Bays Adisopathy

10.1517/14796678.1.1.39 © 2004 Future Medicine Ltd ISSN 1479-6678 Future Cardiology (2005) 1(1), 39–59 39

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Adiposopathy: sick fat causes high blood sugar, high blood pressure and dyslipidemiaHarold Bays MD, FACP†,Nicola Abate MD,Manisha Chandalia MD

†Author for correspondence Medical Director/PresidentL-MARC Research CenterLouisville KY, [email protected]

Keywords: adipose autodysharmonia, adiposopathy, diabetes, Food and Drug Administration, hypertension, obesity metabolic cycle, metabolic syndrome, obesity, regulatory

Adiposopathy is defined as pathological adipose tissue function that may be promoted and exacerbated by fat accumulation (adiposity) and sedentary lifestyle in genetically susceptible patients. Adiposopathy is a root cause of some of the most common metabolic diseases observed in clinical practice, including Type 2 diabetes mellitus, hypertension and dyslipidemia. The most common term for the metabolic consequences of adiposopathy is currently ‘the metabolic syndrome’. Drug usage to treat the metabolic syndrome has focused on the safety and efficacy of treatments directed towards individual components of the metabolic syndrome, and not so much upon adiposopathy itself. However, enough is known about the pathophysiology of adiposopathy to propose diagnostic criteria. Regulatory issues are important obstacles to the research and development of new drug treatments for the metabolic syndrome. It is hoped that these obstacles can, to some extent, be addressed and overcome by clearly defining and increasing our understanding of adiposopathy.

It is well known amongst clinicians thatgenetically predisposed patients who acquireexcess body fat and maintain a sedentary lifestyleare at increased risk of developing a number ofdisease states [1], many which constitute impor-tant atherosclerotic coronary heart disease (CHD)risk factors that may lead to CHD events(Figure 1). Among the more common metabolicdisorders often associated with excessive body fatare abnormalities of glucose metabolism (such asdiabetes mellitus), hypertension and dyslipidemia.However, the relationship between excessive bodyfat and adverse metabolic consequences is notabsolute. Obesity alone does not always result inclinical metabolic disease, and not all patientswith these metabolic diseases are overweight.Recent and ongoing research into adipose func-tion and dysfunction seem to be confirming thesebasic and common clinical observations. Studiesare now supporting the concept that it is not thepresence of excess adipose tissue alone, adiposity,that is causally related, but rather it is the dysfunc-tion of adipose tissue, here termed ‘adiposopathy’,that should be identified as the root mechanisticetiology of disorders of glucose metabolism, bloodpressure and lipid metabolism. The implicationsof this alteration in emphasis is certainly of signif-icance for mechanistic research, and is also of greatpractical significance for the clinician.

Adiposopathy: replacing the term ‘metabolic syndrome’Many authors and scientific organizations havecharacterized and applied terminology to theconstellation of metabolic abnormalities often

associated with the accumulation of excessivebody fat. Unfortunately, not everyone agrees onany particular characterization, nor do theyalways agree upon the definition.

For example, the most common current termthat refers to the cluster of metabolicabnormalities associated with disorders in glucosemetabolism, hypertension and dyslipidemia is the‘metabolic syndrome’. A similar clinical presenta-tion has also been termed atherothrombogenicsyndrome, beer-belly syndrome, cardiovascularmetabolic syndrome, chronic cardiovascular riskfactor clustering syndrome, deadly quartet (obes-ity, hyperinsulinemia, hypertension and dyslipi-demia), disharmonious quartet, dysmetabolicsyndrome, dysmetabolic syndrome X, insulinresistance syndrome, insulin resistance-dyslipi-demia syndrome, metabolic cardiovascular syn-drome, metabolic syndrome, metabolic syndromeX, multiple metabolic syndrome, plurimetabolicsyndrome, Reaven’s syndrome, and syndrome X[2–4]. The variety of different terms for a similar orrelated condition reflects the difficulty in applyingone name to a constellation of related, and some-times unrelated metabolic abnormalities, andreflects an unsatisfying attempt to identify oneroot pathophysiologic cause of all of these.

Futher complicating the matter is that differ-ing organizations have different definitions forthe same condition. The National CholesterolEducation Program, Adult Treatment Panel III(NCEP ATP III) [5] and the World HealthOrganization (WHO) [6] have established themost widely used definitions of the metabolicsyndrome (Table 1). The criteria differ in many

REVIEW – Bays, Abate & Chandalia

40 Future Cardiology (2005) 1(1)

respects; for example, while waist circumferenceis a criteria included in the NCEP ATP III defi-nition, waist:hip ratio or body mass index (BMI)ratio is used in the WHO definition. The NCEPATP III definition does not include glucoseintolerance or insulin resistance, while these areimportant criteria in the WHO definition. TheNCEP ATP III does not include albuminuria,while this is a criteria recommended by WHO.

The differing nomenclature and criteria fordiagnosis is not without consequence. Obesity isthe most common metabolic disease indeveloped nations. According to the WHO, over1 billion adults are overweight on a worldwide

basis, with at least 300 million being obese [101].In the USA, the unabated epidemic of obesity isnow such that over 30% of adults are obese andover 60% of adults are either overweight or obese[7]. Of equal concern is that the high prevalenceof obesity among children and adolescents con-tinues to increase – a trend that suggests that theobesity epidemic will continue to increase in thefuture [8]. Largely as a consequence of the obesityepidemic, the increased prevalence of the meta-bolic syndrome might also be considered anepidemic in that it has been estimated that atleast 47 million adults (22% of the population)in the USA are affected [9].

Figure 1. Adiposity and adiposopathy in the development of atherosclerotic coronary artery disease [2].

§Short-term release of free fatty acids (FFAs) may increase pancreatic insulin release. Chronic, long-term FFA exposure may result in decreased

insulin secretion.

Positive caloric balance

Genetic predisposition

Sedentary lifestyle

Adiposity and adiposopathy

Increased release of FFARelease of adipocyte hormones, adipokines, and other factorsInsulin resistance:

(1) Skeletal muscle(genetically predisposed)

Insulin resistance:

(2) Liver(genetically predisposed)

(3) Pancreatic β-cells(genetically predisposed)

Hyperglycemia Hyperglycemia

Hyperglycemiadyslipidemia

Decreased release of insulin§:

Lumen

Damaged vesselAtherosclerotic plaque

Vascular damage

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Adiposopathy – REVIEW

Given the enormity of this disease burden andthe known public health consequences, it wouldseem reasonable that extraordinary efforts bemade towards preventing, treating, and poten-tially curing the metabolic syndrome. However,the conduct and reporting of clinical trials todemonstrate efficacy in the treatment of the

metabolic syndrome have been hampered by thelack of consistent terminology, the lack ofuniform diagnostic definitions and the differentcriteria reported in different clinical studies. Forexample, in recognition that increased body fat isoften directly related to the development of themetabolic syndrome, investigators have oftensubstituted BMI for measurement of waist cir-cumference, which is a listed criteria accordingto the NCEP ATP. Sometimes, the substitutioncutoff value has been greater than 30 kg/m2,while at other times greater than 25 kg/m2 hasbeen used [2]. This is because from a practicalstandpoint, BMI is routinely obtained in clinicaltrials, while waist circumference is not.

Further complicating the matter is that not allclinicians are clear on the similarities anddifferences between the metabolic syndrome andother associated conditions. Not all clinicians areaware that patients with Type 2 diabetes may ormay not have metabolic syndrome, and patientswith metabolic syndrome may or may not havediabetes. Moreover, even researchers are not cer-tain whether insulin resistance syndrome andmetabolic syndrome are the same, or have thesame treatment goals [3].

In addition, the criteria to define themetabolic syndrome is largely based onepidemiological and cross-sectional observationsmainly obtained in European descent popula-tion, and were subsequently generalized to vari-ous ethnic groups. Subsequent studies haverevealed that aspects of the metabolic syndromeprofoundly differ among ethnic groups. Evenwithin the European descent populations, thereare additional features of the metabolic syn-drome that could be a better predictor of risk ofmetabolic and CHD risk.

It is also noteworthy that the scientificorganizations that have defined metabolicsyndrome have not required that the componentsof the metabolic syndrome be due to any unifyingand underlying metabolic process. Yet an increasein abdominal girth, hypertriglyceridemia, lowhigh-density lipoprotein cholesterol (HDL-C)levels, high blood pressure and elevated glucosecan all individually be the result of diseases andconditions that are entirely unrelated to oneanother, and thus not reasonably be connected toany one causality or syndrome. This may help toexplain why the diagnosis of the metabolic syn-drome may not be a predictor of 11 year CHDmortality among patients with Type 2 diabetesmellitus, and its diagnosis may not provide furtherpredictive value compared with knowledge of its

Table 1. Comparison of NCEP ATP III and WHO criteria for Metabolic Syndrome.

NCEP ATP III

Three or more of the following must be present:

Waist circumference§ MenWomen

> 102 cm (>40 inches)> 88 cm (>35 inches)

Plasma TG Men/women ≥ 1.7 mmol/L (≥ 150 mg/dL)

Plasma HDL cholesterol MenWomen

< 1.0 mmol/L (< 40 mg/dL)< 1.3 mmol/L (<50 mg/dL)

Blood pressure Men/women ≥ 130/≥ 85 mmHg

Fasting blood glucose Men/women ≥ 6.1 mmol/L (≥ 110 mg/dL)

WHO§§

At least one of the following must be present:

Impaired fasting glycemia

Men/women ≥ 6.1 mmol/L (≥ 110 mg/dL) and < 7.0 mmol/L (< 126 mg/dL)

Impaired glucose tolerance

FastingPost-load

< 7.0 mmol/L (< 126 mg/dL) and ≥ 7.8 mmol/L (≥140 mg/d:L)

Diabetes FastingPost-load

≥ 7.0 mmol/L (≥ 126 mg/dL)≥ 11.1 mmol/L (≥ 200 mg/dL)

Insulin resistance Men/women Glucose uptake below lowest quartile for background population under investigation

In addition, two or more of the following:

Arterial blood pressure Men/women ≥ 140/90 mmHg

Lipid abnormalities: Plasma TG orPlasma HDL cholesterol

Men/women

MenWomen

≥ 1.7 mmol/L (≥ 150 mg/dL)

< 0.9 mmol/L (<35 mg/dL)< 1.0 mmol/L (<39 mg/dL)

Central obesity:Waist:hip ratio

orBMI

MenWomen

Men/women

> 0.9> 0.85

> 30 kg/m2

Microabuminuria:Urinary albumin excretion rateorAlbumin:creatinine ratio

Men/women

Men/women

≥ 20 µg/min

≥ 30 mg/g§ In Asian populations, these values are commonly revised to a waist circumference in men and women of 90 cm and 80 cm, respectively.§§ See Lancet 363, 157–163 (2004) for the WHO BMI definition for Asians.BMI: Body Mass Index; HDL: High-density lipoprotein; NCEP ATP: National Cholesterol Education Program Adult Treatment Panel; TG: Triglyceride; WHO: World Health Organization. (Reprinted with permission from [2] by permission of Cambridge Medical Publications, all rights reserved).

