Tips to Reduce Belly Fat Fast

Flat Belly Fix

In Flat Belly Fix program, you learn the easy, tested and trusted method that saved the creator of this program (Todd Lamb) beautiful wife Tara from a life battling Type 2 Diabetes and experiencing possibly death. It was a very nasty experience with the couple during those times, but with the determination of Todd, he labored ceaselessly to finding a way out for his depressed and unhappy wife. Now they live together both happy and contented. Having used the same technique for people around (seeing the wonders it did to his wife) and also recording so much success, Todd Lamb wants to relate this secret to the world, to create this same atmosphere of joy produced in his immediate environment. Hence, he was motivated to put together this workable program. You also get to learn the secret to having a flat belly, and a healthy and fit body that has been hidden from you for so long now. The creator if this program is positive about the efficacy of this program and is so excited for you to personally experience what happens when you apply The 21 Day Flat Belly Fix in your life. More here...

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Leptin Leptin Resistance and the Metabolic Syndrome

Metabolic syndrome is defined by the concomitant presence of at least three of the following characteristics waist greater than 102 cm (men) and 88 cm (women), serum high-density lipoprotein cholesterol concentration lower than 1.0 (men) and 1.3 mmol liter (women), serum triglyceride concentration greater than 1.7 mmol liter, blood pressure greater than 130 85 mmHg, and serum glucose concentration greater than 6.1 mmol liter 103 . The prevalence of the metabolic syndrome increases with aging, rising from about 4 at the age of 20 years to almost 50 at the age of 60 years 104 . Concomitant with increased prevalence of metabolic syndrome is increased body fat 105, 106 and particularly visceral fat. Visceral fat has been recognized as a main factor in the pathogenesis of the metabolic syndrome 107 . Body fat distribution is associated with several components of the metabolic syndrome in the elderly 108 . In addition to the role of total visceral fat, it was hypothesized that peptides...

Impaired Glucose Metabolism and Metabolic Syndrome

The metabolic syndrome is characterized by the concurrence of several cardiovascular risk factors central obesity, dyslipidemia, elevated blood pressure, and high fasting glucose levels. Insulin resistance, a common pathogenetic factor underlying these risk factors, may lead to the development of DM-2 and increased risk of CVD. Intra-abdominal adiposity, sedentary lifestyle, and a genetic predisposition are prime etiologic factors 9 . In the Amsterdam Growth and Health LongitudinalStudy the prevalence of the metabolic syndrome among young subjects (mean age 36 years) was 18.3 in men and 3.2 in women. Individuals with the metabolic syndrome showed reduced distensibility and compliance of the carotid and femoral arteries compared to those without risk factors. Stiffness ofthe muscular femoral artery was greater than that of the elastic carotid artery 9 . Other studies of the metabolic syndrome are in agreement with these findings 10-13 . In middle-aged Japanese men the number of...

The Metabolic Syndrome

The metabolic syndrome is a recently defined constellation of known risk factors that has been associated with an increased risk of cardiovascular disease as well as the development of diabetes. While many of the cardiometabolic risk factors have the tendency to cluster in patients, the components of the metabolic Table 7.5 NCEP ATP III criteria for the metabolic syndrome. From reference 33, with permission Increased waist circumference (in men 40 inches ( 102 cm) syndrome occur together with great frequency. Several definitions of the metabolic syndrome exist including ones from the NCEP ATP III, the WHO, and the International Diabetes Federation. In general, most definitions endorse the following basic criteria a measure of abdominal adiposity, hypertriglyceridemia, low HDL cholesterol levels, hypertension, and evidence of impaired glucose metabolism. The NCEP ATP III defines the metabolic syndrome as any three of the following elevated triglycerides (a 150 mg dL), low HDL...

Metabolic syndrome

The term metabolic syndrome refers to a clustering of specific CVD risk factors whose underlying pathophysiology is likely insulin resistance (9). Although several sets of diagnostic criteria exist (WHO 81 , NCEP 82 , IDF 83 ), waist circumference, dyslipidemia, elevated blood pressure, and glucose intolerance are shared by all. Uncertainty about the mechanism of pathogenesis has resulted in a debate to determine whether metabolic syndrome is a syndrome or an independent CVD risk factor (84). This is reviewed in detail in Chapter 20.

Current Antipsychotics

Atypical antipsychotics possess strong serotonin (5-HT2A) receptor antagonism in addition to D2 antagonism, which is believed to attenuate EPS. However, these agents are largely ineffective against negative symptoms and cognitive deficits, with the exception of clozapine in regards to negative symptoms. Many atypicals exhibit their own side effects that may include metabolic syndrome (weight gain and diabetes) and associated cardiovascular risks 4 .

Plasma Adiponectin Levels and Adiposity

Besides total fat mass, body fat distribution appears to be another important determinant of adiponectin production. Intra-abdominal fat is an independent negative predictor of plasma adiponectin (65). In both lean and obese individuals, adiponectin mRNA abundance and protein levels in intra-abdominal fat are much lower than in subcutaneous fat. Furthermore, hypoadiponectinemia has been found to be closely associated with both congenital and HIV-related lipodystrophy, a disease characterized by body fat redistribution (15).

Classification and evolution of increased cardiometabolic risk states

It has been accurately observed that certain risk factors in humans appear to 'cluster' with clinical states such as obesity and type 2 diabetes. Specifically, this risk factor clustering, and the association with insulin resistance, led investigators to propose the existence of a unique pathophysiological condition1. Many names have been provided to describe this clinical state including 'metabolic syndrome', 'syndrome X', and 'insulin resistance syndrome'1. The particular names that refer to this risk factor clustering describe the human condition characterized by the presence of co-existing traditional risk factors for cardiovascular disease (CVD), such as hypertension, dyslipidemia, glucose intolerance, obesity, and insulin resistance, in addition to non-traditional CVD risk factors, such as inflammatory processes and abnormalities of the blood coagulation system2-6. Table 1.1 lists conditions and components associated with the clustering of risk factors. As seen, the components...

Plasminogen Activator Inhibitor1

Although PAI-1 is primarily derived from platelets and the endothelium, it has been demonstrated that most of the elevated concentrations of this regulatory protein of the coagulation cascade in inflammatory and obese states is attributable to an upregulated expression by adipose tissue itself (12,58). Therefore, WAT represents a quantitatively relevant source of PAI-1 production, with consequently increased circulating concentrations present in obesity. Stromal cells have been shown to be the main PAI-1 producing cells in human fat, with a fivefold higher expression in the visceral than in the subcutaneous depots, which is in agreement with the strong relationship observed between circulating PAI-1 concentrations and visceral fat accumulation (59). However, whether adipose tissue itself directly contributes to circulating PAI-1, or whether it exerts an indirect effect via adipokines, such as TNF-a , IL-1 , and TGF- , to stimulate PAI-1 production by other cells has not been clearly...

Vascular Endothelial Growth Factor

VEGF is a well-recognized angiogenic factor that induces migration and proliferation of vascular endothelial cells (12). VEGF is encoded by a single gene however, four isoforms are produced by alternative splicing, which have been implicated in both normal blood vessel development and in pathogenic neovascularization and atherosclerosis. In obese patients serum concentrations of the 164-amino-acid-long isoform has been observed to be dependent on intra-abdominal fat accumulation (70). VEGF mRNA expression has been identified in various cell types, including endothelial, epithelial, and mesenchymal cells. Recently, attention has been focused on the altered expression profile of VEGF in omental WAT obtained from obese individuals (71). Given the growth potential of adipose tissue, it is not surprising that adipocytes express an angiogenic factor like VEGF implicated in vascular bed expansion to support fat mass accretion. The participation of VEGF in vascular inflammation and remodeling...

Leptin and pathophysiology of the immune system

On the other hand, an excess of leptin in the circulation that occurs in obesity and overweight could have a role in pathological conditions mediated by an excess of immune response (73). This proinflammatory state may be relevant for cardiovascular disease and the risk for myocardial infarction that is increased in obese people. Moreover, leptin, together with other adipokines, could be a common link between obesity and cardiovascular risk in metabolic syndrome. Because obese people do not respond to leptin properly, central versus peripheral leptin resistance may underlie the pathophysiology of obesity, and therefore, the study of leptin signaling at central versus peripheral levels may improve our understanding of the mechanisms involved in the metabolic and immune alterations in the metabolic syndrome that lead to increased cardiovascular risk. These molecular defects may connect the thrifty phenotype with the proinflammatory phenotype in a common trait that turns out to be lethal...

