Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity

When caloric intake exceeds caloric expenditure, the positive caloric balance and storage of energy in adipose tissue often causes adipocyte hypertrophy and visceral adipose tissue accumulation. These pathogenic anatomic abnormalities may incite metabolic and immune responses that promote Type 2 diabetes mellitus, hypertension and dyslipidemia. These are the most common metabolic diseases managed by clinicians and are all major cardiovascular disease risk factors. ‘Disease’ is traditionally characterized as anatomic and physiologic abnormalities of an organ or organ system that contributes to adverse health consequences. Using this definition, pathogenic adipose tissue is no less a disease than diseases of other body organs. This review describes the consequences of pathogenic fat cell hypertrophy and visceral adiposity, emphasizing the mechanistic contributions of genetic and environmental predispositions, adipogenesis, fat storage, free fatty acid metabolism, adipocyte factors and inflammation. Appreciating the full pathogenic potential of adipose tissue requires an integrated perspective, recognizing the importance of ‘cross-talk’ and interactions between adipose tissue and other body systems. Thus, the adverse metabolic consequences that accompany fat cell hypertrophy and visceral adiposity are best viewed as a pathologic partnership between the pathogenic potential adipose tissue and the inherited or acquired limitations and/or impairments of other body organs. A better understanding of the physiological and pathological interplay of pathogenic adipose tissue with other organs and organ systems may assist in developing better strategies in treating metabolic disease and reducing cardiovascular disease risk.     

Is adiposopathy (sick fat) an endocrine disease?

Objective: To review current consensus and controversy regarding whether obesity is a ‘disease’, examine the pathogenic potential of adipose tissue to promote metabolic disease and explore the merits of ‘adiposopathy’ and ‘sick fat’ as scientifically and clinically useful terms in defining when excessive body fat may represent a ‘disease’. Methods: A group of clinicians and researchers, all with a background in endocrinology, assembled to evaluate the medical literature, as it pertains to the pathologic and pathogenic potential of adipose tissue, with an emphasis on metabolic diseases that are often promoted by excessive body weight. Results: The data support pathogenic adipose tissue as a disease. Challenges exist to convince many clinicians, patients, healthcare entities and the public that excessive body fat is often no less a ‘disease’ than the pathophysiological consequences related to anatomical abnormalities of other body tissues. ‘Adiposopathy’ has the potential to scientifically define adipose tissue anatomic and physiologic abnormalities, and their adverse consequences to patient health. Adiposopathy acknowledges that when positive caloric balance leads to adipocyte hypertrophy and visceral adiposity, then this may lead to pathogenic adipose tissue metabolic and immune responses that promote metabolic disease. From a patient perspective, explaining how excessive caloric intake might cause fat to become ‘sick’ also helps provide a rationale for patients to avoid weight gain. Adiposopathy also better justifies recommendations of weight loss as an effective therapeutic modality to improve metabolic disease in overweight and obese patients. Conclusion: Adiposopathy (sick fat) is an endocrine disease.     

Adiposopathy and bariatric surgery: is ‘sick fat’ a surgical disease?

Objective: To review how bariatric surgery in obese patients may effectively treat adiposopathy (pathogenic adipose tissue or ‘sick fat’), and to provide clinicians a rationale as to why bariatric surgery is a potential treatment option for overweight patients with type 2 diabetes, hypertension, and dyslipidaemia. Methods: A group of clinicians, researchers, and surgeons, all with a background in treating obesity and the adverse metabolic consequences of excessive body fat, reviewed the medical literature regarding the improvement in metabolic disease with bariatric surgery. Results: Bariatric surgery improves metabolic disease through multiple, likely interrelated mechanisms including: (i) initial acute fasting and diminished caloric intake inherent with many gastrointestinal surgical procedures; (ii) favourable alterations in gastrointestinal endocrine and immune responses, especially with bariatric surgeries that reroute nutrient gastrointestinal delivery such as gastric bypass procedures; and (iii) a decrease in adipose tissue mass. Regarding adipose tissue mass, during positive caloric balance, impaired adipogenesis (resulting in limitations in adipocyte number or size) and visceral adiposity are anatomic manifestations of pathogenic adipose tissue (adiposopathy). This may cause adverse adipose tissue endocrine and immune responses that lead to metabolic disease. A decrease in adipocyte size and decrease in visceral adiposity, as often occurs with bariatric surgery, may effectively improve adiposopathy, and thus effectively treat metabolic disease. It is the relationship between bariatric surgery and its effects upon pathogenic adipose tissue that is the focus of this discussion. Conclusions: In selective obese patients with metabolic disease who are refractory to medical management, adiposopathy is a surgical disease.     