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single components [10]. In fact, even in patientswithout diabetes mellitus, diagnosis of themetabolic syndrome appears to be inferior toestablished prediction models for either Type 2diabetes or CHD, such as the Diabetes PredictingModel and Framingham Risk Score [11].

The bottomline is that most clinicians knowfrom their clinical practice experience that selectpatients with the metabolic syndrome are at highrisk for development of atherosclerotic CHD anddiabetes mellitus. To some extent, these conse-quences are supported in the medical literature[12]. Clinicians also have the intuitive sense that along-term commitment towards treating thesemultiple metabolic risk factors improves thehealth of their patients, which is again supportedby the medical literature [13]. However, while reg-ulatory agencies such as the US Food and DrugAdministration (FDA) recognize the existence ofthe metabolic syndrome, they have yet to estab-lish criteria in order to grant an indication for itstreatment. This lack of indication criteria for thetreatment of the metabolic syndrome impairs thedevelopment of pharmaceutical agents to treat theunderlying root cause and/or pathophysiology,and instead promotes continued research effortsfocusing on drug treatment for the componentsof the metabolic syndrome. In other words, whilespecific regulatory criteria exists for grantingapproval for an indication for treatment of thecomponents of the metabolic syndrome (such asType 2 diabetes mellitus, hypertension and dysli-pidemia), no such approvable ‘indication’ criteriaexists for treatment of the metabolic syndromeitself, that often reflects underlying metabolicprocesses that may promote these conditions.

Accumulating scientific data suggest that inmost patients, it is the dysfunction of adipose tis-sue (adiposopathy) that is the root mechanisticaetiology of abnormalities of glucose metabolism,blood pressure and lipid metabolism (Figure 1).These scientific data are substantiated by the com-mon clinical observation that many patients whogain weight develop these metabolic abnormali-ties, and if these same patients subsequently loseweight, then these metabolic abnormalitiesimprove or may potentially resolve. If it becomesgenerally accepted that dysfunction of adipose tis-sue is the root mechanistic pathophysiologic etiol-ogy of the metabolic abnormalities that composethe metabolic syndrome in the majority ofpatients, then it may be time to replace the termmetabolic syndrome (a term largely reflective ofsometimes unrelated consequence), and replace itwith ‘adiposopathy’ (a term more focused on

unified underlying causality). It may then be timeto focus on adiposopathy as a primary treatmenttarget, and to establish clear criteria for its diagno-sis, and for granting an indication for its treat-ment. It may be time to acknowledge thatadiposopathy is not only a disease, but a geneticdisease state of a specific organ that:

• Can be worsened by poor dietary and lifestylehabits, concurrent diseases, and perhaps cer-tain drugs, such as corticoid steroids and somepsychotropic drugs [1];

• A disease that leads to significant morbidityand mortality;

• A disease that can be improved with favorabledietary and lifestyle habits and pharmaceuticalagents; and

• A disease whose correction will decreasemorbidity and mortality

Subsequently, clinical trials can be betterdesigned and directed towards establishing amore rational direction of treatment comparedwith the current focus upon the often unrelatedcomponents of the metabolic syndrome.

Sick fat (adiposopathy) causes Type 2 diabetes mellitusOverall, only approximately 12% of US adultpatients with a BMI ≥ 27 kg/m2 have Type 2diabetes mellitus [102]. Conversely, 67% of USpatients diagnosed with Type 2 diabetes mellitushave a BMI ≥ 27 kg/m2, while 46% have a BMIgreater than 30 kg/m2 [103]. Thus, not all patientswho are overweight have Type 2 diabetes mellitus,in fact only a minority do, (Figure 2) and not allpatients with Type 2 diabetes mellitus are over-weight, although the majority are. Therefore,while excessive body fat clearly increases the risk ofType 2 diabetes mellitus, excess body fat alone isnot sufficient towards development of Type 2 dia-betes mellitus.

Admittedly, adiposopathy is not the onlycause of Type 2 diabetes mellitus. Other causeswould include metabolic disorders that affectpancreatic function, such as some cases of hemo-chromatosis and chronic pancreatitis. Knownmetabolic abnormalities that might directly pro-mote insulin resistance include hypercortisolism,excessive growth hormone and hyperthyroidism.Furthermore, certain populations exist that mayhave an inherent decrease in pancreatic function.

However, for the majority of patients it isreasonable to conclude that it is the combinationof adiposity, genetic predisposition and perhaps asedentary lifestyle that leads to fat dysfunction,



and it is this adiposopathy that results in Type 2diabetes mellitus (Figure 1).

While in the past adipose tissue was thoughtto mainly function as an inert storage organ,adipose tissue is now known to be a very activeorgan from many metabolic standpoints (Table 2)

[14]. Several fat-derived metabolites, hormones,enzymes, cytokines and other factors may havevarying degrees of effects upon the activity ofinsulin, including the induction of insulinresistance (Table 3) [15,16].

One of the most well-described consequencesof adiposopathy, if not one of the most well-described results of abnormal fat function, is theabnormal increase in the fasting and postpran-dial release of nonesterified or free fatty acids(FFAs) [15]. Short-term (2 to 6 h) elevations inFFA levels may enhance insulin secretion.However, longer term FFA exposure is detrimen-tal, and may result in insulin resistance in theliver and muscle, as well as diminishedpancreatic β-cell insulin production – which hassometimes been termed ‘lipotoxicity’ [15]. The

excessive release of FFA from fat cells appears tobe more prevalent in patients geneticallypredisposed to development of Type 2 diabetesmellitus, and a reduction in FFA levels has beenshown to improve insulin activity [15].

In addition to the abnormal release of FFA,adiposopathy is also manifest by the abnormalrelease of cytokines and other factors that con-tribute to diminished insulin activity (Table 3).Finally, adiposopathy often appears to be mani-fested by not only abnormalities in fat function,but also abnormalities in fat distribution.Patients with visceral, upper body fat (android)distribution tend to have more insulin resistanceand hyperinsulinemia compared with those withmore lower body fat (gynoid) [15]. In fact, itmight be argued that the accumulation of vis-ceral and subcutaneous truncal fat reflects a dys-functional adipose organ, and is a grossanatomical manifestation of adiposopathy.

Just as there is great variance in thefunctionality and dysfunctionality of adiposetissue, there is also variance in the distribution of

Figure 2. Prevalence of common weight-related metabolic diseases based uponbody mass index [102,104].

§ Tested fasting plasma glucose of equal to or greater than 126 mg/dl or self-reported as having responded positively to "Have you ever been told by a doctor that you have diabetes or sugar diabetes?" Excludes gestational and Type 1 diabetes.§§ Tested BP of equal to or greater than 140 mmHg systolic or 90 mmHg diastolic or selfreported as having responded positively to "Have you ever been told by a doctor or health professional that you had hypertension, also called high blood pressure?"§§§ Tested total cholesterol of 240 mg/dl or self-reported as having responded positively to "Have you ever been told by a doctor or health professional that your blood cholesterol level was high?"BMI: Body mass index.(Reprinted with permission from [2] by permission of Cambridge Medical Publications, all

rights reserved).

Type 2 diabetes§ Hypertension§§ Hypercholesterolemia§§§

0

10

20

30

40

50

60

% o

f ad

ult

s by

BM

I cat

ego

ry

BMI (kg/m2)

18.5–24.9 25.0–26.9 27.0–29.9 30.0–34.9 35§§

Comorbidities increase with increasing BMI



body fat among individuals and populations, andadipose tissue function and distribution are

related. For example, some obese patients aremetabolically healthy, and have beencharacterized as ‘metabolically healthy, but obese’(MHO). [17]. These obese patients appear to be‘protected’ or ‘resistant’ [17] to the typicalmetabolic consequences often associated withexcess body fat. It has been suggested that MHOis not an unusual presentation, accounting for asmuch as 20% of the obese population [17]. Whileit may initially seem counterintuitive that somany obese patients could present with theabsence of impaired glucose intolerance, hyper-tension or dyslipidemia, one might speculate thatthose with MHO simply represent individualswho have little to no genetic predisposition toadiposopathy. In other words, irrespective of theirincreased body fat, MHO patients are likely tomaintain normally functional adipose tissue astheir fat mass increases. In fact, the additional adi-pose tissue in these individuals may provide addi-tional “healthy” fat functionality, and thusaccount for a protective effect. As such, it hasbeen suggested that weight loss in these patientsmight be ‘counterproductive’ and potentiallyharmful [17,19].

By maintaining favorable fat function andavoiding the adverse metabolic consequences ofadiposopathy, MHO patients do not develophigh blood pressure, or abnormalities of glucoseand/or lipid abnormalities. With regard to fat dis-tribution, it is interesting that MHO patientshave been shown to have less visceral fat thanobese patients with obesity-related metabolicabnormalities, such as those found with the met-abolic syndrome [17]. Thus, a significant percent-age of the general population appears not to bepredisposed to adiposopathy, irrespective of theonset of obesity. This lack of adiposopathy pre-disposition is manifested by a lack of obesity-related pathological fat dysfunction, a lack ofobesity-related high blood pressure and metabolicabnormalities of glucose and lipid metabolismand a relative lack of accumulation of visceral fat.

