ABSTRACT
The liberation of energy stores from adipocytes is critical to support survival in times of energy deficit; however, uncontrolled or chronic lipolysis associated with insulin resistance and/or insulin insufficiency disrupts metabolic homeostasis1,2. Coupled to lipolysis is the release of a recently identified hormone, fatty-acid-binding protein 4 (FABP4)3. Although circulating FABP4 levels have been strongly associated with cardiometabolic diseases in both preclinical models and humans4-7, no mechanism of action has yet been described8-10. Here we show that hormonal FABP4 forms a functional hormone complex with adenosine kinase (ADK) and nucleoside diphosphate kinase (NDPK) to regulate extracellular ATP and ADP levels. We identify a substantial effect of this hormone on beta cells and given the central role of beta-cell function in both the control of lipolysis and development of diabetes, postulate that hormonal FABP4 is a key regulator of an adipose-beta-cell endocrine axis. Antibody-mediated targeting of this hormone complex improves metabolic outcomes, enhances beta-cell function and preserves beta-cell integrity to prevent both type 1 and type 2 diabetes. Thus, the FABP4-ADK-NDPK complex, Fabkin, represents a previously unknown hormone and mechanism of action that integrates energy status with the function of metabolic organs, and represents a promising target against metabolic disease.
Subject(s)
Fatty Acid-Binding Proteins , Islets of Langerhans , Phosphotransferases , Adipocytes/metabolism , Diabetes Mellitus/metabolism , Fatty Acid-Binding Proteins/metabolism , Humans , Insulin/metabolism , Islets of Langerhans/enzymology , Islets of Langerhans/physiology , Lipolysis , Nucleosides/metabolism , Phosphotransferases/metabolismABSTRACT
OBJECTIVE: Obesity is a major risk factor of atherosclerotic cardiovascular disease. Circulating free fatty acid levels are known to be elevated in obese individuals and, along with dietary saturated fatty acids, are known to associate with cardiovascular events. However, little is known about the molecular mechanisms by which free fatty acids are linked to cardiovascular disease. APPROACH AND RESULTS: We found that administration of palmitate, a major saturated free fatty acid, to mice markedly aggravated neointima formation induced by carotid artery ligation and that the neointima primarily consisted of phenotypically modulated smooth muscle cells (SMCs). In cultured SMCs, palmitate-induced phenotypic modulation was characterized by downregulation of SMC differentiation markers, such as SM α-actin and SM-myosin heavy chain, and upregulation of mediators involved in inflammation and remodeling of the vessel wall, such as platelet-derived growth factor B and matrix metalloproteinases. We also found that palmitate induced the expression of proinflammatory genes via a novel toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor-κB/NADPH oxidase 1/reactive oxygen species signaling pathway: nuclear factor-κB was activated by palmitate via toll-like receptor 4 and its adapter, MyD88, and once active, it transactivated Nox1, encoding NADPH oxidase 1, a major reactive oxygen species generator in SMCs. Pharmacological inhibition and small interfering RNA-mediated knockdown of the components of this signaling pathway mitigated the palmitate-induced upregulation of proinflammatory genes. More importantly, Myd88 knockout mice were resistant to palmitate-induced exacerbation of neointima formation. CONCLUSIONS: Palmitate seems to promote neointima formation by inducing inflammatory phenotypes in SMCs.
