Obesity

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Page 1 of 17http://emedicine.medscape.com/article/123702-overview

Obesity Author: Osama Hamdy, MD, PhD, FACE; Chief Editor: George T Griffing, MD more...

Updated: Sep 24, 2012

BackgroundObesity is a substantial public health crisis in the United States and in the rest of the industrialized world. Theprevalence is increasing rapidly in numerous industrialized nations worldwide. This growing rate represents apandemic that needs urgent attention if obesity’s potential toll on morbidity, mortality, and economics is to beavoided. Research into the complex physiology of obesity may aid in avoiding this impact (see the image below).(See Etiology and Epidemiology.)

Central nervous system neurocircuitry for satiety and feeding cycles.

The annual cost of managing obesity in the United States alone amounts to approximately $100 billion, of whichapproximately $52 billion are direct costs of health care. These costs amount to approximately 5.7% of all health-related expenditures in the United States. The cost of lost productivity due to obesity is approximately $3.9 billion,and another $33 billion is spent annually on weight-loss products and services. (See Treatment and Medication.)

Measurements of obesity

Obesity represents a state of excess storage of body fat. Although similar, the term overweight is puristicallydefined as an excess body weight for height. Normal healthy men have a body fat percentage of 15-20%, whilenormal healthy women have a percentage of approximately 25-30%.[1] Because differences in weight amongindividuals are only partly due to variations in body fat, body weight is a limited, although easily obtained, index ofobesity.

The body mass index (BMI), also known as the Quetelet index, is used far more commonly than body fat

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percentage to define obesity. In general, BMI is closely correlated with the degree of body fat in most settings;however, this correlation is weaker at low BMI. BMI = weight/height2, with weight being in kilograms and heightbeing in meters (the weight in pounds X 0.703/height in inches2).

The body fat percentage can be indirectly estimated by using the Deurenberg equation, as follows: body fatpercentage = 1.2(BMI) + 0.23(age) - 10.8(sex) - 5.4, with age being in years and sex being designated as 1 formales and 0 for females. This equation has a standard error of 4% and accounts for approximately 80% of thevariation in body fat.

Although the BMI is typically closely correlated with percentage body fat in a curvilinear fashion, some importantcaveats to its interpretation apply. In mesomorphic (muscular) persons, BMIs that usually indicate overweight ormild obesity may be spurious, whereas in some persons with sarcopenia (as seen in elderly individuals and inpersons of Asian descent, particularly from South Asia), a typically normal BMI may conceal underlying excessadiposity characterized by increased percentage fat mass and reduced muscle mass.

In view of these limitations, some authorities advocate a definition of obesity based on percentage body fat. Formen, a percentage of body fat greater than 25% defines obesity, with 21-25% being borderline. For women, over33% defines obesity, with 31-33% being borderline.

Other indices used to estimate the degree and distribution of obesity include the 4 standard skin thicknesses (ie,subscapular, triceps, biceps, suprailiac) and various anthropometric measures, of which waist and hipcircumferences are the most important.

Dual-energy X-ray absorptiometry (DEXA) scanning is mostly used by researchers to accurately measure bodycomposition, particularly fat mass and fat-free mass. It has an additional advantage of measuring regional fatdistribution. However, DEXA scanning cannot distinguish between subcutaneous and visceral abdominal fatdeposits. The current criterion standard techniques for measuring visceral fat volume are abdominal CT scanning(at L4-L5) and MRI techniques. These methods are limited to clinical research.

Classification of obesity

Although several classifications and definitions for degrees of obesity are accepted, the most widely acceptedclassifications are those from the World Health Organization (WHO), based on BMI. The WHO designationsinclude the following:

Grade 1 overweight (commonly and simply called overweight) - BMI of 25-29.9 kg/m2

Grade 2 overweight (commonly called obesity) - BMI of 30-39.9 kg/m2

Grade 3 overweight (commonly called severe or morbid obesity) - BMI greater than or equal to 40 kg/m2

The surgical literature often uses a different classification to recognize particularly severe obesity. The categoriesare as follows:

Severe obesity - BMI greater than 40 kg/m2

Morbid obesity - BMI of 40-50 kg/m2

Super obese - BMI greater than 50 kg/m2

The definition of obesity in children involves BMIs greater than the 85th (commonly used to define overweight) orthe 95th (commonly used to define obesity) percentile, respectively, for age-matched and sex-matched controlsubjects.

The BMI cutoff for observed risk in different Asian populations varies from 22-25 kg/m2; for high risk, it varies from26-31 kg/m2.[2]

Comorbidities associated with obesity

Obesity is associated with a host of potential comorbidities that significantly increase the potential morbidity andmortality associated with the condition. Although no cause-and-effect relationship is exhaustively demonstrated forall of these comorbidities, amelioration of these conditions after substantial weight loss suggests that obesityprobably plays an important role in their development. (See Presentation.)

Overweight and obese individuals are at increased risk for the following health conditions:

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Cardiometabolic syndromeType 2 diabetesHypertensionDyslipidemiaCoronary heart diseaseOsteoarthritisStrokeGall bladder diseaseObstructive sleep apneaGastroesophageal reflux disease (GERD)Some cancers (endometrial, breast, and colon)

Apart from total body fat mass, accumulating data suggest that regional fat distribution also substantially affectsthe incidence of comorbidities associated with obesity.[3] High abdominal fat content (including visceral and, to alesser extent, subcutaneous abdominal fat) is strongly correlated with worsened metabolic and clinicalconsequences of obesity. As a result, android obesity, which is predominantly abdominal, is more predictive ofadipose-related comorbidities than gynecoid obesity, which has a relatively peripheral (gluteal) distribution.

Waist circumferences greater than 94 cm (37 in) in men and greater than 80 cm (31.5 in) in women and waist-to-hip ratios greater than 0.95 in men and greater than 0.8 in women are the thresholds for significantly increasedpotential cardiovascular risk. Circumferences of 102 cm (40 in) in men and 88 cm (35 in) in women indicate amarkedly increased potential risk requiring urgent therapeutic intervention; these are the thresholds used in theAdult Treatment Panel III (ATPIII) definition of the metabolic syndrome. These thresholds are much lower inEuropean and Asian populations.

An elevated BMI during adolescence (within the range currently considered normal) strongly associates with therisk of developing obesity-related disorders later in life.[4] Changes in BMI during early adulthood (age 25-40 y) areassociated with a worse biomarker profile related to obesity than changes in BMI during later adulthood.[5] This isconsistent with most emerging data regarding timing of changes in BMI and later health consequences.

Apart from the metabolic complications associated with obesity, a paradigm of increased intra-abdominal pressurehas been recognized. This pressure effect is most apparent in the setting of marked obesity (BMI ≤50) and isespoused by bariatric surgeons.[6]

Given findings from bariatric surgery and animal models, this change in pressure may play a (potentially major)role in the pathogenesis of comorbidities of obesity, such as pseudotumor cerebri, lower-limb stasis, ulcers,dermatitis, thrombophlebitis, reflux esophagitis, abdominal hernias, and possibly hypertension and nephroticsyndrome.