Adipokine dysregulation and adipose tissue inflammation in human obesity

Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including type 2 diabetes, cardiovascular diseases, nonalcoholic fatty liver disease and cancer. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins and growth and vasoactive factors, collectively termed adipokines that influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity‐related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodelling and fibrosis together with an altered secretion of adipokines. This review describes how adipose tissue becomes inflamed in obesity and summarizes key players and molecular mechanisms involved in adipose inflammation.     

Life style-related disease

Diabetes mellitus, hyperlipidemia, hypertension and atherosclerotic diseases have recently defined as typical life style-related diseases. A common background of these life style-related diseases is overnutrition and its consequence, obesity. Recent advances in the biology of adipose tissue have revealed that adipose is not simply an energy storage organ but it also secretes a variety of molecules which affect the metabolism of the whole body. Through a systematic search of active genes in adipose tissue, we found that adipose tissue, especially visceral fat expressed numerous genes for secretory proteins. Among them, plasminogen activator inhibitor-1(PAI-1) was over expressed in the visceral fat in an animal model of obesity. Plasma level of PAI-1 was closely correlated with visceral adiposity in human. Thus, PAI-1 secreted from visceral fat may play an important role in vascular disease in visceral obesity. Adiponectin, a novel adipose-specific gene product, is abundantly presented in human plasma. This molecule has been shown to have protective roles against atherosclerotic vascular changes and its plasma level is negatively correlated with visceral adiposity. In conclusion, dysregulated secretion of these adipose-specific secretory proteins(adipocytokines) may have important roles in the development of life style-related diseases, especially atherosclerotic diseases.     

Circulating preptin levels in normal,impaired glucose tolerance,and type 2 diabetic subjects

Despite the fact that controversy remains around the underlying pathophysiological processes leading to the development of the metabolic syndrome (insulin resistance and/or hyperinsulinemia versus abdominal obesity), there is increased recognition that abdominal obesity is the most prevalent form of the metabolic syndrome. Although it has been well established that there is a greater prevalence of chronic metabolic diseases such as diabetes and cardiovascular diseases in obese patients than among normal weight individuals, obesity is a remarkably heterogeneous condition and not every obese patient is characterized by co‐morbidities. In this regard, body fat distribution, especially visceral adipose tissue accumulation, has been found to be a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic and proinflammatory metabolic abnormalities referred to as the metabolic syndrome. Due to its anatomic location and peculiar metabolic, hyperlipolytic activity, the expanded visceral adipose depot is a key correlate of the altered cardiometabolic risk profile observed among individuals with a high‐risk abdominal obesity phenotype. Evidence suggests that this dysmetabolic profile is predictive of a substantially increased risk of coronary heart disease even in the absence of classical risk factors. Finally, a moderate weight loss in initially abdominally obese patients is associated with a preferential mobilization of visceral adipose tissue, which in turn leads to substantial improvements in the metabolic risk profile predictive of a reduced risk of coronary heart disease and of type 2 diabetes.     

Is visceral obesity the cause of the metabolic syndrome?