Role of obesity and body fat distribution in cardiometabolic risk

Additional risks (1) waist circumference 40 inches in men and 35 inches in women (2) weight gain of 5 kg since age 18-20 years (3) poor aerobic fitness and (4) Southeast Asian descent Additional risks (1) waist circumference 40 inches in men and 35 inches in women (2) weight gain of 5 kg since age 18-20 years (3) poor aerobic fitness and (4) Southeast Asian descent

Potential Therapeutic Applications

The first results of phase III clinical studies of rimonabant in obesity were presented in March 2004 79,80 . 1036 overweight or obese patients (BMI between 27 and 40kgjm2) with untreated dyslipidemia (high triglycerides and or low HDL cholesterol) were randomized to receive either a daily, fixed dose of rimonabant (5 or 20 mg) or placebo along with a mild hypocaloric diet. Patients treated for one year with rimonabant (20 mg per day) lost 8.6 kg (versus 2.3 kg in the placebo group). In addition to weight loss, the study was designed to assess a number of important associated cardiovascular risk factors. Rimonabant (20mg) was associated with a significant reduction in waist circumference, triglycerides and C-reactive protein and an increase in HDL-cholesterol. Importantly, the number of patients classified as having metabolic syndrome 81 was reduced from 52.9 at baseline to 25.8 at one year 82 . These robust data were replicated in another phase III study (RIO-Europe) involving 1507...

Acc Inhibitors In Longterm Efficacy Studies

Despite the relatively large number of publications in the area of ACC inhibition, there have been few disclosures reporting the effects of long-term administration of ACC inhibitors on metabolic syndrome-related endpoints. Recently, two disclosures reported the results of studies of the balanced ACC1 ACC2 inhibitor 2 in mouse models of metabolic syndrome 48,49 . In the first study, 2 was administered in chow to ob ob mice at doses of 50 and 100 mg kg for 8 weeks. Treatment with 2 resulted in increased glucose and triglyceride levels and decreased insulin levels in blood. The AUC and peak glucose response in an oral glucose tolerance test (OGTT) were also increased. After 6 weeks, the 100 mg kg dose group was lowered to 20 mg kg. This resulted in normalization of triglyceride and glucose levels, but insulin levels remained low. Body weight decreased in the 100 mg kg dosing group, but food intake remained approximately the same for all the animals in the study. It was concluded that 2...

Human inflammatory bowel disease

Abnormalities of adipose tissue in the mesentery, including adipose tissue hypertrophy and fat wrapping, have been long recognized on surgical specimens as characteristic features of Crohn's disease. However, the importance, origin, and significance of the mesenteric fat hypertrophy in this chronic inflammatory disease are unknown. Desreumaux and colleagues evaluated this phenomenon and quantified intra-abdominal fat in patients with CD vs UC by using magnetic resonance imaging (51). By applying this technique they were able to demonstrate a significant accumulation of intraabdominal fat in patients with CD. This mesenteric obesity, present from the onset of disease, is associated with overexpression of PPARy as well as TNF-a mRNA, as evaluated by RT-PCR studies (51). In a subsequent study, the same group could demonstrate an overexpression of leptin mRNA in the mesenteric adipose tissue in inflammatory bowel disease, whereas no difference could be detected between UC and CD. The...

Endocannabinoid System

A recently characterized physiologic system that plays a major role in modulating energy metabolism is the endocannabinoid-CB1 receptor system (Figure 4.9)31'32. The discovery of this system represents a significant advance in understanding mechanisms contributing to the development of obesity and as such, provides targets for new pharmacological approaches to target abdominal obesity and its related metabolic

Metabolism or storage

Receptor (knockout mice) are lean and appear to be resistant to diet-induced obesity32. Because of these observations, it was postulated that by blocking the CB1 receptor, this approach would represent an innovative approach for the management of high-risk abdominal obesity and the related cardiometabolic risk38. The results from recently completed phase III clinical trials in overweight obese patients suggests that this approach may indeed yield substantial clinical benefits6,40,41. The observations reported in animal studies appear to be quite compatible with the human condition. Specifically, an overstimulation of the endocanna-binoid system in human abdominal obesity has been suggested to lead to fat cell hypertrophy and to markedly reduced plasma adiponectin levels, which are well-described features of abdominal obesity43. Furthermore, it was reported that the low plasma adiponectin concentration observed in viscerally obese patients was a key factor responsible for their...

Clinical Implications of Leptin Physiology in the Elderly

In recent years, investigators have hypothesized that leptin may be involved in the pathogenesis of chronic disease states including diabetes, metabolic syndrome, dyslipidemia, anorexia, and malnutrition as well as hypertension, atherosclerosis, osteoporosis, and osteoarthritis 2-5 . Although these diseases are highly prevalent in old age, existing data on the role of leptin in a specific disease state has not been unequivocal. Furthermore, the available literature data were not always obtained in an elderly population. Because of this limitation, the second part of the review addresses those diseases in which the role of leptin has been supported by relevant and unequivocal findings from data collected in elderly populations.

Typeii Diabetes Mellitus

Reaven (1988) suggested that insulin resistance might be a common denominator for obesity, Type-II diabetes hypertension and hyperlipidaemia (metabolic syndrome) and should be treated rigorously to avoid coronary heart disease, the most common cause of morbidity and mortality in Type-II diabetes mellitus. However, it still remains to be proven that effective blood glucose control will reduce the mortality of the disease (Turner and Holman, 1990).

Animal Models of Osteoporosis or Increased Bone Formation

Transgenic mice expressing A-FosB not only develop a severe and progressive osteosclerotic phenotype characterized by increased bone formation, but also show pronounced decrease in adipogenesis with decreased abdominal fat, low serum leptin levels, and a reduced number of adipocytes in the bone marrow (46). The inhibitory effect of A-FosB on adipocyte differentiation appears to occur at early stages of stem cell commitment, affecting C EBPP functions (154).

Leptin and Glucose Metabolism

Resistance, evaluated by homeostasis model assessment of insulin resistance (HOMA), even after adjusting for age and fat mass 92 . In this study leptin, waist size, and age as a group accounted for up to 31-33 of insulin level and HOMA total variance, respectively 92 . In contrast, about 22 of insulin level and HOMA were accounted for by leptin alone 92 . An independent association between leptin and insulin concentration after adjustment for BMI has also been observed by Zimmet et al. 34 . This study examined Polynesian men and women with a wide age-range with and without diabetes. Donahue et al. 93 reported an association between leptin and insulin resistance as evaluated by euglycemic-hyperinsulinemic clamp in 49 young to middle age men and women even after adjusting for body fat percentage. The role of leptin in determining insulin resistance in elderly men and women has recently received further support in a study comparing metabolic characteristics of normo- and hyperlipemic...

Arterial Stiffness and Coronary Artery Calcification

Finally, two larger studies (reported as abstracts) have reported strong associations between coronary calcification and cfPWV. First, in a study of 484 older adults (aged 70-96) from the Cardiovascular Health Study, the association between aortic stiffness (cfPWV) and both coronary and aortic calcification was evaluated. Among the older women (mean age 79 years), higher aortic stiffness was associated with higher quartiles of both coronary and aortic calcification after adjustment for age and mean arterial pressure 22 . The absence of an association among these older men may also be due to a survival bias. Second, in a cross-sectional analysis of 477 overweight postmenopausal women (aged 52-62) with no history of coronary heart disease, the prevalence of any coronary calcium was higher among those with higher levels of arterial stiffness (cfPWV) 23 . A 1-SD increase in cfPWV was associated with a 38 increase in odds of coronary calcification. These associations remained significant...

Endothelial Dysfunction

Studies have investigated which components of the metabolic syndrome are closely linked with endothe-lial dysfunction as assessed by changes in coronary flow in response to an agonist (Figure 6.17)26. Specifically waist circumference, systolic blood pressure, and insulin resistance were significantly negatively correlated with coronary vasodilatation. This suggests the greater the extent of obesity, the higher the blood pressure and the greater the extent of insulin resistance the worse the degree of endothelial dys-function26.

Acquired partial lipodystrophy

Also known as Barraquer-Simmons syndrome, more than 250 patients with acquired partial lipodystrophy (APL) have been reported in the literature (46). APL is characterized by the gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in a cephalocaudal sequence, sparing the lower extremities. Often, excess fat accumulation is seen over the lower abdomen, gluteal region, thighs, and calves. The onset of fat loss usually occurs during childhood or adolescence, at a median age of 7 yr, whereas the excess fat accumulation is noted to occur at the onset of puberty or with weight gain and glucocorticoid therapy. Fat loss occurs in a gradual process over a period of few months up to 2 yr, and 75 of patients have discernible fat loss before 13 yr of age. Women are reportedly affected four times more often than men (46). Whole-body MRI studies in affected patients confirmed the loss of subcutaneous fat from face, neck,...

Neuropeptides in cachexia

Marks et al. studied the role of melanocortin receptors in transducing the prolonged metabolic derangement observed in experimental cancer. These investigators demonstrated that the cachexia (poor appetite and weight loss) induced by cancer can be both reversed and prevented by administration of AgRP. Prevention of tumor-induced hypophagia with early and repeated AgRP injections resulted in maintenance of normal food intake. To further demonstrate that central melanocortin blockade attenuates cancer cachexia, they investigated this metabolic syndrome in MC4R knockout (KO) mice. The MC4-RKO animals had normal feeding and growth even when bearing a carcinoma that produced classic cachexia in wild-type (WT) control animals. These data clearly indicate that hypothalamic MC4-R plays a role in transducing cachexigenic stimuli from the periphery (54).