A study by Losina et al exploring the association of obesity with knee osteoarthritis found that a substantial numberof quality-adjusted life years among persons in the study were lost due to knee osteoarthritis and obesity, mostnotably among black and Hispanic women.[7]

Some reports, including those by Adelman and colleagues and by Kasiske and Jennette, suggest an associationbetween severe obesity and focal glomerulosclerosis.[8, 9, 10] These complications, in particular, improvesubstantially or resolve early after bariatric surgery, well before clinically significant weight loss is achieved.

The so-called Pickwickian syndrome, named after the boy who was obese in Charles Dickens’s novel ThePickwick Papers, is a combined syndrome of obesity-related hypoventilation (associated with severe mechanicalrespiratory limitations to chest excursion, caused by severe obesity) and sleep apnea (which may be fromobstructive and/or central mechanisms). Obstructive sleep apnea is common among men with collar size greaterthan 17 in (43 cm) and women with collar size greater than 16 in (41 cm).

There is evidence linking obesity to psoriasis although data is sparse. One study of 89049 obese women found anassociation between high BMI and an increased risk of psoriatic arthritis.[11]

AnatomyThe adipocyte, which is the cellular basis for obesity, is increasingly found to be a complex and metabolicallyactive cell. At present, the adipocyte is being perceived as an endocrine gland with several peptides andmetabolites that may be relevant to the control of body weight, and these are being studied intensively.[12]

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Among the products of the adipocyte involved in complex intermediary metabolism are cytokines, tumor necrosisfactor-alpha, interleukin 6, lipotransin, monocyte chemo-attracting protein-1 (MCP-1), plasminogen activatorinhibitor-1 (PAI-1), adipocyte lipid-binding protein, acyl-stimulation protein, prostaglandins, adipsin, perilipins,lactate, leptin, adiponectin, monobutyrin, and phospholipid transfer protein.[13]

Among critical enzymes involved in adipocyte metabolism are endothelial-derived lipoprotein lipase (lipid storage),hormone-sensitive lipase (lipid elaboration and release from adipocyte depots), acyl-coenzyme A (acyl-CoA)synthetases (fatty acid synthesis), and a cascade of enzymes (beta-oxidation and fatty acid metabolism). Theongoing flurry of investigation into the intricacies of adipocyte metabolism has not only improved our understandingof the pathogenesis of obesity but has also offered several potential targets for therapy.

Another area of active research is investigation of the cues for the differentiation of preadipocytes to adipocytes.With the recognition that this process occurs in white and brown adipose tissue, even in adults, its potential role inthe development of obesity and the relapse to obesity after weight loss has become more important than before.Among the identified factors in this process are transcription factors peroxisome proliferator-activated receptors-gamma (PPAR-gamma), retinoid-X receptor ligands, perilipin, adipocyte differentiation-related protein (ADRP), andCCAAT enhancer-binding proteins (C/EBP) alpha, beta, and delta.

One study showed that an elevated level of plasma procalcitonin within the normal range is associated withobesity, although it appears that this is not an independent variable, since it reflects a state of distress orinflammation.[14]

EtiologyThe etiology of obesity is far more complex than the simple paradigm of an imbalance between energy intake andenergy output. Although this concept allows easy conceptualization of the various mechanisms involved in thedevelopment of obesity, obesity is far more than simply the result of too much eating and/or too little exercise. (Seeenergy-balance equation below.)

Energy balance equation.

However, the prevalence of inactivity in industrialized countries is considerable and relevant. In the United States,only approximately 22% of adults and 25% of adolescents report notable regular physical activity. Approximately25% of adults in the United States report no remarkable physical activity during leisure, while approximately 14%of adolescents have similar reports of inactivity.

Two major groups of factors with a balance that variably intertwines in the development of obesity are genetics,which is presumed to explain 40-70% of the variance in obesity, and environmental factors.

From genetic point of view, obesity may be caused by a single gene or by multiple genes defects. The exact geneor genes that contribute to common forms of human obesity have not been clearly identified. Several geneticstudies suggest polymorphisms in several genes, including those for the melanocortin-4 receptor, the beta-3-adrenergic receptor, and the peroxisome-proliferator-activated receptor (PPAR)-gamma 2. Polymorphism of thesegenes is clearly associated with obesity. Obesity also has strong heritability genetic factors. This has been madeclear in several twin and adoptee studies, in which obese individuals who were reared separately followed thesame weight pattern of their biological parents and of their identical twins. Metabolic rate, spontaneous physicalactivity, and thermic response to food seem to be heritable to a variable extent.

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On the other hand, many hormones, neurotransmitters, and neurogenic signals affect appetite and food intake.Endocannabinoids, through their effects on endocannabinoid receptors, increase appetite, enhance nutrientabsorption, and stimulate lipogenesis. Melanocortin hormone, through its effects on various melanocortinreceptors, modifies appetite. Several gut hormones play significant roles in inducing satiety, including glucagonlikepeptide-1 (GLP-1), neuropeptide YY (PYY), and cholecystokinin. Leptin and pancreatic amylin are other potentsatiety hormones. On the other hand, ghrelin, which is secreted from the stomach fundus, is a major hungerhormone.

A study by Freeman et al found that having an overweight or obese father and healthy weight mother significantlyincreased the odds of childhood obesity; however, the reverse scenario, having an obese mother and healthyweight father, was not associated with an increased risk of obesity in childhood.[15]

Although the high prevalence of obesity in the children of parents who are obese and the high concordance ofobesity in identical twins suggest a substantial genetic component to the pathogenesis of obesity, the seculartrends of the last few decades, which have been coincident with changes in dietary habits and activity, alsosuggest an important role for environmental factors.

Smell plays an important role in feeding behavior.[16] The olfactory threshold was measured in 8 lean individualsbefore and during 2-hour hyperinsulinemic euglycemia insulin clamp and was compared with the threshold in lean,fasted subjects. Increased insulin led to reduced smelling capacity, potentially reducing the pleasantness of eating.Therefore, insulin action in the olfactory bulb may be involved in the process of satiety and may be of interest inthe pathogenesis of obesity for clinicians.

Leptin

Friedman and colleagues discovered leptin (from the Greek word leptos, meaning thin) in 1994 and ushered in anexplosion of research and a great increase in knowledge about regulation of the human feeding and satiationcycle. Since this discovery, neuromodulation of satiety and hunger with feeding has been found to be far morecomplex than the old, simplistic model of the ventromedial hypothalamic nucleus and limbic centers of satiety andthe feeding centers of the lateral hypothalamus. (The potential for possible leptin sensitizers may assist inchanging feeding habits.)

Leptin is a 16-kd protein produced predominantly in white subcutaneous adipose tissue and, to a lesser extent, inthe placenta, skeletal muscle, and stomach fundus in rats. Leptin has myriad functions in carbohydrate, bone, andreproductive metabolism that are still being unraveled, but its role in body-weight regulation is the main reason itcame to prominence.

