NUTRITION Short Research Paper (85 pts.). Write a short paper (3+ pages of writing) about your three references. Your paper should explain & discuss the major points of each reference. For resea

Dr. Berthoud has received research funding from the NIH. Dr. Heymsfield has received fees for serving on advisory boards from Janssen Pharmaceuticals, Tanita, Merck, and Medifast.

Manuscript received July 22, 2017; revised manuscript received October 3, 2017, accepted November 6, 2017. Listen to this manuscript’s audio summary by JACCEditor-in-Chief Dr. Valentin Fuster. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGYVOL. 71, NO. 1, 2018 ª2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIERISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2017.11.011 2 parallel discussions: 1 from an energetic and 1 from a nutritional standpoint. Here, we focus mainly on the former, due in large part because there is considerable consensus for the mechanisms of energy balance regulation, whereas there is confusion and controversy regarding optimal nutrient composition(3,4).

The distinction between the causes and con- sequences of obesity must be given due consideration, as also the importance of understanding obesity-independent and obesity-dependent pathophysiology of comorbidities including CVD.

On the basis of observations that individ- ual adult body weight is remarkably stable and refractory to short-term experimental up or down perturbations under constant envi- ronmental conditions, most scientists agree that body weight or adiposity is actively regulated or defended(5). New insights sug- gest that the elevated body weight/adiposity in many obese subjects is defended just as it is in normal weight subjects(6),supporting the notion that obesity is a disease, thus shifting the blame from the person to the physiology.

Genome-wide association study–based data suggest a genetic predisposition for obesity with identification of more than 140 genetic chromosomal regions related to obesity(7). Gene expression related to BMI and gen- eral adiposity is highly enriched in the central ner- vous system(8). However, only a few genes with a large effect size on BMI have yet been identified.

These are the genes encoding components of leptin and melanocortin signaling, as well as paternally expressed genes along a specificregionofchromo- some 15 responsible for Prader-Willi syndrome(9).In contrast to such monogenetic cases, common obesity is thought to be associated with a large number of genes with small effect sizes.

A widely held view is that obesity results from an interaction between environment/lifestyle and ge- netic susceptibility. Several hypotheses have been put forward to explain the existence of obesity sus- ceptibility genes. The“thrifty”gene hypothesis posits that genes promoting energy intake and high fuel efficiency were selected over genes promoting energy-guzzling during human evolution(10).The “drifty”gene hypothesis argues that the evolutionary selection pressure for genes keeping body weight/ adiposity to a minimum relaxed when humans invented weapons andfire about 2 million years ago, and thus were no longer threatened by predators,with the consequence of a random drift of genes allowing increased adiposity(11).

The early origins of adult disease hypothesis sug- gests that obesity can develop in offspring from mothers exposed to metabolic hardship such as un- dernutrition, obesity, and diabetes(12).Oneofthe molecular mechanisms responsible for early-life metabolic programming is epigenetic modification of genes through methylation, histone modifications, chromatin remodeling, and noncoding RNA alter- ations(13). Importantly, such epigenetically deter- mined increased risk foradultobesitycanbe transmitted to future generations, further acceler- ating the obesity epidemic. Thus,finding the tools and therapies to break the vicious circle of epigenetic programming is an important target of obesity research.

Given the disproportionally high expression of obesity-associated genes and epigenetic modifica- tions in the central nervous system, it is highly likely that obesity genes act, not only within the hypotha- lamic homeostatic regulator of energy balance, but also within neural circuits that are involved in interactions with an obesogenic environment, including circuits underlying reward-based decision making, learning and memory, delayed discounting, and spatial orientation. CONTROLLING FOOD INTAKE IN AN ENVIRONMENTOFPLENTY Although the brain primarily regulates food intake as a behavior, it relies on information from the rest of the body and from the environment to make the decision to eat or not to eat. Well over 50 years ago, seminal studies established the hypothalamus as a key hub for the detection of hunger and organization of eating behavior(14).Sincethen,theimportanceofthe hypothalamus has been confirmed, with much detail addedtoitsfunctionalandchemicalanatomy(15).In addition, the importance of crosstalk (Figure 1)be- tween the hypothalamus and other brain regions, as well as with the periphery, has been recognized(16).

A key function of the basomedial hypothalamus is to detect shortages in nutrient supply, both short term and long term, and translate them into behavior.

To this end, separate groups of chemically distinct neurons (agouti-related peptide/neuropeptide Y [AGRP/NPY] and proopiomelanocortin/cocaine and amphetamine regulated transcript [POMC/CART]) are sensitive to circulating metabolites and hormones signaling availability of energy, such as leptin, ghre- lin, insulin, and glucose, in addition to neural signals reflecting the nutritional status of the gut conveyed ABBREVIATIONS AND ACRONYMS BMI= body mass index CI= confidence interval CVD= cardiovascular disease CVOT= cardiovascular outcomes trial FDA= Food and Drug Administration HF= heart failure HgA 1c=glycosylated hemoglobin ILI= intensive lifestyle intervention LAGB= laparoscopic adjustable gastric band LV= left ventricular MACE= major adverse cardiovascular events MRI= magnetic resonance imaging NB= naltrexone/bupropion PHEN/TPM= phentermine/ topiramate RCT= randomized controlled trial RYGB= Roux-en-Y gastric bypass SG= sleeve gastrectomy T2D= type 2 diabetes Gaddeet al. JACC VOL. 71, NO. 1, 2018 Pathophysiology and Management of Obesity JANUARY 2/9, 2018:69–84 70 throughthevagusnerveandbrainstem(5).Even though every tissue and cell has its own evolution- arily conserved energy sensor, and much of energy needs can be covered by cell- and tissue-autonomous andperipheralreflexes without involving the brain, the hypothalamus should thus be considered a master energy sensor that integrates past, current, and future needs of the entire body with prevailing or expected environmental conditions(17).Thus,any interference with the normal functions of this hypo- thalamic circuitry leads to impairments in energy balance regulation, and much research effort is directed to this circuitry.

It is increasingly clear that the integrative capacity of the hypothalamus is also enriched by extensive crosstalk with other brain areas such as the cortex and limbic system, which are concerned with processing external sensory information, cognitive and emotional control, and reward-based decision mak- ing. Even before it is tasted and absorbed, food can have powerful effects on the brain through visual and olfactory stimuli. This is particularly important for humans in an environment with high food availability and constant reminders of appetizing food by condi- tioned stimuli and the media. Neuroimaging studies have identified several key brain nodes and networks that are differentially affected by visual food stimuli under conditions of fasting, weight loss (induced by both calorie restriction and bariatric surgery), refeeding, overfeeding, exercise, hormone infusion, leanness and obesity, as well as voluntary cognitive control(18). Besides areas obviously involved in processing of visual stimuli, a salience network, associated with the motivation, desire, and craving for food, particularly palatable and high-energy food (alsoreferredtoas“wanting”), consisting of areas in the frontal cortex, ventral and dorsal striatum, and amygdala was found to be more activated in obese versus lean subjects(19). An inhibitory network centered around the dorsolateral prefrontal cortex is activated in subjects instructed to resist craving(20), and this ability of cognitive self-control is greater in patients with the highest weight loss after gastric bypass surgery(21). Furthermore, connectivity be- tween the salience and inhibitory network and other cortical areas (referred to as hedonic controls), as well as the hypothalamus (homeostatic controls) is different in lean versus obese subjects(22).There- fore, the classical dichotomy between homeostatic and hedonic controls has given way to a more unified and integrative or allostatic control system and an effective strategy to prevent or treat obesity based on targeting multiple pathways(17).Regulation of intake of specificnutrientsisstill poorly understood, even though it has direct and powerful implications onmetabolic and cardiovas- cular diseases. Whether the same neural system responsible for controlling total calories is also responsible for controlling intake of carbohydrates, fats, and proteins, and what conveys specificity re- mains to be demonstrated. The neural control of salt intake may serve as a blueprint for deciphering such specificity in the circuitry(23). MAXIMIZING ENERGY EXPENDITURE IN THE MODERN WORLD Besides energy intake, energy expenditure is the other important determinant of energy balance and body weight. Much of the control of energy expen- diture is tightly coupled to the controls of food intake FIGURE 1 Neural Pathways and Systems Controlling Ingestive Behavior and Energy Balance Cortico-limbic systems Reward, Learning & Memory, Executive Control HypothalamusMaster nutrient sensor Incentive motivation Hindbrain Oromotor & autonomic controls, Satiation Ingest choose, select stop, rejectTaste GutAbsorbed and stored nutrients Visual, Olfactory & Auditory Stimuli and Cues Foraging & Procurement Endocrine & Autonomic Outflow Schematic diagram shows the 3 heavily interconnected major brain areas constituting the core processor for the control of ingestive behavior and its relation to the gastrointes- tinal tract and other peripheral organs involved in energy storage and utilization. The hindbrain is mainly concerned with meal size control, because it possesses all the ele- ments to detect sensory information mediated by vagal afferents and circulating fac- tors, and generate motor output associated with the ingestion, digestion, and absorption of food. The corticolimbic system, consisting of large cortical areas, basal ganglia, hip- pocampus, and amygdala, is intimately connected to the hypothalamus and brainstem, and provides the emotional, cognitive, and executive support for ingestive behavior.