Subject(s)
Carotid Artery Injuries/metabolism , Fatty Acids/metabolism , Myocytes, Smooth Muscle/metabolism , Neointima/metabolism , Obesity/metabolism , Palmitates/metabolism , Animals , Carotid Artery Injuries/pathology , Disease Models, Animal , Fatty Acids/pharmacology , Ligation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Differentiation Factor 88/genetics , Myocytes, Smooth Muscle/cytology , NADH, NADPH Oxidoreductases/genetics , NADH, NADPH Oxidoreductases/metabolism , NADPH Oxidase 1 , Neointima/chemically induced , Obesity/pathology , Palmitates/pharmacology , Phenotype , Reactive Oxygen Species/metabolism , Signal Transduction/physiology , Toll-Like Receptor 4/metabolismABSTRACT
Introduction: CAPTURE was a cross-sectional, non-interventional study (NCT03786406, NCT03811288) investigating the prevalence and characteristics of cardiovascular disease (CVD) in adults with type 2 diabetes (T2D) across 13 countries worldwide. Here we present the findings for Japan. Materials and methods: Data were collected from adults aged ≥ 20 years (aged ≥ 18 years in countries outside Japan) with T2D who were managed in clinics or hospitals in 2019. Standardized methodology was used for all countries. The prevalence of CVD and its subtypes was estimated, weighted by care setting (clinics versus hospitals). Results: Among participants from Japan (total: 800; clinics: 440; hospitals: 360), mean (standard deviation) age was 65.6 (11.2) years and glycated hemoglobin 7.2% (0.9). Sixty-seven percent of participants were male, 57.8% had diabetes duration > 10 years, 49.8% had body mass index ≥ 25 kg/m2 and 63.1% had hypertension. The weighted prevalences (95% confidence interval [CI]) of CVD and atherosclerotic CVD were 37.3% (34.2;40.3) and 33.5% (30.6;36.4), respectively. The prevalence (95% CI) of the most common subtypes of CVD was: carotid artery disease 20.5% (18.2;22.8), coronary heart disease 11.9% (9.7;14.1) and cerebrovascular disease 10.4% (8.3;12.5). Conclusions: These contemporary data from the CAPTURE study on CVD prevalence in adults with T2D in Japan show that approximately one in three adults with T2D had established CVD, which is comparable to the prevalence in the global study cohort. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00612-y.
ABSTRACT
AIMS: To understand glucagon-like peptide-1 receptor agonist (GLP-1RA) use in patients with type 2 diabetes (T2D) in Japan. METHODS: Characteristics of people receiving GLP-1RAs between 2016 and 2020 in the J-DREAMS database were investigated. Changes in HbA1c, body weight (BW), body mass index (BMI), and proportion reaching HbA1c targets were analysed in GLP-1RA-naïve patients 6-24 months after GLP-1RA initiation. RESULTS: The proportion of patients with GLP-1RA prescriptions increased from 3.6% to 9.6% during 2016-2020. Among GLP-1RA-naïve patients (n = 569), HbA1c reduced -|0.6% (95% confidence interval [CI] -0.7, -0.5; -6 mmol/mol [95% CI -7, -5]) 6 months after treatment initiation and stabilised until 24 months (P < 0.001); mean BW and BMI reduced -1.05 kg (95% CI -1.31, -0.80) and -0.43 kg/m2 (95% CI -0.53, -0.32), respectively, at 6 months (P < 0.001). The proportion of GLP-1RA-naïve patients with HbA1c < 7.0% (<53 mmol/mol) and <8.0% (<64 mmol/mol) increased from 16% to 27% and 43% to 65%, respectively, and an HbA1c reduction of ≥1.0% (≥11 mmol/mol) was observed in 33% of patients after 6 months (P < 0.001). CONCLUSIONS: This study shows increased GLP-1RA prescriptions over 5 years. HbA1c and BW reduced 6 months after GLP-1RA initiation in patients with T2D in a Japanese real-world setting.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Glucagon-Like Peptide-1 Receptor/agonists , Retrospective Studies , East Asian People , Glycated Hemoglobin , Body WeightABSTRACT
Introduction: The CAPTURE study estimated the global prevalence of established cardiovascular disease (CVD) and characterized the usage of glucose-lowering agents (GLAs) in adults with type 2 diabetes (T2D) across 13 countries. The purpose of this secondary analysis of data from the Japanese sites within CAPTURE (NCT03786406, NCT03811288) was to provide data about medication usage stratified by CVD status among Japanese participants with T2D. Materials and methods: Data on GLA usage (including those with proven cardiovascular [CV] benefits) in Japanese participants with T2D managed in clinics or hospitals were collected and stratified by CVD subgroups. Results: There were 800 Japanese participants in the CAPTURE study (n = 502 [no CVD group], n = 298 [CVD group], n = 268 [atherosclerotic CVD subgroup]). Oral antidiabetic agents and insulin were used by 88.5% and 23.4%, respectively, of participants overall. Among participants with established CVD, dipeptidyl peptidase-4 inhibitors (65.1%) were most frequently used, followed by biguanides (50.7%) and insulins (26.2%). The pattern was similar among participants with atherosclerotic CVD. A lower proportion of participants in the CVD group used glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) with proven CV benefits versus the no CVD group (GLP-1 RAs: 7.0% vs. 8.6%; SGLT-2is: 13.4% vs. 19.1%). Conclusion: This analysis of the CAPTURE study provided a comprehensive overview of prescription patterns for the treatment of T2D in Japan. Use of GLAs with proven CV benefit was low, even in participants with established CVD, which was comparable to the findings from the global cohort. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00638-w.