Another subgroup of patients that under-scores the need to focus on fat function and/ordysfunction includes those who are ‘metaboli-cally obese, but normal weight’ (MONW).These individuals are often young, ‘normal’weight individuals with premature signs of insu-lin resistance, hyperinsulinemia and dyslipi-demia [17]. It has been suggested that the fatdysfunction of these individuals correlates to anincrease in intra-abdominal, or visceral fat, andthat increased visceral fat (relative tosubcutaneous peripheral fat) is dysfunctional

Table 2. Examples of endocrine and metabolic factors released from fat cells [1,15,18].

Examples of hormones/adipokines released from adipose tissue

LeptinAdiponectin (adipoQ or adipocyte complement-related protein of 30 kDa/Acrp30)Interleukin-6Resistin (FIZZ3 or Serine/cysteine rich adipocyte-specific secretory factor/ADSF)Tumor necrosis factor

Examples of other enzymes, molecules, or factors described as being released from adipose tissue

Acylation-stimulating protein (ASP)AdipophilinAdipsinAgouti proteinAngiotensinogenApolipoprotein ECalumeninCalvasculinCholesteryl ester transfer protein (CETP)Collagen type VI alpha 3Complement factor C3EndothelinEntactin/nidogenEstrogenFasting-induced adipose factor (FIAF)Free fatty acidsGelsolinGalectin-12HaptoglobinHippocampal cholinergic neurostimulating peptide (HCNP)Insulin-like growth factor (IGF-1)LactateLipocalinsLipoprotein lipaseMacrophage inhibitory factor (MIF)MetalloproteasesMetallotioneinMonobutyrinNitric oxide synthaseOsteonectin (Secreted protein, acidic and rich in cysteine / SPARC)PerilipinsPhospho-enolpyruvate carboxykinase (PEPCK)Phospholipid transfer proteinPigment epithelium-derived factorPlasminogen activator inhibitor (PAI-1)Pref-1Protease inhibitors (such as cystatin C and colligin-1)Prostaglandins I2 & F2 prostacyclinsRetinol-binding proteinSerine protease inhibitorsStromal cell-derived factors, such as stromal cell-derived 1 precursor (SDF-1 or pre-B growth stimulating factor) Tissue factorTransforming growth factor beta (TGF-β)



and metabolically harmful [17,20,21]. It has alsobeen suggested that fat dysfunction may corre-late with subcutaneous truncal, but notsubcutaneous peripheral fat accumulation[20–23]. Thus, adiposopathy appears to be notonly associated with abnormalities in secretionof adipocyte hormones, cytokines, factors, andother molecules, but also associated with anincrease in intra-abdominal or possibly subcuta-neous truncal fat which all leads to an increasedrisk of. high blood pressure, and abnormalitiesof glucose and lipid metabolism.

Taken together, MHO and MONW patientsdemonstrate the point that it is not simply theabnormal increase in normal adipose tissue thatreliably predicts subsequent adverse metabolicconsequences of adiposopathy. Instead, it is thesufficient presence of or sufficient increase ininadequately functional or blatantly dysfunc-tional adipose tissue that is the essential,underlying pathology. Emerging from thisparadigm are two other concepts: the ‘obesitymetabolic cycle’ and ‘adipose autodysharmonia’.

As noted above, the predisposition todysfunctional adipose tissue is largely genetic, andin many cases exacerbated by adiposity and seden-tary lifestyle (Figure 1). One of the more importantconsequences of adiposopathy is the promotion ofinsulin resistance and hyperinsulinemia. In anenvironment where adipose tissue remains rela-tively sensitive to insulin (a growth factor) whileother organs such as skeletal muscle and liverbecome more and more insensitive to insulin,hyperinsulinemia may ensue, which in turn maylead to increased adipose tissue and subsequentworsening of adipose function. This worseningadiposopathy may cause yet further insulin resist-ance among other body organs. Adiposopathy,followed by insulin resistance and hyperinsuline-mia, followed by worsening adiposity and adi-posopathy, followed by even greater insulinresistance has been termed the ‘obesity metaboliccycle’ [1]. The fact that increased insulin levels mayincrease adipose tissue mass may help to explainwhy antidiabetes drugs that lower blood sugarthrough increased insulin levels may furtherincrease body weight, while antidiabetes drugsthat lower blood sugar through increasing insulinsensitivity (without increase or perhaps decrease ininsulin levels) are often associated with no weightgain, or perhaps modest weight loss [1].

Also as noted above, the location of adipositymay provide clues as to when adiposedysfunction is most likely to occur. Indeed, stud-ies of human fat depots (abdominal subcutane-ous, mesenteric and omental) have shown thateven after multiple doublings, preadipocytesretain the characteristics of the fat depots fromwhich they had originated [24]. This suggests thatsubcutaneous and visceral fat may be geneticallypredisposed to have significantly different func-tions. Thus, within the same individual, variousfat depots may exhibit functional conflicts inwhich well-functioning subcutaneous peripheralfat may be providing favorable metabolic bene-fits, while at the same time, malfunctioningsubcutaneous truncal and visceral fat may be

Table 3. Examples of adipose tissue-derived hormones, enzymes and other factors that have been associated with changes in insulin activity§ (adapted from [16]).

Factor Selected functions Associatedinsulin activity

Examples of adipocyte hormones

Leptin Signals CNS to decrease appetite/nutrient intakeSignals the CNS to increase caloric expenditureIncreases insulin sensitivity

↑

Adiponectin Increased adiponectin increases insulin sensitivityAssociated with decreased hepatic glucose production

↑

Resistin May increase insulin resistance ↓

Examples of adipocyte cytokines

TNF-α Increases tissue resistance to insulin, particularly during sepsis and cancer

↓

IL-6 Regulates T- and B-cell functionIncreases insulin resistance

↓

Examples of other select adipocyte proteins or factors

Angiotensinogen Converted in the circulation to angiotensin II, resulting in vasoconstriction and subsequently:- May increase blood pressure- May increase insulin resistance- May decrease pancreatic insulin secretion

↓

Plasminogen activator inhibitor-1

Inhibits tissue plasminogen activatorInhibits activation of fibrinolytic cascadeMay increase the risk of thrombosisMay interfere with insulin signaling

↓ (?)

Adipsin and acylation stimulating protein

Increases clearance of circulating free fatty acids, triglyceride synthesis and glucose uptake in adipose tissue.

↑

§ These effects upon insulin activity are largely based upon animal studies, and not always definitively known to occur, nor be of significance in humans.IL: Interleukin; TNF: Tumor necrosis factor.(Reprinted from [2] by permission of Cambridge Medical Publications, all rights reserved).



inciting detrimental metabolic effects, a fracassituation that might be termed ‘adiposeautodysharmonia’.

An extreme clinical example on howdysfunction of adipose tissue may result indiabetes mellitus, even in absence of obesity, isdemonstrated in patients with lipodystrophy, adisease where lack of adipose tissue and leptindeficiency results in excessive caloric intake,increased plasma nonesterified free fatty acidsand elevated triglycerides concentrations. Inmany individuals who lack sufficient functionalfat, ‘ectopic’ fat is deposited in skeletal muscleand liver, with post-receptor defects in insulinaction at the level of skeletal muscle [26]. In otherwords, lipodystrophy is an example of how themetabolic abnormalities of fat metabolism inabsence of obesity may result in similarconsequences on glucose disposal typically seenin many obese patients.

Yet another illustrative example of howabnormal function of fat tissue (adiposopathy)results in metabolic consequences leading to an

increased predisposition to Type 2 diabetes andCHD can be found amongst Asian Indians.Many persons originating from the Indiansubcontinent manifest insulin resistance, even inthe absence of obesity [27–29]. A study of thispopulation has revealed that FFA levels are higherand insulin-mediated FFA suppression isimpaired in Asian Indian men compared withCaucasians [27]. In addition, leptin levels arehigher and adiponectin levels are lower in Asianmen compared with Caucasians [27].Furthermore, non-obese Asian Indians typicallyexhibit high levels of C-reactive protein [29]. Fromthese scientific observations, it has been proposedthat the increased genetic predisposition to adi-posopathy, coupled with increasing body fat (adi-posity), that accounts for the increased prevalenceof Type 2 diabetes mellitus and CHD in this eth-nic group [27]. Thus, this is an illustrative exampleof how adiposopathy (not necessarily adiposity)has been shown to be the root mechanistic causeof many of the same metabolic abnormalitiesfound with the metabolic syndrome in a specificethnic group. In fact, it has even been suggestedthat the metabolic syndrome may not be souncommon even among the general US popula-tion of mildly overweight adults [32]. Some esti-mate that the prevalence of the so-called MONWpatients may be as high as 13–18% [17].

Sick fat (adiposopathy) causes high blood pressureAmong overweight adult patients with a BMIbetween ≥ 25 kg/m2 and less than 30 kg/m2,22–33% have hypertension, and among patientswith BMI ≥ 30 kg/m2, greater than 40% havehypertension [103]. Conversely, the prevalence ofhypertension among adults who are not over-weight (BMI less than 25 kg/m2), is less than

Table 4. Mean plasma lipid levels at diagnosis of Type 2 diabetes in the UK Prospective Diabetes Study [25].

Men Women

Lipid variable Type 2 diabetes (n = 2139)

Nondiabetic control (n = 52)

Type 2 diabetes (n = 1574)

Nondiabetic control (n = 143)

TC mg/dL (mmol/L) 213 (5.5) 205 (5.3) 224 (5.8) 217 (5.6)

LDL-C mg/dL (mmol/L) 139 (3.6) 132 (3.4) 151 (3.9)§§ 135 (3.5)

HDL-C mg/dL (mmol/L)

39 (1.0)§ 43 (1.1) 43 (1.1)§§ 55. (1.4)

TG mg/dL (mmol/L) 159 (1.8)§§ 103 (1.2) 159 (1.8)§§ 95 (1.1)§p < 0.02; §§p < 0.001 versus control.HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; TC: Total cholesterol; TG: Triglyceride. (Reprinted from [2] by permission of Cambridge Medical Publications, all rights reserved).

Table 5. LDL subclass phenotypes in Type 2 diabetes [30,31].

