SGLT2i and GLP-1RA in Cardiometabolic and Renal Diseases: From Glycemic Control to Adipose Tissue Inflammation and Senescence

Background. Over the last few years, the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) has increased substantially in medical practice due to their documented benefits in cardiorenal and metabolic health. In this sense, and in addition to being used for glycemic control in diabetic patients, these drugs also have other favorable effects such as weight loss and lowering blood pressure, and more recently, they have been shown to have cardio and renoprotective effects with anti-inflammatory properties. Concerning the latter, the individual or associated use of these antihyperglycemic agents has been linked with a decrease in proinflammatory cytokines and with an improvement in the inflammatory profile in chronic endocrine-metabolic diseases. Hence, these drugs have been positioned as first-line therapy in the management of diabetes and its multiple comorbidities, such as obesity, which has been associated with persistent inflammatory states that induce dysfunction of the adipose tissue. Moreover, other frequent comorbidities in long-standing diabetic patients are chronic complications such as diabetic kidney disease, whose progression can be slowed by SGLT2i and/or GLP-1RA. The neuroendocrine and immunometabolism mechanisms underlying adipose tissue inflammation in individuals with diabetes and cardiometabolic and renal diseases are complex and not fully understood. Summary. This review intends to expose the probable molecular mechanisms and compile evidence of the synergistic or additive anti-inflammatory effects of SGLT2i and GLP-1RA and their potential impact on the management of patients with obesity and cardiorenal compromise.

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Flavonoids in adipose tissue inflammation and atherosclerosis: one arrow, two targets

Clinical Science ◽

10.1042/cs20200356 ◽

2020 ◽

Vol 134 (12) ◽

pp. 1403-1432 ◽

Cited By ~ 2

Author(s):

Manal Muin Fardoun ◽

Dina Maaliki ◽

Nabil Halabi ◽

Rabah Iratni ◽

Alessandra Bitto ◽

...

Keyword(s):

Adipose Tissue ◽

Fruits And Vegetables ◽

Metabolic Diseases ◽

Therapeutic Agents ◽

Adipose Tissue Inflammation ◽

Cellular Mechanisms ◽

Tissue Inflammation ◽

Cholesterol Levels ◽

Naturally Occurring ◽

Pro Inflammatory Cytokines

Abstract Flavonoids are polyphenolic compounds naturally occurring in fruits and vegetables, in addition to beverages such as tea and coffee. Flavonoids are emerging as potent therapeutic agents for cardiovascular as well as metabolic diseases. Several studies corroborated an inverse relationship between flavonoid consumption and cardiovascular disease (CVD) or adipose tissue inflammation (ATI). Flavonoids exert their anti-atherogenic effects by increasing nitric oxide (NO), reducing reactive oxygen species (ROS), and decreasing pro-inflammatory cytokines. In addition, flavonoids alleviate ATI by decreasing triglyceride and cholesterol levels, as well as by attenuating inflammatory mediators. Furthermore, flavonoids inhibit synthesis of fatty acids and promote their oxidation. In this review, we discuss the effect of the main classes of flavonoids, namely flavones, flavonols, flavanols, flavanones, anthocyanins, and isoflavones, on atherosclerosis and ATI. In addition, we dissect the underlying molecular and cellular mechanisms of action for these flavonoids. We conclude by supporting the potential benefit for flavonoids in the management or treatment of CVD; yet, we call for more robust clinical studies for safety and pharmacokinetic values.

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Obesity and Breast Cancer: A Case of Inflamed Adipose Tissue

Cancers ◽

10.3390/cancers12061686 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1686 ◽

Cited By ~ 3

Author(s):

Ryan Kolb ◽

Weizhou Zhang

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Molecular Mechanisms ◽

Breast Cancer Incidence ◽

Menopausal Status ◽

Epidemiological Data ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Cancer Subtypes ◽

Increased Risk

Obesity is associated with an increased risk of estrogen receptor-positive breast cancer in postmenopausal women and a worse prognosis for all major breast cancer subtypes regardless of menopausal status. While the link between obesity and the pathogenesis of breast cancer is clear, the molecular mechanism of this association is not completely understood due to the complexity of both obesity and breast cancer. The aim of this review is to highlight the association between obesity and breast cancer and discuss the literature, which indicates that this association is due to chronic adipose tissue inflammation. We will discuss the epidemiological data for the association between breast cancer incidence and progression as well as the potential molecular mechanisms for this association. We will focus on the role of inflammation within the adipose tissue during the pathogenesis of breast cancer. A better understanding of how obesity and adipose tissue inflammation affects the pathogenesis of breast cancer will lead to new strategies to reduce breast cancer risk and improve patient outcomes for obese patients.

