Energy provisioning and inflammasome activation: The pivotal role of AMPK in sterile inflammation and associated metabolic disorders

2020 ◽  
Vol 19 ◽  
Author(s):  
Akhila Hosur Shrungeswara ◽  
Mazhuvancherry Kesavan Unnikrishnan
Keyword(s):  
Metabolic Regulation ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Sedentary Lifestyle ◽  
Sterile Inflammation ◽  
Inflammasome Activation ◽  
Common Denominator ◽  
Low Grade ◽  
Sudden Increase ◽  
Free Environment

Background: Body defenses and metabolic processes probably co-evolved in such a way that rapid, energyintensive acute inflammatory repair is functionally integrated with energy allocation in a starvation/ infection / injury-prone primitive environment. Disruptive metabolic surplus, aggravated by sedentary lifestyle, induces chronic under-activation of AMPK, the master regulator of intracellular energy homeostasis. Sudden increase in chronic, dysregulated ‘sterile’ inflammatory disorders probably results from a shift towards calorie rich, sanitized, cushioned, injury/ infection free environment, repositioning inflammatory repair pathways towards chronic, non-microbial, ‘sterile’, ‘low grade’, ‘parainflammation’. AMPK, (at the helm of energy provisioning) supervises the metabolic regulation of inflammasome activation, a common denominator in lifestyle disorders. Discussion: In this review we discuss various pathways linking AMPK under-activation and inflammasome activation. AMPK under-activation, the possible norm in energy-rich sedentary lifestyle, could be the central agency that stimulates inflammasome activation by multiple pathways such as: [1] decreasing autophagy, and accumulation of intracellular DAMPs, (particulate crystalline molecules, advanced glycation end-products, oxidized lipids etc.) [2] stimulating a glycolytic shift (pro-inflammatory) in metabolism, [3] promoting NF-kB activation and decreasing Nrf2 activation, [4] increasing reactive oxygen species (ROS) formation, unfolded protein response( UPR) and endoplasmic reticulum (ER) stress. Conclusion: The ‘inverse energy crisis’, associated with calorie-rich, sedentary lifestyle, advocates dietary and pharmacological interventions for treating chronic metabolic disorders by overcoming / reversing AMPK under-activation.

scholarly journals NLRP3 Inflammasome Activation in Adipose Tissues and Its Implications on Metabolic Diseases

2020 ◽  
Vol 21 (11) ◽  
pp. 4184 ◽  
Author(s):  
Kelvin Ka-Lok Wu ◽  
Samson Wing-Ming Cheung ◽  
Kenneth King-Yip Cheng
Keyword(s):  
Adipose Tissue ◽  
Nlrp3 Inflammasome ◽  
Metabolic Disorders ◽  
Immune Cell ◽  
Diabetic Patients ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Adipose Tissues ◽  
Adipose Tissue Dysfunction ◽  
Nlrp3 Inflammasome Activation

Adipose tissue is an active endocrine and immune organ that controls systemic immunometabolism via multiple pathways. Diverse immune cell populations reside in adipose tissue, and their composition and immune responses vary with nutritional and environmental conditions. Adipose tissue dysfunction, characterized by sterile low-grade chronic inflammation and excessive immune cell infiltration, is a hallmark of obesity, as well as an important link to cardiometabolic diseases. Amongst the pro-inflammatory factors secreted by the dysfunctional adipose tissue, interleukin (IL)-1β, induced by the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, not only impairs peripheral insulin sensitivity, but it also interferes with the endocrine and immune functions of adipose tissue in a paracrine manner. Human studies indicated that NLRP3 activity in adipose tissues positively correlates with obesity and its metabolic complications, and treatment with the IL-1β antibody improves glycaemia control in type 2 diabetic patients. In mouse models, genetic or pharmacological inhibition of NLRP3 activation pathways or IL-1β prevents adipose tissue dysfunction, including inflammation, fibrosis, defective lipid handling and adipogenesis, which in turn alleviates obesity and its related metabolic disorders. In this review, we summarize both the negative and positive regulators of NLRP3 inflammasome activation, and its pathophysiological consequences on immunometabolism. We also discuss the potential therapeutic approaches to targeting adipose tissue inflammasome for the treatment of obesity and its related metabolic disorders.

scholarly journals Central 5-HTR2C in the Control of Metabolic Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ting Yao ◽  
Jiehui He ◽  
Zhicheng Cui ◽  
Ruwen Wang ◽  
Kaixuan Bao ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Metabolic Regulation ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Molecular Pathways ◽  
Metabolic Hormones ◽  
Obesity Drugs ◽  
G Protein Coupled ◽  
The Brain