LDL subclass (%)

Population n A Intermediate B

Men

DiabeticNondiabetic

2987

2847

2129

5124

Women

DiabeticNondiabetic

54543

3485

309

366

Patterns A, Intermediate and B were determined by LDL diameter measurementPattern A: larger, potentially less atherogenic particles.Patten B: small, dense, potentially more atherogenic particlesLDL: Low-density lipoprotein.(Reprinted from [2] by permission of Cambridge Medical Publications, all rights reserved).



25%, yet hypertension is still found in thesenonoverweight individuals [102,103,105]. So whileBMI is directly associated with high bloodpressure, particularly among patients less than60 years of age [33], not all patients who areoverweight have hypertension (although manydo) (Figure 2), and not all patients with hyperten-sion are overweight. Therefore, while excessivebody fat clearly increases the risk of hypertension,excess body fat alone is not sufficient towardsdevelopment of hypertension.

Admittedly, adiposopathy is not the onlycause of hypertension. Other causes wouldinclude pheochromocytoma, primaryhyperaldosteronism, hypercortisolism, hyperthy-roidism, renal artery stenosis and various kidneydiseases. Furthermore, certain familial or geneticsyndromes exists that strongly predisposeindividuals to hypertension.

However, the majority of patients (> 90%)with high blood pressure have what is called‘essential hypertension’. Adiposity is perhaps the

greatest risk factor for essential hypertension.Excessive body fat may lead to promoters ofincreased blood pressure, such as fat cellsecretory products that result in increasemineralocorticoid release [34], and effects uponthe renin–angotensin system (Table 2), andsympathetic nervous system, all which representadipose dysfunction (adiposopathy). Further-more, independent of adipose function or dys-function, excess body fat may physicallycompress the kidney and increase the incidenceof sleep apnea associated with obesity – whichalso may increase the risk of hypertension.

Sick fat (adiposopathy) causes dyslipidemiaAmong US adult patients with a BMI between≥ 25 kg/m2 and 30 kg/m2, 19–30% havehypercholesterolemia (≥ 240 mg/dl). Amongpatients with a BMI > 30 kg/m2, greater than20–30% have hypercholesterolemia [103,105].Conversely, among US adults who are not over-weight (BMI < 25 kg/m2), less than 25% havehypercholesterolemia, although hypercholestero-lemia is still present in these nonoverweight indi-viduals [102,103,105]. So while BMI is directlyassociated with dyslipidemia, particularly amongpatients less than 60 years of age [33], not allpatients who are overweight have hypercholeste-rolemia, although many do (Figure 2), and not allpatients with hypercholesterolemia are over-weight. Therefore, while excessive body fatincreases the risk of hypercholesterolemia, excessbody fat alone is not sufficient towards develop-ment of hypercholesterolemia. Furthermore,while there does appear to be a linear relation-ship between adiposity and blood pressure, glu-cose levels and waist circumference (with aninverse linear relationship with HDL-C levels),this relationship appears to peak within a BMIrange of 30–40 kg/m2 for alipoprotein B, lowdensity lipoprotein cholesterol (LDL-C) andtriglycerides, with subsequent decreased levelswith increasing obesity. This suggests that mor-bidly obese patients may have some lipid riskprofiles more favorable than less obese patients[35], and again underscores the complexity of therelationship of adiposity with fat function.

Admittedly, adiposopathy is not the only causeof dyslipidemia. Other secondary causes wouldinclude hypothyroidism, diabetes mellitus andcertain types of liver or kidney diseases.Furthermore, specific genetic abnormalities maybe present, such as familial hypercholesterolemia,which is due to defective or absent LDL particle

Table 6. The atherogenic effect of diabetes dyslipidemia.

Potential atherogenic effects of small dense LDL:• Increased susceptibility of LDL particles to undergo oxidation• Increased permeability of arterial endothelia to LDL particles• Conformational change in apolipoprotein B in small, dense LDL particles

leading to decreased affinity for LDL receptor.• Present in association with insulin resistance syndrome• Present in association with high TG and low HDL cholesterol

Abnormalities associated with elevated TG levels and thus potential for increased CHD risk:• Accumulation of lipoprotein (chylomicron and VLDL) remnants• Association with presence of small, dense LDL particles• Association with presence of low HDL cholesterol levels• Increased risk of thrombosis coagulability:- Increased PAI-1- Increased Factor VIIc- Activation of prothrombin to thrombin

Abnormalities associated with low HDL cholesterol levels and potential for increased CHD risk:• Reduction of direct antioxidant/anti-inflammatory effects on the vessel

wall via impaired HDL-mediated:- Stabilization of prostacyclin production and/or prolongation of prostacyclin half-life.- Decrease in endothelial expression of cell adhesion molecules in response to cytokines and otherwise restoration of endothelial dysfunction.• Reduced endothelial nitric oxide production and reduce antiplatelet and

anticoagulant effects• Reduced peripheral cholesterol transport/flux.

CHD: Coronary heart disease; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; PAI-1: Plasminogen activator inhibitor-1; TG: Triglyceride.VLDL: Very-low-density lipoprotein.(Reproduced from [2] by permission of Cambridge Medical Publications, all rights reserved and adapted with kind permission from Baylor College of Medicine, Houston, TX, USA [106]).



receptors, and results in severehypercholesterolemia irrespective of body fat.

Although hypercholesterolemia may beassociated with adiposity, the type ofdyslipidemia most associated with the metabolicsyndrome and Type 2 diabetes mellitus is fastinghypertriglyceridemia, low HDL-C levels (Table 4),and abnormalities of lipoprotein particle size andsubclass distribution (Table 5) [2,36]. Figure 3 illus-trates how adiposopathy may lead to increasedFFA release, fatty liver, and then to fasting hyper-triglyceridemia as the result of increased very-low-density lipoprotein (VLDL) particle produc-tion. The subsequent exchange of cholesterolwith triglycerides between VLDL and HDL par-ticles through cholesteryl ester transfer protein, aswell as LDL particles, results in triglyceride-richHDL and LDL particles. This process also leadsto cholesterol-rich VLDL and IDL-atherogenicremnant particles. Once the triglyceride-rich

HDL particles undergo lipolysis through variouslipases, the HDL particle becomes smaller andmore dense, leading to increased renal clearanceand decreased HDL blood levels; this is associ-ated with an increased risk of CHD. Once thetriglyceride-rich LDL particles undergo lipolysisthrough various lipases, the LDL particlebecomes more small and dense, leading to what istermed ‘pattern B’; this is also associated with anincrease risk of risk of CHD (Table 6).

Thus, it is reasonable to conclude that it is thecombination of adiposity, genetic predisposition,and perhaps sedentary lifestyle that leads to fatdysfunction, and it is this adiposopathy thatresults in an atherogenic dyslipidemia [39].

Adiposopathy: treatmentsCurrent treatments for adiposopathy includethose that treat obesity (as it is obesity that oftenexacerbates the root cause of the metabolic

Figure 3. Fasting atherogenic lipid profile associated with metabolic syndrome and Type 2 diabetes mellitus (elevated TG, decreased HDL-C and increased prevalence of small dense LDL particles).

Adapted from [37]. This figure does not depict the important contribution of postprandial hypertriglyceridemia, which often occurs in these same patients wherein elevated postprandial chylomicrons (from the intestine) may also contribute to hypertriglyceridemia, the atherogenic lipid profile described above, and the creation of chylomicron remnant particles, which may be significantly atherogenic [38].

TG

Smalldense LDL

↑ FFA

Adiposopathy

CETP

CETP

CholesterolCholesterol

CholesterolCholesterol

TGTG

TG

Lipases

Lipases

HDL

VLDL

LDLLDL

Renal clearance

Fatty liver

TG

Smalldense HDL

TG



syndrome) and those that treat the metabolicconsequences, such as drug treatments for Type 2diabetes mellitus, hypertension and dyslipidemia.

Antiobesity agents Adiposity, along with sedentary lifestyle ingenetically susceptible individuals, leads toworsening adiposopathy. It has been theorizedthat enlargement of fat cells alone might largelyaccount for fat cell dysfunction [15]. In fact, it isthe enlargement of fat cells that best correlateswith insulin resistance as compared with othermeasures of adiposity, and enlarged fat cells are astrong, independent predictor of the develop-ment of Type 2 diabetes mellitus [15]. Currentantiobesity agents such as orlistat (Xenical®) andsibutramine (Reductil®, Merida®) have bothbeen shown to reduce body weight and alsoimprove many metabolic abnormalities of glu-cose and lipid metabolism that are otherwiseassociated with increased CHD risk [1]. Thisillustrates an important principle that: ‘the devel-opment of any effective antiobesity agent mustnot only reduce fat mass (adiposity), but mustalso correct fat dysfunction (adiposopathy) inorder to maximize metabolic health’ [1]. Someinvestigational antiobesity agents indevelopment have already demonstrated reduc-tion in the incidence of the metabolic syndrome[1]. In order to gain approval for clinical use,other antiobesity agents in development willlikely have to demonstrate similar improvementsin metabolic function.

Antidiabetes drugs Antidiabetes drugs may also improve glucosemetabolism, and thus improve thehyperglycemia consequence of adiposopathy.

Current antidiabetes agents have little impactupon blood pressure, and varying effects uponlipid levels (Table 7) [40]. It is with special interestthat some antidiabetes agents may improve fatdifferentiation and function, while at the sametime, paradoxically increase body weight.Through a large number of DNA microarrays, ithas been shown that large differences existbetween lean and obese mice in expression ofgenes. Specifically, the expression of many genesnormally associated with adipocyte differentia-tion appeared to be downregulated with obesity[41]. Recruitment of functional fat cells throughdifferentiation is one potential treatment optiontowards improving glucose metabolism throughimproved fat function and reduction of themetabolic consequences of adiposopathy.

