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May 2009

General and abdominal adiposity and risk of death in Europe.

BACKGROUND: Previous studies have relied predominantly on the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) to assess the association of adiposity with the risk of death, but few have examined whether the distribution of body fat contributes to the prediction of death. METHODS: We examined the association of BMI, waist circumference, and waist-to-hip ratio with the risk of death among 359,387 participants from nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). We used a Cox regression analysis, with age as the time variable, and stratified the models according to study center and age at recruitment, with further adjustment for educational level, smoking status, alcohol consumption, physical activity, and height. RESULTS: During a mean follow-up of 9.7 years, 14,723 participants died. The lowest risks of death related to BMI were observed at a BMI of 25.3 for men and 24.3 for women. After adjustment for BMI, waist circumference and waist-to-hip ratio were strongly associated with the risk of death. Relative risks among men and women in the highest quintile of waist circumference were 2.05 (95% confidence interval [CI], 1.80 to 2.33) and 1.78 (95% CI, 1.56 to 2.04), respectively, and in the highest quintile of waist-to-hip ratio, the relative risks were 1.68 (95% CI, 1.53 to 1.84) and 1.51 (95% CI, 1.37 to 1.66), respectively. BMI remained significantly associated with the risk of death in models that included waist circumference or waist-to-hip ratio (P<0.001). CONCLUSIONS: These data suggest that both general adiposity and abdominal adiposity are associated with the risk of death and support the use of waist circumference or waist-to-hip ratio in addition to BMI in assessing the risk of death.

N Engl J Med. 2008 Nov 13;359(20):2105-20

Abdominal obesity and the spectrum of global cardiometabolic risks in US adults.

OBJECTIVE: To compare the association of obesity and abdominal obesity with cardiometabolic risk factor burden and global estimated coronary heart disease (CHD) risk among multiethnic US adults. DESIGN: Cross-sectional, survey study. SUBJECTS: A total of 4,456 participants (representing 194.9 million adults) aged 20-79 years in the 2003-2004 National Health and Nutrition Examination Survey (NHANES). MEASUREMENTS: Body mass index (BMI) and waist circumference (WC) measures, CHD risk factors and a 10-year estimated CHD risk based on Framingham algorithms. Obesity was defined as a BMI >or=30 kg/m(2) and abdominal obesity as a WC >88 cm in women and >102 cm in men. High CHD risk status included diabetes, cardiovascular disease (CVD) or a 10-year Framingham risk score of >20%. RESULTS: Overall, abdominal obesity was present in 42.3% of men and 62.5% of women and in 53.6% of whites, 56.9% of blacks and 50.5% of Hispanics (P<0.001 between gender and ethnicity). However, using International Diabetes Federation (IDF)-recommended WC cut points for Hispanics, the prevalence of abdominal obesity was 78.3%. Mean levels of low-density lipoprotein cholesterol (LDL-C), systolic and diastolic blood pressure, fasting glucose and C-reactive protein increased, and high-density lipoprotein cholesterol (HDL-C) decreased (P<0.001) according to BMI and WC categories, although these associations were attenuated in blacks for blood pressure, LDL-C, HDL-C and triglycerides. Of those with high WC, 25-35% had >or=3 cardiometabolic risk factors. High CHD risk among those with high WC was most common in men (27.9%) and non-Hispanic whites (23.9%). Persons with a high vs normal WC, adjusted for age, gender, ethnicity and BMI were more likely to have >or=3 cardiometabolic risk factors (odds ratio (OR)=5.1, 95% confidence interval (CI)=3.9-6.6) and were classified as high CHD risk (OR=1.5, 95% CI=1.1-2.0). CONCLUSION: The association of abdominal obesity with risk factors varies by ethnicity and is independently associated with high CHD risk status, further validating its clinical significance.

Int J Obes (Lond). 2009 Feb;33(2):239-48

“Sick fat,” metabolic disease, and atherosclerosis.

