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Title: Role of proinflammatory and anti-inflammatory adipokines in metabolic diseases
Authors: Supriya, Rashmi
Degree: Ph.D.
Issue Date: 2018
Abstract: The prevalence of metabolic disorders such as metabolic syndrome (MetS) and diabetes is increasing worldwide. Type 2 diabetes is projected to be the 7th leading cause of death by 2030, as estimated by the World Health Organization. The signs and symptoms of type 2 diabetes are not always obvious, but it is often diagnosed during a routine check-up because the symptoms are often mild and develop gradually over many years. Symptoms include central obesity, elevated fasting plasma glucose, elevated blood pressure, high serum triglycerides, and low high-density lipoprotein levels. The clustering of these medical conditions is sometimes referred to as prediabetes or MetS and leads to diabetes, cancer or cardiovascular disorders. The interactions between the components of the clinical phenotype (central obesity, insulin resistance, hypertension and dyslipidaemia) of metabolic disorders might contribute to the development of a proinflammatory state. Adipokines (secreted by adipose tissue) and cytokines (secreted by macrophages) offer links between metabolism and inflammation. Researchers propose that anti-inflammatory and proinflammatory adipokine equilibrium is necessary to prevent metabolic disorders. Therefore, the present thesis aims to explore the unique roles of adipokines in differentiating the risk factors of metabolic diseases. In addition, it also aims to determine the role of adipokines as a biomarker for worsening conditions of metabolic diseases. This thesis was designed to investigate the role of proinflammatory and anti-inflammatory adipokines in metabolic disorders via four studies. In the first study, the distinctive influence of central obesity on other cardiometabolic risk factors of MetS was investigated by adipokine profiling. In the second study, the consequences of hypertension and obesity were differentiated based on proinflammatory and anti-inflammatory adipokine profiles. Further, in the third study, the role of adipokines as indicators was explored to determine the beneficial role of a one-year yoga intervention in MetS subjects with high-normal blood pressure. Finally, in the last study, the critical role of adipokines in diagnosing worsening type 2 diabetic conditions was investigated by determining the pathogenesis of doxorubicin (an anticancer drug) in diabetic muscle in which insulin signalling and muscle atrophy markers were not indicative of any exacerbation. Central obesity is always emphasized in metabolic syndrome (MetS). This study examined the circulatory adipokines in adults with different cardiometabolic characteristics to reveal the interacting influence of central obesity with other MetS cardiometabolic risk factors, including hyperglycaemia, hypertriglyceridemia, dyslipidaemia and hypertension. Eighty-three blood samples were selected from an archived sample pool of 1,492 Hong Kong Chinese adults who were previously screened for MetS according to the guideline of the United States National Cholesterol Education Program Expert Panel Adult Treatment Panel III criteria1. Insulin and 11 adipokines, namely, visfatin, chemerin, plasminogen activator inhibitor-1, resistin, C-C motif chemokine ligand 2, interleukin-6, interleukin-8, interleukin-10, tumour necrosis factor-α, leptin, and adiponectin, were assessed. Our generalized estimating equation (GEE) analyses revealed significant interaction effects between central obesity and the cluster of the other 4 MetS cardiometabolic risk factors on TNF-α, adiponectin, and leptin (P < 0.05). TNF-α, adiponectin and leptin differentiate and demonstrate the interacting influence of central obesity with other MetS cardiometabolic risk factors. Central obesity and hypertension are common risk factors for metabolic syndrome and cardiovascular diseases. The prevalence of myocardial infarctions has been reported to be higher in adult women when compared to adult men in the United States. Additionally, obese females have 6 times whereas obese males have only 1.5 times more chance to develop hypertension compared to their non-obese counterparts. The interacting influence on adipokines from central obesity and hypertension is largely unknown. Adipokines have been proposed as the links between obesity and hypertension, and this study aimed to differentiate the effects of central obesity and hypertension by examining the circulatory profile of adipokines including adiponectin, PAI-1, leptin, and TNF-α. A total of 387 women aged 58 ±11 years (selected from a pool of 1492 Hong Kong Chinese adults), who were previously screened for metabolic syndrome1 were examined with a 2 x 2 factorial design for central obesity (waist circumference ≥ 80 cm) and hypertension (≥ 140/90 mmHg). Subjects with hyperglycemia, hypertriglyceridemia, and dyslipidemia were excluded to eliminate their confounding effects. Our generalized estimating equation (GEE) analyses revealed significant interaction effects between central obesity and hypertension on the serum abundances of adiponectin and TNF-α. Significant main effects of central obesity were observed on the increases in PAI-1 and leptin. In conclusion, blood profiling of adiponectin and TNF-α reveals the complications of the interaction of central obesity with hypertension in middle-aged and older women, suggesting the existence of inter-relationship between these two-common cardiovascular risk factors MetS is a cluster of conditions - visceral obesity, dyslipidaemia, hyperglycaemia, and hypertension.