The hypothalamus via its connections with the other areas is central for the drive to eat and can potently modulate peripheral organs by autonomic and endocrine outflow.

Reproduced with permission from Berthoud et al.(17). JACC VOL. 71, NO. 1, 2018 Gaddeet al. JANUARY 2/9, 2018:69–84 Pathophysiology and Management of Obesity 71 andembeddedinthepowerful integrative hypotha- lamic energy sensor and regulator of body weight and adiposity. If we accept the notion that adult body weight is actively defended, any increase in energy expenditure will be compensated by increased energy intake. This outcome is supported by many, but not all, human studies using exercise to increase energy expenditure and reduce body weight(24). Thus, se- lective increase of energy expenditure as a strategy to reduce body weight/adiposity would only work if it can be at least partially uncoupled from this compensatory increase in food intake, and decipher- ing the molecular mechanisms involved in coupling energy expenditure to energy intake would go a long way infinding novel obesity therapies. Interestingly, complete uncoupling appears to occur in the activity- based rodent model of anorexia nervosa, where ro- dents paradoxically reduce food intake in the face of increased expenditure in a running wheel(25).Iden- tification of this powerful uncoupling process could provide useful molecular targets for a new class of antiobesity drugs that would prevent the compensa- tory increase in food intake typically observed after a bout of physical activity(24).Alternatively,strategies to cognitively influence this uncoupling process would also be valuable. By not replacing, but enhancing, the effects of physical activity, such an approach would take advantage of the many other beneficial effects of exercise on cardiovascular(26) and mental health(27).

BMI, BODY SHAPE AND COMPOSITION, AND DISEASE RISK The patient’ssizeandshapecanbeusedtoestimate their risk of developing cardiovascular and other noncommunicable chronic diseases. The 2 most available measures of body size are height and weight. Asfirst reported in 1842 by Adolphe Quetelet, weight varies across adults as height squared(28).

Several carefully analyzed large samples of men and women of variable ethnicity have largely confirmed Quetelet’s seminal observation(29). By dividing weight by height squared (kg/m 2), a shape index is created that is independent of height.

The emerging area of nutritional epidemiology 5 decadesagopromptedAncelKeysandhiscolleagues to seek a simple shape index highly correlated with weight, but independent of height(30).Thein- vestigators examined several shape indices relative to adiposity as assessed with underwater weighing and skinfold anthropometry methods. The highest corre- lation between the evaluated adiposity measures and a shape index was for weight/height 2, renamed fromQuetelet’s Index to BMI. Numerous studies that have since examined the relations between BMI and clin- ical outcomes have suggested that disease risk and mortality rates are higher in people with BMI at the low and high ends of population BMI distributions.

Some debate continues on the“optimum”BMI for maintaining health and longevity(31),butthereis near universal acceptance of ranges consistent with good health(32).

BMI ranges for Americans and Europeans for un- derweight, normal weight, overweight, and obese are<18.5, 18.5 to 24.9, 25 to 29.9, and$30 kg/m 2, respectively(32). Various health panels(32,33)have further stratifiedobesitybyBMIcutpoints:30to 34.9 kg/m 2(class I), 35 to 39.9 kg/m 2(class II), $40 kg/m 2(class III),$50 kg/m 2(class IV), and $60 kg/m 2(class V). Recommended cutpoints for overweight and obesity are lower in some Asian nations(34).

Adiposity, definedaspercentfat,increasesasa curvilinear function of BMI. Fat-free mass, including the mass of skeletal muscles and visceral organs, also increases in relation to BMI(29). Left ventricular (LV) mass, including LV wall thickness and internal di- mensions, is larger with greater adiposity, particularly at BMI$30 kg/m 2(35).TherisksofLVhypertrophy, hypertension,CVD,atrialfibrillation, and heart failure (HF), all increase in relation to BMI(2,36–39).HF relative risk for every 5-unit increment in BMI was recently reported as 1.41 with a 95% confidence in- terval (CI) of 1.34 to 1.47 for HF incidence and 1.26 with a 95% CI of 0.85 to 1.87 for HF mortality(39).Ten-and 30-year risk scores in simplified Framingham models include BMI as a CVD predictor variable(40).

BMI as a measure of adiposity and health outcomes at the individual level is often challenged because percent fat and risk for any given BMI can be highly variable secondary to patient sex, age, race/ethnicity, cardiovascularfitness levels, and many other factors (41,42). BMI should be evaluated as part of the initial patient assessment but interpreted with the knowl- edge that additional history, physical examination, and laboratory studies are important at arriving at an accurate risk assessment and treatment plan(32).

Although both cross-sectional and longitudinal ob- servations link BMI with a range of cardiovascular effects and outcomes, some controversy surrounds the“obesity paradox”(43). A number of studies report associationswith obesity as defined by BMI and“protective”effectsinpatientsinwhomHFhas been diagnosed(43). Although the mechanisms un- derlying the obesity paradox are unknown, attention is now being directed at measures of body composi- tion beyond BMI as an adiposity phenotype(43,44). Gaddeet al. JACC VOL. 71, NO. 1, 2018 Pathophysiology and Management of Obesity JANUARY 2/9, 2018:69–84 72 Not all adipose tissue depots are associated with the same magnitude of chronic disease risk, an observation that launched a search for body size and shape measures with predictive value beyond BMI.

Waist circumference is a body size measure that en- circles subcutaneous and visceral adipose tissues, some visceral organs, skeletal muscle, and bone.

Although highly correlated with BMI (Figure 2), waist circumference measurements in some studies add to or exceed the disease risk predictive value of BMI alone(45). As an example, Yusuf et al.(46)found that the odds ratio for acute myocardial infarction in acase-controlstudywassignificant for waist circumference (1.77, 95% CI: 1.59 to 1.97) even after adjustment for BMI (p<0.0001, top vs. bottom quintiles). By contrast, Aune et al.(39)found in a meta-analysis of 23 prospective studies that a 10-cm waist circumference increment (relative risk 1.41 [95%CI:1.34to1.47])anda5-UBMIincrement(1.29 [95% CI: 1.21 to 1.37]) were both associated with increased risk of HF.