Obesity And Abdominal Adiposity

The problem of obesity has reached epidemic proportions in the majority of developed nations worldwide. The World Health Organization (WHO) has reported that over 1 billion adults worldwide meet the definition for overweight (body mass index (BMI) of greater than 25 kg m2) and at least 300 million adults meet criteria for clinical obesity (BMI of greater than 30 kg m2)17. Obesity is associated with a myriad of medical conditions including coronary artery disease, peripheral arterial disease, cerebrovascular disease, congestive heart failure, the metabolic syndrome, hypertension, insulin resistance, type 2 diabetes mellitus, dyslipidemia, obstructive sleep apnea, liver disease, and degenerative joint disease. A subset of obese patients demonstrate abdominal obesity or adiposity which is defined by increasing waist circumference, sagittal abdominal diameter, and waist-to-hip ratio. Waist circumference and sagittal abdominal diameter have been shown to correlate best with intra-abdominal...

Blood Lipids and Coronary Heart Disease

In early studies, low-density lipoprotein cholesterol concentrations have been associated with coronary artery disease17 and this finding was confirmed in numerous subsequent studies. For clinical purposes, LDL levels have been defined as optimal (190 mg dL). Another lipoprotein, HDL is associated inversely with the risk of coronary heart disease. HDL is involved in reverse cholesterol transport, which reduces tissue cholesterol levels and may provide a protective effect. Low HDL cholesterol levels are recognized as a common and powerful risk factor for coronary artery disease.18 The AHA guidelines suggest that levels of HDL lower than 40 mg dL result in an elevated risk for coronary artery disease. Two additional forms of LDL may be atherogenic particles and should be given consideration for their association with elevated risk. These are LP(a) and small dense low-density lipoproteins. The association of LP(a) with coronary disease is independent of serum LDL cholesterol levels.19...

Role of tnfa in linking obesity to insulin resistance

TNF-a was first shown by Hotamisligil et al. to be overexpressed in adipose tissue from several strains of obese rodents (24). Weisberg et al. have shown that macrophages are the main source of TNF-a in adipose tissue (14). TNF-a expression is higher in visceral fat (VF) of rodents than in subcutaneous (sc) fat (25). In addition, TNF-a has been shown to impair insulin signaling in cultured cells by three separate molecular mechanisms. TNF-a activates serine threonine kinases that phosphorylate and impair the function of key elements in the insulin signaling pathway (26). First, TNF-a mediates a serine phosphorylation of IRS-1 (27). This alteration impairs insulin signaling by making IRS-1 resistant to subsequent insulin-stimulated tyrosine phosphorylation. Second, TNF-a phosphorylates and activates a protein tyrosine phosphatase that normally terminates insulin action, thus playing a role in the self-limiting nature of insulin signaling (28). Third, TNF-a phosphorylates and...

Role of resistin in insulin resistance

Whether resistin is expressed in human adipose tissue is not clear. McTernan et al. found such expression and reported that resistin is relatively highly expressed in the omental visceral fat and the abdominal subcutaneous fat, with lower expression in subcutaneous fat on the thigh (48). This finding is in contrast to the findings of Savage et al. and Nagaev et al., who did not detect resistin in human adipose tissue (49,50). Whereas resistin is expressed mainly in adipocytes in mice (43), Fain et al. reported that most of the resistin secreted by human fat explants is derived from nonadipocytes (51). The reason for the differences in these studies is unclear. Human resistin is only 59 similar to the mouse protein, and this may portend important differences in the endocrine functions of adipocytes and resistin between rodents and humans (52). Furthermore, insulin and TNF-a, both elevated in obesity, have been found to inhibit resistin expression, which may explain the low levels of...

Other possible mediators of insulin resistance

Visfatin is a recently discovered adipokine that is produced by adipocytes (68), and is expressed in visceral fat at much higher levels than in subcutaneous fat (69). Serum visfatin increases with VF, but not sc fat, in humans and mice. Visfatin has been shown to have insulin-sensitizing properties when administered to insulin-resistant mice. Mice that are heterozygous for a targeted mutation in the visfatin gene display a small impairment in glucose tolerance, whereas homozygous mice die in utero. Visfatin binds to the insulin receptor and activates downstream signaling, but does not compete for binding with insulin. Visfatin has the ability to stimulate glucose transport in cultured muscle and adipose cells and to inhibit glucose output in cultured hepatocytes. Apart from cytokines, the most important candidate for linking obesity to insulin resistance is circulating nonesterified (or free) fatty acids. Reaven et al. reported that type 2 diabetes is associated with elevations in...

Lifestyle Modification in the Infertile Patient With PCOS

Obesity is a very common feature of women with PCOS, with an estimated prevalence of 35-63 among women with the disorder (3). Ghrelin homeostasis and measures of hunger and satiety are significantly impaired in subjects with PCOS, although not affected by dietary composition (4). Abdominal obesity, characterized by a waist-to-hip ratio of more than 0.8, has been reported in 63 of women with PCOS whether they are obese or not (5,6). Obesity, particularly abdominal, is often associated with insulin resistance and hyperinsulinemia, which stimulates the biosynthesis of androgens and the decreased hepatic production of sex hormone-binding globulin (SHBG). Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, and, possibly, high dietary lipid intake may be mechanisms by which obesity worsens the degree of hyperandrogenism and ovulatory function in PCOS (7). Obesity is associated with a reduced chance...

Assessment of overweight and obesity in epidemiological studies of disease

BMI may be a less valid indicator of adiposity among the elderly, who tend to have a shift of fat from peripheral to central sites with a concomitant increase in waist-to-hip ratio (WHR) at the same level of BMI (13). For such populations, and with increasing evidence of health risks associated with abdominal (visceral) fat, two measures of central adiposity, the WHR and, more recently, waist circumference, have been commonly used in epidemiological studies.

Nuclear Receptors in the Control of Lipid Metabolism

Nuclear hormone receptors are found at the heart of virtually every biological process. In addition to their functions in mediating steroid hormone effects, the role of this superfamily in maintaining metabolic homeostasis has been illuminated by the identification of dietary fats and their metabolites as ligands for several subfamilies. These receptors, in response to derivatives of fatty acids, cholesterol, and bile acids, constitute a transcriptional network controlling glucose and lipid metabolism as well as inflammation, all of which are key determinants of metabolic diseases, including dyslipidemia, insulin resistance, and atherosclerosis. In line with this, synthetic, high-affinity ligands developed to target these receptors have either been used or shown promise in the treatment of metabolic syndrome. For instance, the thiazolidinedione (TZD) class of drugs, one of the leading drug treatments of diabetes, specifically targets PPARgamma. This chapter discusses the metabolic...

Atherosclerosis and Coronary Artery Disease

A cross-sectional study by Takami et al. (88) of 849 Japanese men aged 20 to 78 yr investigated the relationship between body fatness (particularly abdominal fat) and carotid atherosclerosis. They found that general adiposity (as measured by BMI), WC, waist-to-hip ratio (WHR), abdominal subcutaneous fat, and intra-abdominal fat were all correlated with carotid IMT after adjustment for age and smoking habits. Adjustment for BMI eliminated all other associations except those of WHR with IMT, suggesting that in this population abdominal fat is not as strongly associated with carotid atherosclerosis as is general body fatness. The Progetto ATENA study is a large (more than 5000 participants) ongoing investigation of the causes of CVD and cancer in Italian females aged 30 to 69 yr. Within that study, De Michele et al. (89) reported on a sub-sample of 310 women and concluded that BMI and WHR were significant predictors of carotid wall thickness independent of other cardiovascular risk...

Type 2 Diabetes Mellitus

Several prospective studies in numerous countries have demonstrated an elevated risk of diabetes mellitus as weight increases (75-77). The development of type 2 diabetes is associated with weight gain after age 18 yr in both men and women such that the relative risk of diabetes increases by approx 25 for each additional unit of BMI over 22 (109). Moreover, cross-sectional and longitudinal studies show that abdominal obesity is a major risk factor for type 2 diabetes (74,82,91). There is strong evidence that weight loss reduces blood glucose levels and hemoglobin A1c levels in patients with type 2 diabetes. Moreover, in three European cohorts ( 17,000 men) followed for more than 20 yr, nondiabetic men with higher blood glucose had a significantly higher risk of

Long Term Health Consequences of PCOS

Insulin resistance is associated with diabetes, hypertension, dyslipidemia, endothelial dysfunction, a procoagulant state, and cardiovascular disease (see Chapters 28 and 29). Recently, the National Cholesterol Education Program Adult Treatment Panel defined the metabolic syndrome as the presence of three of the five following risk factors waist circumference greater than 88 cm in females fasting serum glucose 110 mg dL or more, fasting serum triglycerides greater than 150 mg dL serum high-density lipoprotein cholesterol less than 50 mg dL and blood pressure greater than 130 85 mmHg (60). The metabolic syndrome has been found to be present in 43-46 of women with PCOS, a twofold higher prevalence compared with women in the general population of the same age (61,62).