Atherosclerotic coronary heart disease (CHD) is the most common cause of morbidity and mortality among men and women in developed nations. The obesity epidemic contributes to the increasing prevalence of high blood sugar (as may be found in patients with diabetes mellitus and metabolic syndrome), high blood pressure, and dyslipidemia--all CHD risk factors. Metabolic syndrome describes the common clinical finding wherein component CHD risk factors cluster within a single patient, but this term does not identify any unified pathophysiologic process. However, a component of the metabolic syndrome is abdominal obesity, which does reflect an anatomic manifestation of a “common-soil” pathophysiologic process that promotes the onset of CHD risk factors, and thus increases CHD risk. Adiposopathy (“sick fat”) is anatomically characterized by visceral adiposity and adipocyte hypertrophy; it is manifested physiologically by a net increase in release of free fatty acids and by pathogenic adipose tissue metabolic/immune responses that promote metabolic disease and increase CHD risk. Understanding the relation of adiposopathy to CHD risk factors and recognizing the importance of treating both the “cause and effect” of metabolic diseases are critical toward a comprehensive approach in reducing CHD risk. Regarding the “cause,” clinicians and their patients should be diligent regarding appropriate nutritional and lifestyle interventions that may favorably affect health. Regarding the “effect,” clinicians and their patients should be equally diligent toward appropriate pharmaceutical interventions that reduce CHD risk factors when nutritional and lifestyle interventions do not sufficiently achieve desired metabolic treatment goals.

Am J Med. 2009 Jan;122(1 Suppl):S26-37

The role of fat topology in the risk of disease.

Clustering of multiple risk factors such as impaired glucose metabolism, lipid disorders and hypertension has been shown to be the major background of atherosclerotic diseases, and disease entities such as the metabolic syndrome represent a highly atherogenic state. Although these common risks may generally co-exist by accident in one individual, clustering of multiple risk factors in the metabolic syndrome does not occur by accident, and there should be a key player for the syndrome. In 1983, we reported the method for fat analysis using computed tomography scan, which enables us to analyze intra-abdominal visceral adiposity as well as subcutaneous fat. Visceral fat accumulation has been shown to cause impaired glucose metabolism, lipid disorders, and hypertension, and therefore it is considered to be a key player in the metabolic syndrome. To clarify the mechanism by which visceral fat accumulation causes a variety of metabolic and vascular diseases, we studied the molecular characteristics of adipose tissue and adipocytes by investigating expressed genes in visceral and subcutaneous adipocytes and revealed that adipocytes, especially visceral adipocytes, secrete a variety of bioactive substances, the so-called adipocytokines. We showed that visceral fat accumulation causes abnormalities in adipocytokine secretion, such as hypersecretion of plasminogen activator inhibitor 1, which is related to thrombogenic vascular diseases. More importantly, we discovered an important benign adipocytokine named adiponectin, which protects against the development of diabetes mellitus, hypertension, inflammation, and atherosclerotic vascular diseases. Plasma levels of adiponectin decreased in individuals with visceral fat accumulation, and hypoadiponectinemia caused by visceral fat accumulation might be one of the major causes of metabolic syndrome.

Int J Obes (Lond). 2008 Dec;32 Suppl 7:S83-92

Adipokines: inflammation and the pleiotropic role of white adipose tissue.

White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name ‘adipocytokines’ or ‘adipokines’. However, since most are neither ‘cytokines’ nor ‘cytokine-like’, it is recommended that the term ‘adipokine’ be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. The adipokinome (which together with lipid moieties released, such as fatty acids and prostaglandins, constitute the secretome of fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFalpha, IL-1beta, IL-6, IL-8, IL-10, transforming growth factor-beta, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1.

Br J Nutr. 2004 Sep;92(3):347-55

The biology of obesity.