The mechanistic basis (Central Illustration)attrib- uted to the associations between waist circumference and risk is the capture of patient variance in mesen- teric and omental adiposity, hepatic steatosis, and other known anatomic changes linked with obesity- related pathophysiological derangements(2).Atpre- sent, the mixed results ofstudies positioning BMI against waist circumference lead us to continue sup- port of the current obesity guidelines suggesting that waist circumference be measured in people with a BMI between 25 and 34.9 kg/m 2to refine risk predic- tion, with levels of>88 cm and>102 cm considered high in women and men, respectively(32).Waist circumference measurements at BMI$35 kg/m 2add little predictive value beyond that of BMI alone because most patients already have waist circumfer- ence levels above the cutpoints(32). FIGURE 2 Interrelations Among Adiposity Biomarkers 70 Men 60 50 40 % Body Fat30 20 10 0 0 5 10 15 20 25 30 BMI (kg/m 2) 35 40 45 50 55 60 65 70 75 Women 70 60 50 40 % Body Fat30 20 10 0 0 5 10 15 20 25 30 BMI (kg/m 2) 35 40 45 50 55 60 65 70 75 Waist Circumference (cm) 225 200 UW NW OW OB I II III VIV 175 150 125 100 75 50 25 BMI (kg/m 2) 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75I II III V IV UW NW OW OB Waist Circumference (cm) 225 200 175 150 125 100 75 50 25 BMI (kg/m 2) 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 (Upper panels)Percent (%) body fat measured by dual-energy x-ray absorptiometry versus BMI in participants of the National Health and Nutrition Survey (1999 to 2006). The data werefit with polynomial regression lines (R 2men, 0.61; women, 0.68; both p<0.001). Note the curvilinear relation between body mass index (BMI) and % fat and the wide range of % body fat at any given level of BMI.(Lower panels)Waist circumference versus BMI in the same group of subjects as in theupper panels(R 2men 0.84; women 0.80; both p<0.001).Horizontal linesare shown at waist circumference cutpoints (>102 cm men,>88 cm women), above which health risks increase within the BMI range 24.9 to 34.9. No additional waist circumference predictive value is present with BMI levels$35.Vertical linesidentify BMI ranges for underweight (UW), normal weight (NW), overweight (OW), and obesity (OB) classes I to V. Definitions of severe obesity are variable in the medical literature. JACC VOL. 71, NO. 1, 2018 Gaddeet al. JANUARY 2/9, 2018:69–84 Pathophysiology and Management of Obesity 73 CENTRAL ILLUSTRATION Adiposity-Associated Major Risk Factors for Developing HF and Other Weight-Related Comorbidities Gadde, K.M. et al. J Am Coll Cardiol. 2018;71(1):69–84.

Increased plasma levels of free-fatty acids and cytokines, intracellular non-adipose tissue lipids (e.g., liposomes), and ectopic adipose tissuedepots (e.g., within the visceral compartment) can contribute to systemic inflammation, insulin resistance, and overactivity of the sympathetic nervous system. The metabolic and anatomic effects of excess adiposity can lead to the development of type 2 diabetes, nonalcoholic fatty liver disease, obesity-related dyslipidemias, high blood pressure, and osteoarthritis. The cascade of these pathophysiological mechanisms and associated diseases are the main contributors to obesity-related heart failure. HF¼heart failure; RAAS¼renin-angiotensin aldosterone system; SNS¼sympathetic nervous system. Gaddeet al. JACC VOL. 71, NO. 1, 2018 Pathophysiology and Management of Obesity JANUARY 2/9, 2018:69–84 74 Several additional shape indices that include waist circumference measurements are available that purportedly show improved associations with percentbodyfat,visceraladiposity,healthrisks, and mortality rates than BMI or waist circumference alone. These include“a body shape index”(47)and the“body roundness index”(48). Other measures such as waist-to-hip circumference ratio, waist-to- height ratio, and body adiposity index have also been reported to be associated with cardiovascular risk factors in some studies, but not in others (46,49,50).

Although body weight, height, and circumferences are the main somatic measures that can be applied in the clinical setting, more advanced technologies can probe other lipid depots associated with CVD risk. In addition to within the visceral compartment, adipose tissue is found embedded in discrete locations around the myocardium and kidney, within skeletal muscles, and in several other anatomic sites(2,51).Associa- tionsbetweenthesizeoftheseadiposetissuede- posits and clinical outcomes have been reported with quantification by magnetic resonance imaging (MRI), computed tomography, and echocardiography(52).

Small lipid droplets, the size of which can be quan- tified using MRI, also reside within the cytoplasm of cardiomyocytes, skeletal muscle cells, hepatocytes, and pancreatic b-cells(52). These ectopic lipid de- positshavealsobeenlinkedwithpathologicalstates that include cardiomyopathies, liver diseases, and adult-onset diabetes(53).

Relatively small thermogenic brown adipose tissue deposits and beige adipocytes are present to a varying extent in adults and can be quantified with imaging methods such as positron-emission tomography and MRI(51). Thermogenic brown adipocytes are found within supraclavicular, mediastinal, and other de- posits, and are characterized by mitochondria that have uncoupling protein-1 that can be stimulated through cold exposure and sympathetic nervous system mechanisms(2). Beige adipocytes, found embedded within white adipose tissue, are also thermogenic and can be activated by exercise, cold exposure, and hormonal actions(2). MEDICAL EVALUATION OF PATIENTS WITH OBESITY Recent practice guidelines for the management of obesity(32)recommend assessment of BMI at least annually for all adult patients seen in clinical prac- tices. Waist circumference measurement provides additional information to determine the risk of comorbidities, especially CVD risk. For patients withoverweight and obesity, standard assessment in- cludes medical history including medical conditions and medications that could be contributing to weight gain, sleep apnea, history of weight gain, family his- tory of obesity, dietary and physical activity habits, environmental and cultural factors impacting weight, pattern of weight changes over the years, and history of weight loss attempts; and physical examination, blood pressure assessment, and fasting glucose and lipid measures. For patients receiving medications that are known to induce weight gain, alternative treatment choices should be considered, when possible. MANAGEMENT OF PATIENTS WITH OBESITY Weight loss should be recommended for all patients with obesity and also for overweight patients in the presence of comorbid conditions such as pre- diabetes, diabetes, hypertension, and dyslipidemia.

For most patients who need to lose weight for medi- calreasons,theinitialgoalshouldbe5%to10% weight loss over thefirst 6 months(32). A common theme of various professional guidelines developed in the United States, Europe, and elsewhere for management of patients with obesity is the emphasis on a multimodal lifestyle intervention that includes dietary changes, increase in physical activity, and behavior modification. Pharmacotherapy, medical devices, and bariatric surgery are other treatment options for patients needing additional interventions.

It is important to recognize that currently, the diag- nosis of obesity is made with a formula that uses height and weight, not on the basis of a specific biomarker. Hence, the contributing causes of obesity and its pathophysiology might not be the same for all patients. Therefore, thereis considerable heteroge- neity of response(54)to approved and established treatments, whether these are lifestyle modifications, drug therapies, or surgical interventions. In numerous analyses of the moderators and mediators of response to therapeutic interventions for obesity, themostconsistentfactorthatappearstopredict long-term weight loss success is the rate of initial weight loss(55).Hence,whenemployingnonsurgical interventions for obesity, it would be prudent to choose an alternative or augmentation approach when the current modality has yielded less than optimal results after 3 to 4 months.

LIFESTYLE INTERVENTIONS To successfully achieve clinically meaningful weight loss of 5% to 10%, a comprehensive, intense lifestyle intervention is needed that includes at least 14 JACC VOL. 71, NO. 1, 2018 Gaddeet al. JANUARY 2/9, 2018:69–84 Pathophysiology and Management of Obesity 75 in-person sessions within 6 months(32). Effective weight loss interventions, which include dietary modification via the prescription of a calorie-reduced diet, increased exercise or physical activity, and behavioral strategies to foster adherence to dietary and physical activity recommendations, can be delivered via individual or group sessions, with both approaches being effective at promoting weight loss.