Developmental Effects Physical Activity and Diet

Lower lung function and increased risk of death from obstructive airways disease as adults was increased in those exposed to famine in early and mid-gestation, but not in late gestation (49). Interestingly, in follow-up studies, the prevalence of obesity was higher in 19-yr-old men exposed to famine during early to mid-gestation (50), and maternal malnutrition during early gestation was associated with higher BMI and waist circumference in 50-yr-old women but not in men (51). Pembrey et al. (52) described in a recent study that food and tobacco consumption may have sex-specific, male line transgenerational effects on health and that these transmissions are mediated by the sex chromosomes, X and Y.

Mechanism Linking Obesity and PCOS

Hyperandrogenism is postulated to result from either or both increased adrenal and ovarian androgen production. The predominance of abdominal obesity, insulin resistance, glucose intolerance, hypertension, and other conditions suggests that the metabolic syndrome may be more common in PCOS, and indeed this has been reported by a number of investigators (7). It is therefore obvious that for adequate treatment of patients with androgen excess, there needs to be a reduction in hyperinsulinemia and insulin resistance as well as in obesity per se. Both weight reduction and increases in physical activity are highly effective in increasing insulin sensitivity. These interrelated and yet separate issues are the focus of the following discussion.

Laboratory Findings in CR Nonhuman Primates

The characteristics of CR monkeys are summarized in Table 2 72 and Fig. 12A-C 73 . CR monkeys weigh less 74 and have less total and abdominal obesity than controls 75 . In addition, CR reduces body temperature and induces a transient reduction in metabolic rate 76 . Young male CR monkeys also exhibit delayed sexual and skeletal maturation 72, 74 . In addition, several lines of evidence suggest that CR improves the disease risk in rhesus monkeys 72 . CR monkeys have reduced blood glucose and insulin levels and improved insulin sensitivity 75 . CR also reduces blood pressure and lowers the serum triglyceride and cholesterol levels 77 . In

Effects of kidney disease on associations of adiposity with cardiovascular risk factors and cardiovascular disease

However, there are three problems with the suggestion that adiposity is protective in dialysis patients. First, the real paradox of the BMI paradox in dialysis patients is the possible association of high BMI with inflammation, yet with decreased mortality. Adipocytes are rich sources of proinflammatory cytokines such as IL-6 and TNF-a, which in turn stimulate the production of C-reactive protein (CRP) in the liver (46). It was shown in a cross-sectional study that abdominal adiposity is strongly associated with elevated CRP levels in dialysis patients (47). Further, the cross-sectional associations of high BMI, abdominal adiposity, and other components of metabolic syndrome (48-50) with inflammation in stage III CKD have been demonstrated. Therefore, the current evidence suggests that in stages III and V of CKD, obesity is associated with inflammation as in the general population.

Association Between Obesity and Bony Properties 221 Bone Mineral Density and Content and BMI

The literature examining the association between obesity and bony properties has predominantly focused on bone mineral density (BMD) and bone mineral content (BMC). Compared with normal-weight people, overweight individuals (BMI 26) have higher BMD and BMC at both weight-bearing (e.g., femur) and non-weight-bearing (e.g., radius) sites (30). Nevertheless, the association between obesity, defined as an increased BMI, and BMD BMC is not this simplistic and is dependent on several other factors, including body composition. Abdominal obesity, body weight, and muscle strength have emerged as strong correlates of BMD in older persons (31). Although certain parameters of body composition, such as abdominal obesity, are strongly associated with BMD, gender is arguably the strongest factor that mediates the obesity-BMD relationship. In both men and women, decreased BMD occurs after the age of 50 (32), although women demonstrate greater variability than men. In particular, lean body mass and...

Obesity as Risk for Onset of OA

Although a larger-than-normal BMI is a risk factor for OA, particularly at the knee, there is a paucity of data examining the specific features of body composition that mediate this risk. Although it is well documented that adipose tissue distribution is a risk factor for a number of metabolic complications, particularly central abdominal fat and increased risk of diabetes, cardiovascular disease, and mortality, independent of degree of obesity (50), central fat does not appear to be a risk for the onset of OA at the hand or knee (28). This finding may infer a stronger biomechanical, rather than metabolic, predisposition toward the onset of OA.

StearoylcoA Desaturases

Criture Cursive Flech

Well as fatty liver diseases, such as steatosis and nonalcoholic steato-hepatatis (NASH) 12-16 . However, mechanism-based side effects have been reported and appear to be due to a deficit of unsaturated FAs in peripheral tissues like skin and pancreas 9,17 . Reported skin side effects included loss of hair (alopecia) and eye fissure 18 . Additionally, using antisense oligonucleotides to inhibit SCD in a mouse model of hyperlipi-demia and atherosclerosis (LDLr- - Apob100 100), it has been demonstrated that SCD inhibition increased atherosclerosis independently of improvements in obesity and insulin resistance and argued against SCD1 inhibition as a safe therapeutic approach for treatment of the metabolic syndrome 19 . The development of atherosclerosis could not be prevented with dietary oleic acid. However, in a follow-up study, fish oils were able to fully prevent the development of atherosclerosis following SCD inhibition. It is proposed that fish oils antagonize the inflammatory...

Potential Therapeutic Indications

Several lines of evidence implicate elevated 11p-HSD1 activity in the etiology and or maintenance of type 2 diabetes and metabolic syndrome. There is a higher level of 11p-HSD1 mRNA and activity in adipose tissue of obese humans 11,12,14,39 and rodents 40 . Chronic high-fat feeding decreases 11 p-HSD1 activity and mRNA in fat of C57Bl 6J mice, suggesting that this serves as an adaptive mechanism attempting to protect against the adverse metabolic consequence of high-fat feeding 41 . Interestingly, A J mice chronically fed a high-fat diet become obese but are less hyperinsulinemic than C57Bl 6J mice, and this is associated with lower basal adipose tissue 11 p-HSD 1 activity and mRNA and a more pronounced decrease in activity with high-fat feeding 41 . This suggests that lower local synthesis of active glucocorticoid in A J mice confers protection from dysregulated glucose homeo-stasis due to high-fat feeding. Transgenic overexpression of 11p-HSD1 in adipose tissue of mice produces...

Body Fat Distribution

Metabolic syndrome, insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, polycystic ovary syndrome the body fat may be considered an even more important assessment. In past studies, body fat distribution has been generally assessed by anthropometric measurements consisting of waist circumference, the waist-to-hip ratio (WHR), or skin fold thicknesses (Figure 3.5). When using skin fold measures, the most commonly utilized has been the subscapular-to-triceps ratio, or a sum of central-to-peripheral skinfolds12. Regardless of which is utilized, these measures are used to classify the subject as having either upper body, i.e. 'central' or abdominal obesity, or lower body obesity. In lay terms, these body types have been referred to as the 'apple-' or 'pear-shape' phenotypes (Figure 3.6). Abdominal adiposity, in addition to being significantly associated with the metabolic abnormalities that constitute the cardiometabolic syndrome, is Figure 3.5 Visceral...

The Interactions Between Stress Lipid Profiles Cortisone HPA Axis and Inflammation Immunity

The HPA axis, the mediator of cortisol, also plays a central role in the homeostatic processes in human. Subjects with abdominal obesity show several signs of a perturbed regulation of the HPA axis. This is known to occur after chronic, submissive stress. In contrast, perceived environmental stress depends on personality characteristics 111 . Rosmond et al. found that men with cluster A personality disorders showed centralized body fat distribution independent of dexamethasone suppression. In contrast, men with impulsive (cluster B) and anxious (cluster C) personality disorders often have abdominal obesity in combination with a blunted dexamethasone suppression test, indicating a HPA axis disturbance 111 . Rosmond and Bjorntorp also addressed the potential effect of HPA axis activity on established anthropometric, metabolic, and hemodynamic risk factors for cardiovascular disease, type 2 diabetes mellitus, and stroke 112 . Strong and consistent correlations were found not only within...

Metformin Weight Loss and PCOS

One of the best studies relating to metformin use in androgen excess was that by Pasquali et al. (12). They randomized patients with PCOS or obesity alone who were weight index-matched to a lifestyle-modification program including diet plus metformin or placebo. After 6 months the frequency of menstrual cycles was better with metformin, and metformin was superior to placebo alone in the loss of weight, reduction in waist circumference and visceral fat, and reduction in testosterone. There was no differential benefit of metformin on fasting serum glucose, insulin, or SHBG. Patients with androgen excess responded better than matched patients with obesity to metformin with respect to reduction of visceral fat and testosterone, but not in terms of weight loss, weight circumference, fasting serum glucose, or insulin. In a placebo-controlled, double-blind study, Tang et al. (17) randomized 143 oligo- amenorrheic obese women with PCOS to metformin (850 mg) or placebo twice daily for 6...