The major role of leptin in body-weight regulation is to signal satiety to the hypothalamus and, thus, reduce dietaryintake and fat storage while modulating energy expenditure and carbohydrate metabolism to prevent further weightgain. Unlike the Ob/Ob mouse model in which this peptide was first characterized, most humans who are obeseare not leptin deficient but rather leptin resistant. Therefore, they have elevated levels of circulating leptin.

A study by Lieb et al indicated that higher circulating leptin levels are associated with a greater risk of congestiveheart failure and cardiovascular disease but that leptin does not offer incremental prognostic information beyondBMI. The authors assayed plasma leptin in 818 elderly participants in the Framingham Heart Study.[17] Leptinlevels, which were higher in women, were strongly correlated with BMI. On follow-up (mean, 8 y), it was found thatcongestive heart failure had developed in 129 participants (out of 775 individuals who had been free of congestiveheart failure), a first cardiovascular disease event had occurred in 187 participants (out of 532 individuals who hadbeen free of cardiovascular disease), and 391 persons had died.

Murray et al first reported on a sequence variant within the leptin gene that enhances the intrinsic bioactivity ofleptin, leading to reduced weight rather than obesity.[18] This sequence variant within the leptin gene is associatedwith delayed puberty as well.

Monogenic models for obesity in humans and experimental animals

Although more than 90% of human cases of obesity are polygenic, the recognition of monogenic variants hasgreatly enhanced our knowledge of the etiopathogenesis of obesity.[19]

Proopiomelanocortin (POMC) and alpha–melanocyte-stimulating hormone (alpha-MSH) act centrally on themelanocortin receptor 4 (MC 4) to reduce dietary intake.[20] Genetic defects in POMC production and mutations in

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the MC4 gene are described as monogenic causes of obesity in humans.[21] Of particular interest is the fact thatpatients with POMC mutations tend to have red hair because of the resultant deficiency in MSH production. Also,because of their diminished levels of adrenocorticotropic hormone (ACTH), they tend to have central adrenalinsufficiency.

Data suggest that as many as 5% of children who are obese have MC4 or POMC mutations. If confirmed, thesewould be the most common identifiable genetic defects associated with obesity in humans (band 2p23 for POMCand band 18q21.3 for MC4).

Ob/Ob mice were the prototypical mice that enabled the discovery of leptin. These mice lack the leptin gene andare overweight and hyperphagic. A few humans with a similar genetic defect and similar phenotypic consequenceshave been identified. This variant of obesity, although minor in the grand scheme of human obesity, is exquisitelysensitive to leptin injection, with reduced dietary intake and profound weight loss. (The involved band is at 7q31.)

Db/Db mice have mutations of the leptin receptor in the hypothalamus. Fa/Fa mice also have leptin-receptormutations. Like the Ob/Ob mice, these mice have early onset obesity and hyperphagia, but they also have normalor elevated leptin levels.

Human counterparts of this model are rare; their conditions are associated with hyperphagia, hypogonadotropichypogonadism, and defective thyrotropin secretion but are not associated with hypercortisolism, hyperglycemia,and hypothermia, as occurs in Db/Db mice (involvement at band 1p31). The leptin receptor belongs to the cytokinereceptor families and is activated through the Janus kinases/signal transducers and activators of transcription(JAK/STAT) mechanisms.

Prohormone convertase, an enzyme that is critical in protein processing, appears to be involved in the conversionof POMC to alpha-MSH. Rare patients that have been identified as having alterations in this enzyme have hadclinically significant obesity, hypogonadotropic hypogonadism, and central adrenal insufficiency. This is one of thefew models of obesity not associated with insulin resistance. (The involved band is 5q15-21.)

PPAR-gamma is a transcription factor that is involved in adipocyte differentiation. All humans described so far withmutations of the receptor (at band 3p25) have had severe obesity.

Additional factors in obesity

In addition to the monogenic models of obesity mentioned above, genome-wide linkage analyses and microarraytechnology have revealed a rapidly growing list of potential obesity-susceptibility genes. Among those that arebeing actively studied are genes on chromosome arms 2p, 10p, 5p, 11q, and 20q.

Just as Helicobacter pylori was found to be the cause of peptic ulcer disease, evolving data suggest that a notableinflammatory, and possibly infective, etiology may exist for obesity. Adipose tissue is known to be a repository ofvarious cytokines, especially interleukin 6 and tumor necrosis factor alpha.

Data have shown that adenovirus-36 infection is associated with obesity in chickens and mice. Other data suggestthat, although humans who are not obese have a 5% prevalence of adenovirus-36 infection, humans who areobese have an adenovirus-36 prevalence of 20-30%.

Factors to be considered in the development of obesity include the following:

Metabolic factorsGenetic factorslevel of activityBehaviorEndocrine factorsRace, sex, and age factorsEthnic and cultural factorsSocioeconomic statusDietary habitsSmoking cessationPregnancy and menopausePsychologic factorsHistory of gestational diabetesLactation history in mothers

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Epidemiology

Occurrence in the United States

Approximately 100 million adults in the United States are at least overweight or obese, including approximately35% of women and 31% of men older than age 19 years. The numbers among children are even more imposingthan these figures, although the 2009-2010 NHANES updates on the US obesity prevalence rates surprisinglyshow a leveling-off of obesity in children.[22]

Although the prevalence of obesity has steadily increased over the years, updated data indicate a potentialstabilization of obesity trends in the United States.[22, 23]

During the past 20 years, the prevalence of obesity and being overweight has increased sharply for adults in theUnited States. Data from 2 National Health and Nutrition Examination Surveys (NHANES) show that among adultsaged 20-74 years, the prevalence of obesity increased from 15% (in the 1976-1980 survey) to 32.9% (in the 2003-2004 survey). According to the US Center for Disease Control and Prevention (CDC), after a quarter century ofincreases, obesity prevalence has not measurably increased in the past few years but levels are still high—in2007, at 34% of US adults aged 20 and older.[24]

The prevalence of obesity in children in the United States increased markedly between the time of the NHANES 2and 3 trials. Approximately 20-25% of children are either overweight or obese, and the prevalence is even greaterthan this in some minority groups, including Pima Indians, Mexican Americans, and African Americans.[24]

A study by Ludwig et al found that neighborhoods with high levels of poverty are associated with increases in theincidence of extreme obesity and diabetes. Although the mechanisms behind this association is unclear, furtherinvestigation is warranted.[25]

International occurrence

The prevalence of obesity worldwide is increasing, particularly in the industrialized nations of the Northernhemisphere, such as the United States, Canada, and most countries of Europe. Available data from theMultinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project suggest that atleast 15% of men and 22% of women in Europe are obese.[26, 27]

Similar data now are being reported in other parts of the world, including from many developing nations. Reportsfrom countries such as Malaysia, Japan, Australia, New Zealand, and China detail an epidemic of obesity in thepast 2-3 decades. Data from the Middle Eastern countries of Bahrain, Saudi Arabia, Egypt, Jordan, Tunisia, andLebanon, among others, indicate this same disturbing trend, with levels of obesity often exceeding 40% and beingparticularly worse in women than in men.