Peroxisome proliferator-activated receptor(PPAR) γ agonists [16], such as thiazolidinediones(TZDs), represent antidiabetes agents thatimprove glycemic control, enhance hepatic andmuscle insulin sensitivity, and improve β-cellfunction. TZDs are associated with weight gaindirectly proportional to the reduction in hemo-globin A1c (HbA1c) [15]. Additionally, obeseindividuals appear to respond better to TZDsthan lean subjects. This may be attributable tothe fact that PPARγ is a critical transcription fac-tor in the differentiation of preadipocytes intoadipocytes [42]. Thus, by recruiting morefunctional fat cells, TZDs cause a markedreduction in plasma FFA concentration andinhibit lipolysis in patients with Type 2 diabetesmellitus [15]. TZDs may also:• Inhibit the expression of the leptin gene in adi-

pocytes with a decline in leptin levels;• Improve fat distribution with a decrease in

intra-abdominal fat;

Table 7. Effects of antidiabetes agents upon lipid levels.

Treatment Triglycerides High-density lipoprotein cholesterol

Low-density particle size

Low-density particle number

Lifestyle changes Potential decrease Potential increase Potential decrease Potential decrease

Insulin secretagogues No change No change No change No change

Metformin Inconsistent; occasionally decreased

Inconsistent; occasionally increased

No change or minimal increase

No change or minimal decrease

α-Glucosidase inhibitors

No change No change No change No change

Thiazolidinediones No change with rosiglitazone; 15–20% decrease with pioglitazone

5–10% increase Probable to substantial increase

5% increase with rosiglitazone; no change with pioglitazone

Insulin Decrease No change Probable increase No change

(Reproduced from [16,40]).



• Decrease hepatic fat content associated with animprovement in hepatic insulin sensitivity; and

• Decrease in intracellular concentration ofmetabolites of muscle triglycerides that best

predicts the improvement in muscle sensitivityto insulin.

Although some of the weight gain associated withTZDs is due to an increase in fluid retention, it is

Table 8. Prevention trials of lipid-altering therapy including patients with diabetes.

Trial Diabetic number

Total number in study

Lipid-altering drug (mg/day)

CHD risk versus placebo in diabetic patients (%)

Primary prevention

CARDS* 2838 2838 Atorvastatin 10 -37 (p = 0.001)

AFCAPS 155§ 6605 Lovastatin 40‡ -44 (p = NS)

HPS 2912 7150 Simvastatin 40 -33 (p = 0.0003)

ASCOT 2532 10,305 Atorvastatin 10 -16 (p = NS)

PROSPER 623 5804 Pravastatin 40 +27 (p = NS)

HHS 135 4081 Gemfibrozil 1200 -68 (p = NS)

Secondary prevention

4SRe-analysis¶

202483

4444 Simvastatin 20–40 -55 (p = 0.002)-42(p = 0.001)

CARE 586 4159 Pravastatin 40 -25 (p = 0.05)

LIPID** 1077 9014 Pravastatin 40 -19 (p = NS)

LIPS 202 1677 Fluvastatin 80 -47 (p = 0.04)

HPS 3051 13,386 Simvastatin 40 -18 (p = 0.002)

4D§§ 1255 1255 Atorvastatin 20 -8 (p = NS)

VA-HIT‡‡ 769 2351 Gemifbrozil 1200 -32 (p0.004)

DAIS§§ 418 418 Fenofibrate 200 -23 (p = NS)

Diabetes trials in progress

FIELD 9795 9795 Fenofibrate 200

ASPEN 2200 2200 Atorvastatin 10

Prevention trials of lipid-altering therapy including patients with metabolic syndrome.

Primary

WOSCOPS 1691§§§ 6595 Pravastatin 40 27% Reduction in CHD risk

Secondary

4S post hoc analysis

458§§§ 4444 Simvastatin 20–40 52% reduction (p = 0.00009) in major coronary events

CDP 563§§§ 8341 Niacin 3000 9% reduction in total 5-year mortality25% reduction in risk of nonfatal myocardial infarction in metabolic syndrome patients without HDL-C criterionAn additional analysis noted that the most pronounced benefits of treatment were seen in metabolic syndrome patients with low HDL-C (< 40 mg/dl)

*CARDS was the only primary prevention trial in this group that was prospective. ‡Mean dose was 30mg. §The figure of 155 in AFCAPS/TexCAPS includes subjects with diagnosis of diabetes (n = 71 placebo and 84 drug treated). However, an alternative figure often cited is a 239 figure that

included subjects with diagnosis of diabetes mellitus or fasting glucose ≥ than 126 mg/dL (n = 113 placebo and n = 126 drug treated). ¶The 483 patients represented a re-analysis wherein diabetes was defined according to fasting glucose ≥126 mg/dl. **782 patients identified themselves as

having diabetes, with another 295 having probable undiagnosed diabetes based upon fasting glucose levels for a total of 1077. ‡‡Of the patients on this study, 627 had history of diabetes, with another 142 found to have fasting glucose levels ≥ 126 mg/dl at baseline. This gives the total of 769

patients. §§These were prospective trials, and not post hoc analysis (as were the rest of the studies in this secondary prevention group. §§§ Number of patients with the metabolic syndrome). NS: Not significant(Reprinted from [2] by permission of Cambridge Medical Publications, all rights reserved).



also true that through the successful recruitmentof preadipocytes into adipocytes, some of theresulting fat weight gain is an indicator of theefficacy of the TZD. Other indicators ofimprovement in adiposopathy with the creationof ‘healthier’ fat with TZDs are:

• The reduction in FFA levels;

• Inhibition of resistin, tumor necrosis factor,and plasminogen activator inhibitor (PAI)-1gene expression in adipocytes and reductionin their circulating levels;

• Stimulation of adiponectin gene expression inadipocytes and increase in adiponectin levels;

• Improvement in pancreatic β-cell functionwith a reduction in islet fat content and pres-ervation of islet cell histology and β-cell mass.

In addition to TZDs, investigationalantidiabetes drugs are in development, such asdual PPAR α/γ agents (e.g., tezaglitazar, muragl-itazar) [16,43,44] that likewise, have actions uponmolecular targets with the potential to improveglucose metabolism, improve dyslipidemia,reduce ‘lipotoxicity’, and generally improveadiposopathy [16,50].

Antihypertensive drugs Antihypertensive drugs have been shown toreduce CHD events in patients with diabetesmellitus, as well as reduction in other

complications of diabetes mellitus [51], with thebest choice of first agents being those that mightimprove endothelial dysfunction (such as withangiotensin-converting enzyme inhibitors andaldosterone receptor antagonists), followed by theliberal use of addition antihypertensive agents inorder to maximize blood pressure control [52].

Lipid-altering drugsLipid-altering drugs are also one of the few drugtreatments that have been shown to reduce CHDoutcomes in patients with glucose abnormalities[16] (Table 8). Thus, lipid-altering drugs will con-tinue to be recommended for high risk metabolicsyndrome patients [5], and will continue to be animportant treatment option to reduce CHDevents in patients with adiposopathy.

ConclusionAbnormal fat function, termed adiposopathy, is amajor contributing factor in the development ofthe most common metabolic diseases encounteredin the clinical practice of medicine. Through abetter understanding of the pathophysiology, andthrough established criteria for its diagnosis, thetreatment of adiposopathy holds promise for thereduction in morbidities and mortality – particu-larly through a reduction in CHD, and a reduc-tion in the presence or onset of Type 2 diabetesmellitus, hypertension and dyslipidemia.

Table 9. Regulatory considerations for granting approval of a treatment indication for a new metabolic drug [45].General principles for approval of a new drug• Must have reasonable clinical trial data conducted through adequate and applicable methods that

demonstrate the drug is safe and effective under the conditions of use when prescribed, recommended or suggested in the proposed labeling.

Specific principles for metabolic drugs• Although in most cases, no minimum level of efficacy is established for approval of metabolic drug

treatments [45,46], in general, these drugs usually require certain objective minimum improvement in target metabolic parameters as weighed against potential risk.

• Approved antihypertensive drugs have generally achieved > 4–5 mm/Hg reduction in blood pressure [47,48].

• Approved antidiabetes drugs have generally achieved at least about a 1% reduction in hemoglobin A1c.

• Approved systemic lipid-altering drugs must generally achieve an LDL-C lowering of at least 15%, and perhaps lower (12%) for non-systemic lipid-altering drugs [45].

• Approved anti-obesity drugs must generally achieve mean placebo-subtracted weight loss ≥ 5% at the end of 1 year, with the proportion of subjects who lose ≥ 5% of baseline body weight is greater in drug- vs placebo-treated group [49].

• The mechanism of action and known experience of the metabolic drug must be scientifically and reasonably expected to improve patient outcomes, and in cases of new drugs with novel mechanisms of action, demonstrate at least surrogate outcome benefits irrespective of the efficacy on the metabolic treatment target. For example, a novel HDL-raising drug would require at least ≥ 2 different imaging modalities to obtain an initial approved indication for HDL-raising, possibly with postapproval confirmatory clinical endpoint studies.



Adiposopathy: future perspectives & regulatory considerationsWhile regulatory indications exist for treatmentof the components of metabolic syndrome (e.g.,diabetes mellitus, hypertension, anddyslipidemia), an indication for the treatment ofthe metabolic syndrome itself remains elusive.The approval of drugs for treatment ofadiposopathy and the metabolic syndromepresent special challenges. No clinical trial hasdemonstrated patient outcomes that benefit froma single drug which improves multiple CHD risk

factors, and thus regulatory agencies have notfound global risk factor reduction as anacceptable criterion to grant drug approval,labeling or promotion [45]. Examples of suggestedregulatory criteria that must be met in order togrant approval of a specific indication for a newdrug are listed in Table 9.

As can be seen from this table, other metabolicdisease drugs (such as antihypertensive drugs, anti-diabetes agents and lipid-altering drugs), havefairly clear criteria to obtain an approvableindication. The main reason as to why these drug

Table 10. The 1982 revised criteria for classification of systemic lupus erythmatosis.