Common behavioral strategies include self- monitoring of diet and physical activity, regular or daily weighing, behavioral contracts, goal setting, and stimulus control (e.g., limiting the locations where one eats). Comprehensive lifestyle in- terventions that incorporate portion-controlled foods and daily weighing are effective at promoting weight loss over the short and long term(56,57). Face-to-face counseling is considered most effective, with elec- tronic treatments receiving moderate strength of evidence, and telephone-based treatments having low evidence(32).

After achieving initial weight loss, long-term weight loss maintenance remains challenging and continued participation in comprehensive weight loss treatment for 1 or more years is necessary(32).The focus of treatment during follow-up is maintaining adherence to dietary and physical activity recom- mendations. Weight loss maintenance is facilitated by continued and regular personal contact with pro- fessionals, rather than by more passive approaches, such as newsletters(56). Continued use of portion- controlled foods as part of a healthy meal plan also facilitates long-term weight loss maintenance(57).A higher level of physical activity is generally needed for weight maintenance(58), and it is important to recognize that exercise, independent of weight loss, confers significant health effects(59).

Internet-based weight loss treatments are avail- able, though many are passive and low in treatment intensity, which likely limits their efficacy. For example, randomized participation in a weight loss program delivered via a commercial website resulted in weight loss of only 1% after 4 and 12 months(60).

Maintaining utilization of Internet-based in- terventions has proven to be challenging(61).None- theless, Internet-based interventions that promote more intensive treatment have been found to be more efficacious(62,63).

Weight loss applications or“apps”for smart- phones and other portable devices are a logical extension of Internet-based interventions. Weight loss apps are very popular, yet only a small percent- age (w15%) included 5 or more evidence-based practices for weight management(64). Despite theirpopularity, weight loss apps have limited evidence of efficacy(65), though smartphone-based approaches and apps that rely on evidence-based weight loss principles have been found to promote clinically meaningful weight loss that is commensurate with the amount of weight loss observed in face-to-face interventions(66). EFFECTSOFWEIGHTLOSSACHIEVEDWITH LIFESTYLE INTERVENTIONS ON CVD Weight loss of 5% to 10% results in improvements in cardiometabolic risk factors(32).TheDPP(Diabetes Prevention Program) study is the largest and longest randomized controlled trial (RCT) to date that exam- ined the effect of weight loss achieved with diet and exercise on the onset of diabetes among participants who were at risk(67). The study randomized 3,234 patients with pre-diabetes to an intensive lifestyle intervention (ILI) to promote weight loss, metformin, or placebo. Over a mean follow-up of 2.8 years, the ILI, metformin, and placebo groups lost 5.6, 2.1, and 0.1 kg, respectively. The ILI and metformin reduced the incidence of diabetes by 58% and 31%, respec- tively, relative to placebo. At the 10-year follow-up from randomization, the metformin group main- tained their modest weight loss, whereas the ILI group regained much of their initial weight loss(68).

Importantly, the ILI and metformin groups reduced diabetes incidence by 34% and 18%, respectively, compared with placebo, cumulatively over the 10-year period, although the incidence rates were similar among the 3 groups in the 5.7-year follow-up when the ILI group experienced weight regain. These results emphasized the importance of weight loss, as well as weight loss maintenance, on diabetes risk.

The Look AHEAD (Action for Health in Diabetes) trial examined the effect of weight loss with lifestyle intervention among patients with established T2D. A total of 5,145 overweight/obese adults, 45 to 74 years of age, with T2D were randomized to an ILI or a control group consisting of diabetes support and ed- ucation. At 1 year, patientsassigned to ILI had greater weight loss (8.6% vs. 0.7%), greater reduction in glycosylated hemoglobin (HgA 1c) (7.3% to 6.6% vs.

7.3% to 7.2%), improvedfitness level, and greater improvements in a host of disease risk factors, such as blood pressure and lipid profile(69). After a median 10-year follow-up when the study was stopped on the basis of a futility analysis(70),theILIgrouphad greater weight loss (6.0% vs. 3.5%) and greater reductions in HgA 1c, but there was no difference between groups (1.83 vs. 1.92 events per 100 Gaddeet al. JACC VOL. 71, NO. 1, 2018 Pathophysiology and Management of Obesity JANUARY 2/9, 2018:69–84 76 person-years;hazardratio0.95;95%CI:0.83to1.09; p¼0.51) in major adverse cardiovascular events (MACE) (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitali- zation for angina). These results suggested that a modest weight loss (2.5% greater weight loss relative to control) via diet and exercise alone might not be sufficient to reduce adverse cardiovascular events at the group level, though the use of statins and improved medical management of CVD risk factors might have diminished the differences between the groups. A recent analysis found that baseline HgA 1c and general health distinguished participants who didanddidnotbenefit from the intervention(71).

This analysis revealed that 85% of participants in the intervention group averted cardiac events, but 15% had increased rate of events, which might have negatively affected the main study results.

EFFECT OF DIETS ON CVD RISK FACTORS Some studiesfind that diet type affects disease risk factors even in the context of similar weight loss. For example, a low-carbohydrate diet resulted in larger improvements in high-density lipoprotein and tri- glycerides after 1 year compared with a low-fat con- ventional diet, even though both diets yielded similar weight loss(72).Alargesubsequentstudyfound similar results over 2 years(73).Specifically, both a low-carbohydrate and a low-fat diet promoted weight loss ofw7% over 2 years, but the low-carbohydrate diet was associated with greater increases in high-density lipoprotein levels and had more adverse effects. Nevertheless, a meta-analysis of low- carbohydrate high-protein diets found that long-term benefits of such diets are marginal(74),and some authors have argued to end the debate over the “best diet”and to focus on adherence to dietary and exercise recommendations, which is the most consistent predictor of weight loss(75). It is unlikely that any single diet works best for all people, and it is conceivable that diet type interacts with personal factors to affect responses to different diets, as indi- cated by interest in personalized or precision medi- cine. At least 1 study has demonstrated meaningful differences in weight loss in response to diets based on baseline levels of fasting plasma glucose; specif- ically, people with elevated fasting plasma glucose levels lose more weight and better maintain weight loss with low glycemic load diets that include more whole grains andfiber(76).

The DASH (Dietary Approaches to Stop Hyper- tension) study compared the effects of 3 diets for8 weeks on blood pressure(77).The3dietswere a control diet, a diet richin fruits and vegetables, and a“combination diet”rich in fruits, vegetables, and low-fat dairy products with reduced saturated and total fat. Relative to control diet, the combi- nation diet ( 5.5 and 3.0 mm Hg for systolic and diastolic, respectively) and the fruit and vegetable diet ( 2.7 and 1.9 mm Hg) reduced blood pressure.

Similar results were obtained after adjusting for weight change. For the combination diet, the effect was larger among subjects with hypertension at baseline ( 11.4 and 5.5 mm Hg vs. control diet for systolic and diastolic blood pressure, respectively).

Mediterranean diets have been found to protect against cardiovascular disease in epidemiological studies. A large RCT tested the effect of 2 Mediterra- nean diets (one that was supplemented with extra- virgin olive oil, and another that was supplemented with mixed nuts) compared with a control diet on the primary prevention of cardiovascular events(78) among 7,447 subjects 55 to 80 years of age with a mean BMI of 30 and high CVD risk. After a median follow-up of 4.8 years, relative to the control diet, both Mediterranean diets reduced the incidence of MACE (hazard ratios 0.70 and 0.72).