Information from the Caribbean and from South America highlights similar trends. Although data from Africa on thisissue are scant, a clear and distinct secular trend of profoundly increased BMIs is observed when people fromAfrica immigrate to the northwestern regions of the world. Comparisons of these indices among Nigerians andGhanaians residing in their native countries with indices in recent immigrants to the United States show this trendpoignantly.

Conservative estimates suggest that as many as 250 million people (approximately 7% of the estimated currentworld population) are obese. Two to 3 times more people than this are probably overweight. Althoughsocioeconomic class and the prevalence of obesity are negatively correlated in most industrialized countries,including the United States, this correlation is distinctly reversed in many relatively undeveloped areas, includingChina, Malaysia, parts of South America, and sub-Saharan Africa.

Finucane et al conducted a comprehensive, constructive study that revealed growing global trends in BMI. Thisstudy may serve as wake-up call and initiate large-scale interventions in an effort to combat increasing bodyweight and associated adverse health consequences.[28]

Race-related demographics

Obesity is a cosmopolitan disease that affects all races worldwide. However, certain ethnic and racial groupsappear to be particularly predisposed. The Pima Indians of Arizona and other ethnic groups native to NorthAmerica have a particularly high prevalence of obesity. In addition, Polynesians, Micronesians, Anurans, Maoris of

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the West and East Indies, African Americans, and Hispanic populations (either Mexican or Puerto Rican in origin)in North America also have particularly high predispositions to the development of obesity.

Secular trends clearly emphasize the importance of environmental factors (particularly dietary issues) in thedevelopment of obesity. In many genetically similar cohorts of the high-risk ethnic and racial groups mentionedabove, the prevalence of obesity in their countries of origin is low, but this rate changes considerably whenmembers of these groups emigrate to the affluent countries of the Northern Hemisphere, where they alter theirdietary and activity habits. These findings form the core concept of the thrifty gene hypothesis that Neal andcolleagues espoused.

Age-related demographics

In the United States, as previously stated, approximately 35% of women and 31% of men older than age 19 yearsare overweight or obese, as are approximately 20-25% of children.

As evidenced in secular trends, children, and particularly adolescents, who are obese have a high probability ofgrowing to be adults who are obese; hence, the bimodal distribution of obesity portends a large-scale obesityepidemic in the next few decades. Taller children generally tend to be more obese than shorter peers, are moreinsulin-resistant, and have increased leptin levels.[29]

Adolescent obesity poses a serious risk for severe obesity during early adulthood, particularly in non-Hispanicblack women. This would call for stronger emphasis on reduction during early adolescence specifically targetinggroups with greater risk.[30]

PrognosisThe association between obesity and morbidity is not in doubt. However, the previous notion that the increasedmortality and morbidity in patients who are obese was not entirely due to comorbidities was controversial.

Results from several observational studies detailed by the Expert Panel on the Identification, Evaluation, andTreatment of Overweight Adults, as well as results from reports by Allison, Bray, and others, exhaustively showthat obesity on its own is associated with increased cardiovascular morbidity and mortality and greater all-causemortality.[31, 32, 33]

For a person with a BMI of 25-28.9 kg/m2, the relative risk for coronary heart disease is 1.72. This riskprogressively increases with an increasing BMI. Therefore, with BMIs greater than 33 kg/m2, the relative risk is3.44. Similar trends were demonstrated in the relationship between obesity and stroke or congestive heart failure.Overall, obesity is estimated to increase the cardiovascular mortality rate 4-fold and the cancer-related mortalityrate 2-fold.[34] As a group, people who are severely obese have a 6- to 12-fold increase in the all-cause mortalityrate.

Morbidity and mortality

Data from insurance databases and large, prospective cohorts, such as findings from the Framingham andNHANES studies, clearly indicate that obesity is associated with a substantial increase in morbidity and mortalityrates. Although the exact magnitude of the attributable excess in mortality associated with obesity (about 112,000-365,000 excess deaths annually) has been disputed, obesity is indisputably the greatest preventable health-related cause of mortality after cigarette smoking.[31]

Some evidence suggests that, if unchecked, trends in obesity in the United States may be associated with overallreduced longevity of the population in the next few years. Data also show that obesity is associated with anincreased risk and duration of lifetime disability. Furthermore, obesity in middle age is associated with poor indicesof quality of life at old age.

The mortality data appear to have a U - or J -shaped conformation in relation to weight distribution.[35] However,the degree of obesity (generally indicated by the BMI) at which mortality discernibly increases in African Americansand Hispanic Americans is greater than in white Americans; this observation suggests a notable racial spectrumand difference in this effect

Underweight was associated with substantially high risk of death in a study of Asian populations. A high BMI isalso associated with an increased risk of death, except in Indians and Bangladeshis.[36]

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A study by Boggs et al found that the risk of death from any cause among black women increased with a BMI of 25or higher, which is similar to the pattern observed among whites. Waist circumference appeared to be associatedwith an increased risk of death only among women who were not obese.[37]

The optimal BMI in terms of life expectancy is about 23-25 for whites and 23-30 for blacks. Emerging data suggestthat the ideal BMI for Asians is substantially lower than that for whites.[2]

For persons with severe obesity (BMI ≥40), life expectancy is reduced by as much as 20 years in men and byabout 5 years in women. Coexisting obesity and smoking are associated with even greater risks than these forpremature mortality.

A study by Berrington de Gonzalez et al confirmed health advantages of normal BMI (20-24.9) and reinforced thatoverweight and underweight lead to an increased death risk.[38]

Factors that modulate the morbidity and mortality associated with obesity include the following:

Age of onset and duration of obesitySeverity of obesityAmount of central adiposityOther comorbiditiesGenderlevel of cardiorespiratory fitnessRace

Morbidity in elderly persons

A longitudinal study by Stessman et al of more than 1000 individuals indicated that a normal BMI, rather thanobesity, is associated with a higher mortality rate in elderly people. The investigators determined that a unitincrease in BMI in female members of the cohort could be linked to hazard ratios (HRs) of 0.94 at age 70 years,0.95 at age 78 years, and 0.91 at age 85 years. In men, a unit increase in BMI was associated with HRs of 0.99 atage 70 years, 0.94 at age 78 years, and 0.91 at age 85 years. According to a time-dependent analysis of 450cohort members followed from age 70 to age 88 years, a unit increase in BMI produced an HR of 0.93 in womenand in men.[39]

Similar results to those in the Stessman study were found in a Japanese investigation of 26,747 older persons(aged 65-79 years at baseline). Tamakoshi et al found no elevation in all-cause mortality risk in overweight(measured as BMI 25.0-29.9 in this study) or obese (BMI ≥30.0) males; slightly elevated hazard ratios were foundin women in the obese group, but not in the overweight group, in comparison with women in the mid–normal-rangegroup. In contrast, an association was found between a low BMI and an increased risk of all-cause mortality, evenamong persons in the lower-normal BMI range.[40]

Patient Education

In studies among low-income families, adults and adolescents noted caloric information when reading labels.[41]

However, this information did not affect food selection by adolescents or parental food selections for children.

