agonist oxymetazoline. These results should facilitate the design of more selective therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.
Topics: Humans; Oxymetazoline; Cryoelectron Microscopy; Receptors, Adrenergic, alpha-1; Norepinephrine; Tamsulosin
PubMed: 37339967
DOI: 10.1038/s41467-023-39310-x