Criterion§ definition1. Malar rash a) Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds2. Discoid rash a) Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions3. Photosensitivity a) Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation4. Oral ulcers a) Oral or nasopharyngeal ulceration, usually painless, observed by physician5. Arthritis a) Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion6. Serositis

a) Pleuritis convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion orb) Pericarditis documented by ECG or rub or evidence of pericardial effusion

7. Renal disordera) Persistent proteinuria > 0.5 g/day or > 3+ if quantitation not performed orb) Cellular casts may be red cell, hemoglobin, granular, tubular, or mixed

8. Neurologic disordera) Seizures in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance orb) Psychosis in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance

9. Hematologic disordera) Hemolytic anemia with reticulocytosis orb) Leukopenia < 4000/mm3 total on 2 or more occasions orc) Lymphopenia < 1500/mm3 on 2 or more occasions ord) Thrombocytopenia < 100,000/mm3 in the absence of offending drugs

10. Immunologic disordera) Positive LE cell preparation orb) Anti-DNA: antibody to native DNA in abnormal titer orc) Anti-Sm: presence of antibody to Sm nuclear antigen ord) False positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test

11. Antinuclear antibody a) An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any

point in time and in the absence of drugs known to be associated with "drug-induced lupus" syndrome

§The classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person shall be said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation [53].



treatments have specific criteria and metabolicsyndrome drugs do not, is because currently, themetabolic syndrome is not itself a treatment target.As a result, the FDA does not recognize ‘a single,universal, measurable, and directly treatable rootpathogenic mechanism underlying the syndrome

that would establish the metabolic syndrome perse, as a specific treatment target’ [45]. However, ifadiposopathy becomes accepted as a directly meas-urable and treatable root pathogenic mechanismfor the vast majority of patients with the metabolicsyndrome, this opens the possibility of guidance

Table 11. Proposed diagnostic criteria for the diagnosis of adiposopathy.Criterion§ definitionMajor criteria1. Adiposity

• Body mass index (BMI) ≥ 30 kg/m2§§ or• Waist circumference > 102 cm (> 40 in) in men, or > 88 cm (> 35 in) in women or• Waist:hip ratio > 0.9 in men, or > 0.85 in women

2. Abnormalities in glucose metabolism• Fasting glucose blood levels ≥ 100 mg/dl (6.0 mmol/l) or• 1 h post oral 75 g glucose load glucose blood level ≥ 140 mg/dl (mmol/l) or• Use of antidiabetes drug treatment in Type 2 diabetes mellitus

3. Hypertension• Systolic blood pressure ≥ 130 mm/Hg or diastolic blood pressure ≥ 85 mg/Hg or• Use of antihypertensive drug treatment for high blood pressure

4. Dyslipidemia• Fasting triglyceride level > 150 mg/dl (>1.7 mmol/l) or• Fasting HDL-C level < 40 mg/dl (<1.0 mmol/l) in men or < 50 mg/dl (<1.3 mmol) in women or• Use of lipid-altering drug treatment for high triglycerides or low HDL-C levels

Minor criteria1. Microalbuminuria§§§

• Urinary albumin excretion rate > 20 µg/min or• Albumin:creatinine ratio ≥ 30 mg/g

2. Onset of androgenemia in women, especially with signs and symptoms of polycystic ovarian syndrome• Elevated total testosterone or DHEAS in women, and possibly an increase in prolactin levels

3. Hepatosteatosis• Otherwise unexplained elevated hepatic transaminases, possibly with hepatic imaging revealing

findings consistent with fatty liver4. Hypercoagulable state

• Otherwise unexplained thrombotic clinical event in patients with elevated BMI, with possibly an increase in plasminogen activator inhibitor (PAI-1)

5. Abnormalities of lipoprotein particle size and subclass distribution [36]

• Decreased LDL particle size with increased prevalence of "pattern B"6. Hormone abnormalities of fat cell dysfunction

• Elevated fasting insulin levels, elevated leptin levels, and or decreased adiponectin levels§§§§ or• Elevated insulin/leptin to adiponectin ratio

7. Metabolic markers of fat cell dysfunction• Elevated fasting or postprandial free fatty acid levels

8. Inflammatory markers of fat cell dysfunction• Elevated cytokine production (tumor necrosis factor and/or interleukin-6), with elevated

C-reactive protein§The presence of major and minor criteria to diagnose adiposopathy require that these findings are clinically not entirely due to etiologies other than dysfunctional adipose tissue. For example, an increase in waist circumference solely due to ascites, increase in blood sugars solely due to chronic pancreatitis, hypertension solely due to pheochromocytoma, and dyslipidemia solely due to familial dyslipidemia syndromes would not be included in the diagnostic criteria for adiposopathy. Also it should be noted that although an increase in cancer risk has been described with adiposity, and although this increase in cancer risk may be associated with adiposopathy, an increase

in cancer risk is not included in this proposed diagnostic criteria. §§BMI may not be as accurate as waste

circumference & waist:hip ratio in assessing adiposopathy at the highest weight individuals (≥ 40 kg/m2), and

possibly lower weight individuals (≤ 25 kg/m2). §§§Albuminuria might be considered a surrogate for microvascular

disease, and is a diagnostic criteria in the WHO classification of the Metabolic Syndrome. §§§§The relationship of elevated leptin levels and obesity are well-established [1]. In obese humans, adiponectin may be more consistently related to insulin sensitivity as opposed to other adipokines such as resistin, TNF-α, and IL-6 [54].



towards the research and development of drugsthat improve fat function and thus treatments forthe metabolic abnormalities associated with themetabolic syndrome.

Such an acceptance would allow scientificorganizations to first define adiposopathy.Although adiposopathy would likely have a varietyof both phenotypic and laboratory criteria fordiagnosis that would change over time, this kindof approach and diagnostic criteria is not unprece-dented. Systemic lupus erythematosis (SLE) hasboth phenotypic and serologic criteria for diagno-sis, and this classification allows more uniformconduct of clinical trials for drug treatment(Table 10). Similar guidance in the conduct of clini-cal trials of drug treatment could be achievedthrough an accepted definition of adiposopathy,that would also likely evolve over time.

So how would adiposopathy best be defined?Table 11 is a proposal for diagnostic criteria of adi-posopathy that incorporates both major andminor criteria. As with the SLE criteria describedabove, clinical, observational and serological find-ings are included in the diagnostic criteria. Onecould therefore speculate that a proposed classifi-cation of adiposopathy could be based upon anal-ogous criteria. Particularly for the purpose ofidentifying patients in clinical studies andresponse to therapy, a person could be said tohave adiposopathy if any three or more of themajor criteria, with two minor criteria equivalentto one major criteria.

But obviously, much remains to be done todetermine which criteria best select foradiposopathy, with particular attention to whichaspects of abnormal fat function lead to anincrease in CHD risk – the most common causeof mortality in patients so affected, although can-cer risk may also be increased. Furthermore, itwould be important to discover whichconsequences of adiposopathy, if appropriatelytreated with diet, physical exercise or drugs, aremost associated with a reduction in clinical mor-bidity and mortality. But clearly, a greater focus onidentifying and evaluating the treatment of fatdysfunction that often leads to the many of com-ponents of the metabolic syndrome holds promiseas a superior approach in the targeted manage-ment of patients. It would allow for a morefocused evaluation of the efficacy of interventionssuch as diet, exercise, and related pharmaceuticalagents upon a common, unifying etiology of themost common metabolic diseases of our time.

In other words, clinical trials directed atcorrecting fat dysfunction (adiposopathy) would

be easier targeted and conducted, compared withclinical trials directed at an array of abnormalitiesassociated with the metabolic syndrome. This isbecause the trials would then be focused on theunderlying root pathophysiologic cause. Onceimprovement in adiposopathy was shown toimprove patient outcomes, then pharmacologicagents might be able to obtain an indication fortreatment of adiposopathy, without necessarilyhaving to always prove more hard outcomesbenefits for each drug that is developed.

For example, the FDA does not requireoutcome data for approval of an antidiabetesagent [45]. This is because improving glucosemetabolism alone is accepted as being beneficialto patients. Thus, the approved indication of anew antidiabetes agent is most often for theimprovement in high glucose levels alone, whosepresence may be asymptomatic in many patients.Demonstration of improvement in patient out-comes is not required, such as a reduction inadverse end-organ events attributed to diabetes.Similarly, new antihypertensive drugs can obtainan approved indication for the treatment of highblood pressure alone, despite presenting noclinical symptoms in many patients. Demonstra-tion of improvement in patient outcomes is notalways required, such as proven cardiovascular orrenal outcomes benefits. Lipid-altering drugs haveoften been granted an approved indication forimprovement of lipid levels, (despite presentingno clinical symptoms in many patients), withoutproven benefits towards reduction in CHD.

Just as with the above metabolic diseases, thepresence of adiposopathy may also be largelyasymptomatic in many individuals. However

• If it was accepted that adiposopathy was the rootpathophysiologic cause of many, if not mostcases of patients who express the metabolic syn-drome (even without specific symptoms);

• If it could be shown that adiposopathy was awell-validated predictor of morbidity andmortality;

• If it can be shown and accepted thatimprovement in fat dysfunction improvespatient metabolic health (such as animprovement in, or a reduction in the onset ofType 2, high blood pressure and dyslipidemia);and

• If it could be demonstrated that correction ofadiposopathy resulted in improved patient hardoutcomes, (such as reduction in CHD events);

then it is conceivable that drugs could obtainapproval for the indication of treatment of



adiposopathy alone. Once the above wereestablished using the model of diabetes mellitus,hypertension and dyslipidemia therapies, drugswith indications for the treatment of adiposopathywould then not necessarily always require verylarge, difficult and sometimes prohibitively expen-sive CHD outcomes studies in order for theapproval to potentially benefit patients who nownumber in epidemic proportions.

While the impact upon the clinical andresearch community of such an approach wouldbe substantial, it would not necessarily be over-whelming. In a practical research example, thefuture of antiobesity agent development wouldlikely require two parallel programs: one clinicaltrial program focused upon treatment of obesityitself through fat reduction (adiposity), andanother clinical trial program focused uponimprovement in fat dysfunction (adiposopathy)(Figure 4). To a large extent, this is already beingdone. Existing antiobesity agents, such as orlistatand sibutramine, have both demonstratedimprovement in weight reduction, as well as

improvements in many metabolic parameterswith reductions in CHD risk factors [1].