The National Health and Nutrition Examination Survey (NHANES) found that patients who received a formaldiagnosis of overweight/obese from a healthcare provider demonstrated a higher rate of dietary change and/orphysical activity than did persons whose overweight/obese condition remained undiagnosed. These findings areimportant for any clinician caring for overweight/obese patients.[24]

A meta-analysis by Waters et al of 55 studies assessing educational, behavioral, and health promotioninterventions in children aged 0-18 years found that these interventions reduced BMI (standardized meandifference in adiposity, 0.15 kg/m2).[42] The study concluded that child obesity prevention programs have beneficialeffects.

For patient education information, see the Diabetes Center, as well as Obesity, Weight Loss and Control, HighCholesterol, Cholesterol levels (Cholesterol Charts - What the Numbers Mean), and Lifestyle CholesterolManagement.

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Contributor Information and DisclosuresAuthorOsama Hamdy, MD, PhD, FACE Medical Director, Obesity Clinical Program, Director of Inpatient DiabetesManagement, Joslin Diabetes Center; Assistant Professor of Medicine, Harvard Medical School

Osama Hamdy, MD, PhD, FACE is a member of the following medical societies: American Association ofClinical Endocrinologists and American Diabetes Association

Disclosure: Merck Inc Honoraria Speaking and teaching

Coauthor(s)Elena Citkowitz, MD, PhD, FACP Clinical Professor of Medicine, Yale University School of Medicine; Director,Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of StRaphael

Elena Citkowitz, MD, PhD, FACP is a member of the following medical societies: American College ofPhysicians, American Heart Association, National Lipid Association, and Sigma Xi

Disclosure: Nothing to disclose.

Gabriel I Uwaifo, MD Associate Professor, Section of Endocrinology, Diabetes and Metabolism, LouisianaState University School of Medicine in New Orleans; Adjunct Professor, Joint Program on Diabetes,Endocrinology and Metabolism, Pennington Biomedical Research Center in Baton Rouge

Gabriel I Uwaifo, MD is a member of the following medical societies: American Association of ClinicalEndocrinologists, American College of Physicians-American Society of Internal Medicine, American DiabetesAssociation, American Medical Association, American Society of Hypertension, and Endocrine Society


Elif Arioglu, MD Assistant Professor of Medicine, Division of Endocrinology and Metabolism, University ofMichigan Medical School

Elif Arioglu, MD is a member of the following medical societies: American College of Physicians-AmericanSociety of Internal Medicine, American Diabetes Association, American Medical Association, and EndocrineSociety


Chief EditorGeorge T Griffing, MD Professor of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for theAdvancement of Science, American College of Medical Practice Executives, American College of PhysicianExecutives, American College of Physicians, American Diabetes Association, American Federation for MedicalResearch, American Heart Association, Central Society for Clinical Research, Endocrine Society, InternationalSociety for Clinical Densitometry, and Southern Society for Clinical Investigation


Additional ContributorsRomesh Khardori, MD, PhD, FACP Former Professor, Department of Medicine, Former Chief, Division ofEndocrinology, Metabolism, and Molecular Medicine, Southern Illinois University School of Medicine

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association ofClinical Endocrinologists, American College of Physicians, American Diabetes Association, and EndocrineSociety


Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical CenterCollege of Pharmacy; Editor-in-Chief, Medscape Drug Reference

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Disclosure: Medscape Salary Employment

Additional ContributorsRomesh Khardori, MD, PhD, FACP Former Professor, Department of Medicine, Former Chief, Division ofEndocrinology, Metabolism, and Molecular Medicine, Southern Illinois University School of Medicine

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association ofClinical Endocrinologists, American College of Physicians, American Diabetes Association, and EndocrineSociety


Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical CenterCollege of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References

1. Gallagher D, Heymsfield SB, Heo M, Jebb SA, Murgatroyd PR, Sakamoto Y. Healthy percentage body fatranges: an approach for developing guidelines based on body mass index. Am J Clin Nutr. Sep2000;72(3):694-701. [Medline].

2. Shiwaku K, Anuurad E, Enkhmaa B, Kitajima K, Yamane Y. Appropriate BMI for Asian populations.Lancet. Mar 27 2004;363(9414):1077. [Medline].

3. Wijga AH, Scholtens S, Bemelmans WJ, de Jongste JC, Kerkhof M, Schipper M, et al. Comorbidities ofobesity in school children: a cross-sectional study in the PIAMA birth cohort. BMC Public Health. Apr 92010;10:184. [Medline]. [Full Text].

4. Tirosh A, Shai I, Afek A, Dubnov-Raz G, Ayalon N, Gordon B, et al. Adolescent BMI trajectory and risk ofdiabetes versus coronary disease. N Engl J Med. Apr 7 2011;364(14):1315-25. [Medline].

5. Montonen J, Boeing H, Schleicher E, Fritsche A, Pischon T. Association of changes in body mass indexduring earlier adulthood and later adulthood with circulating obesity biomarker concentrations in middle-aged men and women. Diabetologia. Jul 2011;54(7):1676-83. [Medline].

6. Sugerman HJ, Kellum JM, Engle KM, Wolfe L, Starkey JV, Birkenhauer R, et al. Gastric bypass fortreating severe obesity. Am J Clin Nutr. Feb 1992;55(2 Suppl):560S-566S. [Medline].

7. Losina E, Walensky RP, Reichmann WM, Holt HL, Gerlovin H, Solomon DH, et al. Impact of obesity andknee osteoarthritis on morbidity and mortality in older Americans. Ann Intern Med. Feb 152011;154(4):217-26. [Medline].

8. Adelman RD, Restaino IG, Alon US, Blowey DL. Proteinuria and focal segmental glomerulosclerosis inseverely obese adolescents. J Pediatr. Apr 2001;138(4):481-5. [Medline].

9. Kasiske BL, Napier J. Glomerular sclerosis in patients with massive obesity. Am J Nephrol. 1985;5(1):45-50. [Medline].

10. Jennette JC, Charles L, Grubb W. Glomerulomegaly and focal segmental glomerulosclerosis associatedwith obesity and sleep-apnea syndrome. Am J Kidney Dis. Dec 1987;10(6):470-2. [Medline].

11. Li W, Han J, Qureshi AA. Obesity and risk of incident psoriatic arthritis in US women. Ann Rheum Dis.May 9 2012;[Medline].