In summary, weight loss achieved with diet and exercise improves cardiometabolic risk factors, re- duces the incidence of diabetes, and improves gly- cemic control(67–69)in patients with pre-diabetes and diabetes, although failing to reduce MACE at the group level among patients with type 2 diabetes after 10 years in the Look AHEAD trial(70);arecentpost hoc analysis, however, found that 15% of participants in the intervention group who were characterized by mild or well-treated diabetes and a negative percep- tion of their health had increased rate of events, which might have contributed to the failure tofind a mean group effect(71).Bloodpressurecanbe improved, even without large weight loss, by eating a diet that is high in fruits, vegetables, and low-fat dairy,andlowinsaturatedfatandtotalfat(77); however, the long-term effects of such a diet on morbidity and mortality have not been examined. For prevention of MACE in patients at high risk, the evi- dence to date supports Mediterranean diets supple- mented with olive oil or nuts(78).Finally,the2013 Guidelines for the Management of Overweight and Obesity in Adults specify that clinicians should consider the effects of weight loss diets on all risk factors and should work with nutrition professionals to prescribe a weight loss diet that addresses the needs of the individual patient(32). JACC VOL. 71, NO. 1, 2018 Gaddeet al. JANUARY 2/9, 2018:69–84 Pathophysiology and Management of Obesity 77 PHARMACOTHERAPY Pharmacotherapy should be a consideration for pa- tients with a BMI of$30 kg/m 2and BMI of$27 kg/m 2 with weight-related comorbidities such as T2D(32), and is the next logical therapeutic approach for pa- tients who have historically failed to benefitfrom lifestyle modification approaches and for those with difficulty maintaining weight loss over the long term.

Patients should be counseled about what to expect from medications, including the beneficial and adverse effects. With the exception of orlistat, all currently approved antiobesity medications help pa- tients limit their caloric intake and achieve better compliance with their diet plan. Reduction in energy intake is achieved primarily via enhancement of satiety and reduction in hunger and food cravings (79). Because medications do not modify the choices patients make with regard to food selection, it is still important to counsel the patients about lifestyle changes, such as avoiding energy-dense foods. As is the case with all nonsurgical weight loss in- terventions, there is some weight regain when currently approved antiobesity medications are continued beyond a year, and more weight is regained when the medication is stopped(80).

Because obesity is a chronic condition, when a patient is continuing to benefitfromanantiobesitymedica- tion and tolerating it well, and if there are no safety issues that limit chronic use, consideration should be given to continuing the medication as long as benefit outweighs risk. Clinical trials data provide very little guidance to the clinician with regard to making the right selection for a specificpatient.Weightlossin thefirst 3 to 4 months is the only consistent predictor of further success with all currently available anti- obesity medications. In most cases, if 5% weight loss is not achieved after 3 to 4 months, discontinue drug therapy, barring a few cases when there is significant improvement in comorbidities despite marginal weight loss(80).

Four medications—phentermine, diethylpropion, phendimetrazine, and benzphetamine—all structur- ally related to amphetamine, and approved for short- term use only, have been available for well over 50 years in the United States. Phentermine is by far the most prescribed antiobesity medication in the United States, perhaps due to its low cost and ease of use. In two recent 12-week RCTs, both conducted in Korea, phentermine 30 mg/day was associated with >6% weight loss relative to placebo(81,82).Ina28- week RCT conducted in the United States, phenter- mine 15 mg/day led to 4.4% placebo-subtractedweight loss(83). Common adverse effects of phen- termine and other drugs in this class are dry mouth, constipation, and insomnia. There is some abuse po- tential with these drugs, more so with phendime- trazine and benzphetamine.

Of the 5 medications (Table 1) currently approved in the United States for long-term weight manage- ment, orlistat is the only one with a purely peripheral mechanism of action. Available since 1999 in many countries, it is a gastric and pancreatic lipase inhibitor that reduces absorption of fat in the gut, thereby decreasing caloric intake. In RCTs of 1- to 2-years duration, orlistat treatment led tow3% weight loss relative to placebo(84,85). In a 4-year RCT, orlistat treatment yieldedw2.4% placebo-subtracted weight loss and decreased incidence (6.2% vs. 9.0%) of dia- betes among patients withobesity and pre-diabetes (86). Currently, orlistat is the only weight loss drug approved for use in adolescents. Despite its good safety profile, orlistat’s use is limited by its gastro- intestinal adverse effects, including oily stools/spot- ting,flatus, and fecal urgency. Patients should be advised to take a daily multivitamin supplement to make up for reduced absorption of fat-soluble vitamins.

Lorcaserin is a serotonergic drug with selective agonism for 5-HT 2C receptors. In 3 RCTs, lorcaserin treatment achieved 3.0% to 3.6% placebo-subtracted weight loss at 1 year(87–89).Whenlorcaserinwas continued for the second year, nearly one-half of the weight lost was regained(87). Prescribing informa- tion for lorcaserin recommends discontinuation of the drug if weight loss is<5% after 12 weeks. Yet, in a recently published trial, only 28% of patients on lor- caserin achieved 5% weight loss at 12 weeks(90).

Overall, lorcaserin is tolerated well, but its efficacy is marginal. In light of the observations of valvular heart disease in patients treated with the withdrawn sero- tonergic drugs fenfluramine and dexfenfluramine, echocardiographic assessments were performed in RCTs of lorcaserin revealing a relative risk of 1.16 (95% CI: 0.81 to 1.67) for the drug. The Food and Drug Administration (FDA) required a cardiovascular out- comes trial (CVOT), which is underway.

Liraglutide is a glucagon-like peptide-1 (GLP-1) re- ceptor agonist, approved at 1.8 mg for T2D and at a higher dose of 3.0 mg for obesity. It is administered as daily subcutaneous injection. Liraglutide results in 4.0% to 5.4% placebo-subtracted weight loss at 1 year (91,92). In one of the trials in which double-blind treatment was extended for an additional 2 years, 2.0% of pre-diabetic patients on liraglutide developed diabetes compared with 6.2% on placebo(93).Ina Gaddeet al. JACC VOL. 71, NO. 1, 2018 Pathophysiology and Management of Obesity JANUARY 2/9, 2018:69–84 78 weight maintenance trial, obese patients who lost an average 6.0% with a low-calorie diet, achieved an additional 6.2% weight loss with liraglutide (vs. 0.2% for placebo) over a year(94).ACVOTwithamedian follow-up of 3.8 years demonstrated lower MACE incidence with liraglutide 1.8 mg among patients with T2D(95). Nausea and diarrhea are very common with liraglutide, especially in thefirst month.

Phentermine/topiramate (PHEN/TPM) is thefirst combination therapy approved in the United States for the treatment of obesity in 2012. Of all the currently approved antiobesity drugs, PHEN/TPM has themostrobustefficacy, with a placebo-subtracted 1-year weight loss of 8.6% to 9.3% at the 15/92 mg dose in 2 large RCTs(96,97). Topiramate, an antiepi- leptic drug, is reported to carry teratogenic risk of oral clefts; therefore, a negative pregnancy test is required for women of childbearing potential before starting PHEN/TPM and monthly thereafter. Paresthesia is the most common adverse effect of PHEN/TPM, espe- cially at the start of therapy. Adverse effects related to mood and memory need close attention of the clinician. The complex dose titration of PHEN/TPM and its potential for inducing cognitive and mood- related adverse effects requires a skilled clinician.

Naltrexone/bupropion (NB) is the second combi- nation therapy for obesity, approved in late 2014.In 1-year RCTs, at the recommended dose of 32/360 mg/day, NB is associated with 3.3% to 4.8% placebo-subtracted weight loss(98–100).Weightloss with NB is not associated with improvement in blood pressure or lipids. Nausea is a very frequent and bothersome adverse effect of NB therapy, leading to high dropout rates in RCTs. NB is also associated with heart rate and blood pressure increases that con- cerned the FDA to require a CVOT, which unfortu- natelywasstoppedduetoinappropriatedisclosureof data by the sponsor while the trial was ongoing(101).

NB requires complex dose titration.

In summary, 5 medications are currently approved in the United States for long-term management of obesity, with placebo-subtracted weight loss ranging fromw9% for PHEN/TPM tow3% for lorcaserin and orlistat(102). MEDICAL DEVICES Six FDA-approved medical devices (Table 2), including a laparoscopic adjustable gastric band (LAGB), are available for obesity management. We will discuss the LAGB procedure in the bariatric sur- gery section.