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Tart Cherry Reduces Inflammation in Adipose Tissue of Zucker Fatty Rats and Cultured 3T3-L1 Adipocytes

Nutrients ◽

10.3390/nu10111576 ◽

2018 ◽

Vol 10 (11) ◽

pp. 1576 ◽

Cited By ~ 7

Author(s):

Shasika Jayarathne ◽

April Stull ◽

Alexandra Miranda ◽

Shane Scoggin ◽

Kate Claycombe-Larson ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid Synthase ◽

Related Factor ◽

Mrna Levels ◽

Nuclear Factor ◽

Adipose Tissue Inflammation ◽

Tart Cherry ◽

Tissue Inflammation ◽

Anti Inflammatory

Obesity increases adipose tissue inflammation and secretion of pro-inflammatory adipokines, which have systemic effects on the organism’s health status. Our objective was to dissect mechanisms of anti-inflammatory effects of tart cherry (TC) in adipose tissue of Zucker fatty rats, and cultured 3T3-L1 adipocytes. Rats were fed either a control diet, or 4% TC powder diets for eight weeks. Body and epididymal fat pad weights were not significantly different between control and TC groups. However, rats fed the TC diet had significantly reduced adipose tissue inflammation (p < 0.05), as determined by reduced mRNA levels of pro-inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), interleukin-1beta (IL-1β), monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS), and CD-11b, and increased mRNA levels of type-1 arginase (Arg-1) anti-inflammatory marker. Consistent with these in vivo results, TC significantly decreased expression of IL-6 mRNA and protein levels in lipopolysaccharide (LPS) stimulated adipocytes compared to those stimulated with LPS, but no TC. Moreover, both in vivo (rat adipose tissue) and in vitro (3T3-L1 adipocytes), phosphorylation of p65-NF-κB subunit was significantly reduced by TC. Additionally, TC decreased mRNA expression of fatty acid synthase (FASN), and increased expression of peroxisome proliferator-activated receptor alpha (PPARα), master regulator of lipid oxidation, and anti-oxidant markers nuclear factor erythroid-derived 2-related factor (NRFs) in both models. In conclusion, our findings indicate that TC downregulates inflammation in part via the nuclear factor kappa B (NF-κB) pathway in adipose tissue. Thus, TC may serve as a potential intervention to reduce obesity-associated inflammation.

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Improvements in glycemic control after gastric bypass occur despite persistent adipose tissue inflammation

Obesity ◽

10.1002/oby.21524 ◽

2016 ◽

Vol 24 (7) ◽

pp. 1438-1445 ◽

Cited By ~ 26

Author(s):

Mario Kratz ◽

Derek K. Hagman ◽

Jessica N. Kuzma ◽

Karen E. Foster-Schubert ◽

Chun P. Chan ◽

...

Keyword(s):

Gastric Bypass ◽

Adipose Tissue ◽

Glycemic Control ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation

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The Role of the Immune System in Obesity and Insulin Resistance

Journal of Obesity ◽

10.1155/2013/616193 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 68

Author(s):

Payal S. Patel ◽

Eric D. Buras ◽

Ashok Balasubramanyam

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Immune System ◽

Stress Responses ◽

Innate Immune System ◽

Metabolic Diseases ◽

Innate Immune ◽

Metabolic Dysfunction ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation

The innate immune system provides organisms with rapid and well-coordinated protection from foreign pathogens. However, under certain conditions of metabolic dysfunction, components of the innate immune system may be activated in the absence of external pathogens, leading to pathologic consequences. Indeed, there appears to be an intimate relationship between metabolic diseases and immune dysfunction; for example, macrophages are prime players in the initiation of a chronic inflammatory state in obesity which leads to insulin resistance. In response to increases in free fatty acid release from obese adipose depots, M1-polarized macrophages infiltrate adipose tissues. These M1 macrophages trigger inflammatory signaling and stress responses within cells that signal through JNK or IKKβpathways, leading to insulin resistance. If overnutrition persists, mechanisms that counteract inflammation (such as M2 macrophages and PPAR signaling) are suppressed, and the inflammation becomes chronic. Although macrophages are a principal constituent of obese adipose tissue inflammation, other components of the immune system such as lymphocytes and mast cells also contribute to the inflammatory cascade. Thus it is not merely an increased mass of adipose tissue that directly leads to attenuation of insulin action, but rather adipose tissue inflammation activated by the immune system in obese individuals that leads to insulin resistance.