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BACKGROUND: It has been proposed that bone marrow-derived cells infiltrate the neointima, where they differentiate into smooth muscle (SM) cells; however, technical limitations have hindered clear identification of the lineages of bone marrow-derived "SM cell-like" cells. METHODS AND RESULTS: Using a specific antibody against the definitive SM cell lineage marker SM myosin heavy chain (SM-MHC) and mouse lines in which reporter genes were driven by regulatory programs for either SM-MHC or SM α-actin, we demonstrated that although some bone marrow-derived cells express SM α-actin in the wire injury-induced neointima, those cells did not express SM-MHC, even 30 weeks after injury. Likewise, no SM-MHC(+) bone marrow-derived cells were found in vascular lesions in apolipoprotein E(-/-)mice or in a heart transplantation vasculopathy model. Instead, the majority of bone marrow-derived SM α-actin(+) cells were also CD115(+)CD11b(+)F4/80(+)Ly-6C(+), which is the surface phenotype of inflammatory monocytes. Moreover, adoptively transferred CD11b(+)Ly-6C(+) bone marrow cells expressed SM α-actin in the injured artery. Expression of inflammation-related genes was significantly higher in neointimal subregions rich in bone marrow-derived SM α-actin(+) cells than in other regions. CONCLUSIONS: It appears that bone marrow-derived SM α-actin(+) cells are of monocyte/macrophage lineage and are involved in vascular remodeling. It is very unlikely that these cells acquire the definitive SM cell lineage.
Subject(s)
Antigens, Differentiation/metabolism , Bone Marrow Cells/metabolism , Bone Marrow Transplantation , Cell Differentiation , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Vasculitis/metabolism , Animals , Antigens, Differentiation/genetics , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Bone Marrow Cells/pathology , Disease Models, Animal , Heart Transplantation , Humans , Inflammation/etiology , Inflammation/genetics , Inflammation/metabolism , Inflammation/pathology , Mice , Mice, Knockout , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/pathology , Transplantation, Homologous , Vasculitis/etiology , Vasculitis/genetics , Vasculitis/pathologyABSTRACT
AIMS/INTRODUCTION: The prevalence of obesity is rising in Japan and represents a considerable unmet medical need. The Awareness, Care and Treatment in Obesity MaNagement - International Observation (ACTION-IO) study was designed to identify the perceptions, attitudes and barriers to obesity care among people with obesity (PwO) and healthcare professionals (HCPs) in Japan. MATERIALS AND METHODS: An online, cross-sectional survey was carried out in 11 countries, including Japan. RESULTS: The survey was completed by 2,001 PwO and 302 HCPs in Japan. Fewer PwO (58%) than HCPs (85%) perceived obesity as a chronic disease. Most PwO (81%) thought that weight loss was their own responsibility, and waited a considerable time before seeking support from their HCP (mean 6 years). Most PwO (64%) had made one or more serious weight loss attempt in the past. In contrast, a serious attempt at losing weight was reported by HCPs for just 21% of their patients. Just 24% of PwO had weight discussions with an HCP in the past 5 years; of those, 56% expressed positive feelings after such a conversation, and just 2% felt offended. Lack of patient motivation (68%) and patient disinterest (61%) were reported by HCPs as barriers to weight management conversations. A higher proportion of obesity specialists (37%) than non-specialists (22%) thought their patients were motivated to lose weight. CONCLUSIONS: Our Japanese dataset shows a need to raise awareness of the pathophysiological basis and clinical management of obesity among PwO and HCPs. The largely positive feelings expressed by PwO after weight loss conversations should encourage HCPs to initiate earlier discussions before obesity-related complications occur.