Despite the fact that controversy remains around the underlying pathophysiological processes leading to the development of the metabolic syndrome (insulin resistance and/or hyperinsulinemia versus abdominal obesity), there is increased recognition that abdominal obesity is the most prevalent form of the metabolic syndrome. Although it has been well established that there is a greater prevalence of chronic metabolic diseases such as diabetes and cardiovascular diseases in obese patients than among normal weight individuals, obesity is a remarkably heterogeneous condition and not every obese patient is characterized by co-morbidities. In this regard, body fat distribution, especially visceral adipose tissue accumulation, has been found to be a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic and proinflammatory metabolic abnormalities referred to as the metabolic syndrome. Due to its anatomic location and peculiar metabolic, hyperlipolytic activity, the expanded visceral adipose depot is a key correlate of the altered cardiometabolic risk profile observed among individuals with a high-risk abdominal obesity phenotype. Evidence suggests that this dysmetabolic profile is predictive of a substantially increased risk of coronary heart disease even in the absence of classical risk factors. Finally, a moderate weight loss in initially abdominally obese patients is associated with a preferential mobilization of visceral adipose tissue, which in turn leads to substantial improvements in the metabolic risk profile predictive of a reduced risk of coronary heart disease and of type 2 diabetes.     

Phentermine,topiramate and their combination for the treatment of adiposopathy (‘sick fat’) and metabolic disease

Positive caloric balance often causes pathologic adipocyte and adipose tissue anatomical and functional changes (termed adiposopathy or ‘sick fat’), which may lead to pathogenic adipocyte and adipose tissue responses and metabolic disease. Fat weight loss may improve adiposopathy, and thus improve metabolic disease in overweight patients. Unfortunately, the efficacy of non-surgical weight loss therapies is often limited due to redundant physiological systems that help ‘protect’ against starvation and/or negative caloric balance. One strategy to overcome these limitations is to combine weight loss drug therapies having complementary mechanisms of action, thereby affecting more than one physiologic process influencing body fat accumulation. Phentermine is a noradrenergic sympathomimetic amine approved for short-term treatment of obesity. Topiramate is a sulfamate-substituted monosaccharide derivative of the naturally occurring sugar monosaccharide D-fructose approved as a treatment for migraine headaches and seizure disorders. Although known to facilitate weight loss since its approval, topiramate monotherapy does not have a regulatory indication as an anti-obesity agent. Phentermine HCl/topiramate controlled-release (PHEN/TPM CR) is a combination agent containing immediate-release phentermine and controlled-release topiramate. Clinical trials involving thousands of patients demonstrate PHEN/TPM CR to be effective in improving the weight of patients, and also effective in improving adiposopathy-associated metabolic diseases. This review examines the pathophysiology of adiposopathy as a contributor to metabolic disease, the data supporting phentermine monotherapy, topiramate monotherapy and their combination as anti-obesity and anti-adiposopathy agents, and the preliminary evidence supporting PHEN/TPM CR as a generally well-tolerated and effective agent to improve metabolic disease.     

Anthropometric correlates of total body fat, abdominal adiposity, and cardiovascular disease risk factors in a biracial sample of men and women

ObjectiveTo investigate associations between anthropometric measurements and total body fat, abdominal adipose tissue, and cardiovascular disease risk factors in a large biracial sample.Patients and MethodsThis study is limited to cross-sectional analyses of data from participants attending a baseline visit between January 26, 1996, and February 1, 2011. The sample included 2037 individuals aged 18 to 69 years: 488 African American women (24%), 686 white women (34%), 196 African American men (9%), and 667 white men (33%). Anthropometry included weight; hip circumference; waist circumference; waist-hip, waist-height, and weight-height ratios; body adiposity index; and body mass index. Body fat and percentage of fat were measured by dual-energy x-ray absorptiometry, and abdominal visceral and subcutaneous adipose tissue were measured by computed tomography. Bivariate correlations, logistic regression models, and receiver operator characteristic curves were used, and analyses were stratified by sex and race.ResultsIn each sex-by-race group, all anthropometric measures were highly correlated with percentage of fat, fat mass, and subcutaneous adipose tissue and moderately correlated with visceral adipose tissue, with the exception of the waist-hip ratio. The odds of having an elevated cardiometabolic risk were increased more than 2-fold per SD increase for most anthropometric variables, and the areas under the curve for each anthropometric measure were significantly greater than 0.5.ConclusionSeveral common anthropometric measures were moderately to highly correlated with total body fat, abdominal fat, and cardiovascular disease risk factors in a biracial sample of women and men. This comprehensive analysis provides evidence of the linkage between simple anthropometric measurements and the purported pathways between adiposity and health.     