Clinical Laboratory Tools to Diagnose Inflammation

In view of the above low-grade systemic inflammation is integral in the pathobiology of metabolic syndrome X and its associated conditions. Clinical laboratory tools to analytically assess and diagnose inflammation will be as discussed in the following section. Several studies revealed that no sex- or ethnicity-specific alterations are seen with CRP. No significant differences were found in the distribution of CRP concentration among Caucasian, African-American, and Mexican-American men 80 . A comparable CRP distribution was found in Japanese men, with slightly lower concentrations in Japanese women 81 . Indian Asians, who are racially at high-risk of developing metabolic syndrome X, have been shown to have a 17 higher geometric mean for CRP concentration than whites 82 . This difference was not, however, statistically significant when results were adjusted for central obesity and insulin resistance 82 . Most studies have reported that there is no relation between age and CRP...

Atherogenic Dyslipidemia

Insulin Cholesterol Relationship

Insulin resistant states such as the metabolic syndrome are commonly associated with an atherogenic dyslipidemia that contributes to significantly higher risk of atherosclerosis and cardiovascular disease. Emerging evidence suggests that insulin resistance and its associated metabolic dyslipidemia result from perturbations in key molecules of the insulin signaling Figure 5.15 Schematic of the most fundamental defect in patients with metabolic syndrome which is resistance to the cellular actions of insulin, particularly resistance to insulin-stimulated glucose uptake. Insulin insensitivity appears to cause hyper-insulinemia, enhanced hepatic gluconeogenesis and increased glucose output. Reduced suppression of lipolysis in adipose tissue leads to a high free fatty acid flux, and increased hepatic very-low-density lipoprotein (VLDL) secretion causing hypertrigly-ceridemia and reduced plasma levels of high-density lipoprotein (HDL) cholesterol Figure 5.15 Schematic of the most fundamental...

The Relationships Between Lipid Profile Levels Depression and Suicide Attempts

Depression and Metabolic Syndrome. Abnormal serum albumin levels and lipid profiles have both been observed in patients with major depression, as well as cardiovascular disease, diabetes mellitus, and endstage renal disease. Depressive symptoms are very common in patients with these chronic illnesses. Recent clinical data have shown that cardiovascular disease, diabetes mellitus, end-stage renal disease, and obesity are all related to metabolic syndromes 68-74 , and especially insulin resistance 75, 76 . However, the data examining major depression without physical illness and insulin resistance are still scarce. In the future, the biological relationship between depression and physical illness needs to be more fully explored.

Aimin Xu Yu Wang and Karen S L

Key Words Adipokine adiponectin obesity metabolic syndrome diabetes. Adiponectin also termed ACRP30, AdipoQ, Apml, and GBP28 is one of the most abundant adipokines produced by adipocytes. This adipokine was first characterized in mice as a transcript selectively expressed during the differentiation of preadipocytes into mature adipocytes (1). The human homolog was subsequently identified as the most abundant transcript in adipose tissue during large-scale random sequencing of a human adipose tissue cDNA library (2). The human adiponectin gene was localized to chromosome 3q27, a region highlighted as a genetic susceptibility locus for type 2 diabetes and metabolic syndrome. Since 2001, adiponectin has attracted much attention because of its potential antidia-betic, antiatherogenic, and anti-inflammatory activities. Numerous animal experiments and clinical studies have demonstrated the utility of adiponectin as a plasma biomarker of metabolic syndrome and a possible therapeutic target...

Nuclear Receptors as Potential Therapeutic Targets for Metabolic Diseases

Metabolic syndrome is a collection of obesity-related metabolic dysfunctions, including hyperlipidemia, decreased HDL-c, insulin resistance, hypertension, and atherosclerosis. Given their roles in regulating key metabolic pathways, nuclear hormone receptors are current and prospective drug targets to treat these diseases. One reason for the success of nuclear receptor targeted drugs is their ability to have a robust effect on a pathway due to the regulation of multiple target genes within that pathway. Of course the multifaceted effects of nuclear hormone receptors can also be a drawback, when undesirable side effects are the result. reducing the metabolic syndrome. Beta-carotene (BC) compounds naturally occurring in the 9-cis conformation are hydrolyzed to 9-cis RA and have been shown to increase the effectiveness of fibrates.152 In one study, 22 subjects on fibrates treatment were divided into a placebo and 9-cis BC treatment group.152 A statistically significant increase in HDL and...

Impaired Glucose Tolerance Impaired Fasting Glucose Insulin Resistance And Diabetes

148 Fasting Glucose High

While diabetes has been a well-established cardiovascular risk factor, impaired glucose tolerance, impaired fasting glucose, and insulin resistance are emerging risk factors that are also associated with the metabolic syndrome as well as the development of overt diabetes. In general, impaired glucose tolerance is determined with an oral glucose tolerance test, impaired fasting glucose is detected by serum glucose after a fast, and insulin resistance is suggested by an elevated fasting serum insulin level. Figure 7.17 Hazard ratios for the incidence of cardiovascular disease associated with prehypertension and abnormalities of glucose metabolism. Hazard ratios were compared with the group of normal glucose tolerance and normal blood pressure and adjusted for age, gender, body mass index, waist circumference, low- and high-density lipoprotein cholesterol levels, triglycerides, physical activity, smoking, and alcohol use. NGT, normal glucose tolerance IGT, impaired...

P Michael Conn Series Editor

Weetman, 2008 Energy Metabolism and Obesity Research and Clinical Applications, edited by Patricia A. Donohoue, 2008 Polycystic Ovary Syndrome Current Controversies, from the Ovary to the Pancreas, edited by Andrea Dunaif, Jeffrey R. Chang, Stephen Franks, and Richard S. Legro, 2008 The Metabolic Syndrome Epidemiology, Clinical Treatment, and Underlying Mechanisms, edited by Barbara C. Hansen and George

Adipokines Inhibitory Yin and Stimulatory Yang Signals in Inflammation

Celsus's description (first century AD) of inflammation signs includes rubor et tumor cum calor et dolor. Inflammation is an essential biological response aiming at recovering from injury, wound healing being a paradigm of such a homeostatic phenomenon. However, what begins as a protective response becomes a damaging process in excess hence, inflammation is increasingly recognized as the underlying basis of a significant number of diseases. Recent studies based on a pangenomic approach in human subcutaneous WAT revealed that a panel of inflammatory molecules was upregulated in obese compared to lean subjects (ref. 12and references therein). Of note, a calorie-restriction diet improved the anti-inflammatory profile of obese subjects via increase of antiinflammatory and decrease of proinflammatory molecules (12). Further, weight loss resulted in decrease of adipose macrophage number and an increased production of interleukin (IL)-10, a well-known anti-inflammatory cytokine (13). These...

Adiponectin as a potent antiinflammation adipocytokine

As mentioned before, CRP is a typical marker of inflammation increased levels of CRP are now considered to be a risk factor for atherosclerosis (39). A number of studies have shown that there is a reciprocal association of adiponectin and CRP in plasma in healthy subjects and in subjects with a variety of diseases, including type 2 diabetes, metabolic syndrome, and end-stage kidney disease (40,41). The mechanism of this reciprocal association of CRP and adiponectin remains to be clarified. Our group detected the expression of adiponectin mRNA in human adipose tissue and demonstrated a significant inverse correlation between the CRP and adiponectin mRNA (27). In addition, CRP mRNA levels in white adipose tissue in adiponectin KO mice are

Clinical Phenotypes in Depression and Molecular Levels

Depression is a physical and psychological disorder that affects every aspect of human physiology. Stewart and Atlas have discussed the chaos between depression and metabolic syndrome 71 . As we know, some 69 Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001 24 683-689.

Acquired generalized lipodystrophy

Acquired generalized lipodystrophy (AGL) is another rare disorder and has been reported in approx 80 patients (47). It is characterized by selective loss of AT from large regions of the body occurring after birth. AT loss usually involves face, trunk, and extremities, and sometimes also spreads to the palms and soles. Intra-abdominal fat may also be lost, although retro-orbital and bone marrow fat are generally well preserved. The loss of AT may occur precipitously, within a few weeks, or may be more insidious over several months. In some patients, fat loss is preceded by the appearance of tender, inflamed subcutaneous nodules caused by panniculitis, but in others the disease is associated with autoimmune diseases such as juvenile dermatomyositis, Sjogren's syndrome, juvenile rheumatoid arthritis, chronic active hepatitis, and autoimmune hemolytic anemia. However, in more than half the reported cases of AGL, neither panniculitis nor autoimmune diseases have been reported. Although...

Noncompetitive inhibitors

In a recent patent application, mice treated with a related iron chela-tor, deferasirox (DFS), showed reduced body weight while on a high fat diet compared to untreated controls. Additionally, DFS was claimed to improve whole body metabolism and energy expenditure as measured by increased O2 consumption and CO2 production as well as a reduction in white adipose and visceral fat, despite little difference between food intake in the control and treated animal groups 25 .