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The Absence of Adiponectin Alters Niacin’s Effects on Adipose Tissue Inflammation in Mice

Nutrients ◽

10.3390/nu12082427 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2427

Author(s):

Emily C. Graff ◽

Han Fang ◽

Desiree Wanders ◽

Robert L. Judd

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Inflammatory Markers ◽

Adipose Tissue Inflammation ◽

High Fat ◽

Tissue Inflammation ◽

Low Fat Diet ◽

Expression Of Genes ◽

Ccl2 Expression ◽

Anti Inflammatory

Obesity is an immunometabolic disease associated with chronic inflammation and the dysregulation of pro- and anti-inflammatory cytokines. One hallmark of obesity is reduced concentrations of the anti-inflammatory adipokine, adiponectin. Pharmacologic doses of niacin produce multiple metabolic benefits, including attenuating high-fat diet (HFD)-induced adipose tissue inflammation and increasing adiponectin concentrations. To determine if adiponectin mediates the anti-inflammatory effects of niacin, male C57BL/6J (WT) and adiponectin null (Adipoq-/-) mice were maintained on a low-fat diet (LFD) or HFD for 6 weeks, before being administered either vehicle or niacin (360 mg/kg/day) for 5 weeks. HFD-fed mice had increased expression of genes associated with macrophage recruitment (Ccl2) and number (Cd68), and increased crown-like structure (CLS) number in adipose tissue. While niacin attenuated Ccl2 expression, there were no effects on Cd68 or CLS number. The absence of adiponectin did not hinder the ability of niacin to reduce Ccl2 expression. HFD feeding increased gene expression of inflammatory markers in the adipose tissue of WT and Adipoq-/- mice. While niacin tended to decrease the expression of inflammatory markers in WT mice, niacin increased their expression in HFD-fed Adipoq-/- mice. Therefore, our results indicate that the absence of adiponectin alters the effects of niacin on markers of adipose tissue inflammation in HFD-fed mice, suggesting that the effects of niacin on tissue cytokines may involve adiponectin.

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Fetuin-A regulates adipose tissue macrophage content and activation in insulin resistant mice through MCP-1 and iNOS: Involvement of IFNγ-JAK2-STAT1 pathway

Biochemical Journal ◽

10.1042/bcj20210442 ◽

2021 ◽

Author(s):

Dipanjan Chattopadhyay ◽

Snehasis Das ◽

Suktara Guria ◽

Soumyadeep Basu ◽

Sutapa Mukherjee

Keyword(s):

Adipose Tissue ◽

Macrophage Polarization ◽

Interferon Γ ◽

Adipose Tissue Inflammation ◽

Fetuin A ◽

Monocyte Chemoattractant Protein 1 ◽

Tissue Inflammation ◽

Tissue Macrophage ◽

Adipose Tissue Macrophage ◽

Anti Inflammatory

In the context of obesity-induced adipose tissue inflammation, migration of macrophages and their polarization from predominantly anti-inflammatory to proinflammatory subtype is considered a pivotal event in the loss of adipose insulin sensitivity. Two major chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and Fetuin A (FetA), have been reported to stimulate macrophage migration into inflamed adipose tissue instigating inflammation. Moreover, FetA could notably modulate macrophage polarization, yet the mechanism(s) is unknown. The present study was undertaken to elucidate the mechanistic pathway involved in the actions of FetA and MCP-1 in obese adipose tissue. We found that FetA knockdown in high fat diet (HFD) fed mice could significantly subdue the augmented MCP-1 expression and reduce adipose tissue macrophage (ATM) content thereby indicating that MCP-1 is being regulated by FetA. Additionally, knockdown of FetA in HFD mice impeded the expression of inducible nitric oxide synthase (iNOS) reverting macrophage activation from mostly proinflammatory to anti-inflammatory state. It was observed that the stimulating effect of FetA on MCP-1 and iNOS was mediated through interferon γ (IFNγ) induced activation of JAK2-STAT1-NOX4 pathway. Furthermore, we detected that the enhanced IFNγ expression was accounted by the stimulatory effect of FetA upon the activities of both cJun and JNK. Taken together, our findings revealed that obesity-induced FetA acts as a master upstream regulator of adipose tissue inflammation by regulating MCP-1 and iNOS expression through JNK-cJun-IFNγ-JAK2-STAT1 signaling pathway. This study opened a new horizon in understanding the regulation of ATM content and activation in conditions of obesity-induced insulin resistance.