Three intragastric balloons are approved for use upto6monthstoassistweightlossamongpatients TABLE 1 Drugs for Long-Term Weight Management Drug1-Year Weight Loss, Placebo-Subtracted Adverse Events Precautions Contraindications and Limitations Orlistatw3% Fecal urgency, fecal incontinence, flatus with discharge, oily spottingDaily multivitamin to make up for malabsorption of fat-soluble vitaminsChronic malabsorption syndrome; cholestasis Lorcaserin 3.0% to 3.6% Headache, dizziness, fatigue, nausea, dry mouth, constipation, cough, hypoglycemia in patients with diabetesMonitor for symptoms of serotonin toxicity. Monitor for signs and symptoms of valvular heart disease.Safety of use in patients taking antidepressants is unknown Liraglutide 4.0% to 5.4% Nausea, vomiting, diarrhea, constipation, dyspepsia, abdominal pain, headache, fatigue, hypoglycemia, increased lipaseCauses thyroid C-cell tumors in rats and mice. Discontinue if pancreatitis is suspected.Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Do not use with insulin or other GLP-1 agonists.

Phentermine/topiramate 8.6% to 9.3% Paresthesia, dizziness, insomnia, dysguesia, constipation, dry mouthSmall increase in heart rate. Monitor electrolytes to detect metabolic acidosis and elevated creatinine.

Monitor closely for depression, anxiety, and memory problems.Glaucoma; hyperthyroidism; within 2 weeks of taking MAOIs.

REMS requires negative pregnancy test before treatment and monthly thereafter to reduce the risk of teratogenicity Naltrexone/bupropion 3.3% to 4.8% Nausea, vomiting, headache, dizziness, insomnia, dry mouth, diarrheaMonitor for suicidal ideation and behavior. Monitor for increases in heart rate and blood pressure. Rare cases of hepatotoxicityUncontrolled hypertension; seizure disorders; chronic opioid use; anorexia nervosa or bulimia; during withdrawal from alcohol, barbiturates, benzodiazepines, and antiepileptic drugs; within 2 weeks of taking MAOIs; coadministration with other bupropion-containing products Pregnancy is a contraindication for all. Lorcaserin and phentermine/topiramate are Schedule IV controlled substances. For orlistat, weight loss is based on various meta-analyses. For all others, weight losses shown are from phase 3 trials. When multiple doses were tested, the weight loss shown is for the most effective dose.

MAOIs¼monoamine oxidase inhibitors; REMS¼risk evaluation and mitigation strategy.

JACC VOL. 71, NO. 1, 2018 Gaddeet al. JANUARY 2/9, 2018:69–84 Pathophysiology and Management of Obesity 79 withBMIof30to40kg/m 2.Orbera(ApolloEndo- surgery, Austin, Texas) is a single balloon that is introduced in the stomach via an endoscopic pro- cedure. Once in place, the balloon isfilled with 400 to 700 ml of saline to expand. ReShape (ReShape Medical, San Clemente, California) is similar except it uses 2 balloons. Obalon (Obalon Therapeutics, Carlsbad, California) is a swallowable capsule that opens once inside the stomach and the balloon is filled with air via an inflation catheter. All 3 gastric balloons are for use up to 6 months only. Some weight is regained in the months following removal of the devices.

The Maestro Rechargeable System (EnteroMedics, St. Paul, Minnesota) is a form of vagal nerve blockade that is thought to work by suppressing neural communication between the stomach and the brain, leading to increased satiety and decreased caloric intake(103). Electrodes placed on the trunks of the vagus nerve at the gastroesophageal junction are connected to a rechargeable pulse generator called a neuroregulator, which is secured subcutaneously.

Obviously, it is more invasive than the gastric bal- loons and requires surgeons skilled in laparoscopic procedures.

AspireAssist (Aspire Bariatrics, King of Prussia, Pennsylvania) is a device that consists of a gastro- stomy tube that connects to a skin port outside of the abdomen. The patient attaches an external connectorand tubing to the skin port, opens the port valve, and flushes out food 20 to 30 min after each meal. To prevent obstruction in the tube, food needs to be thoroughly chewed. Serum electrolytes should be monitored. Some patients may need potassium sup- plementation. For a detailed discussion of medical devices for weight management, refer to a recent comprehensive review by Lee and Dixon(104). BARIATRIC SURGERY Bariatric surgery has gained considerable popularity in the past decade, with about half a million proced- ures performed annually worldwide(105).Surgeryis indicated for patients with BMI$40 kg/m 2 and$35 kg/m 2inthepresenceofweight-related comorbidities such as T2D, with lower BMI cutoffs for LAGB. Common surgical procedures are sleeve gastrectomy (SG) (58%), Roux-en-Y gastric bypass (RYGB) (38%), LAGB (3%), and biliopancreatic diver- sion with duodenal switch (1%), for which minimal outcomes data exist(106). RYBG is associated with themostweightlossinlong-termfollow-upstudies (Table 3). In one study of 2,410 patients, weight losses at 4-year follow-up for RYGB, SG, and LAGB were 27%, 18%, and 11%, respectively(107).

LAGB is the least invasive of the 4 procedures and involves laparoscopic placement of an adjustable sil- iconebandaroundthegastricfundus.Advantagesof TABLE 2 Medical Devices for Weight Management Device IndicationsWeight Loss vs.

Control Adverse Events Contraindications Intragastric balloons Orbera BMI 30–40 kg/m 2 Up to 6 months10.2% vs. 3.3% Abdominal pain, bloating, nausea Rare cases of gastrointestinal obstruction or perforationPrior GI surgery, inflammatory GI disease, gastroduodenal ulcers, large hiatal hernia, esophageal structural abnormalities, esophageal motility disorders, gastric mass, severe coagulopathy, hepatic insufficiency or cirrhosis, serious mental disorders, alcoholism or drug addiction, unable to use proton pump inhibitors during device use, or receiving aspirin, NSAIDs, or blood thinners ReShape Duo 6.8% vs. 3.3% Obalon 6.6% vs. 3.4% (at 6 months) Electrical stimulation systems Maestro BMI 35–45 kg/m 2 Long-term use9.2% vs. 6.0%* (at 1 yr)Pain at neuroregulator disc site, heart burn, abdominal pain, nausea, belchingCirrhosis, portal hypertension, esophageal varices, large hiatal hernia Gastric emptying systems AspireAssist Age>22 yrs BMI 35–55 kg/m 2 Long-term use12.1% vs. 3.5% (at 1 yr)Pain, abdominal discomfort, nausea, change in bowel habits, electrolyte abnormalities, irritation or infection at sitePrior GI surgery, esophageal stricture, severe gastroparesis, inflammatory GI disease, severe ulcers or bleeding conditions, or gastric masses, chronic abdominal pain, coagulation disorders, moderate-to-severe anemia, hepatic insufficiency or cirrhosis, serious pulmonary or cardiovascular disease, eating disorders, physical or mental disability that could affect compliance, poor general health *Control was sham stimulation.

BMI¼body mass index; GI¼gastrointestinal; NSAID¼nonsteroidal anti-inflammatory drug.

Gaddeet al. JACC VOL. 71, NO. 1, 2018 Pathophysiology and Management of Obesity JANUARY 2/9, 2018:69–84 80 thisprocedurearethatitcanbedoneinanoutpatient setting, has the least complications, and is reversible.

Twobanddevices,Lap-Band(ApolloEndosurgery) and Realize (Ethicon, Somerville, New Jersey), were FDA approved. The Realize Band was discontinued in early 2017. LAGB results in 14% to 30% weight loss after a year(108). Although weight regain is more common with LAGB relative to other procedures, there is long-lasting benefit for some patients (104,108).

In the SG procedure, a staple line is placed along the greater curvature of the stomach followed by removal of approximately 80%ofthelateralaspectof the stomach in a vertical fashion. SG has gained popularity in the past decade due to procedural ease and less frequency of serious complications(106).