12. Martinelli CE, Keogh JM, Greenfield JR, Henning E, van der Klaauw AA, Blackwood A, et al. Obesity dueto melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height,fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion. J Clin EndocrinolMetab. Jan 2011;96(1):E181-8. [Medline].

13. Hamdy O. The role of adipose tissue as an endocrine gland. Curr Diab Rep. Oct 2005;5(5):317-9.[Medline].

10/31/12 12:22 PMObesity


14. Abbasi A, Corpeleijn E, Postmus D, Gansevoort RT, de Jong PE, Gans RO, et al. Plasma procalcitonin isassociated with obesity, insulin resistance, and the metabolic syndrome. J Clin Endocrinol Metab. Sep2010;95(9):E26-31. [Medline].

15. Freeman E, Fletcher R, Collins CE, et al. Preventing and treating childhood obesity: time to target fathers.Int J Obes (Lond). Jan 2012;36(1):12-5. [Medline].

16. Ketterer C, Heni M, Thamer C, Herzberg-Schäfer SA, Häring HU, Fritsche A. Acute, short-termhyperinsulinemia increases olfactory threshold in healthy subjects. Int J Obes (Lond). Aug2011;35(8):1135-8. [Medline].

17. [Best Evidence] Lieb W, Sullivan LM, Harris TB, Roubenoff R, Benjamin EJ, Levy D, et al. Plasma leptinlevels and incidence of heart failure, cardiovascular disease, and total mortality in elderly individuals.Diabetes Care. Apr 2009;32(4):612-6. [Medline]. [Full Text].

18. Murray PG, Read A, Banerjee I, Whatmore AJ, Pritchard LE, Davies RA, et al. Reduced appetite andbody mass index with delayed puberty in a mother and son: association with a rare novel sequencevariant in the leptin gene. Eur J Endocrinol. Apr 2011;164(4):521-7. [Medline].

19. Reinehr T, Kleber M, de Sousa G, et al. Leptin concentrations are a predictor of overweight reduction in alifestyle intervention. Int J Pediatr Obes. May 13 2009;1-9:[Medline].

20. Cummings DE, Schwartz MW. Melanocortins and body weight: a tale of two receptors. Nat Genet. Sep2000;26(1):8-9. [Medline].

21. Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P. Melanocortin-4 receptor mutationsare a frequent and heterogeneous cause of morbid obesity. J Clin Invest. Jul 2000;106(2):253-62.[Medline]. [Full Text].

22. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and trends in body mass index amongUS children and adolescents, 1999-2010. JAMA. Feb 1 2012;307(5):483-90. [Medline].

23. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of bodymass index among US adults, 1999-2010. JAMA. Feb 1 2012;307(5):491-7. [Medline].

24. Yaemsiri S, Slining MM, Agarwal SK. Perceived weight status, overweight diagnosis, and weight controlamong US adults: the NHANES 2003-2008 Study. Int J Obes (Lond). Aug 2011;35(8):1063-70. [Medline].

25. Ludwig J, Sanbonmatsu L, Gennetian L, et al. Neighborhoods, obesity, and diabetes--a randomized socialexperiment. N Engl J Med. Oct 20 2011;365(16):1509-19. [Medline].

26. Molarius A, Seidell JC, Sans S, Tuomilehto J, Kuulasmaa K. Varying sensitivity of waist action levels toidentify subjects with overweight or obesity in 19 populations of the WHO MONICA Project. J ClinEpidemiol. Dec 1999;52(12):1213-24. [Medline].

27. Molarius A, Seidell JC, Sans S, Tuomilehto J, Kuulasmaa K. Waist and hip circumferences, and waist-hipratio in 19 populations of the WHO MONICA Project. Int J Obes Relat Metab Disord. Feb 1999;23(2):116-25. [Medline].

28. Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, et al. National, regional, andglobal trends in body-mass index since 1980: systematic analysis of health examination surveys andepidemiological studies with 960 country-years and 9·1 million participants. Lancet. Feb 122011;377(9765):557-67. [Medline].

29. Metcalf BS, Hosking J, Frémeaux AE, Jeffery AN, Voss LD, Wilkin TJ. BMI was right all along: tallerchildren really are fatter (implications of making childhood BMI independent of height) EarlyBird 48. Int JObes (Lond). Apr 2011;35(4):541-7. [Medline].

30. The NS, Suchindran C, North KE, Popkin BM, Gordon-Larsen P. Association of adolescent obesity withrisk of severe obesity in adulthood. JAMA. Nov 10 2010;304(18):2042-7. [Medline]. [Full Text].

31. Allison DB, Fontaine KR, Manson JE, Stevens J, VanItallie TB. Annual deaths attributable to obesity in theUnited States. JAMA. Oct 27 1999;282(16):1530-8. [Medline].

10/31/12 12:22 PMObesity


32. [Guideline] Expert Panel on the Identification, Evaluation, and Treatment of Overweight Adults. Clinicalguidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executivesummary. Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults. Am JClin Nutr. Oct 1998;68(4):899-917. [Medline].

33. Bray GA. Health hazards of obesity. Endocrinol Metab Clin North Am. Dec 1996;25(4):907-19. [Medline].

34. Jiao L, Berrington de Gonzalez A, Hartge P, Pfeiffer RM, Park Y, Freedman DM, et al. Body mass index,effect modifiers, and risk of pancreatic cancer: a pooled study of seven prospective cohorts. CancerCauses Control. Aug 2010;21(8):1305-14. [Medline]. [Full Text].

35. Flegal KM, Graubard BI, Williamson DF, Gail MH. Excess deaths associated with underweight,overweight, and obesity. JAMA. Apr 20 2005;293(15):1861-7. [Medline].

36. Zheng W, McLerran DF, Rolland B, Zhang X, Inoue M, Matsuo K, et al. Association between body-massindex and risk of death in more than 1 million Asians. N Engl J Med. Feb 24 2011;364(8):719-29.[Medline].

37. Boggs DA, Rosenberg L, Cozier YC, Wise LA, Coogan PF, Ruiz-Narvaez EA, et al. General andabdominal obesity and risk of death among black women. N Engl J Med. Sep 8 2011;365(10):901-8.[Medline].

38. Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, et al. Body-mass indexand mortality among 1.46 million white adults. N Engl J Med. Dec 2 2010;363(23):2211-9. [Medline]. [FullText].

39. [Best Evidence] Stessman J, Jacobs JM, Ein-Mor E, Bursztyn M. Normal body mass index rather thanobesity predicts greater mortality in elderly people: the Jerusalem longitudinal study. J Am Geriatr Soc.Dec 2009;57(12):2232-8. [Medline].

40. [Best Evidence] Tamakoshi A, Yatsuya H, Lin Y, Tamakoshi K, Kondo T, Suzuki S, et al. BMI and all-cause mortality among Japanese older adults: findings from the Japan collaborative cohort study. Obesity(Silver Spring). Feb 2010;18(2):362-9. [Medline].

41. Elbel B, Gyamfi J, Kersh R. Child and adolescent fast-food choice and the influence of calorie labeling: anatural experiment. Int J Obes (Lond). Apr 2011;35(4):493-500. [Medline].