Obesity is a multidisciplinary area, the ‘biology’ of which encompasses: (1) the fundamental mechanisms of energy balance and its regulation; (2) the biological basis for the development of obesity; (3) adipose tissue function; (4) the biological description of the obese state; (5) the pathological consequences of obesity; (6) the physiological basis for treatment strategies. At a mechanistic level, important developments in recent years include the identification of novel neuroendocrine factors in the control of appetite (such as cocaine- and amphetamine-regulated transcript, the orexins, the endocannabinoids) and the discovery of new peripheral signals (such as leptin, ghrelin). Despite the identification of additional uncoupling proteins (UCP2, UCP3), mitochondrial uncoupling in brown adipose tissue through UCP1 remains the only major mechanism for adaptive thermogenesis. White adipose tissue (WAT) has now moved centre stage in energy balance and obesity research, and there are three main reasons: (1) it is the organ which defines obesity; (2) it is the source of a critical endocrine signal in the control of body weight; (3) it secretes a range of diverse protein factors, termed adipokines, some of which are directly implicated in the pathologies associated with obesity. WAT is now recognised as a key endocrine organ, communicating both with the brain and peripheral tissues through the adipokines. Obesity is characterised by mild inflammation, and WAT may be the main locus of the inflammatory state, producing cytokines, chemokines, acute-phase proteins and angiogenic factors. It has been suggested that inflammation in obesity is principally an adaptive response to hypoxia in clusters of adipocytes within the expanding adipose mass.

Proc Nutr Soc. 2005 Feb;64(1):31-8

Obesity and inflammation: lessons from bariatric surgery.

BACKGROUND: Obesity is associated with a series of comorbid conditions that are characterized by an inflammatory state. The purpose of this review is to update knowledge about obesity, adipose tissue, and inflammation. METHODS: Review of the published literature using search terms of adipose, inflammation, obesity, and insulin resistance in combinations. RESULTS: Adipose tissue elaborates proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha, with greater secretion from the stromal vascular fraction than from adipocytes and with greater secretion from visceral than subcutaneous adipose tissue sites. This proinflammatory state is associated with insulin resistance and ameliorated by weight loss, with concurrent increase in production of the anti-inflammatory adipokine adiponectin. CONCLUSION: Although these associations between obesity and inflammation are clearly important, many questions remain unresolved. It is unclear if benefits of weight loss pertain only to those with a proinflammatory profile, who receive a particular type of obesity surgical procedure, or whether these benefits are sustained over a lifetime. The outcomes associated with anti-inflammatory nutrient supplementation, with or without weight loss, in the obese would also increase our understanding.

JPEN J Parenter Enteral Nutr. 2008 Nov-Dec;32(6):645-7

Patterns of abdominal fat distribution: the Framingham Heart Study.

OBJECTIVE: The prevalence of abdominal obesity exceeds that of general obesity. We sought to determine the prevalence of abdominal subcutaneous and visceral obesity and to characterize the different patterns of fat distribution in a community-based sample. RESEARCH DESIGN AND METHODS: Participants from the Framingham Heart Study (n = 3,348, 48% women, mean age 52 years) underwent multidetector computed tomography; subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were assessed. Sex-specific high SAT and VAT definitions were based on 90th percentile cut points from a healthy referent sample. Metabolic risk factors were examined in subgroups with elevated SAT and VAT. RESULTS: The prevalence of high SAT was 30% (women) and 31% (men) and that for high VAT was 44% (women) and 42% (men). Overall, 27.8% of the sample was discordant for high SAT and high VAT: 19.9% had SAT less than but VAT equal to or greater than the 90th percentile, and 7.9% had SAT greater than but VAT less than the 90th percentile. The prevalence of metabolic syndrome was higher among women and men with SAT less than the 90th percentile and high VAT than in those with high SAT but VAT less than the 90th percentile, despite lower BMI and waist circumference. Findings were similar for hypertension, elevated triglycerides, and low HDL cholesterol. CONCLUSIONS: Nearly one-third of our sample has abdominal subcutaneous obesity, and >40% have visceral obesity. Clinical measures of BMI and waist circumference may misclassify individuals in terms of VAT and metabolic risk.