Subject(s)
Health Knowledge, Attitudes, Practice , Health Personnel/psychology , Obesity Management , Obesity/psychology , Patient Acceptance of Health Care/psychology , Adolescent , Adult , Aged , Aged, 80 and over , Asian People/psychology , Cross-Sectional Studies , Female , Humans , Japan , Male , Middle Aged , Perception , Young AdultABSTRACT
INTRODUCTION: The incidence and prevalence of type 2 diabetes mellitus (T2D) are increasing in Japan, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used to treat the disease. The objective of this study was to use a discrete choice experiment (DCE) to characterize patient preferences for clinical treatment features of two GLP-1 RAs-dulaglutide 0.75 mg and semaglutide 0.50 mg-among patients with T2D in Japan. METHODS: Adult patients with T2D in Japan were administered the DCE via a web-based survey. The DCE examined patient preferences for five treatment attributes (each described by two or three levels), including method of administration, HbA1c change, reduction in cardiovascular (CV) risk, weight change, and common side effects (i.e., nausea). Results were analyzed using multinomial and mixed logit models, and predicted choice probability was calculated to determine the overall probability that either dulaglutide or semaglutide DCE levels were preferred. One DCE choice task included a direct comparison of the dulaglutide 0.75 mg versus semaglutide 0.50 mg treatment profiles. RESULTS: 190 subjects completed the survey; 29 were excluded after failing the predefined internal validity assessments. In the final analysis sample (N = 161), the attribute with the largest effect on the subjects' choices was reduction in CV risk, followed by HbA1c change and common side effects. Patients' predicted choice probability for the semaglutide profile was 78%, versus 22% for the dulaglutide profile. 28% of patients were "very willing" to initiate treatment with semaglutide's product profile, versus 6% for dulaglutide. CONCLUSION: In this study, reduction in CV risk and HbA1c change were the key drivers of GLP-1 RA medication preference in Japanese patients with T2D. Overall, the majority of the patients preferred a product with attribute levels reflecting the semaglutide 0.50 mg profile, with a known CV risk reduction benefit and superior HbA1c reduction. FUNDING: Novo Nordisk.
ABSTRACT
The short-chain fatty acid propionate is a potent inhibitor of molds that is widely used as a food preservative and endogenously produced by gut microbiota. Although generally recognized as safe by the U.S. Food and Drug Administration, the metabolic effects of propionate consumption in humans are unclear. Here, we report that propionate stimulates glycogenolysis and hyperglycemia in mice by increasing plasma concentrations of glucagon and fatty acid-binding protein 4 (FABP4). Fabp4-deficient mice and mice lacking liver glucagon receptor were protected from the effects of propionate. Although propionate did not directly promote glucagon or FABP4 secretion in ex vivo rodent pancreatic islets and adipose tissue models, respectively, it activated the sympathetic nervous system in mice, leading to secretion of these hormones in vivo. This effect could be blocked by the pharmacological inhibition of norepinephrine, which prevented propionate-induced hyperglycemia in mice. In a randomized, double-blind, placebo-controlled study in humans, consumption of a propionate-containing mixed meal resulted in a postprandial increase in plasma glucagon, FABP4, and norepinephrine, leading to insulin resistance and compensatory hyperinsulinemia. Chronic exposure of mice to a propionate dose equivalent to that used for food preservation resulted in gradual weight gain. In humans, plasma propionate decreased with weight loss in the Dietary Intervention Randomized Controlled Trial (DIRECT) and served as an independent predictor of improved insulin sensitivity. Thus, propionate may activate a catecholamine-mediated increase in insulin counter-regulatory signals, leading to insulin resistance and hyperinsulinemia, which, over time, may promote adiposity and metabolic abnormalities. Further evaluation of the metabolic consequences of propionate consumption is warranted.