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Resolution of Adipose Tissue Inflammation

The Scientific World JOURNAL ◽

10.1100/tsw.2010.77 ◽

2010 ◽

Vol 10 ◽

pp. 832-856 ◽

Cited By ~ 48

Author(s):

Ana González-Périz ◽

Joan Clària

Keyword(s):

Adipose Tissue ◽

Lipid Mediators ◽

Current Status ◽

Critical Event ◽

Low Grade ◽

Adipose Tissue Inflammation ◽

Nonalcoholic Fatty Liver ◽

Tissue Inflammation ◽

Inflammatory State ◽

Anti Inflammatory

The presence of the so-called “low-grade” inflammatory state is recognized as a critical event in adipose tissue dysfunction in obesity. This chronic “low-grade” inflammation in white adipose tissue is powerfully augmented through the infiltration of macrophages, which, together with adipocytes, perpetuate a vicious cycle of macrophage recruitment and secretion of free fatty acids and deleterious adipokines that predispose the development of obesity-related comorbidities, such as insulin resistance and nonalcoholic fatty liver disease. In the last decade, many factors have been identified that contribute to mounting uncontrolled inflammation in obese adipose tissue. Among them, bioactive lipid mediators derived from the cyclooxygenase and 5-lipoxygenase pathways, which convert the ω-6-polyunsaturated fatty acid (PUFA) arachidonic acid into potent proinflammatory eicosanoids (i.e., prostaglandins [PGs] and leukotrienes), have emerged. Interestingly, the same lipid mediators that initially trigger the inflammatory response also signal the termination of inflammation by stimulating the biosynthesis of anti-inflammatory and proresolving lipid autacoids. This review discusses the current status, characteristics, and progress in this class of “stop signals”, including the lipoxins, which were the first identified ω-6 PUFA–derived lipid mediators with potent anti-inflammatory properties; the recently described ω-3 PUFA–derived lipid mediators resolvins and protectins; and the cyclopentenone PGs of the D series. Special emphasis is given to the participation of these bioactive lipid autacoids in the resolution of adipose tissue inflammation and in preventing the development of obesity-related complications.

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Obesity-Induced Adipose Tissue Inflammation as a Strong Promotional Factor for Pancreatic Ductal Adenocarcinoma

Cells ◽

10.3390/cells8070673 ◽

2019 ◽

Vol 8 (7) ◽

pp. 673 ◽

Cited By ~ 9

Author(s):

Hui-Hua Chang ◽

Guido Eibl

Keyword(s):

Adipose Tissue ◽

Pancreatic Ductal Adenocarcinoma ◽

Visceral Adipose Tissue ◽

Metabolic Diseases ◽

The United States ◽

Ductal Adenocarcinoma ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Genetically Engineered Mouse Model ◽

Visceral Adipose

Pancreatic ductal adenocarcinoma (PDAC) is expected to soon become the second leading cause of cancer related deaths in the United States. This may be due to the rising obesity prevalence, which is a recognized risk factor for PDAC. There is great interest in deciphering the underlying driving mechanisms of the obesity–PDAC link. Visceral adiposity has a strong correlation to certain metabolic diseases and gastrointestinal cancers, including PDAC. In fact, our own data strongly suggest that visceral adipose tissue inflammation is a strong promoter for PDAC growth and progression in a genetically engineered mouse model of PDAC and diet-induced obesity. In this review, we will discuss the relationship between obesity-associated adipose tissue inflammation and PDAC development, with a focus on the key molecular and cellular components in the dysfunctional visceral adipose tissue, which provides a tumor permissive environment.

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