Diabetes Care. 2009 Mar;32(3):481-5

The effect of training in reduced energy density eating and food self-monitoring accuracy on weight loss maintenance.

BACKGROUND: Failure to maintain weight losses in lifestyle change programs continues to be a major problem and warrants investigation of innovative approaches to weight control. OBJECTIVE: The goal of this study was to compare two novel group interventions, both aimed at improving weight loss maintenance, with a control group. METHODS AND PROCEDURES: A total of 103 women lost weight on a meal replacement-supplemented diet and were then randomized to one of three conditions for the 14-week maintenance phase: cognitive-behavioral treatment (CBT); CBT with an enhanced food monitoring accuracy (EFMA) program; or these two interventions plus a reduced energy density eating (REDE) program. Assessments were conducted periodically through an 18-month postintervention. Outcome measures included weight and self-reported dietary intake. Data were analyzed using completers only as well as baseline-carried-forward imputation. RESULTS: Participants lost an average of 7.6 +/- 2.6 kg during the weight loss phase and 1.8 +/- 2.3 kg during the maintenance phase. Results do not suggest that the EFMA intervention was successful in improving food monitoring accuracy. The REDE group decreased the energy density (ED) of their diets more so than the other two groups. However, neither the REDE nor the EFMA condition showed any advantage in weight loss maintenance. All groups regained weight between 6- and 18-month follow-ups. DISCUSSION: Although no incremental weight maintenance benefit was observed in the EFMA or EFMA + REDE groups, the improvement in the ED of the REDE group’s diet, if shown to be sustainable in future studies, could have weight maintenance benefits.

Obesity (Silver Spring). 2008 Sep;16(9):2016-23

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats.

AIMS/HYPOTHESIS: Leptin resistance is generally considered a consequence of obesity. We postulated that leptin resistance is associated with diminished hypothalamic leptin signalling capacity and that leptin resistance is causal to obesity. We assessed maximal leptin-mediated binding of the transcription factor signal transducer and activator of transcription 3 (STAT3), and the response to high-fat feeding in lean leptin-resistant rats. MATERIALS AND METHODS: Recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control vector were administered by intracerebroventricular injection to lean F344 x BN rats for up to 150 days, and food consumption, body weight, serum leptin and glucose tolerance were measured. Leptin-mediated hypothalamic transcription factor binding was assessed at day 150 following an intracerebroventricular injection of 2 mug leptin. Rats pretreated with either control or rAAV-leptin vector for 94 days were given a high-fat diet, and energy intake, body weight gain and adiposity were examined. RESULTS: The rAAV-leptin-treated rats initially responded to leptin gene delivery then became leptin-resistant. They displayed persistent submaximal hypothalamic leptin signalling and enhanced insulin sensitivity, yet maximal hypothalamic signalling capacity was decreased by more than 50%. On a high-fat diet, the leptin-resistant rats consumed more energy, gained more weight and accumulated greater visceral fat mass than controls. CONCLUSIONS/INTERPRETATION: The maximal hypothalamic leptin signalling capacity was diminished in leptin-resistant rats receiving central rAAV-leptin gene therapy. Moreover, this leptin-invoked leptin resistance perturbs the regulation of energy homeostasis in response to high fat exposure, producing augmented energy consumption. This, coupled with potential hypersensitivity to insulin, creates a milieu favouring fat deposition. Our data suggest that leptin resistance is both a consequence and cause of obesity.

Diabetologia. 2005 Jun;48(6):1075-83

Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease.