New insights into adipose tissue dysfunction in insulin resistance

In a state of caloric excess, adipose tissue plays an essential role by storing lipids. Its expandability determines the onset of metabolic syndrome (central obesity, dyslipidemia, glucose intolerance and hypertension). When the adipocyte endoplasmic reticulum is no longer capable of processing the excess nutrients, the so-called "endoplasmic reticulum stress" develops. This triggers efflux of free fatty acids from adipocytes into the circulation and causes triglyceride overload in skeletal muscle, liver and pancreas. Adipose tissue hypoxia then develops, due to the failure of vasculature to expand with adipocyte hypertrophy. Increased catabolism in mitochondria leads there to oxidative stress. Both phenomena cause deranged adipokine secretion and low-grade inflammation. Inflammatory cytokines, reactive oxygen species and ectopic lipid deposition are the main mediators of insulin resistance and vascular impairment, which both lead finally to diabetes type 2 and cardiovascular disease. Recently, fibrosis of adipose tissue was also demonstrated in obesity, contributing to the interplay of deleterious factors forcing inflammation. The present paper reviews recent evidence for adipose tissue dysfunction, trying to define causes and consequences. In conclusion, insulin resistance and associated complications originate from excess lipids, which cannot be stored without limit in adipose tissue, thus affecting its integrity and adipokine secretion.     

The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences

BACKGROUND: As the prevalence of adiposity soars in both developed and developing nations, appreciation of the close links between obesity and disease increases. The strong relationships between excess adipose tissue and poor health outcomes, including cardiovascular disease, diabetes, and cancer, mandate elucidation of the complex cellular, hormonal, and molecular pathophysiology whereby adiposity initiates and maintains adverse health effects. Content: In this report we review adipocyte metabolism and function in the context of energy imbalance and postprandial nutrient excess, including adipocyte hypertrophy and hyperplasia, adipocyte dysfunction, and other systemic consequences. We also discuss implications for laboratory evaluation and clinical care, including the role of lifestyle modifications. Chronic energy imbalance produces adipocyte hypertrophy and hyperplasia, endoplasmic reticulum stress, and mitochondrial dysfunction. These processes lead to increased intracellular and systemic release of adipokines, free fatty acids, and inflammatory mediators that cause adipocyte dysfunction and induce adverse effects in the liver, pancreatic beta-cells, and skeletal muscle as well as the heart and vascular beds. Several specialized laboratory tests can quantify these processes and predict clinical risk, but translation to the clinical setting is premature. Current and future pharmacologic interventions may target these pathways; modest changes in diet, physical activity, weight, and smoking are likely to have the greatest impact. Summary: Adipocyte endoplasmic reticulum and mitochondrial stress, and associated changes in circulating adipokines, free fatty acids, and inflammatory mediators, are central to adverse health effects of adiposity. Future investigation should focus on these pathways and on reversing the adverse lifestyle behaviors that are the fundamental causes of adiposity.     

Convergence of adipocyte hypertrophy,telomere shortening and hypoadiponectinemia in obese subjects and in patients with type 2 diabetes

ObjectiveAlthough telomere shortening has been linked with type 2 diabetes and most variables of adiposity, a shortcoming of such studies is the measurement of telomere length in leukocytes. Therefore, we tested the association among adipocyte cell size, telomere length (both subcutaneous and visceral adipose tissue) and systemic levels of adiponectin in obese subjects and patients with type 2 diabetes compared to control subjects.MethodsHuman subcutaneous and visceral adipose tissues were obtained from the subjects who have undergone bariatric surgery or other abdominal surgeries. The study groups comprised: i) control subjects, ii) type 2 diabetes patients, iii) obese subjects without diabetes and iv) obese subjects with diabetes. Adipocyte cell size was measured by histological staining. Adiponectin levels were measured by ELISA. Telomere length was determined by Real-time PCR and lipid peroxidation was assessed by fluorimetry.ResultsCompared to control subjects, adipocyte size (both subcutaneous and visceral) from obese, diabetic and obese–diabetic subjects was significantly larger [p < 0.001]. Individuals with adipose hypertrophy also exhibited shortened telomeres and hypoadiponectinemia. Pearson correlation analysis revealed that both visceral and subcutaneous fat cell size showed a positive correlation with FBS, HbA1c, HOMA-IR, LDL, total cholesterol, triglycerides and negatively correlated with HDL and adiponectin. Regression analysis revealed that the association between shortened telomeres and hypoadiponectinemia was lost when adjusted for adipocyte cell size.ConclusionAdipocyte hypertrophy appears to be strongly associated with shortened telomeres, hypoadiponectinemia and poor glycemic and lipid control. Interestingly, these molecular alterations seen in lean diabetics reflect a state of ‘metabolic obesity’.     