Low Highdensity Lipoprotein Levels

While much of the current focus of therapy for dys-lipidemia centers on management of high LDL cholesterol, low HDL cholesterol levels have also been established as a major cardiovascular risk factor. In fact, the pattern of low HDL cholesterol levels with normal LDL cholesterol levels appears to represent a significant percentage of patients with coronary artery disease when compared with isolated high LDL cho-lesterol32. Low HDL cholesterol levels are also an important part of the criteria for the metabolic syndrome, which includes a constellation of other risk factors that place patients at a markedly increased risk for cardiovascular events. Low HDL cholesterol is defined by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol Based on these data, patients should be assessed for low HDL cholesterol as both an independent risk factor for cardiovascular disease and an important component...

Glucose Insulin and Potential Mechanisms of Vascular Stiffening

Among patients with diabetes 15 or the metabolic syndrome, arterial stiffening is observed across all age groups. In children with severe obesity, arterial wall stiffness and endothelial dysfunction are accompanied by low plasma apolipoprotein A-I levels, insulin resistance, and android fat distribution, changes that may be the main risk factors for the early events leading to atheroma formation 16 . The positive correlation between insulin resistance and central arterial stiffness and the close relationship between the extent of metabolic changes and the degree of arterial stiffness suggest that insulin resistance is a primary underlying factor. In animal models of insulin-resistant diabetes, chronic hyperglycemia and hyperinsulinemia increase local angio-tensin II production and expression of vascular Ang II type I receptors via stimulation of TGF- 1, upregulate plasminogen activator inhibitor-1, and downregulate matrix metalloprotease activity, all of which play a critical role in...

Mediators of Inflammation

Low-Grade Systemic Inflammation in Metabolic Syndrome X Interleukin-6 and TNF-a increase neutrophil O2* generation 36, 48 . Superoxide anion inactivates NO and PGI2 causing endothelial dysfunction, enhanced thrombosis, and atherosclerosis 49, 50 . All are common in type 2 diabetes. On the other hand, optimal production of NO inactivates O2* thereby preventing arresting thrombosis and atheroslcerosis 50, 51 . This observation indicates that increased oxidative stress could be another factor that contributes to development of type 2 diabetes, hypertension, and other components of metabolic syndrome X 38, 39, 50-52 . It is now known that adipose tissue produces several biologically active molecules that have important actions on the immune response and inflammation. Three of these molecules are adiponectin, resistin, and corti-costerone. Adiponectin has antiinflammatory actions and its plasma concentration is inversely related to insulin resistance and the severity of type 2...

Identification of Associated Morbidities

Once the diagnosis (specific or functional) is established, related morbidities should be identified. For example, PCOS and the HAIR-AN syndrome are associated with important metabolic dysfunction, including the metabolic syndrome. As such, it is recommended that patients diagnosed with these disorders undergo measurement of fasting lipids and insulin and glucose levels following an oral glucose load (75 g).

Reflections

Aging is the dominant process altering vascular stiffness, wave reflections, and PP. There is however an extreme variability of the age-mediated changes 21 . This variability is influenced by the histopathological particularities of arterial tissue (muscular or musculo-elastic), and mostly by the presence of other CV risk factors inside the microenvironment. In subjects with middle-age hypertension, when other CV risk factors (tobacco consumption, diabetes mellitus, dyslipidemia, obesity ) are not or minimally present, high MAP contributes dominantly to the increase of arterial stiffness, whereas MAP-independent structural and functional changes in stiffness play a more important role in older subjects, as described earlier 3, 21 . MAP-independent increase of arterial stiffness largely predominates in subjects with endothelial dysfunction as observed prematurely in the evolution of patients with diabetes mellitus, metabolic syndrome, obesity, end-stage renal disease or finally with...

Gema Frhbeck

In the search for mechanisms of obesity-mediated vascular pathology, attention has been focused on the role played by adipose tissue, a multifunctional organ involved not only in fat storage but also in the production of numerous hormones, growth factors, and cytokines with pleiotropic features. In the last decade the list of adipose-derived factors shown to be implicated either directly or indirectly in the regulation of vascular homeostasis through effects on blood pressure, inflammation, athero-genesis, coagulation, fibrinolysis, angiogenesis, proliferation, apoptosis, and immunity has increased at a phenomenal pace. By definition, adipocytokines are cytokines produced by adipocytes. Although adipose tissue secretes a wide variety of factors, strictly speaking, not all of them can be contemplated as cytokines. Interleukin-6, tumor necrosis factor-a, leptin, adipsin, resistin, adiponectin, and visfatin fall within the category that satisfies the stricter requirements to be properly...

Obesity

Lished that hyperinsulinemia, insulin resistance, and other obesity-related metabolic abnormalities are significantly associated with overall accumulation of fat in the body, there is now substantial evidence that the specific distribution of fat is important as outlined in Chapter 3. Excessive accumulation of fat in the upper body's so-called truncal region, or central obesity, is a better predictor of morbidity than excess fat in the lower body, the so-called lower body segment obesity10,12,13.

Adiponectin

During the last years adiponectin has been shown to exhibit particular cardioprotec-tive properties (16). Adiponectin has been proved to participate in processes related to atherosclerotic plaque formation prevention such as inhibition of monocyte adhesion to endothelial cells by decreasing NFkB signaling through a cAMP-dependent pathway (45,48). In addition, adiponectin has been reported to protect atherosclerotic rodent models such as ob ob and apoE-deficient mice from both atherosclerosis and T2DM (8,16). The findings relating hypoadiponectinemia with obesity-associated metabolic syndrome and atherosclerosis in animals have a clinical parallel in humans as evidenced by studies showing a negative correlation of adiponectin with markers of inflammation (49,50). The hypoadiponectinemia characteristic of obesity is inversely correlated to insulin resistance and CRP levels (16). In addition, patients with CHD exhibit lower adiponectin concentrations compared with age- and body mass...

Glucose metabolism

Abnormalities in glucose tolerance are commonly noted in individuals with central obesity. As outlined in Chapter 1, it is now well accepted that the presence of insulin resistance in an individual will need to be compensated for by hyperinsulinemia in order to maintain normal glucose tolerance. In those individuals who develop diabetes, a progressive loss of the insulin secretory capacity fails to compensate for the insulin resistance and results in a progressive hyper-glycemia (see Chapter 1). Thus, an individual with obesity and insulin resistance, depending on the stage of compensation for the insulin resistance, may have euglycemia, impaired fasting glucose, impaired glucose tolerance, or overt hyperglycemia confirming the diagnosis of type 2 diabetes.

Yuji Matsuzawa

Key Words Visceral fat metabolic syndrome hypoadiponectinemia C-reactive protein acute coronary syndrome insulin resistance. Excess body fat, especially intra-abdominal visceral fat accumulation, is associated with a number of disease conditions, including dyslipidemia, type 2 diabetes, hypertension, and cardiovascular disease (1). Therefore, visceral fat accumulation estimated by waist circumference is adopted as an essential component of metabolic syndrome, which has been recently classified as a highly atherogenic state. Recent research, including ours, has shown that adipose tissue secretes various bioactive substances, collectively referred to as adipocytokines, that may directly contribute to the pathogenesis of conditions associated with obesity (2). Thus, adipose tissue seems to be an endocrine organ that can affect the function of other organs, including the vascular walls, through secretion of various adipocytokines. These adipocytokines include heparin-binding epidermal...

Conclusion

Enzymes involved in TG synthesis continue to represent challenging and intriguing targets for small-molecule intervention against the worldwide epidemic of obesity, metabolic syndrome, and type 2 diabetes, as well as smaller market indications from rare familial diseases to veterinary use. There is also intriguing evidence that inhibition of these enzymes may be beneficial for diseases unrelated to the area of metabolic disorders, such as hepatitis C virus and cancer. The challenges of developing drugs that act on interconnected life-sustaining metabolic pathways are being met with next-generation medicines that are targeted toward individual tissues and organs. Over the next several years, longer term safety and efficacy profiles of intestine-selective MTP inhibitors such as lomitapide (23), implitapide (24), and JTT-130, as well as the DGAT1 inhibitor PF-04620110 (19), and other small-molecule inhibitors of enzymes in the TG synthesis pathway are expected to emerge. These results,...

PHSD1 Inhibitors

Early inhibitors of 11p-HSD1 were natural product analogs that generally had low 11p-HSD1 potency and poor selectivity over 11p-HSD2. Compounds such as carbenoxolone demonstrated modest in vivo effects on markers of metabolic syndrome, but were generally poor pharmacological tools because of issues such as selectivity. These inhibitors, as well as early work on thiazole analogs, were reviewed in 2003 53 . Subsequently, more in vivo results and several new chemical entities have been published in both the peer-reviewed and patent literature 54 . Thiazoles, triazoles, amides, and some miscellaneous derivatives have all demonstrated 11p-HSD1 potency as well as selectivity over 11p-HSD2. This review will focus on recent advances and compounds with published pharmacological data 55 .