Subject(s)
Fatty Acid-Binding Proteins/metabolism , Glucagon/metabolism , Propionates/pharmacology , Animals , Female , Glucagon/pharmacology , Glycogen/metabolism , Humans , Insulin Resistance , Male , Mice , Mice, Inbred C57BL , Weight Gain/drug effectsABSTRACT
Although previous studies have indicated important roles of palmitate, a saturated fatty acid, in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), it remains unclear how palmitate contributes to inflammation and fibrosis in the liver. Administration of palmitate in high fat diet (HFD)-fed but not basal diet (BD)-fed mice resulted in an increase in serum alanine aminotransferase (ALT) levels. Surprisingly, combined administration of very low dose lipopolysaccharide in palmitate-treated mice led to a marked increase in serum ALT levels despite BD-fed conditions. Administration of palmitate alone in BD-fed mice caused inflammatory cell infiltration and liver fibrosis mediated by the toll-like receptor 4 pathway without ALT elevation. In addition, a significant correlation between serum free fatty acid levels and liver fibrosis stage was observed in patients with NAFLD. These results indicate that palmitate may play crucial roles in the pathogenesis of NAFLD in the presence of gut-derived endotoxin.
Subject(s)
Endotoxins/toxicity , Gastrointestinal Tract/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Palmitates/toxicity , Alanine Transaminase/blood , Animals , Chemokines/metabolism , Diet, High-Fat , Endotoxins/blood , Inflammation/pathology , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Cirrhosis/complications , Liver Cirrhosis/pathology , Macrophages/drug effects , Macrophages/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Models, Biological , Neutrophils/drug effects , Neutrophils/metabolism , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/complications , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolismABSTRACT
Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process. We show that cold adaptation induces Nrf1 in BAT to increase proteasomal activity and that this is crucial for maintaining ER homeostasis and cellular integrity, specifically when the cells are in a state of high thermogenic activity. In mice, under thermogenic conditions, brown-adipocyte-specific deletion of Nfe2l1 (Nrf1) resulted in ER stress, tissue inflammation, markedly diminished mitochondrial function and whitening of the BAT. In mouse models of both genetic and dietary obesity, stimulation of proteasomal activity by exogenously expressing Nrf1 or by treatment with the proteasome activator PA28α in BAT resulted in improved insulin sensitivity. In conclusion, Nrf1 emerges as a novel guardian of brown adipocyte function, providing increased proteometabolic quality control for adapting to cold or to obesity.
Subject(s)
Adipose Tissue, Brown/metabolism , Endoplasmic Reticulum/genetics , NF-E2-Related Factor 1/genetics , Obesity/genetics , Proteasome Endopeptidase Complex/genetics , Acclimatization/genetics , Acclimatization/physiology , Animals , Cold Temperature , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Stress/genetics , Gene Deletion , Homeostasis , Humans , Inflammation/genetics , Inflammation/physiopathology , Insulin Resistance/genetics , Mitochondria/genetics , Mitochondria/metabolism , Models, Animal , Obesity/physiopathology , Proteasome Endopeptidase Complex/metabolism , Thermogenesis/geneticsABSTRACT
The finding of islet inflammation in type 2 diabetes (T2D) and its involvement in ß cell dysfunction has further highlighted the significance of inflammation in metabolic diseases. The number of intra-islet macrophages is increased in T2D, and these cells are the main source of proinflammatory cytokines within islets. Multiple human studies of T2D have shown that targeting islet inflammation has the potential to be an effective therapeutic strategy. In this Review we provide an overview of the cellular and molecular mechanisms by which islet inflammation develops and causes ß cell dysfunction. We also emphasize the regulation and roles of macrophage polarity shift within islets in the context of T2D pathology and ß cell health, which may have broad translational implications for therapeutics aimed at improving islet function.