Visceral adiposity as a target for the management of the metabolic syndrome

Atherosclerosis, the underlying cause of atherosclerotic cardiovascular disease (ACVD), develops due not only to a single cardiovascular risk factor but to a variety of complex factors. The concept of the multiple cardiometabolic risk factor clustering syndrome has been proposed as a highly atherogenic state, independent of hypercholesterolemia and smoking. Body fat distribution, especially visceral fat accumulation, is a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic, and proinflammatory metabolic abnormalities referred to as the metabolic syndrome, with dysfunctional adipocytes and dysregulated production of adipocytokines (hypoadiponectinemia). Medical research has focused on visceral adiposity as an important component of the syndrome in Japanese subjects with a mild degree of adiposity compared with Western subjects. For the prevention of ACVD at least in Japan, it might be practical to stratify subjects with multiple risk factors for atherosclerotic cardiovascular disease based on visceral fat accumulation. Visceral fat reduction through health promotion programs using risk factor-oriented approaches may be effective in reducing ACVD events, as well as producing improvement in risks and hypoadiponectinemia. This review article discusses visceral adiposity as a key player in the syndrome. Visceral fat reduction with life-style modification is a potentially useful strategy in the prevention of ACVD in patients with the metabolic syndrome.     

Adiposopathy: how do diet,exercise and weight loss drug therapies improve metabolic disease in overweight patients?

An increase in bodyweight is generally associated with an increased risk of excessive fat-related metabolic diseases (EFRMD), including Type 2 diabetes mellitus, hypertension and dyslipidemia. However, not all patients who are overweight have EFRMD, and not all patients with EFRMD are significantly overweight. The adipocentric paradigm provides the basis for a unifying, pathophysiological process whereby fat gain in susceptible patients leads to fat dysfunction (‘sick fat’), and wherein pathological abnormalities in fat function (adiposopathy) are more directly related to the onset of EFRMD than increases in fat mass (adiposity) alone. But just as worsening fat function worsens EFRMD, improved fat function improves EFRMD. Peroxisome proliferator-activated receptor-γ agonists increase the recruitment, proliferation and differentiation of preadipocytes (‘healthy fat’) and cause apoptosis of hypertrophic and dysfunctional (including visceral) adipocytes resulting in improved fat function and improved metabolic parameters associated with EFRMD. Weight loss interventions, such as a hypocaloric diet and physical exercise, in addition to agents such as orlistat, sibutramine and cannabinoid receptor antagonists, may have favorable effects upon fat storage (lipogenesis and fat distribution), nutrient metabolism (such as free fatty acids), favorable effects upon adipose tissue factors involved in metabolic processes and inflammation, and enhanced ‘cross-talk’ with other major organ systems. In some cases, weight loss therapeutic agents may even affect metabolic parameters and adipocyte function independently of weight loss alone, suggesting that the benefit of these agents in improving EFRMD may go beyond their efficacy in weight reduction. This review describes how adiposopathy interventions may affect fat function, and thus improve EFRMD.     