Most people with MetS have been diagnosed with hypertension. MetS is associated with the development of diabetes mellitus, stroke, and cardiovascular diseases. Interestingly, the prevalence of elevated blood pressure among people with MetS has been reported as high as 85%. Our previous study indicated that subjects with MetS showed a significant decrease in the waist circumference and a decreasing trend in blood pressure after 1-year of yoga intervention. Therefore, this study was designed to further investigate the effect of yoga intervention on MetS subjects with high normal blood pressure by exploring modulations in pro-inflammatory adipokines (leptin, chemerin, visfatin and plasminogen activator inhibitor-1 or PAI-1) and anti-inflammatory adipokine (adiponectin). 97 Hong Kong Chinese individuals aged 57.6 ± 9.1 with MetS and high-normal blood pressure (systolic pressure ≥ 130 mmHg or diastolic pressure ≥ 85 mmHg) MetS (defined by United States National Cholesterol Education Program Expert Panel Adult Treatment Panel (NCEP ATP III) guidelines2), were randomly assigned to control (n = 45) and yoga group (n = 52). Subjects in control group were not given any intervention but were contacted monthly to monitor their health status. Subjects in yoga group underwent a yoga training program with three 1-hour yoga sessions weekly for 1 year. Serum harvested were assessed for adipokines including leptin, chemerin, visfatin, PAI-1, and adiponectin. Generalized estimating equation (GEE) was used to examine the interaction effect between 1-year of time (pre vs. post) and intervention (control vs. yoga) on adipokines and MetS risk factors. The results of this study revealed significant interaction effects between time and intervention on leptin, chemerin and adiponectin. Main effect of intervention was observed on PAI-1. These results demonstrated that 1-year yoga training decreased pro-inflammatory adipokines (leptin, chemerin, and PAI-1) and increased anti-inflammatory adipokine (adiponectin) in adults with MetS and high-normal blood pressure. These findings support the beneficial complementary role of yoga in managing MetS by favorably modulating the circulatory adipokines. The anti-cancer agent doxorubicin (DOX) has been demonstrated to worsen insulin signalling, engender muscle atrophy, trigger proinflammation, and induce a shift to anaerobic glycolytic metabolism in skeletal muscle. The myotoxicity of DOX in diabetic skeletal muscle remains largely unclear. The fourth study examined the effects of DOX on insulin signalling, muscle atrophy, pro-/anti-inflammatory microenvironments, and glycolysis metabolic regulation in the skeletal muscle of db/db diabetic and db/+ non-diabetic mice. DOX had no effects on insulin signalling markers (Glut4, pIRS1Ser636/639, and pAktSer473) or muscle atrophy markers (muscle mass, MuRF1, and MAFbx) in diabetic muscle. However, DOX exposure resulted in the enhancement of a proinflammatory favouring microenvironment (as indicated by TNF-α, HIFα, and pNFkBp65), accompanied by a diminished anti-inflammatory favouring microenvironment (as shown by IL15, PGC-1α, and pAMPKß1Ser108). The metabolism in diabetic muscle was shifted to anaerobic glycolysis after DOX exposure as demonstrated by our analyses of PDK4, LDH, and pACCSer79. The results showed that there might be a link between inflammatory modulation and the dysregulation of aerobic glycolytic metabolism in DOX-injured diabetic skeletal muscle. These findings help to understand the pathogenesis of DOX-induced myotoxicity in diabetic muscle. Therefore, we conclude that adipokines (proinflammatory and anti-inflammatory) play an important role as a biomarker in metabolic disorders. Knowledge about the modulation of pro- and anti-inflammatory adipokines with changes in the major risk factors for MetS, including obesity, hypertension, high triglycerides, low high-density lipoprotein, and high fasting blood glucose, might help in differentiating the inflammatory and metabolic molecular pathways that cause metabolic diseases. Additionally, the modulation (proinflammatory decreases and anti-inflammatory increases) of adipokines contributes to understanding the beneficial effects of yoga in subjects with high-normal blood pressure and MetS in whom other risk factors of MetS are not indicative of the beneficial effects of yoga. Further, the modulation (proinflammatory increases and anti-inflammatory decreases) of adipokines helps to understand and detect the worsening effects of doxorubicin injection in diabetic skeletal muscle in which insulin signalling and muscle atrophy markers are not indicative of the exacerbation. Although numerous effects of adipocytokines have been reported in recent studies, further investigation of their signalling pathways is still needed to understand how they are eventually integrated. It will be important to focus on how adipocytokine signalling participates with intracellular cascades triggered by other factors in the immune cells. Understanding the mechanism of action of adipocytokines may be crucial in the development of novel therapeutic approaches for treating metabolic disorder-induced inflammatory diseases.
Subjects: Hong Kong Polytechnic University -- Dissertations
Metabolism -- Disorders
Adipose tissues
Fat cells
Pages: 270 pages : color illustrations
Appears in Collections:Thesis

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