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Advanced Science (Weinheim,... Oct 2023White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert...
White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert with Cgi-58, catalyzes the first lipolytic reaction. The sympathetic nervous system (SNS) stimulates lipolysis via neurotransmitter norepinephrine that activates adipocyte β adrenergic receptors (Adrb1-3). In obesity, adipose Adrb signaling and lipolysis are impaired, contributing to pathogenic WAT expansion; however, the underling mechanism remains poorly understood. Recent studies highlight importance of N -methyladenosine (m6A)-based RNA modification in health and disease. METTL14 heterodimerizes with METTL3 to form an RNA methyltransferase complex that installs m6A in transcripts. Here, this work shows that adipose Mettl3 and Mettl14 are influenced by fasting, refeeding, and insulin, and are upregulated in high fat diet (HFD) induced obesity. Adipose Adrb2, Adrb3, Atgl, and Cgi-58 transcript m6A contents are elevated in obesity. Mettl14 ablation decreases these transcripts' m6A contents and increases their translations and protein levels in adipocytes, thereby increasing Adrb signaling and lipolysis. Mice with adipocyte-specific deletion of Mettl14 are resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and nonalcoholic fatty liver disease (NAFLD). These results unravel a METTL14/m6A/translation pathway governing Adrb signaling and lipolysis. METTL14/m6A-based epitranscriptomic reprogramming impairs adipose Adrb signaling and lipolysis, promoting obesity, NAFLD, and metabolic disease.
Topics: Animals; Mice; Adrenergic Agents; Insulin Resistance; Lipolysis; Methyltransferases; Non-alcoholic Fatty Liver Disease; Obesity; RNA
PubMed: 37526326
DOI: 10.1002/advs.202301645 -
Hypertension Research : Official... Mar 2024
Topics: Humans; Cohort Studies; Retrospective Studies; Risk Factors; Acute Kidney Injury; Adrenergic Antagonists; Kidney
PubMed: 38135846
DOI: 10.1038/s41440-023-01546-x -
Oncoimmunology 2023Compelling evidence supports the hypothesis that stress negatively impacts cancer development and prognosis. Irrespective of its physical, biological or psychological...
Compelling evidence supports the hypothesis that stress negatively impacts cancer development and prognosis. Irrespective of its physical, biological or psychological source, stress triggers a physiological response that is mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic adrenal medullary axis. The resulting release of glucocorticoids and catecholamines into the systemic circulation leads to neuroendocrine and metabolic adaptations that can affect immune homeostasis and immunosurveillance, thus impairing the detection and eradication of malignant cells. Moreover, catecholamines directly act on β-adrenoreceptors present on tumor cells, thereby stimulating survival, proliferation, and migration of nascent neoplasms. Numerous preclinical studies have shown that blocking adrenergic receptors slows tumor growth, suggesting potential clinical benefits of using β-blockers in cancer therapy. Much of these positive effects of β-blockade are mediated by improved immunosurveillance. The present trial watch summarizes current knowledge from preclinical and clinical studies investigating the anticancer effects of β-blockers either as standalone agents or in combination with conventional antineoplastic treatments or immunotherapy.
Topics: Humans; Adrenergic beta-Antagonists; Catecholamines; Hypothalamo-Hypophyseal System; Neoplasms; Pituitary-Adrenal System; Clinical Trials as Topic
PubMed: 38126031
DOI: 10.1080/2162402X.2023.2284486 -
Developmental Cell Oct 2023Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a...
Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.
Topics: Animals; Mice; Humans; Cell Line, Tumor; Cell Differentiation; Tretinoin; Neuroblastoma; Adrenergic Agents; Piperazines; Pyridines
PubMed: 37734383
DOI: 10.1016/j.devcel.2023.08.028 -
Brain, Behavior, and Immunity Oct 2023Stress-induced β2-adrenergic receptor (β2AR) activation in B cells increases IgG secretion; however, the impact of this activation on antibody affinity and the...
Stress-induced β2-adrenergic receptor (β2AR) activation in B cells increases IgG secretion; however, the impact of this activation on antibody affinity and the underlying mechanisms remains unclear. In the current study, we demonstrate that stress in mice following ovalbumin (OVA) or SARS-CoV-2 RBD immunization significantly increases both serum and surface-expressed IgG binding to the immunogen, while concurrently reducing surface IgG expression and B cell clonal expansion. These effects were abolished by pharmacological β2AR blocking or when the experiments were conducted in β2AR -/- mice. In the second part of our study, we used single B cell sorting to characterize the monoclonal antibodies (mAbs) generated following β2AR activation in cultured RBD-stimulated B cells from convalescent SARS-CoV-2 donors. Ex vivo β2AR activation increased the affinities of the produced anti-RBD mAbs by 100-fold compared to mAbs produced by the same donor control cultures. Consistent with the mouse experiments, β2AR activation reduced both surface IgG levels and the frequency of expanded clones. mRNA sequencing revealed a β2AR-dependent upregulation of the PI3K pathway and B cell receptor (BCR) signaling through AKT phosphorylation, as well as an increased B cell motility. Overall, our study demonstrates that stress-mediated β2AR activation drives changes in B cells associated with BCR activation and higher affinity antibodies.