It is also noteworthy that rimonabant(currently an investigational selective cannabinoid[CB]-1 receptor antiobesity antagonist [1]) hasalso essentially followed this parallel developmentprogramme approach. Rimonabant has beenshown to cause significant weight reduction after1 year, and thus was effective in reducing adipos-ity [55]. This weight loss benefit was subsequentlyfound to be extended to 2 years [56]. Rimonabanthas also been shown to improve functionalparameters associated with adiposopathy: • From an adipose tissue organ standpoint,

rimonabant decreased waist circumference(presumably resulting in less subcutaneoustruncal and visceral fat) [55,56];

• From an overall metabolic standpoint, rimona-bant increased HDL-C levels, reduced triglyc-eride levels, improved LDL particle size,improved insulin sensitivity (as determined byglucose tolerance testing and homeostasismodel assessment), and reduced C-reactive

Figure 4. Proposed parallel investigational antiobesity agent development program.

Investigational antiobesity agent

Reduction in adiposity Improvement in adiposopathy

• Mean placebo-subtracted weight loss 5% at the end of 1 year• Proportion of subjects who lose 5% of baseline body weight greater in drug- vs placebo-treated group• Sustained weight loss for at least 2 years

Improvement in adipose organ distribution• Reduction in waist circumference• Reduction in waist:hip ratio

Improvement in body metabolism• Improvement in glucose metabolism• Reduction in blood pressure• Improvement in dyslipidemia

Approval for clinical use

Improvement in adipocyte function• Reduction or lack of worsening of albuminuria• Improvement in phenotypic and biochemical findings consistent with polycystic ovarian syndrome• Reduction in liver enzymes in patients with "fatty liver"• Reduction in thrombotic risk or reduction in elevated PAI-1 levels• Improvement in lipoprotein particle size and subclass distribution• Decreased insulin levels• Decrease leptin and/or increase in adiponectinlevels, or decrease in insulin/leptin:adiponectinratio



protein levels; and • From an adipocyte standpoint, rimonabant

increased adiponectin levels, and decreased lep-tin levels [55,56].

It has been suggested that the metabolic benefits ofrimonabant may not totally be explained throughweight reduction [56], with the implication that, inaddition to its appetite suppressive effects uponthe central nervous system [1], CB-1 receptorantagonism may also have direct adipocyte activ-ity. Indeed, animal studies have found that CB-1receptors are found in adipose tissue [57]. Thisraises the possibility that the overall efficacy ofrimonabant is the result of both body weightreduction through CB-1 antagonism-inducedreduction of appetite by its central nervous systemeffects [1], and direct favorable hormonal and met-abolic changes through CB-1 antagonism directlytargeted at the adipocyte [57]. Thus, this has beenan illustrative example of a parallel antiobesitydevelopment programme that has been focusednot only on the treatment of adiposity, but also inthe treatment of adiposopathy.

AcknowledgementsHarold Bays MD, FACPThere was no outside funding/support for this review. In over adecade of clinical research, Dr Bays has served as an ClinicalInvestigator for (and has received research grants from) phar-maceutical companies such as Alteon, Aventis, Bayer, Boe-hringer Ingelheim, Boehringer Mannheim, Bristol-MyersSquibb, Fujisawa, Ciba-Geigy, GelTex, Glaxo, Genetech,Hoechst Roussel, KOS, Lederle, Marion Merrell Dow, Merck,Merck Schering-Plough, Miles, Novartis, Parke-Davis, Pfizer,Purdue, Reliant, Roche, Rorer, Regeneron, Sandoz, Sankyo,Sanofi, Shering Plough, Searle, SmithKline Beacham,Takeda, TAP, UpJohn, Upsher Smith, Warner-Lambert,Wyeth-Ayerst, and AstraZenca. He has also served as a consult-ant, speaker, and/or adviser to and for pharmaceutical compa-nies such as AstraZeneca, Aventis, Bayer, Bristol-MyersSquibb, KOS, Merck, Merck Schering-Plough, Novartis,Ortho-McNeil, Parke-Davis, Pfizer, Roche, Sandoz, Sankyo,Sanofi, Shering Plough, SmithKline Beacham, Takeda,UpJohn, and Warner-Lambert. Nicola Abate MD & Mani-sha Chandalia MD Grants: NIH grants K23-RR16075;MO1-RR-00633 (NIH/DHS/DHHS); CDCH75/CCH523202; AHA 0465017Y.

Executive summary

Background• Abnormal fat function, termed adiposopathy, results in the pathological release of hormones, cytokines and molecules that cause

dysfunction of target tissues.

Adiposopathy: replacing the term ‘metabolic syndrome’• Adiposopathy is most often caused by excessive body fat, but the amount of excessive body fat that results in fat dysfunction is widely

variable among individuals, and even variable among patient populations.• Adiposopathy is a major contributing factor in the development of the most common metabolic diseases encountered in the

clinical practice of medicine – many of which are now incorporated in the term ‘metabolic syndrome’.

Sick fat (adiposopathy) causes Type 2 diabetes mellitus• Adiposopathy causes, or at least contributes to, elevated blood sugars and Type 2 diabetes mellitus in genetically

predisposed individuals.

Sick fat (adiposopathy) causes high blood pressure• Adiposopathy causes, or at least contributes to, elevated blood pressure (hypertension) in genetically predisposed individuals.

Sick fat (adiposopathy) causes dyslipidemia• Adiposopathy causes, or at least contributes to, dyslipidemia in genetically predisposed individuals.

Adiposopathy: treatments• In many cases, adiposopathy can be corrected through interventions that result in fat reduction, such as through diet, physical

exercise and antiobesity agents.• Some aspects of adiposopathy can also be improved through agents that result in increased adipose tissue, such as through

peroxisome proliferator-activated receptor (PPAR) agonists.• Through a better understanding of the pathophysiology, and through established criteria for its diagnosis, the treatment of

adiposopathy holds promise for the reduction in mortality – particularly through a reduction in coronary heart disease (CHD), and a reduction in the presence or onset of Type 2 diabetes mellitus, hypertension and dyslipidemia.

Adiposopathy: future perspectives & regulatory considerations• If its treatment can be shown to reduce CHD risk, or reduction in other hard clinical endpoints such as cancer, and/or a reduction

in subsequent morbidities (such as Type 2 diabetes mellitus, hypertension and dyslipidemia), then adiposopathy may some day become a primary treatment target.

• If regulatory agencies would grant indications for drugs to treat adiposopathy, then this would promote and accelerate research interest and investment towards improving fat function, with the end result being beneficial new treatment modalities for patients who currently have detrimental metabolic consequences of adiposity and adiposopathy.



BibliographyPapers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.1. Bays HE: Current and Investigational

AntiObesity Agents and Obesity Therapeutic Treatment Targets. Obesity Research 12(8), 1197–1211 (2004).

•• Comprehensive review of current antiobesity agents in development, and their physiological rationale. May be most interesting to those involved in antiobesity clinical trials.

2. Bays H, Shepherd J: Diabetes, Metabolic Syndrome and Dyslipidemia. Management Strategies in Diabetes. Cambridge Medical Publications. ISBN 0 904052 88 5.1–28 (2004).

3. Reaven G: The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol. Metab. Clin. North Am. 33(2), 283–303 (2004).

4. Ford ES: Prevalence of the metabolic syndrome in US populations. Endocrinol. Metab. Clin. North Am. 33(2), 333–350 (2004).

5. Third Report of the National Cholesterol Education Programme (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106, 3143–3421 (2002).

6. Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. 15, 539–553 (1998).

7. Flegal KM, Carroll MD, Ogden CL, Johnson CL: Prevalence and trends in obesity among US adults, 1999–2000. JAMA 288, 1723–1727 (2002).

8. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM: Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 291, 2847–2850 (2004).

9. Ford ES, Giles WH, Dietz WH: Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287, 356–359 (2002).

• Standard paper quantifying the epidemic of obesity

10. Bruno G, Merletti F, Biggeri A et al.: Metabolic Syndrome as a Predictor of All-Cause and Cardiovascular Mortality in Type

2 Diabetes. Diabetes Care 27, 2689–2694 (2004).

11. Stern MP, Williams K, Gonzalez-Villalpando et al.: Does the Metabolic Syndrome Improve Identification of Individuals at Risk of Type 2 Diabetes and/or Cardiovascular Disease. Diabetes Care 27, 2676–2681 (2004).

12. Isomaa B, Almgren P, Tuomi T et al.: Cardiovascular Morbidity and Mortality Associated with the Metabolic Syndrome. Diabetes Care 24, 683–689 (2001).

13. Gaede P, Vedel P, Larsen N et al.: Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. 348 (5), 383–393 (2003).

14. Fruhbeck G, Ambrosi JG, Muruzabal FJ, Burrell MA: The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am. J. Physiol. Endocrinol. Metab. 280, E827–E847 (2001).

15. Bays H, Mandarino L, DeFronzo RA. Role of the Adipocyte, FFA, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus. J. Clin. Endocrinol. Metab. 89, 463–478 (2004).

• Describes the authors’ perspective with regard to adipocyte function and dysfunction in the pathogenesis of Type 2 diabetes mellitus, with an emphasis on thiazolidinediones.

16. Bays HE, Stein EA: Pharmacotherapy for Dyslipidemia – Current Therapies and Future Agents. Expert Opin. Pharmacother. 4 (11), 1901–1938 (2003).

• Comprehensive review of lipid-altering drugs in development, and their physiological rationale. May be most interesting to those invovled in lipid-altering drug clinical trials.

17. Karelis AD, St-Pierre DH, Conus F et al.: Metabolic and Body Composition Factors in Subgroups of Obesity: What Do We Know? J. Endocrinol. Metab. 89(6),2569–2575 (2004).

•• The relationship of obesity to metabolic consequences and adipose tissue composition varies among obesity subgroups.

18. Kratchmarova I, Kalume DE, Blagoev B et al.: A Proteomic Approach for Identification of Secreted Proteins During the Differentiation of 3T3-L1 Preadipocytes to Adipocytes. Mol. Cell. Proteomics 1, 213–222 (2002).

• Using a systematic proteomic approach to purify and identify secreted factors that are differentially expressed in preadipocytes versus adipocytes, various novel secreted proteins were found.