In RYGB, a small stomach pouch is created in the upper stomach. The jejunum is then divided and the middle part of it, the Roux limb, is connected to the stomach pouch, thus allowing food to bypass most ofthestomach.Theprocedureismoredemandingthan SG and has a slightly higher rate of complications, but is associated with the largest sustained weight loss with a very high rate of remission of T2D(109,110).

Bariatric surgery is now endorsed by leading dia- betes organizations as an effective intervention for T2D, by inclusion in the treatment algorithm(111)with a recommendation for patients with class III obesityand for those with class II obesity whose hyperglyce- mia is inadequately controlled by lifestyle and medi- cal therapy. Bariatric surgery also leads to a significant reduction in the prevalence of hypertension and dys- lipidemia over 2-year follow-up, although data from RCTs of longer follow-up are inadequate(112).Serious complication rates for bariatric surgery rates have decreased over the years, with recent studies showing perioperative morbidity and mortality rates of 5% and 0.3%, respectively(113,114). CONCLUSIONS Obesity, besides impairing quality of life, is associated with numerous chronic diseases. Fortunately, weight reduction improves management of many of these diseases, especially T2D. Although global obesity prevalence has not decreased, more therapeutic op- tions are available today, thus improving management of patients with obesity and related comorbidities.

ACKNOWLEDGMENT The authors thank Katelyn Daigle for editorial assistance in preparing the manuscript. ADDRESS FOR CORRESPONDENCE: Dr. Kishore M.

Gadde, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70810.

E-mail:[email protected]. TABLE 3 Bariatric Surgery ProcedureWeight Loss*Pros and Cons† 1Year$6Years Pros Cons LAGB 14% to 30% 13% to 14% Shortoutpatientprocedure Adjustable and reversible Low rate of complications Low risk of malabsorption of vitamins and minerals Less long-term weight loss than other bariatric procedures High rates of reoperation for band slippage, obstruction, or erosion Possible progressive dilation of esophagus due to band obstruction RYGB 23% to 43% 25% to 28% Large and sustained long-term weight loss High rates of T2D remission Complex procedure requiring skill Requires hospital stay of 1 to 2 days Higher rate of perioperative com- plications compared with LAGB and SG Late complications that include marginal ulcer, internal hernia, and small bowel obstruction.

Needs long-term vitamin and mineral supplementation Sleeve gastrectomy 20% to 28% 22% Significant weight loss Less complex procedure compared with RYGB CanbeconvertedtoRYGBatalater stage Less risk of vitamin and mineral deficiencies Somewhat higher risk of weight regain compared with RYGB Higher rate of complications compared with LAGB Post-operative GERD Late complications that include chronic obstructive symptoms Biliopancreatic diversion with duodenal switch is not listed in the table because it accounts forw1% of bariatric surgeries. *Source of data: Piché et al.(108).†Adapted from Schauer et al.(113).

GERD¼gastroesophageal reflux disease; LAGB¼laparoscopic adjustable gastric banding; RYGB¼Roux-en-Y gastric bypass; SG¼sleeve gastrectomy; T2D¼type 2 diabetes.

JACC VOL. 71, NO. 1, 2018 Gaddeet al. JANUARY 2/9, 2018:69–84 Pathophysiology and Management of Obesity 81 REFERENCES 1.The GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:13–27.

2.Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and management of obesity.

N Engl J Med 2017;376:1492.

3.Mozaffarian D, Ludwig DS. The 2015 US Dietary Guidelines: lifting the ban on total dietary fat.

JAMA 2015;313:2421–2.

4.de Souza RJ, Bray GA, Carey VJ, et al. Effects of 4 weight-loss diets differing in fat, protein, and carbohydrate on fat mass, lean mass, visceral ad- ipose tissue, and hepatic fat: results from the POUNDS LOST trial. Am J Clin Nutr 2012;95:

614–25.

5.Schwartz MW, Seeley RJ, Zeltser LM, et al.

Obesity pathogenesis: an Endocrine Society sci- entific statement. Endocr Rev 2017;38:267–96.

6.Hall KD, Guo J. Obesity energetics: body weight regulation and the effects of diet composition.

Gastroenterology 2017;152:1718–27.e3.

7.Fall T, Mendelson M, Speliotes EK. Recent ad- vances in human genetics and epigenetics of adiposity: pathway to precision medicine?

Gastroenterology 2017;152:1695–706.

8.Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015;518:197–206.

9.Angulo MA, Butler MG, Cataletto ME. Prader- Willi syndrome: a review of clinical, genetic, and endocrinefindings. J Endocrinol Invest 2015;38:

1249–63.

10.Speakman JR. Thrifty genes for obesity and the metabolic syndrome: time to call off the search? Diab Vasc Dis Res 2006;3:7–11.

11.Speakman JR. Thrifty genes for obesity, an attractive butflawed idea, and an alternative perspective: the’drifty gene’hypothesis. Int J Obes (Lond) 2008;32:1611–7.

12.Barker DJ. Developmental origins of adult health and disease. J Epidemiol Community Health 2004;58:114–5.

13.Cordero P, Li J, Oben JA. Epigenetics of obesity: beyond the genome sequence. Curr Opin Clin Nutr Metab Care 2015;18:361–6.

14.Brobeck JR. Mechanism of the development of obesity in animals with hypothalamic lesions.

Physiol Rev 1946;26:541–59 .

15.Sternson SM, Eiselt AK. Three pillars for the neural control of appetite. Annu Rev Physiol 2017; 79:401–23.

16.Berthoud HR, Munzberg H. The lateral hypo- thalamus as integrator of metabolic and environ- mental needs: from electrical self-stimulation to opto-genetics. Physiol Behav 2011;104:29–39.

17.Berthoud HR, Munzberg H, Morrison CD.

Blaming the brain for obesity: Integration of he- donic and homeostatic mechanisms. Gastroenter- ology 2017;152:1728–38.18.Carnell S, Gibson C, Benson L, et al. Neuro- imaging and obesity: current knowledge and future directions. Obes Rev 2012;13:43–56.

19.Scholtz S, Miras AD, Chhina N, et al. Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding. Gut 2014;63:891–902.

20.Hollmann M, Hellrung L, Pleger B, et al.

Neural correlates of the volitional regulation of the desire for food. Int J Obes (Lond) 2012;36:

648–55.

21.Goldman RL, Canterberry M, Borckardt JJ, et al. Executive control circuitry differentiates degree of success in weight loss following gastric- bypass surgery. Obesity (Silver Spring) 2013;21:

2189–96.

22.Wijngaarden MA, Veer IM, Rombouts SA, et al.

Obesity is marked by distinct functional connec- tivity in brain networks involved in food reward and salience. Behav Brain Res 2015;287:127–34.

23.Berthoud HR, Munzberg H, Richards BK, et al.

Neural and metabolic regulation of macronutrient intake and selection. Proc Nutr Soc 2012;71:

390–400.

24.Franz MJ, VanWormer JJ, Crain AL, et al.

Weight-loss outcomes: a systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up. J Am Diet Assoc 2007; 107:1755–67.

25.Madra M, Zeltser LM. BDNF-Val66Met variant and adolescent stress interact to promote sus- ceptibility to anorexic behavior in mice. Transl Psychiatry 2016;6:e776.

26.King NA, Horner K, Hills AP, et al. Exercise, appetite and weight management: understanding the compensatory responses in eating behaviour and how they contribute to variability in exercise- induced weight loss. Br J Sports Med 2012;46:

315–22.

27.Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci 2008;9:58–65.

28.Quetelet LAJ, Smibert T, editors. A Treatise on Man and the Development of His Faculties [Knox R, translator]. Edinburgh, UK: William and Robert Chambers, 1842.

29.Heymsfield SB, Peterson CM, Thomas DM, et al. Scaling of adult body weight to height across sex and race/ethnic groups: relevance to BMI. Am J Clin Nutr 2014;100:1455–61.

30.Keys A, Fidanza F, Karvonen MJ, et al. Indices of relative weight and obesity. J Chronic Dis 1972; 25:329– 43.