Subject(s)
Cytokines/immunology , Diabetes Mellitus, Type 2/immunology , Insulin-Secreting Cells/immunology , Macrophages/immunology , Animals , Diabetes Mellitus, Type 2/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Insulin-Secreting Cells/pathology , Macrophages/pathologyABSTRACT
The endoplasmic reticulum (ER) plays a critical role in protein, lipid, and glucose metabolism as well as cellular calcium signaling and homeostasis. Perturbation of ER function and chronic ER stress are associated with many pathologies ranging from diabetes and neurodegenerative diseases to cancer and inflammation. Although ER targeting shows therapeutic promise in preclinical models of obesity and other pathologies, the available chemical entities generally lack the specificity and other pharmacological properties required for effective clinical translation. To overcome these challenges and identify new potential therapeutic candidates, we first designed and chemically and genetically validated two high-throughput functional screening systems that independently measure the free chaperone content and protein-folding capacity of the ER. With these quantitative platforms, we characterized a small-molecule compound, azoramide, that improves ER protein-folding ability and activates ER chaperone capacity to protect cells against ER stress in multiple systems. This compound also exhibited potent antidiabetic efficacy in two independent mouse models of obesity by improving insulin sensitivity and pancreatic ß cell function. Together, these results demonstrate the utility of this functional, phenotypic assay platform for ER-targeted drug discovery and provide proof of principle for the notion that specific ER modulators can be potential drug candidates for type 2 diabetes.
Subject(s)
Amides/pharmacology , High-Throughput Screening Assays/methods , Hypoglycemic Agents/pharmacology , Thiazoles/pharmacology , Unfolded Protein Response/drug effects , Animals , Calcium/metabolism , Cell Survival/drug effects , Cytoprotection/drug effects , Diet , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Stress/drug effects , Energy Metabolism/drug effects , Genes, Reporter , Glucose/metabolism , HEK293 Cells , Homeostasis/drug effects , Humans , Insulin/metabolism , Insulin Secretion , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Luciferases/metabolism , Metabolome/drug effects , Mice, Obese , Molecular Chaperones/metabolism , Obesity/genetics , Obesity/pathology , Phenotype , Protein Folding/drug effects , Weight Loss/drug effectsABSTRACT
The lipid chaperone aP2/FABP4 has been implicated in the pathology of many immunometabolic diseases, including diabetes in humans, but aP2 has not yet been targeted for therapeutic applications. aP2 is not only an intracellular protein but also an active adipokine that contributes to hyperglycemia by promoting hepatic gluconeogenesis and interfering with peripheral insulin action. Serum aP2 levels are markedly elevated in mouse and human obesity and strongly correlate with metabolic complications. These observations raise the possibility of a new strategy to treat metabolic disease by targeting serum aP2 with a monoclonal antibody (mAb) to aP2. We evaluated mAbs to aP2 and identified one, CA33, that lowered fasting blood glucose, improved systemic glucose metabolism, increased systemic insulin sensitivity, and reduced fat mass and liver steatosis in obese mouse models. We examined the structure of the aP2-CA33 complex and resolved the target epitope by crystallographic studies in comparison to another mAb that lacked efficacy in vivo. In hyperinsulinemic-euglycemic clamp studies, we found that the antidiabetic effect of CA33 was predominantly linked to the regulation of hepatic glucose output and peripheral glucose utilization. The antibody had no effect in aP2-deficient mice, demonstrating its target specificity. We conclude that an aP2 mAb-mediated therapeutic constitutes a feasible approach for the treatment of diabetes.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Fatty Acid-Binding Proteins/immunology , Adipose Tissue/drug effects , Amino Acid Sequence , Animals , Body Composition/drug effects , Diabetes Mellitus, Type 2/complications , Diet, High-Fat , Fatty Acid-Binding Proteins/chemistry , Fatty Liver/complications , Fatty Liver/pathology , Glucose/metabolism , Humans , Insulin/pharmacology , Male , Metabolome/drug effects , Mice, Inbred C57BL , Mice, ObeseABSTRACT
A 56-year-old man presented with sustained chest pain. Coronary angiography revealed total occlusion of the distal right coronary artery and left anterior descending branch. Left ventriculography depicted a mobile mass in the right sinus of Valsalva originating from the ostium of the right coronary artery. Transesophageal echocardiography (TEE) showed a mobile mass in the sinus of Valsalva and another mobile mass in the aortic arch. The mass at the right sinus of Valsalva was surgically resected, and histologic examination revealed an organized thrombus. Coagulation study showed protein S deficiency. This is the first case of acute myocardial infarction as a result of multiple coronary embolism caused by thrombosis in the right sinus of Valsalva with a second aortic arch thrombosis, contributed by protein S deficiency.