Topics: Mice; Animals; Adrenergic Agents; Phosphatidylinositol 3-Kinases; COVID-19; SARS-CoV-2; Receptors, Adrenergic, beta-2; Immunoglobulin G
PubMed: 37369341
DOI: 10.1016/j.bbi.2023.06.020 -
The World Journal of Biological... 2024Adrenergic dysregulation has been proposed as a possible underlying mechanism in feeding and eating disorders (FED). This review aims to synthesise the current evidence... (Review)
Review
BACKGROUND
Adrenergic dysregulation has been proposed as a possible underlying mechanism in feeding and eating disorders (FED). This review aims to synthesise the current evidence on the role of adrenergic dysregulation in the pathogenesis and management of FED.
METHODS
A systematic review was conducted in MEDLINE, Cochrane Library, and Clinicaltrials.gov. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was adopted. Preclinical, clinical, and pharmacological studies assessing the adrenergic system in FED were included.
RESULTS
Thirty-one out of 1415 recognised studies were included. Preclinically, studies on adrenaline's anorectic impact, receptor subtypes, and effects on hepatic function in rats show that catecholamine anorexia is primarily alpha-adrenergic, whereas beta-adrenergic anorexia can be obtained only after puberty, implying an impact of sexual hormones. Clinically, catecholamine levels may be higher in FED patients than in healthy controls (HC). Individuals with anorexia nervosa (AN) may show higher epinephrine-induced platelet aggregability response than HC. Pharmacological trials suggest that the alpha-2-adrenergic medication clonidine may not lower AN symptoms, but agents regulating the adrenaline-noradrenaline neurotransmission (bupropion, reboxetine, duloxetine, sibutramine) have been found to improve binge eating symptoms.
CONCLUSION
Adrenergic dysregulation may be involved in the pathophysiology of FED. More research is needed to comprehend underlying mechanisms and treatment implications.
Topics: Humans; Rats; Animals; Anorexia; Feeding and Eating Disorders; Anorexia Nervosa; Catecholamines; Epinephrine; Adrenergic Agents; Bulimia Nervosa
PubMed: 37691603
DOI: 10.1080/15622975.2023.2245458 -
The American Journal of the Medical... Apr 2024Decompensated cirrhosis is associated with a significantly increased risk of mortality. Variceal hemorrhage (VH) further increases the risk of mortality, and of future... (Review)
Review
Decompensated cirrhosis is associated with a significantly increased risk of mortality. Variceal hemorrhage (VH) further increases the risk of mortality, and of future variceal bleed events. Non-selective beta-blockers (NSBBs) are effective therapy for primary and secondary prophylaxis of VH and have become the cornerstone of pharmacologic therapy in cirrhosis. Beta-blockers are associated with reduced overall mortality and GI-bleeding related mortality in patients with decompensated cirrhosis; they may also confer hemodynamically independent beneficial effects. Long-term treatment with beta-blockers may improve decompensation-free survival in compensated cirrhosis with clinically significant portal hypertension (CSPH). Carvedilol more effectively lowers the hepatic vein portal gradient than traditional NSBBs and has been shown to improve survival in compensated cirrhosis. Treatment goals in compensated cirrhosis with CSPH should focus on early utilization of beta-blockers to prevent decompensation and reduce mortality.
Topics: Humans; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Adrenergic beta-Antagonists; Carvedilol; Liver Cirrhosis; Hypertension, Portal
PubMed: 38262558
DOI: 10.1016/j.amjms.2024.01.009 -
Current Medical Research and Opinion 2024
Topics: Humans; Adrenergic beta-Antagonists
PubMed: 38597062
DOI: 10.1080/03007995.2024.2324138 -
Basic Research in Cardiology Jul 2023
Topics: Swine; Animals; Metoprolol; Swine, Miniature; Adrenergic beta-Antagonists; Infarction
PubMed: 37439879
DOI: 10.1007/s00395-023-00998-z -
Autonomic Neuroscience : Basic &... Feb 2024Cancer cachexia, characterized by muscle wasting and widespread inflammation, poses a significant challenge for patients with cancer, profoundly impacting both their... (Review)
Review
Cancer cachexia, characterized by muscle wasting and widespread inflammation, poses a significant challenge for patients with cancer, profoundly impacting both their quality of life and treatment management. However, existing treatment modalities remain very limited, accentuating the necessity for innovative therapeutic interventions. Many recent studies demonstrated that changes in autonomic balance is a key driver of cancer cachexia. This review consolidates research findings from investigations into autonomic dysfunction across cancer cachexia, spanning animal models and patient cohorts. Moreover, we explore therapeutic strategies involving adrenergic receptor modulation through receptor blockers and agonists. Mechanisms underlying adrenergic hyperactivity in cardiac and adipose tissues, influencing tissue remodeling, are also examined. Looking ahead, we present a perspective for future research that delves into autonomic dysregulation in cancer cachexia. This comprehensive review highlights the urgency of advancing research to unveil innovative avenues for combatting cancer cachexia and improving patient well-being.
Topics: Animals; Humans; Cachexia; Muscle, Skeletal; Adrenergic Agents; Quality of Life; Neoplasms; Autonomic Nervous System Diseases
PubMed: 38071925
DOI: 10.1016/j.autneu.2023.103136