Leptin is an adipocyte-derived hormone and cytokine that regulates energy balance through a wide range of functions, including several that are important to cardiovascular health. Increased circulating leptin, a marker of leptin resistance, is common in obesity and independently associated with insulin resistance and cardiovascular disease (CVD) in humans. The mechanisms of leptin resistance include genetic mutation, leptin self-regulation, limited tissue access, and cellular or circulating molecular regulation. Evidence suggests that central leptin resistance causes obesity and that obesity-induced leptin resistance injures numerous peripheral tissues, including liver, pancreas, platelets, vasculature, and myocardium. This metabolic- and inflammatory-mediated injury may result from either resistance to leptin’s action in selective tissues, or excess leptin action from adiposity-associated hyperleptinemia. In this sense, the term “leptin resistance” encompasses a complex pathophysiological phenomenon. The leptin axis has functional interactions with elements of metabolism, such as insulin, and inflammation, including mediators of innate immunity, such as interleukin-6. Leptin is even purported to physically interact with C-reactive protein, resulting in leptin resistance, which is particularly intriguing, given C-reactive protein’s well-studied relationship to cardiovascular disease. Given that plasma levels of leptin and

inflammatory markers are correlated and also predict cardiovascular risk, it is conceivable that part of this risk may be mediated through leptin resistance-related insulin resistance, chronic inflammation, type II diabetes, hypertension, atherothrombosis, and myocardial injury. Leptin resistance and its interactions with metabolic and inflammatory factors, therefore, represent potential novel diagnostic and therapeutic targets in obesity-related cardiovascular disease.

J Am Coll Cardiol. 2008 Oct 7;52(15):1201-10

Leptin resistance: a prediposing factor for diet-induced obesity.

Obesity is a resilient and complex chronic disease. One potential causative factor in the obesity syndrome is leptin resistance. Leptin behaves as a potent anorexic and energy-enhancing hormone in most young or lean animals, but its effects are diminished or lacking in the obese state associated with a normal genetic background. Emerging evidence suggests that leptin resistance predisposes the animal to exacerbated diet-induced obesity (DIO). Elevation of central leptin in young, lean rats induces a leptin resistance that precludes obesity on a chow diet but accelerates high-fat (HF)-induced obesity. Similarly, chronic dietary fructose consumption evokes a leptin resistance that causes obesity only upon HF exposure. Inherent central leptin insensitivity also contributes to dietary weight gain in certain obesity-prone rats. Conversely, aged, leptin-resistant animals are obese with continuous chow feeding and demonstrate aggravated obesity when challenged with an HF diet. Additionally, a submaximal central blockade with a leptin antagonist leads to obesity on both chow and HF diets, as is the case in rodents with leptin receptor deficiency of genetic origin. Despite the differences in the incidence of obesity on a chow diet, all of these forms of leptin resistance predispose rodents to aggravated HF-mediated obesity. Moreover, once leptin resistance takes hold, it aggravates DIO, and the leptin resistance and obesity compound one another, promoting a vicious cycle of escalating weight gain.

Am J Physiol Regul Integr Comp Physiol. 2009 Mar;296(3):R493-500

Evaluation of the effects of caffeine in the microcirculation and edema on thighs and buttocks using the orthogonal polarization spectral imaging and clinical parameters.

Gynoid lipodystrophy, also known as cellulite, is a common multifactorial entity that affects millions of women around the world. There have been few scientific articles dealing with its physiology and treatment in the past few years, and vascular changes seem to play an important role in its pathophysiology. Skin microvascular alterations can be observed noninvasively with a new method called orthogonal polarization spectral imaging, which was used to evaluate the effectiveness of an anticellulite drug composed mainly of a 7% caffeine solution. Microcirculatory parameters evaluated were functional capillary density (FCD; number of flowing capillaries per unit area), diameter of the dermic papilla (DPD), and capillary diameter (CD). The clinical parameters analyzed were centimetrical measurements of thighs and hips and the influence of tobacco, alcohol, and physical activities on the efficacy of the treatment. After 1 month of treatment, statistical application of chi-squared and Z approximation tests showed, in treated patients, statistically significant reduction of thigh circumferences in more than 80% of the cases and reduction of hip circumference in 67.7%. FCD, DPD, and CD did not change significantly after treatment. Smoking as well as alcohol consumption and regular physical activity were not significantly related to the centimetrical reduction observed in treated thighs and hips.

J Cosmet Dermatol. 2007 Jun;6(2):102-7