Visceral adiposity as a target for the management of the metabolic syndrome

Abstract

Atherosclerosis, the underlying cause of atherosclerotic cardiovascular disease (ACVD), develops due not only to a single cardiovascular risk factor but to a variety of complex factors. The concept of the multiple cardiometabolic risk factor clustering syndrome has been proposed as a highly atherogenic state, independent of hypercholesterolemia and smoking. Body fat distribution, especially visceral fat accumulation, is a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic, and proinflammatory metabolic abnormalities referred to as the metabolic syndrome, with dysfunctional adipocytes and dysregulated production of adipocytokines (hypoadiponectinemia). Medical research has focused on visceral adiposity as an important component of the syndrome in Japanese subjects with a mild degree of adiposity compared with Western subjects. For the prevention of ACVD at least in Japan, it might be practical to stratify subjects with multiple risk factors for atherosclerotic cardiovascular disease based on visceral fat accumulation. Visceral fat reduction through health promotion programs using risk factor-oriented approaches may be effective in reducing ACVD events, as well as producing improvement in risks and hypoadiponectinemia. This review article discusses visceral adiposity as a key player in the syndrome. Visceral fat reduction with life-style modification is a potentially useful strategy in the prevention of ACVD in patients with the metabolic syndrome.     

Mapping body fat distribution: A key step towards the identification of the vulnerable patient?

Abstract

Although excess body fat is a significant health hazard, estimation of body fat content with the body mass index may not adequately reflect the amount of atherogenic adipose tissue (AT), i.e. visceral and ectopic fat. As opposed to subcutaneous AT that supposedly acts as a metabolic sink buffering excess dietary energy, visceral or intra-abdominal AT depots respond to several external stimuli that trigger lipolysis and secretion of free fatty acids (FFAs). Reaching the liver, FFAs accumulate in the liver and, over time, promote a chronic condition known as non-alcoholic fatty liver disease (NAFLD). The liver of the typical NAFLD patient secretes large amounts of very-low-density lipoproteins, the lipid content of which may accumulate in additional organs (skeletal muscle, heart, and pancreas). Here, we review the evidence emerging from functional and population studies that point towards an important role of ectopic fat accumulation in the pathophysiology of type 2 diabetes and cardiovascular disease. We conclude that although patients with impaired glycemic control or type 2 diabetes are at increased cardiovascular disease (CVD) risk, estimating cardiovascular risk goes wellbeyond the assessment of glycemic control and traditional CVD risk factors, and the estimation of visceral/ectopic fat deposition via readily available imaging techniquesshould be considered.     

Leptin selectively decreases visceral adiposity and enhances insulin action.

Intraabdominal adiposity and insulin resistance are risk factors for diabetes mellitus, dyslipidemia, arteriosclerosis, and mortality. Leptin, a fat-derived protein encoded by the ob gene, has been postulated to be a sensor of energy storage in adipose tissue capable of mediating a feedback signal to sites involved in the regulation of energy homeostasis. Here, we provide evidence for specific effects of leptin on fat distribution and in vivo insulin action. Leptin (LEP) or vehicle (CON) was administered by osmotic minipumps for 8 d to pair-fed adult rats. During the 8 d of the study, body weight and total fat mass decreased similarly in LEP and in CON. However, while moderate calorie restriction (CON) resulted in similar decreases in whole body (by 20%) and visceral (by 21%) fat, leptin administration led to a specific and marked decrease (by 62%) in visceral adiposity. During physiologic hyperinsulinemia (insulin clamp), leptin markedly enhanced insulin action on both inhibition of hepatic glucose production and stimulation of glucose uptake. Finally, leptin exerted complex effects on the hepatic gene expression of key metabolic enzymes and on the intrahepatic partitioning of metabolic fluxes, which are likely to represent a defense against excessive storage of energy in adipose depots. These studies demonstrate novel actions of circulating leptin in the regulation of fat distribution, insulin action, and hepatic gene expression and suggest that it may play a role in the pathophysiology of abdominal obesity and insulin resistance.     