The 5-hydroxytryptamine 2C receptor (5-HTR2C) is a class G protein-coupled receptor (GPCR) enriched in the hypothalamus and the brain stem, where it has been shown to regulate energy homeostasis, including feeding and glucose metabolism. Accordingly, 5-HTR2C has been the target of several anti-obesity drugs, though the associated side effects greatly curbed their clinical applications. Dissecting the specific neural circuits of 5-HTR2C-expressing neurons and the detailed molecular pathways of 5-HTR2C signaling in metabolic regulation will help to develop better therapeutic strategies towards metabolic disorders. In this review, we introduced the regulatory role of 5-HTR2C in feeding behavior and glucose metabolism, with particular focus on the molecular pathways, neural network, and its interaction with other metabolic hormones, such as leptin, ghrelin, insulin, and estrogens. Moreover, the latest progress in the clinical research on 5-HTR2C agonists was also discussed.

scholarly journals Neurovascular Inflammaging in Health and Disease

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1614 ◽  
Author(s):  
Ádám Mészáros ◽  
Kinga Molnár ◽  
Bernát Nógrádi ◽  
Zsófia Hernádi ◽  
Ádám Nyúl-Tóth ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Current Knowledge ◽  
Neurovascular Unit ◽  
Sterile Inflammation ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Intrinsic Factors ◽  
Age Related ◽  
Cellular Debris ◽  
The Central Nervous System

Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging.

scholarly journals Role of NLRP3 Inflammasome Activation in Obesity-Mediated Metabolic Disorders

2021 ◽  
Vol 18 (2) ◽  
pp. 511
Author(s):  
Kaiser Wani ◽  
Hind AlHarthi ◽  
Amani Alghamdi ◽  
Shaun Sabico ◽  
Nasser M. Al-Daghri
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Nlrp3 Inflammasome ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Nlrp3 Inflammasome Activation ◽  
Specific Inhibitors

NLRP3 inflammasome is one of the multimeric protein complexes of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing pyrin and HIN domain family (PYHIN). When activated, NLRP3 inflammasome triggers the release of pro-inflammatory interleukins (IL)-1β and IL-18, an essential step in innate immune response; however, defective checkpoints in inflammasome activation may lead to autoimmune, autoinflammatory, and metabolic disorders. Among the consequences of NLRP3 inflammasome activation is systemic chronic low-grade inflammation, a cardinal feature of obesity and insulin resistance. Understanding the mechanisms involved in the regulation of NLRP3 inflammasome in adipose tissue may help in the development of specific inhibitors for the treatment and prevention of obesity-mediated metabolic diseases. In this narrative review, the current understanding of NLRP3 inflammasome activation and regulation is highlighted, including its putative roles in adipose tissue dysfunction and insulin resistance. Specific inhibitors of NLRP3 inflammasome activation which can potentially be used to treat metabolic disorders are also discussed.

The Inflammation Network in the Pathogenesis of Erectile Dysfunction: Attractive Potential Therapeutic Targets

2020 ◽  
Vol 26 (32) ◽  
pp. 3955-3972
Author(s):  
Ecem Kaya-Sezginer ◽  
Serap Gur
Keyword(s):  
Erectile Dysfunction ◽  
Endothelial Dysfunction ◽  
Metabolic Diseases ◽  
Inflammatory Marker ◽  
Attractive Potential ◽  
Common Denominator ◽  
Low Grade ◽  
Antiinflammatory Drugs ◽  
Male Population ◽  
Low Grade Inflammation

Background: Erectile dysfunction (ED) is an evolving health problem in the aging male population. Chronic low-grade inflammation is a critical component of ED pathogenesis and a probable intermediate stage of endothelial dysfunction, especially in metabolic diseases, with the inclusion of obesity, metabolic syndrome, and diabetes. Objective: This review will present an overview of preclinical and clinical data regarding common inflammatory mechanisms involved in the pathogenesis of ED associated with metabolic diseases and the effect of antiinflammatory drugs on ED. Methods: A literature search of existing pre-clinical and clinical studies was performed on databases [Pubmed (MEDLINE), Scopus, and Embase] from January 2000 to October 2019. Results: Low-grade inflammation is a possible pathological role in endothelial dysfunction as a consequence of ED and other related metabolic diseases. Increased inflammation and endothelial/prothrombotic markers can be associated with the presence and degree of ED. Pharmacological therapy and modification of lifestyle and risk factors may have a significant role in the recovery of erectile response through reduction of inflammatory marker levels. Conclusion: Inflammation is the least common denominator in the pathology of ED and metabolic disorders. The inflammatory process of ED includes a shift in the complex interactions of cytokines, chemokines, and adhesion molecules. These data have established that anti-inflammatory agents could be used as a therapeutic opportunity in the prevention and treatment of ED. Further research on inflammation-related mechanisms underlying ED and the effect of therapeutic strategies aimed at reducing inflammation is required for a better understanding of the pathogenesis and successful management of ED.

Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation

2021 ◽  
Vol 80 (5) ◽  
pp. 467-475
Author(s):  
Yu-Qing Li ◽  
C Shun Wong
Keyword(s):  
Cell Fate ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Neuronal Development ◽  
Adenosine Monophosphate ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Wild Type ◽  
Newborn Neuron ◽  
Negative Effect

Abstract 5′-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.

Associação entre obesidade e resultados graves do tratamento em pacientes com COVID-19

2021 ◽  
Vol 12 (47) ◽  
pp. 138-142
Author(s):  
Giordana Gregório Fritsch ◽  
Michael Wesley Schmidt ◽  
Antônio Carlos Gargioni Filho ◽  
Hussein Nasser Fares
Keyword(s):  
Metabolic Disorders ◽  
Distress Syndrome ◽  
Obesity Paradox ◽  
Low Grade ◽  
Double Burden ◽  
Death Rates ◽  
Worldwide Population ◽  
Low Grade Inflammation ◽  
The Relationship ◽  
Activation Component

The worldwide population is facing a double burden of epidemic, the COVID-19and obesity. This is even more alarming as obesity increases the COVID-19 severity. However, the relationship between obesity and COVID-19 severity is more complex than a simple association with BMI. In particular, obesity has been associated with low death rates in patients with acute respiratory distress syndrome, a fatal comorbidity to COVID-19, possibly due to the obesity paradox. Also, visceral adiposity could be a major risk factor for COVID- -19severity, due to its immune activation component, release of ACE2 and involvement in the cytokine storm, It is also known to correlate with metabolic disorders, low-grade inflammation and higher mortality rates.

scholarly journals The NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Elisa Benetti ◽  
Fausto Chiazza ◽  
Nimesh S. A. Patel ◽  
Massimo Collino
Keyword(s):  
Chronic Inflammation ◽  
Nlrp3 Inflammasome ◽  
Metabolic Disorders ◽  
Inflammasome Activation ◽  
Nucleotide Binding Domain ◽  
Metabolic Inflammation ◽  
Nlrp3 Inflammasome Activation ◽  
Leucine Rich Repeat Protein

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the “inflammasome,” a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1βand IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.

scholarly journals Glucose modulates Drosophila longevity and immunity independent of the microbiota.

2015 ◽  
Author(s):  
Anthony Galenza ◽  
Jaclyn Hutchinson ◽  
Bart Hazes ◽  
Shelagh Campbell ◽  
Edan Foley
Keyword(s):  
Metabolic Disorders ◽  
Animal Health ◽  
Critical Factor ◽  
Longitudinal Survey ◽  
Enteric Infection ◽  
Survival Times ◽  
Germ Free ◽  
Free Environment ◽  
Nutritional Imbalance ◽  
Adult Drosophila

The acquisition of nutrients is essential for maintenance of metabolic processes in all organisms. Nutritional imbalance contributes to myriad metabolic disorders that include malnutrition, diabetes, and even cancer. Recently, the importance of macronutrient ratio of food has emerged as a critical factor to determine health outcomes. Here we show that individual modifications to a completely defined diet markedly impact multiple aspects of organism wellbeing in Drosophila melanogaster. Through a longitudinal survey of several diets we demonstrate that increased levels of dietary glucose significantly improve longevity and immunity in adult Drosophila. Our metagenomic studies, show that relative macronutrient levels not only influence the host, but also have a profound impact on microbiota composition. However, we found that elevated dietary glucose extended the lifespan of adult flies even when raised in a germ-free environment. Furthermore, when challenged with a chronic enteric infection, flies fed a diet with added glucose had increased survival times even in the absence of an intact microbiota. Thus, in contrast to known links between the microbiota and animal health, our findings uncover a novel microbiota-independent response to diet that impacts host wellbeing. As dietary responses are highly conserved in animals, we believe our results offer a general understanding of the association between glucose metabolism and animal health.

scholarly journals Obesity and cahexia as the first manifestations of craniopharingioma

2018 ◽  
Vol 15 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Liudmila I. Astafieva ◽  
Irina S. Klochkova ◽  
Pavel L. Kalinin ◽  
Boris A. Kadashev ◽  
Aleksandr N. Konovalov ◽  
...  
Keyword(s):  
Energy Balance ◽  
Young Women ◽  
Energy Exchange ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
The Other ◽  
Hypothalamic Region ◽  
Clinical Observations

The key structure in the regulation of energy homeostasis is the hypothalamus. The damage of the hypothalamic region can lead to imbalance of energy exchange with the development of obesity or cachexia. The most common metabolic disorders occur in case of craniopharyngiomas. The article presents two clinical observations of papillary craniopharyngioma in young women. Cases were accompanied by different disturbances of the energy balance, in one - with the development of obesity, in the other - cachexia.

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