Results

Hypertension is one of the most common medical disorders associated with obesity. Resolution or improvement of diastolic hypertension occurs in approx 70 of individuals, but occurs more commonly in those patients with a lower postoperative BMI. The severity of cardiac dysfunction decreases, as does the degree of dyspnea associated with congestive heart failure. Arthralgia in major joints such as knee, hips, and vertebrae improves rapidly and most significantly with weight loss. There is a clear correlation of these improvements with the chronicity of the condition and the amount of weight loss. Infertility has been corrected with weight loss in a significant number of females. Last, it has been shown that bariatric surgery is the long-term procedure of choice for severely obese patients with pseudotumor cerebri. It has been shown to have a much higher rate of success than cerebrospinal fluid-peritoneal shunting reported in the literature. It is thought that the resolution of...

Fibrates

Weak activators of PPARa and, as indicated in Table 1, decrease TG levels and increase HDL 28 . Different mechanisms have been proposed by which fibrates elevate plasma HDL levels 29 . Induction of PPARa in the liver leads to increased synthesis of apoA-I, resulting in enhancement of new HDL particles 30 . Studies on mouse hepatocytes indicate down-regulation of SR-B1 protein levels upon treatment with fibrates, possibly influencing clearance of HDL 31 . A metaanalysis of data from 53 clinical studies using fibrates 1, 3, 4 and 5 demonstrated a 25 reduction in the risk of coronary events 17 . A number of clinical studies have demonstrated the beneficial CV-related effects of gemfibrozil treatment. In the Helsinki Heart Study, CVD risk reduction upon gemfibrozil treatment was most pronounced in patients with atherogenic dyslipidemia, metabolic syndrome and diabetes 32,33 . In the veterans affairs high-density lipoprotein cholesterol intervention trial (VA-HIT) study, a 5 increase of...

Adipose mast cells

Potentially contribute to the whole body of adipokinome (see Table 1). At present, the knowledge of the biology of mast cells in adipose tissue is, however, limited as compared to that of macrophages (13,19). Indeed, one has to go back more than 10 yr to find information, for example, about the role of brown adipose tissue-associated mast cell-secreted histamine in thermogenesis (39). Likewise, whereas most studies deal with the effects of adipokines on macrophages or lymphocytes, only a single paper reported a stimulatory effect of leptin on mast cell growth, as demonstrated in biopsies of subcutaneous abdominal adipose tissue from patients with metabolic syndrome (40). Also, our ongoing study on the involvement of neurotrophins in adipose tissue biology demonstrates a prominent immonoreactivity for nerve growth factor (NGF) and its high-affinity receptor tyrosine kinase-A (Trk-A) expressed in the stromal compartment of subcutaneous adipose tissue (Fig. 1). Some recent data about...

Increased

HDL consists of a heterogeneous class of lipoproteins containing approximately equal amounts of lipid and protein (Figure 5.10)9. The various HDL subclasses vary in quantitative and qualitative content of lipids, apolipoproteins, enzymes, and lipid transfer proteins, resulting in differences in shape, density, size, charge, and antigenicity. Beyond reverse cholesterol transport HDL is believed to have other beneficial effects including improving endothelial function (Figure 5.11). HDL also attenuates expression of adhesion molecules and inflammatory cytokines which promote leukocyte extravasation into the vessel wall. Infusion of HDL has been shown to increase nitric oxide synthetase activity promoting vasodilatation. HDL also inhibits the oxidation of LDL and the formation of lipid hydroperoxides which reduce inflammation. Sujects with metabolic syndrome have low levels of HDL which is believed to contribute to their cardiometabolic risk. The biological effects of HDL are...

Conclusions

Leptin resistance may play a central role in the development of the metabolic syndrome with aging. However, further research is necessary to extend these interesting findings from animal studies to humans. 19 Mendoza-Nunez VM, Garcia-Sanchez A, Sanchez-Rodriguez M, Galvan-Duarte RE, Fonseca-Yerena ME. Overweight, waist circumference, age, gender, and insulin resistance as risk factors for hyperleptinemia. Obes Res 2002 10 253-259. 92 Zamboni M, Zoico E, Fantin F, et al. Relation between leptin and the metabolic syndrome in elderly women. J Gerontol A Biol Sci Med Sci 2004 59 M396-M400. 98 Soderberg S, Ahren B, Eliasson M, Dinesen B, Olsson T. The association between leptin and proinsulin is lost with central obesity. J Intern Med 2002 252 140-148.

Creactive Protein

Several studies have shown that there is a significant relationship between individual components of the metabolic syndrome and CRP. The exact relationship varies from component to component (Figure 6.4), but broadly there is a positive relationship with blood pressure, glucose, insulin resistance, obesity, and triglycerides, and a negative relationship with HDL. That CRP levels correspond with individual components of the metabolic syndrome is consistent with the hypothesized role of inflammation in several processes critical to the development of atherothrombosis. Furthermore, several cross-sectional studies have demonstrated that there is a positive relationship between the number of components of the metabolic syndrome and CRP6,7 (Figure 6.5). Among healthy populations such as the Women's Health Study the average CRP levels are higher among subjects with the metabolic syndrome (average range 3.01-5.75 mg L) compared with those without (average range 0.68-1.93 mg L). Thus, some...

Hcm216

9 Metabolic Syndrome, Diabetes and Cardiometabolic Risks in Aging 277 The Metabolic Syndrome and the Concept of Cardiometabolic Risks 278 Clinical Management and Trials with Metabolic Endogenous Sex Hormones and Metabolic Syndrome in the Leptin and Metabolic Syndrome in the Metabolic Syndrome and Oxidative Stress in the Metabolic Syndrome, Diabetes and Cognitive Decline in the Genes Involved in Metabolic Syndrome Relationship Between Metabolic Syndrome and

Epidemiological Data

The possibility that insulin resistance is independently associated with increased arterial stiffness was first suggested by cross-sectional analysis of ARIC (Atherosclerosis Risk in Communities) data. This study explored the relationship between insulin resistance (measured using fasting insulin concentrations) and arterial stiffness measured with ultrasound in 4,701 white and black subjects 9 . In the entire study group, arteries appear to become stiffer at increasing concentrations of fasting glucose and insulin, independent of race or gender. The relationship between glucose and insulin concentrations and stiffness remained significant after adjustment for classic cardiovascular risk factors. This was also true within the non-diabetic subjects, which comprised 95 of the study subjects 9 . In 2,488 adults participating in the Health ABC study, increased serum insulin concentrations and visceral fat volume measured with computed tomography were associated with increased aortic...

Microalbuminuria

Suggest that the prevalence in middle-aged non-diabetics is as high as 10-15 . In a cross-sectional study of approximately 3500 Chinese subjects, the waist-to-hip ratio, systolic and diastolic pressure, serum triglyceride level, fasting plasma glucose, and homeostasis model assessment-insulin resistance (HOMA-IR) were all significantly increased in those subjects with microalbuminuria compared with normal subjects31. The prevalence of microalbuminuria was also significantly increased with an incremental rise in the number of components of the metabolic syndrome (p for trend

Stephen E Borst

Key Words Tumor necrosis factor resistin adiponectin interleukins free fatty acids subcutaneous fat visceral fat insulin signaling. Obesity and type 2 diabetes are the most common metabolic diseases in Western society, together affecting as much as half of the adult population (1). Not only is the prevalence of these conditions high, but it also continues to increase. Insulin resistance is a prediabetic condition, characterized by a failure of target organs to respond normally to insulin. Insulin resistance includes a central component (incomplete suppression of hepatic glucose output) and a peripheral component (impaired insulin-mediated glucose uptake in skeletal muscle and adipose tissue) (2). When increased insulin secretion is no longer sufficient to prevent hyperglycemia, the subject progresses from insulin resistance to type 2 diabetes. Insulin resistance is associated with other conditions such as central obesity, hypertension, and dyslipidemia, all risk factors for...

Pathogenesis of nash

The two-hit hypothesis of NASH pathogenesis suggests that the first hit is the accumulation of excessive fat in the hepatic parenchyma (4,14). This first step has been linked to insulin resistance (IR), which is consistently observed in patients with NAFLD (13). Clinical features of metabolic syndrome (obesity, diabetes mellitus, or hyper-trigyceridemia) are commonly observed in patients with NAFLD (1,17). Furthermore, unexplained elevations in alanine aminotransferase (ALT) levels in individuals with metabolic syndrome suggest that NAFLD is the hepatic manifestation of this syndrome (18). Additionally, patients with NAFLD with more severe forms of IR are at even greater risk of progressive liver disease (4,19). Animal models of NAFLD also have IR, and the use of the insulin-sensitizing agent, metformin, reverses hepatic steatosis (16).