Subject(s)
Embolism/complications , Myocardial Infarction/etiology , Sinus of Valsalva/diagnostic imaging , Anticoagulants/therapeutic use , Coronary Angiography , Coronary Thrombosis/complications , Coronary Thrombosis/diagnostic imaging , Echocardiography, Transesophageal , Embolism/diagnostic imaging , Embolism/therapy , Humans , Male , Middle Aged , Myocardial Infarction/diagnostic imaging , Warfarin/therapeutic useABSTRACT
The epidemic growth in the prevalence of obesity has made the impact of metabolic syndrome on cardiovascular events increasingly significant. Elevated visceral adiposity, the indispensable component of metabolic syndrome, is thought to play a primary role in the increasing incidence of cardiometabolic disorders. Importantly, obesity is not merely the simple expansion of adipose tissue mass; it also involves the activation of inflammatory processes within visceral adipose tissue. Adipose tissue inflammation on the one hand enhances the production of proinflammatory adipokines and on the other hand increases the release of free fatty acids via the activation of lipolysis. The adipokines and free fatty acids secreted from visceral fat then contribute to a cardiometabolic pathology. We herein summarize recent advances in our understanding of the mechanisms by which visceral obesity leads to the activation of inflammation in cardiovascular and metabolic tissues and promotes cardiometabolic disease. Our focus is on Toll-like receptor 4 signaling and free fatty acids as mediators of chronic inflammation in patients with metabolic syndrome and atherosclerosis.
Subject(s)
Heart Diseases/pathology , Inflammation/pathology , Lipid Metabolism Disorders/pathology , Metabolic Syndrome/pathology , Obesity/pathology , Toll-Like Receptors/metabolism , Adiposity , Animals , Heart Diseases/metabolism , Humans , Inflammation/metabolism , Lipid Metabolism Disorders/metabolism , Metabolic Syndrome/metabolism , Obesity/metabolismABSTRACT
Abdominal aortic aneurysm (AAA) is a prevalent vascular disease that can progressively enlarge and rupture with a high rate of mortality. Inflammation and active remodeling of the aortic wall have been suggested to be critical in its pathogenesis. Meanwhile, ω-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) are known to reduce cardiovascular events, but its role in AAA management remains unclear. Here, we show that EPA can attenuate murine CaCl2-induced AAA formation. Aortas from BALB/c mice fed an EPA-diet appeared less inflamed, were significantly smaller in diameter compared to those from control-diet-fed mice, and had relative preservation of aortic elastic lamina. Interestingly, CT imaging also revealed markedly reduced calcification of the aortas after EPA treatment. Mechanistically, MMP2, MMP9, and TNFSF11 levels in the aortas were reduced after EPA treatment. Consistent with this finding, RAW264.7 macrophages treated with EPA showed attenuated Mmp9 levels after TNF-α simulation. These results demonstrate a novel role of EPA in attenuating AAA formation via the suppression of critical remodeling pathways in the pathogenesis of AAAs, and raise the possibility of using EPA for AAA prevention in the clinical setting.