42. Waters E, de Silva-Sanigorski A, Hall BJ, et al. Interventions for preventing obesity in children. CochraneDatabase Syst Rev. Dec 7 2011;12:CD001871. [Medline].

43. Li C, Ford ES, Zhao G, Croft JB, Balluz LS, Mokdad AH. Prevalence of self-reported clinically diagnosedsleep apnea according to obesity status in men and women: National Health and Nutrition ExaminationSurvey, 2005-2006. Prev Med. Jul 2010;51(1):18-23. [Medline].

44. Oreopoulos A, Padwal R, McAlister FA, Ezekowitz J, Sharma AM, Kalantar-Zadeh K, et al. Associationbetween obesity and health-related quality of life in patients with coronary artery disease. Int J Obes(Lond). Sep 2010;34(9):1434-41. [Medline].

45. Galtier-Dereure F, Boegner C, Bringer J. Obesity and pregnancy: complications and cost. Am J Clin Nutr.May 2000;71(5 Suppl):1242S-8S. [Medline].

46. Blüher M, Rudich A, Kloting N, et al. Two patterns of adipokine and other biomarker dynamics in a long-term weight loss intervention. Diabetes Care. Feb 2012;35(2):342-9. [Medline]. [Full Text].

47. [Best Evidence] Stolley MR, Fitzgibbon ML, Schiffer L, Sharp LK, Singh V, Van Horn L, et al. Obesityreduction black intervention trial (ORBIT): six-month results. Obesity (Silver Spring). Jan 2009;17(1):100-6. [Medline].

48. Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations toweight loss. N Engl J Med. Oct 27 2011;365(17):1597-604. [Medline].

49. Jolly K, Lewis A, Beach J, et al. Comparison of range of commercial or primary care led weight reductionprogrammes with minimal intervention control for weight loss in obesity: Lighten Up randomised controlledtrial. BMJ. Nov 3 2011;343:d6500. [Medline]. [Full Text].

10/31/12 12:22 PMObesity


50. Rock CL, Flatt SW, Sherwood NE, Karanja N, Pakiz B, Thomson CA. Effect of a free prepared meal andincentivized weight loss program on weight loss and weight loss maintenance in obese and overweightwomen: a randomized controlled trial. JAMA. Oct 27 2010;304(16):1803-10. [Medline].

51. Maffeis C. Childhood obesity: the genetic-environmental interface. Baillieres Best Pract Res ClinEndocrinol Metab. Apr 1999;13(1):31-46. [Medline].

52. Proimos J, Sawyer S. Obesity in childhood and adolescence. Aust Fam Physician. Apr 2000;29(4):321-7.[Medline].

53. Harsha DW, Bray GA. Body composition and childhood obesity. Endocrinol Metab Clin North Am. Dec1996;25(4):871-85. [Medline].

54. [Best Evidence] Dennis EA, Dengo AL, Comber DL, Flack KD, Savla J, Davy KP, et al. Waterconsumption increases weight loss during a hypocaloric diet intervention in middle-aged and older adults.Obesity (Silver Spring). Feb 2010;18(2):300-7. [Medline]. [Full Text].

55. Dubnov-Raz G, Constantini NW, Yariv H, Nice S, Shapira N. Influence of water drinking on resting energyexpenditure in overweight children. Int J Obes (Lond). Oct 2011;35(10):1295-300. [Medline].

56. Larsen TM, Dalskov SM, van Baak M, Jebb SA, Papadaki A, Pfeiffer AF, et al. Diets with high or lowprotein content and glycemic index for weight-loss maintenance. N Engl J Med. Nov 252010;363(22):2102-13. [Medline].

57. Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Comparison of the Atkins, Ornish, WeightWatchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA. Jan5 2005;293(1):43-53. [Medline].

58. Foster GD, Wyatt HR, Hill JO, Makris AP, Rosenbaum DL, Brill C, et al. Weight and metabolic outcomesafter 2 years on a low-carbohydrate versus low-fat diet: a randomized trial. Ann Intern Med. Aug 32010;153(3):147-57. [Medline]. [Full Text].

59. Wiesner S, Haufe S, Engeli S, Mutschler H, Haas U, Luft FC, et al. Influences of normobaric hypoxiatraining on physical fitness and metabolic risk markers in overweight to obese subjects. Obesity (SilverSpring). Jan 2010;18(1):116-20. [Medline].

60. Villareal DT, Chode S, Parimi N, Sinacore DR, Hilton T, Armamento-Villareal R, et al. Weight loss,exercise, or both and physical function in obese older adults. N Engl J Med. Mar 31 2011;364(13):1218-29. [Medline]. [Full Text].

61. Goodpaster BH, Delany JP, Otto AD, Kuller L, Vockley J, South-Paul JE, et al. Effects of diet and physicalactivity interventions on weight loss and cardiometabolic risk factors in severely obese adults: arandomized trial. JAMA. Oct 27 2010;304(16):1795-802. [Medline]. [Full Text].

62. Hankinson AL, Daviglus ML, Bouchard C, Carnethon M, Lewis CE, Schreiner PJ, et al. Maintaining a highphysical activity level over 20 years and weight gain. JAMA. Dec 15 2010;304(23):2603-10. [Medline].

63. Rejeski WJ, Brubaker PH, Goff DC Jr, Bearon LB, McClelland JW, Perri MG, et al. Translating weight lossand physical activity programs into the community to preserve mobility in older, obese adults in poorcardiovascular health. Arch Intern Med. May 23 2011;171(10):880-6. [Medline].

64. Morgan PJ, Lubans DR, Callister R, Okely AD, Burrows TL, Fletcher R, et al. The 'Healthy Dads, HealthyKids' randomized controlled trial: efficacy of a healthy lifestyle program for overweight fathers and theirchildren. Int J Obes (Lond). Mar 2011;35(3):436-47. [Medline].

65. Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weightgain in women and men. N Engl J Med. Jun 23 2011;364(25):2392-404. [Medline]. [Full Text].

66. Nedeltcheva AV, Kilkus JM, Imperial J, Schoeller DA, Penev PD. Insufficient sleep undermines dietaryefforts to reduce adiposity. Ann Intern Med. Oct 5 2010;153(7):435-41. [Medline]. [Full Text].

67. Heck AM, Yanovski JA, Calis KA. Orlistat, a new lipase inhibitor for the management of obesity.Pharmacotherapy. Mar 2000;20(3):270-9. [Medline].

10/31/12 12:22 PMObesity


68. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. Jul 15 2010;363(3):245-56. [Medline].[Full Text].

69. Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, et al. A one-year randomizedtrial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin EndocrinolMetab. Oct 2011;96(10):3067-77. [Medline].

70. O'Neil PM, Smith SR, Weissman NJ, Fidler MC, Sanchez M, Zhang J, et al. Randomized Placebo-Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 Diabetes Mellitus: The BLOOM-DMStudy. Obesity (Silver Spring). Jul 2012;20(7):1426-36. [Medline].