Hypertriglyceridemia

Hypertriglyceridemia shares similarities with low HDL cholesterol levels in that it is both an important independent risk factor for cardiovascular disease and part of the criteria for the metabolic syndrome. Hypertriglyceridemia is generally diagnosed when triglyceride levels are elevated above 150mg dL33. In a meta-analysis of several large prospective trials, the effect of hypertriglyceridemia on the incidence of cardiovascular disease was investigated56. Hypertriglyceridemia was associated with nearly a 30 increase in the relative risk of cardiovascular disease among men and a 75 increase among women56. Although the relative risk increases attenuated after adjustment for HDL cholesterol levels and other risk factors, a statistically significant increase in risk persisted for both men and women suggesting that hypertriglyceridemia was an independent risk

Adipokines and IR

Visfatin is produced both in visceral and subcutaneous adipose tissue and exerts insulin-like effects in various tissues by binding and activation of the insulin receptor (98). Visfatin is upregulated in obesity (97) either as a simple reflection of visfatin resistance that parallels the IR in metabolic syndrome, or represents an important compensatory pathway leading to lowered glucose levels. Vaspin, visceral adipose tissue-derived member of the serine protease inhibitor (serpin) family, normalizes serum glucose levels by reversing altered gene expression related to IR, including all other adipokines discussed above (99). In humans, vaspin mRNA expression is not detectable in lean subjects, but is a frequent finding in type 2 diabetes (100). This secreted molecule might be an important insulin sensitizer of adipocytic origin and may play an important role in NAFLD. Finally, apelin is an adipokine that is probably related to peripheral IR. It inhibits glucose-stimulated insulin...

Colorectal Cancer

A gender difference, in which obese men are more likely to develop colorectal cancer than obese women, has been observed consistently across studies and populations. The reasons for this gender difference are speculative. One hypothesis is that central adiposity, which occurs more frequently in men, is a stronger predictor of colon cancer risk than peripheral adiposity or general overweight. Support for the role of central obesity in colo-rectal cancer comes from studies reporting that waist circumference and WHR are related strongly to risk of colorectal cancer and large adenomas in men (101). Two recent prospective cohort studies specifically examining the predictive value of anthropometric measurements for risk of colon cancer found waist circumference (102) or WHR (103) to be associated with colon cancer risk, independent of, and with greater magnitude than, BMI, and this result was seen in women as well as in men. However, the association Giovannucci was the first to propose the...

Healthy Volunteers

The use of metformin in the treatment of diabetes is based on over 30 years of clinical experience. Although still controversial in some respects, metformin is regarded as a valuable drug in the treatment of obese non-ketonic hyperinsulinaemic insulin-resistant Type-II diabetics (Dornan et al., 1988). The main clinical effect of metformin is an antidiabetic action. In addition, metformin has weight-reducing and lipid-lowering properties and effects on fibrinolysis (Campbell, 1990) which could be of additional advantage during treatment of obese diabetics suffering from the metabolic syndrome (Vigneri and Goldfine, 1987).

Hypertension

The majority of patients with high BP are overweight, and hypertension is about six times more frequent in obese than lean subjects (90). This represents an estimated 12 increased risk for CHD and 24 increased risk for stroke (72). Although the association between obesity and hypertension is well recognized, the underlying pathophysio-logical mechanisms are still poorly understood. The expansion of extracellular volume and increased CO are characteristic hemodynamic changes that occur with obesity-related hypertension (28). A variety of endocrine, genetic, and metabolic mechanisms have also been linked to the development of obesity hypertension (1,32,91-93). One potential mechanism leading to the development of obesity-induced hypertension may be through leptin-mediated sympathoactivation (94). The association between obesity and hypertension begins in early life. Longitudinal observations of children, adolescents, and young adults enrolled in the Bogalusa Heart Study show that...

Dyslipidemia

The presence of dyslipidemia is well established in obesity. At risk overweight obese individuals commonly present with reduced HDL cholesterol, elevated apolipoprotein B levels, and a prevalence of small, dense low-density lipoprotein (LDL) particles (102). Visceral adiposity, in particular, has a negative impact on the lipid profile it has been suggested that dyslipidemia is the main contributor to the increase in CHD in abdominally obese patients (74). A BMI change of 1 unit is associated with a decrement change in HDL-cholesterol of 1.1 mg dL for young adult men and 0.69 mg dL for young adult women (2). There is evidence that weight loss achieved by lifestyle modification in overweight individuals is accompanied by a reduction in serum triglycerides and an increase in HDL cholesterol (86). Weight loss may also contribute to a reduction in serum total cholesterol and LDL cholesterol levels (87). Moreover, in subjects with type 2 diabetes, aerobic exercise may mediate an improvement...

Gpr40 Family

Function, and suggests a key role for GPR40 in the development of the metabolic syndrome in obesity. GPR41 and GPR43 are receptors for short-chain (C2-C6) fatty acids (SCFAs), which are coupled primarily to Gi o and Gq family G-proteins, respectively 71,72 . Both receptors are expressed prominently in adipose tissue, although GPR43 is present at higher levels in white blood cells. The endogenous ligands, i.e., SCFAs, are produced by bacterial fermentation in the lower gut and are present in blood. Administration of propionate has been shown to reduce food intake in both sheep and chickens and to lower blood glucose concentrations in obese hyperinsulinemic fa fa rats 73-75 . Propionic acid stimulates secretion of the anorexigenic hormone leptin by adipocytes in vitro and increases leptin levels when administered to mice 76 . siRNA gene knockdown experiments and examination of ligand and G-protein specificities suggest that SCFA-stimulated leptin secretion is mediated through GPR41....

Facelift in Males52

Salivary Gland Stones

Fig. 52.5. a The patient's thin lips give him a tense and annoyed Walton Montegut performed fat transfer from abdominal fat appearance. b Fifteen months after secondary face and neck to philtral ridges, white line ridges and lips at the same time lift and forehead rejuvenation at the same time by the author. Fig. 52.5. a The patient's thin lips give him a tense and annoyed Walton Montegut performed fat transfer from abdominal fat appearance. b Fifteen months after secondary face and neck to philtral ridges, white line ridges and lips at the same time lift and forehead rejuvenation at the same time by the author.

Cb1r Antagonists

The endocannabinoid system consists of endogenous ligands (i.e., anandamide and 2-arachidonoyl glycerol) that bind to and activate either of two receptor subtypes, CB1R or CB2R, that are distributed throughout the periphery (gut, liver, spleen, immune cells) and the CNS 4,5 . Endocannabinoids and exogenous can-nabinoids (notably A9-tetrahydrocannabinol, the principal active constituent in Cannabis sativa L., or marijuana) have been shown to stimulate appetite 6 . CB1R was hypothesized to play a role in the regulation of appetite because of its location in the hypothalamus. This was confirmed using a combination of CB1R selective ligands and CB1 knockout (KO) mice 7-11 . Recently, 2-year clinical efficacy data with rimonabant, a selective CB1R antagonist, have been published, claiming rimonabant-treated patients had significantly reduced waist circumference and plasma triglycerides and an increase in HDL cholesterol and adi-ponectin concentrations in addition to significant and...

Visfatin

Visfatin is a recently discovered adipokine, which is apparently produced and secreted mainly by visceral WAT, with putative antidiabetogenic properties by binding to the insulin receptor and exerting an insulinomimetic effect both in vitro and in vivo (52,53). Visfatin was originally identified as pre-B-cell colony-enhancing factor (PBEF), a cytokine with increased presence in the bronchoalveolar lavage fluid of animal models of acute lung injury as well as in the neutrophils of septic patients (11). Despite its name, plasma concentrations of visfatin and visceral visfatin mRNA expression have been reported to correlate with measures of obesity but not with visceral fat mass or waist-to-hip ratio. Moreover, no differences in visfatin mRNA expression between the visceral and subcutaneous fat depots have been observed (54). Regarding its regulation, it has been reported that IL-6 exerts an inhibitory effect on visfatin expression, which is in part mediated by the p44 42...

Flutamide

Some studies reported that this drug is more effective than spironolactone or finasteride in the treatment of hirsutism. However, differences were small, and all these medications gave similar results in a controlled comparative trial (18). Anecdotal evidence suggests that flutamide is more effective than other drugs in treating androgen-dependent acne, although no controlled study has been specifically designed to assess this aspect. Some studies reported that this drug might have favorable effects on visceral fat and on the lipid profile in patients with PCOS (22,23). These effects are of great interest in subjects who frequently show abdominal obesity, insulin resistance, and multiple metabolic abnormalities.

Hirsutism In Abdomen

Hirsute Stomach

Weight gain that is primarily centripetal, especially if associated with extremity wasting, purple striae, easy bruisability, moon facies, and rubor, suggests the presence of Cushing's syndrome, and these patients should be appropriately screened using 24-hour urinary-free cortisol levels or a cortisol level following an overnight dexamethasone suppression test. Other information that should be sought includes the patient's awareness of her body fat distribution, as women with PCOS have a greater prevalence of abdominal obesity (29). Weight gain may also be associated with carbohydrate craving and evidence of postprandial reactive hypoglycemia, particularly in mid-afternoons. For example, Holte and colleagues found that although insulin resistance in obese women with PCOS was reduced by weight loss to similar levels as BMI-matched controls, these patients continued to demonstrate an increased early insulin response to glucose, which could stimulate appetite and persistent weight gain...

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