19. Sims EA: Are there persons who are obese, but metabolically healthy? Metabolism 50(12), 1499–1504 (2001).

20. Abate N, Garg A, Peshock RM, Stray-Gundersen J, Adams-Huet B, Grundy SM: Relationship of generalized and regional adiposity to insulin sensitivity in men with NIDDM. Diabetes 45(12), 1684–1693 (1996).

21. Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM: Relationships of generalized and regional adiposity to insulin sensitivity in men. J. Clin. Invest. 96(1), 88–98 (1995).

•• Subcutaneous truncal fat plays a major role in obesity-related insulin resistance in healthy, non-diabetic men.

22. Goodpaster BH, Thaete FL, Simoneau JA, Kelley DE: Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat. Diabetes 46(10), 1579–1585 (1997).

23. Smith SR, Lovejoy JC, Greenway F et al.: Contributions of total body fat, abdominal subcutaneous adipose tissue compartments, and visceral adipose tissue to the metabolic complications of obesity. Metabolism 50(4), 425–435 (2001).

24. Tchkonia T, Pirtskhalava T, Giorgadze N et al.: Human Preadipocyte Strains Derived from Single Cells by Stably Expressing Telomerase Retain Fat Depot-Specific Characteristics. Oral Presentation. NAASO’s 2004 Annual Meeting. Volume 12. October 2004 supplements Programme Abstracts. Oral Presentation November 14–18, 2004 Las Vegas, USA.

25. UK Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 20, 1683–1687 (1997).

26. Garg A: Acquired and inherited lipodystrophies. N. Engl. J. Med. 350 (12), 1220–1234 (2004).

27. Abate N, Chandalia M, Snell PG, Grundy SM: Adipose tissue metabolites and insulin resistance in nondiabetic Asian Indian men. J. Clin. Endocrinol. Metab. 89(6), 2750–2755 (2004).

•• In absence of obesity, South Asians have changes in plasma adipokines similar to what is found in obese Caucasians.

28. Chandalia M, Abate N, Garg A, Stray-Gundersen J, Grundy SM: Relationship between generalized and upper body obesity to insulin resistance in Asian Indian men. J. Clin. Endocrinol. Metab. 84, 2329–2335, (1999).

• South Asians are more insulin resistant than Caucasians, even when not obese and with even with similar body fat distribution.



29. Chandalia M. Cabo-Chan A.V., Devaraj S., Jialal I., Grundy S.M: Elevated plasma high-sensitivity C-reactive protein concentrations in Asian Indians living in the United States. J. Clin. Endocrinol. Metab. 88, 3773–3776, (2003).

•• South Asians have increased plasma concentrations of hs-CRP even when not obese and even in the absence of type 2 diabetes mellitus.

30. Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM: LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes. Arterioscler. Thromb. 12, 1496–1502 (1992).

31. Selby JV, Austin MA, Newman B, Zhang D, Quesenberry CP Jr, Mayer EJ et al.: LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation 88, 381–387 (1993).

32. St. Onge MP, Janssen I, Heymsfield SB: Metabolic syndrome in normal-weight Americans. Diabetes Care 27, 2222–2228 (2004).

33. Brown CD, Higgins M, Donato KA et al.: Body Mass Index and the Prevalence of Hypertension and Dyslipidemia. Obes. Res. 8(9), 605–619 (2000).

34. Bornstein ME, Zepter VL, Schraven A, et al.: Human adipocytes secrete mineralocorticoid-releasing factors. Proc. Natl Acad. Sci. USA 100(24), 14211–14216 (2003).

35. Livingston E: Serum Lipids are Paradoxically Decreased with Increasing Obesity. Poster 493-P. Volume 12 October 2004 Abstracts NAASO’s 2004 Annual Meeting November 14–18 2004 Las Vegas, Nevada, USA.

• An increase in BMI does not always have a linear relationship with associated metabolic consequences normally associated with obesity.

36. Bays HE, McGovern ME: Once-Daily Niacin Extended-Release/Lovastatin Combination Tablet has More Favorable Effects on Lipoprotein Particle Size and Subclass Distribution Compared to Atorvastatin and Simvastatin. Prev. Cardiol. 6, 179–188 (2003).

37. Bays H: Niacin Extended-Release/Lovastatin: The First Combination Product for Dyslipidemia. Expert Rev. Cardiovasc. Ther. 2(4), 89–105 (2004).

38. Taskinen MR: Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 46, 733–749 (2003).

39. Bays HE: Atherogenic Dyslipidaemia in Type 2 Diabetes and Metabolic Syndrome: Current and Possible Future Treatment Options. Br. J. Diabetes Vasc. Dis. 3(5) 356–360 (2003).

40. Buse J: Lipid changes associated with diabetes therapy. Practical Diabetology 24–29 (2003).

41. Nadler ST, Stoehr JP, Schueler KL et al.: The expression of adipogenic genes is decreased in obesity and diabetes mellitus. PNAS 97(21), 11371–11376 (2000).

•• Murine study in which the expression level of over 11,000 transcripts were analyzed, demonstrating 214 transcript differences in between lean and obese mice.

42. Gregoire FM, Smas CM, Sul HS: Understanding adipocyte differentiation. Physiol. Rev. 78(3), 783–809 (1998).

43. Hegarty BD, Furler SM, Oakes N et al.: Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in vitro – A Study Using the Novel PPAR α/γ Agonist Tesaglitazar. Endocrinology 145, 3158–3164 (2004).

44. Bayes M, Rabasseda X, Prous JR: Gateway to clinical trials. Methods Find. Exp. Clin. Pharmacol. 26(7), 587–612 (2004).

45. Isaacsohn JL, Troendle AJ, Orloff DG: Regulatory issues in the approval of new drugs for diabetes mellitus, dyslipidemia, and the metabolic syndrome. Am. J. Cardiol. 93(11A), 49C–52C (2004).

•• A very important review which includes an author who is a member of the US Food and Drug Administration.

46. Fleming A: FDA approach to the regulation of drugs for diabetes. Am. Heart J. 138(5 Pt 1), S338–S345 (1999).

47. Pasquali SK, Sanders SP, Li JS: Oral antihypertensive trial design and analysis under the pediatric exclusivity provision. Am. Heart J. 144(4), 608–614 (2002).

48. Draft Consensus Document. The European Agency for the Evaluation of Medicinal Products. Evaluation of Medicines for Human Use. ICH Topic E 12 A. Principles for Clinical Evaluation of New Antihypertensive Drugs. London, 1–7, 29 June 2000.

49. Orloff DG: FDA 2004: Revisiting the 1996 Obesity Drug Guidance. PowerPoint Presentation. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2003.

50. Moller DE: New drug targets for Type 2 diabetes and the metabolic syndrome. Nature 414, 821–827 (2001).

51. Ginsberg HN. Treatment for patients with the metabolic syndrome. Am. J. Cardiol. 91(7A), 29E–39E (2003).

52. Garber AJ: The Metabolic Syndrome. Med. Clin. North Am. 88(4), 837–846 (2004).

53. Tan EM, Cohen ES, Fries JF et al.: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).

54. Shadid S, Stehouwer C, Jensen M: Evidence Against an Endocrine Role for Resistin, TNF-α and IL-6 in Upper Body Obesity. Oral Presentation. NAASO’s 2004 Annual Meeting. Volume 12. October 2004 supplements Programme Abstracts. Oral Presentation November 14–18, 2004 Las Vegas, USA.

55. Dale L, Anthenelli R, Despres J-P, Golay A, Sjostrom L: Effects of rimonabant in the reduction of major cardiovascular risk factors. Results from the STRATUS-US Trial (Smoking Cessation in Smokers Motivated to Quit) and the RIO-LIPIDS Trial (Weight Reducing and Metabolic Effects in Overweight/Obese Patients with Dyslipidemia). Late-Breaking Clinical Trials II. American College of Cardiology Scientific Session 2004, March 7–10, 2004, New Orleans, Louisiana, USA

56. Pi-Sunyer FX: Effect of rimonabant on weight reduction and weight maintenance: RIO-NORTH AMERICA (RIO-NA) trial. Late-Breaking Clinical Trials III, American Heart Association Scientific Sessions 2004, November 7–10, 2004, New Orleans, Louisiana, USA.

57. Bensaid M, Gary-Bobo M, Esclangon A et al.: The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol. Pharmacol. 63(4), 908–914 (2003).

Websites101. World Health Organization. Obesity and

overweight facts. www.who.int/hpr/NPH/docs/gs_obesity.pdf (Accessed December 2004).

102. Orlistat website www.xenical.com/hcp/2_hrod.asp Health risks of obesity. (Accessed December 2004).

103. National Institute of Diabetes & Digestive & Kidney Diseases. www.niddk.nih.gov/stastistics/index.htm. Prevalence statistics related to overweight and obesity. (Accessed December 2004)

104. National Center for Health Statistics. http://cdc.gov/nchs/products/elec_prods/subject/nhanes3.htm Third National Health and Nutrition Examination Survey (NHANES III) Public Use Data Files. (Accessed December 2004).

•• Provides striking data and facts from NHANES III regarding obesity.



105. National heart lung and blood institute. The practical guide to the identification, evaluation and treatment of overweight and obesity in adults. www.nhlbi.nih.gov/guidelines/obesity/prctgd_b.pdf (Accessed December 2004).

• Represents a consensus statement from the National Institute of Health, National Heart, Lung and Blood Institute and the North American Association for the Study of Obesity.

106. www.lipidsonline.org/(Accessed December 2004)Ginsberg, H. Diabetic Dyslipidemia and Atherosclerosis

Affiliations• Harold Bays MD, FACP

Medical Director/President, L-MARC ResearchCenter, Louisville, KY, [email protected]

• Nicola Abate MD

Associate Professor of Internal Medicine, Divisionof Endocrinology and Metabolism & Clinical

Nutrition, Director of UT Southwestern Lipid &Heart Disease Risk Management Clinic RiskManagement Clinic, Center for Human Nutri-tion, Dallas, Texas, [email protected]

• Manisha Chandalia MD

Associate Professor of Internal Medicine, Divisionof Endocrinology and Metabolism & ClinicalNutrition, UT Southwestern Lipid & Heart Dis-ease Risk Management Clinic, Risk ManagementClinic, Center for Human Nutrition, Dallas,Texas, [email protected]

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