The concept of cardiometabolic risk: Bridging the fields of diabetology and cardiology

The lack of physical activity and the adoption of poor nutritional habits is the major cause of the obesity epidemic that is currently sweeping the world. The expansion of adipose tissue mass, especially of the visceral adipose tissue depot, is observed in the vast majority of individuals carrying the clinical features of the metabolic syndrome, an important (and reversible) risk factor of type 2 diabetes and cardiovascular disease. As waist circumference can be used as a crude estimate of visceral fat accumulation, its measurement provides further information on cardiovascular and type 2 diabetes risk, at any given body mass index value. However, an elevated waist circumference might also be the result of an increased 'cardioprotective' subcutaneous adipose tissue mass. We have proposed that the measurement of plasma triglycerides along with waist circumference, the so-called 'hypertriglyceridemic waist' might better quantify visceral obesity and its health hazards than waist circumference alone. "Hypertriglyceridemic waist" is thought to represent an altered, dysfunctional, and highly lipolytic adipose tissue that is a major culprit abnormality behind the metabolic syndrome and associated cardiometabolic risk, independently from classical cardiovascular disease risk factors such as age, sex, and plasma low density lipoprotein (LDL) cholesterol levels.     

Adiposopathy: how do diet, exercise and weight loss drug therapies improve metabolic disease in overweight patients?

An increase in bodyweight is generally associated with an increased risk of excessive fat-related metabolic diseases (EFRMD), including Type 2 diabetes mellitus, hypertension and dyslipidemia. However, not all patients who are overweight have EFRMD, and not all patients with EFRMD are significantly overweight. The adipocentric paradigm provides the basis for a unifying, pathophysiological process whereby fat gain in susceptible patients leads to fat dysfunction ('sick fat'), and wherein pathological abnormalities in fat function (adiposopathy) are more directly related to the onset of EFRMD than increases in fat mass (adiposity) alone. But just as worsening fat function worsens EFRMD, improved fat function improves EFRMD. Peroxisome proliferator-activated receptor-gamma agonists increase the recruitment, proliferation and differentiation of preadipocytes ('healthy fat') and cause apoptosis of hypertrophic and dysfunctional (including visceral) adipocytes resulting in improved fat function and improved metabolic parameters associated with EFRMD. Weight loss interventions, such as a hypocaloric diet and physical exercise, in addition to agents such as orlistat, sibutramine and cannabinoid receptor antagonists, may have favorable effects upon fat storage (lipogenesis and fat distribution), nutrient metabolism (such as free fatty acids), favorable effects upon adipose tissue factors involved in metabolic processes and inflammation, and enhanced 'cross-talk' with other major organ systems. In some cases, weight loss therapeutic agents may even affect metabolic parameters and adipocyte function independently of weight loss alone, suggesting that the benefit of these agents in improving EFRMD may go beyond their efficacy in weight reduction. This review describes how adiposopathy interventions may affect fat function, and thus improve EFRMD.     

Adipose tissue and metabolic syndrome: too much,too little or neither

Obesity is strongly associated with metabolic syndrome. Recent research suggests that excess adipose tissue plays an important role in development of the syndrome. On the other hand, persons with a deficiency of adipose tissue (e.g. lipodystrophy) also manifest the metabolic syndrome. In some animal models, expansion of adipose tissue pools mitigates adverse metabolic components (e.g. insulin resistance, hyperglycaemia and dyslipidemia). Hence, there are conflicting data as to whether adipose tissue worsens the metabolic syndrome or protects against it. This conflict may relate partly to locations of adipose tissue pools. For instance, lower body adipose tissue may be protective whereas upper body adipose tissue may promote the syndrome. One view holds that in either case, the accumulation of ectopic fat in muscle and liver is the driving factor underlying the syndrome. If so, there may be some link between adipose tissue fat and ectopic fat. But the mechanisms underlying this connection are not clear. A stronger association appears to exist between excessive caloric intake and ectopic fat accumulation. Adipose tissue may act as a buffer to reduce the impact of excess energy consumption by fat storage; but once a constant weight has been achieved, it is unclear whether adipose tissue influences levels of ectopic fat. Another mechanism whereby adipose tissue could worsen the metabolic syndrome is through release of adipokines. This is an intriguing mechanism, but the impact of adipokines on metabolic syndrome risk factors is uncertain. Thus, many potential connections between adipose tissue and metabolic syndrome remain to unravelled.