71. Goldfield GS, Lorello C, Doucet E. Methylphenidate reduces energy intake and dietary fat intake in adults:a mechanism of reduced reinforcing value of food?. Am J Clin Nutr. Aug 2007;86(2):308-15. [Medline].

72. Gadde KM, Xiong GL. Bupropion for weight reduction. Expert Rev Neurother. Jan 2007;7(1):17-24.[Medline].

73. Grudell AB, Sweetser S, Camilleri M, Eckert DJ, Vazquez-Roque MI, Carlson PJ, et al. A controlledpharmacogenetic trial of sibutramine on weight loss and body composition in obese or overweight adults.Gastroenterology. Oct 2008;135(4):1142-54. [Medline]. [Full Text].

74. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, et al. Effect of sibutramine oncardiovascular outcomes in overweight and obese subjects. N Engl J Med. Sep 2 2010;363(10):905-17.[Medline].

75. Abbott Laboratories agrees to withdraw its obesity drug Meridia. FDA, U.S. Food and Drug Administration.Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm228812.htm.Accessed October 8, 2010.

76. Rosenstock J, Hollander P, Gadde KM, Sun X, Strauss R, Leung A. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in thetreatment of obese type 2 diabetic patients. Diabetes Care. Jun 2007;30(6):1480-6. [Medline].

77. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, et al. Effects of low-dose,controlled-release, phentermine plus topiramate combination on weight and associated comorbidities inoverweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. Apr16 2011;377(9774):1341-52. [Medline].

78. Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, et al. Controlled-releasephentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (SilverSpring). Feb 2012;20(2):330-42. [Medline]. [Full Text].

79. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, et al. Two-year sustained weightloss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweightadults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. Feb2012;95(2):297-308. [Medline]. [Full Text].

80. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, et al. Two-year sustained weightloss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweightadults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. Feb2012;95(2):297-308. [Medline]. [Full Text].

81. Black SC. Cannabinoid receptor antagonists and obesity. Curr Opin Investig Drugs. Apr 2004;5(4):389-94.[Medline].

82. Van Gaal LF, Rissanen AM, Scheen AJ, et al. Effects of the cannabinoid-1 receptor blocker rimonabanton weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from theRIO-Europe study. Lancet. Apr 16-22 2005;365(9468):1389-97..

83. Cox SL. Rimonabant hydrochloride: an investigational agent for the management of cardiovascular riskfactors. Drugs Today (Barc). Aug 2005;41(8):499-508. [Medline].

84. Fernandez JR, Allison DB. Rimonabant Sanofi-Synthélabo. Curr Opin Investig Drugs. Apr 2004;5(4):430-

10/31/12 12:22 PMObesity


5. [Medline].

85. [Best Evidence] Nagao T, Meguro S, Hase T, Otsuka K, Komikado M, Tokimitsu I, et al. A catechin-richbeverage improves obesity and blood glucose control in patients with type 2 diabetes. Obesity (SilverSpring). Feb 2009;17(2):310-7. [Medline].

86. Desilets AR, Dhakal-Karki S, Dunican KC. Role of metformin for weight management in patients withouttype 2 diabetes. Ann Pharmacother. Jun 2008;42(6):817-26. [Medline].

87. Gadde KM, Franciscy DM, Wagner HR 2nd, Krishnan KR. Zonisamide for weight loss in obese adults: arandomized controlled trial. JAMA. Apr 9 2003;289(14):1820-5. [Medline].

88. Lustig RH, Hinds PS, Ringwald-Smith K, Christensen RK, Kaste SC, Schreiber RE. Octreotide therapy ofpediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab. Jun2003;88(6):2586-92. [Medline].

89. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, et al. Inhibition of food intake inobese subjects by peptide YY3-36. N Engl J Med. Sep 4 2003;349(10):941-8. [Medline].

90. Boggiano MM, Chandler PC, Oswald KD, et al. PYY3-36 as an anti-obesity drug target. Obes Rev. Nov2005;6(4):307-22.

91. Roth CL, Enriori PJ, Harz K, et al. Peptide YY is a regulator of energy homeostasis in obese childrenbefore and after weight loss. J Clin Endocrinol Metab. Dec 2005;90(12):6386-91.

92. Sjostrom L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term cardiovascular events. JAMA.Jan 4 2012;307(1):56-65. [Medline].

93. Ashley S, Bird DL, Sugden G, Royston CM. Vertical banded gastroplasty for the treatment of morbidobesity. Br J Surg. Nov 1993;80(11):1421-3. [Medline].

94. Flickinger EG, Pories WJ, Meelheim HD, Sinar DR, Blose IL, Thomas FT. The Greenville gastric bypass.Progress report at 3 years. Ann Surg. May 1984;199(5):555-62. [Medline]. [Full Text].

95. Plecka Östlund M, Marsk R, Rasmussen F, Lagergren J, Näslund E. Morbidity and mortality before andafter bariatric surgery for morbid obesity compared with the general population. Br J Surg. Jun2011;98(6):811-6. [Medline].

96. Søvik TT, Aasheim ET, Taha O, Engström M, Fagerland MW, Björkman S, et al. Weight loss,cardiovascular risk factors, and quality of life after gastric bypass and duodenal switch: a randomized trial.Ann Intern Med. Sep 6 2011;155(5):281-91. [Medline].

97. Salehi M, Prigeon RL, D'Alessio DA. Gastric bypass surgery enhances glucagon-like peptide 1-stimulatedpostprandial insulin secretion in humans. Diabetes. Sep 2011;60(9):2308-14. [Medline]. [Full Text].

98. Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptoragonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. Jan10 2012;344:d7771. [Medline]. [Full Text].

99. Cigaina V. Gastric pacing as therapy for morbid obesity: preliminary results. Obes Surg. Apr 2002;12Suppl 1:12S-16S. [Medline].

100. Klein S, Fontana L, Young VL, et al. Absence of an effect of liposuction on insulin action and risk factorsfor coronary heart disease. N Engl J Med. Jun 17 2004;350(25):2549-57..

101. Cariou B, Zaïr Y, Staels B, Bruckert E. Effects of the new dual PPAR a/d agonist GFT505 on lipid andglucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucosemetabolism. Diabetes Care. Sep 2011;34(9):2008-14. [Medline]. [Full Text].

102. Mittendorfer B, Horowitz JF, DePaoli AM, McCamish MA, Patterson BW, Klein S. Recombinant humanleptin treatment does not improve insulin action in obese subjects with type 2 diabetes. Diabetes. May2011;60(5):1474-7. [Medline].

103. Moon HS, Matarese G, Brennan AM, Chamberland JP, Liu X, Fiorenza CG, et al. Efficacy of metreleptinin obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance.

10/31/12 12:22 PMObesity


Diabetes. Jun 2011;60(6):1647-56. [Medline]. [Full Text].

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