31.Heymsfield SB, Cefalu WT. Does body mass index adequately convey a patient’s mortality risk?

JAMA 2013;309:87–8.

32.Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63:

2985–3023.33.Poirier P, Cornier MA, Mazzone T, et al. Bar- iatric surgery and cardiovascular risk factors: a scientific statement from the American Heart Association. Circulation 2011;123:1683–701.

34.WHO Expert Consultation. Appropriate body- mass index for Asian populations and its implica- tions for policy and intervention strategies. Lancet 2004;363:157–63.

35.Lauer MS, Anderson KM, Kannel WB, et al. The impact of obesity on left ventricular mass and geometry: the Framingham Heart Study. JAMA 1991;266:231–6.

36.Davy KP, Hall JE. Obesity and hypertension:

two epidemics or one? Am J Physiol Regul Integr Comp Physiol 2004;286:R803–13.

37.Staerk L, Sherer JA, Ko D, et al. Atrialfibrilla- tion: epidemiology, pathophysiology, and clinical outcomes. Circ Res 2017;120:1501–17.

38.Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med 2002; 347:305–13.

39.Aune D, Sen A, Norat T, et al. Body mass index, abdominal fatness, and heart failure incidence and mortality: a systematic review and dose-response meta-analysis of prospective studies. Circulation 2016;133:639–49.

40.Pencina MJ, D’Agostino RB Sr., Larson MG, et al. Predicting the 30-year risk of cardiovascular disease: the Framingham Heart Study. Circulation 2009;119:3078–84.

41.Sun Q, van Dam RM, Spiegelman D, et al.

Comparison of dual-energy x-ray absorptiometric and anthropometric measures of adiposity in relation to adiposity-related biologic factors. Am J Epidemiol 2010;172:1442–54.

42.Church TS, LaMonte MJ, Barlow CE, et al.

Cardiorespiratoryfitness and body mass index as predictors of cardiovascular disease mortality among men with diabetes. Arch Intern Med 2005; 165:2114–20.

43.Carbone S, Lavie CJ, Arena R. Obesity and heart failure: focus on the obesity paradox. Mayo Clin Proc 2017;92:266–79.

44.Prado CM, Gonzalez MC, Heyms field SB. Body composition phenotypes and obesity paradox.

Curr Opin Clin Nutr Metab Care 2015;18:535–51.

45.Shen W, Punyanitya M, Chen J, et al. Waist circumference correlates with metabolic syndrome indicators better than percentage fat. Obesity (Silver Spring) 2006;14:727–36.

46.Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005;366:1640–9.

47.Krakauer NY, Krakauer JC. A new body shape index predicts mortality hazard independently of body mass index. PLoS One 2012;7:e39504.

48.Thomas DM, Bredlau C, Bosy-Westphal A, et al. Relationships between body roundness with body fat and visceral adipose tissue emerging from a new geometrical model. Obesity 2013;21:

2264–71. Gaddeet al. JACC VOL. 71, NO. 1, 2018 Pathophysiology and Management of Obesity JANUARY 2/9, 2018:69–84 82 49.Dhana K, Kavousi M, Ikram MA, et al. Body shape index in comparison with other anthropo- metric measures in prediction of total and cause- specific mortality. J Epidemiol Community Health 2016;70:90–6.

50.Bergman RN, Stefanovski D, Buchanan TA, et al. A better index of body adiposity. Obesity (Silver Spring) 2011;19:1083–9.

51.Shen W, Wang Z, Punyanita M, et al. Adipose tissue quantification by imaging methods: a pro- posed classification. Obes Res 2003;11:5–16.

52.Heymsfield SB, Hu HH, Shen W, et al.

Emerging technologies and their applications in lipid compartment measurement. Trends Endo- crinol Metab 2015;26:688–98.

53.Wolf P, Winhofer Y, Kr s sák M, et al. Heart, lipids, and hormones. Endocr Connect 2017;6:

R59–69.

54.Gadde KM, Allison DB. Combination therapy for obesity and metabolic disease. Curr Opin Endocrinol Diabetes Obes 2009;16:353–8.

55.Elfhag K, Rossner S. Who succeeds in main- taining weight loss? A conceptual review of factors associated with weight loss maintenance and weight regain. Obes Rev 2005;6:67–85.

56.Wing RR, Tate DF, Gorin AA, et al. A self- regulation program for maintenance of weight loss. N Engl J Med 2006;355:1563–71.

57.Rock CL, Flatt SW, Sherwood NE, et al. Effect of a free prepared meal and incentivized weight loss program on weight loss and weight loss maintenance in obese and overweight women: a randomized controlled trial. JAMA 2010;304:

1803–10.

58.Hill JO, Wyatt HR. Role of physical activity in preventing and treating obesity. J App Physiol 2005;99:765–70.

59.Thompson PD, Buchner D, Piña IL, et al. Ex- ercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular dis- ease. Circulation 2003;107:3109–16.

60.Womble LG, Wadden TA, McGuckin BG, et al.

A randomized controlled trial of a commercial internet weight loss program. Obes Res 2004;12:

1011–8.

61.Stewart T, Han H, Allen RH, et al. H.E.A.L.T.H.:

efficacy of an internet/population-based behav- ioral weight management program for the U. S.

Army. J Diabetes Sci Technol 2011;5:178–87.

62.Tate DF, Jackvony EH, Wing RR. Effects of Internet behavioral counseling on weight loss in adults at risk for type 2 diabetes: a randomized trial. JAMA 2003;289:1833–6.

63.Tate DF, Jackvony EH, Wing RR. A randomized trial comparing human e-mail counseling, computer-automated tailored counseling, and no counseling in an Internet weight loss program.

Arch Intern Med 2006;166:1620–5.

64.Breton ER, Fuemmeler BF, Abroms LC. Weight loss—there is an app for that! But does it adhere to evidence-informed practices? Transl Behav Med 2011;1:523–9.

65.Thomas JG, Bond DS. Review of innovations in digital health technology to promote weight control. Curr Diab Rep 2014;14:485.66.Martin CK, Miller AC, Thomas DM, et al. Effi- cacy of SmartLoss, a smartphone-based weight loss intervention: results from a randomized controlled trial. Obesity (Silver Spring) 2015;23:

935–42.

67.Diabetes Prevention Program Research Group, Knowler WC, Barrett-Connor E, Fowler SE, et al.

Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.

68.Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, et al.

10-Year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677–86.

69.Look AHEAD Research Group, Pi-Sunyer X, Blackburn G, Brancati FL, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the Look AHEAD trial. Diabetes Care 2007;30:

1374–83.

70.Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 dia- betes. N Engl J Med 2013;369:145–54.

71.Baum A, Scarpa J, Bruzelius E, et al. Targeting weight loss interventions to reduce cardiovascular complications of type 2 diabetes: a machine learning-based post-hoc analysis of heteroge- neous treatment effects in the Look AHEAD trial.

Lancet Diabetes Endocrinol 2017;5:808–15.

72.Foster GD, Wyatt HR, Hill JO, et al.

A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med 2003;348:2082–90.

73.Foster GD, Wyatt HR, Hill JO, et al. Weight and metabolic outcomes after 2 years on a low- carbohydrate versus low-fat diet: a randomized trial. Ann Intern Med 2010;153:147–57.

74.Clifton PM, Condo D, Keogh JB. Long term weight maintenance after advice to consume low carbohydrate, higher protein diets: a systematic review and meta analysis. Nutr Metabo Cardiovasc Dis 2014;24:224–35.

75.Pagoto SL, Appelhans BM. A call for an end to the diet debates. JAMA 2013;310:687 –8.

76.Hjorth MF, Ritz C, Blaak EE, et al. Pretreat- ment fasting plasma glucose and insulin modify dietary weight loss success: results from 3 ran- domized clinical trials. Am J Clin Nutr 2017;106:

499–505.

77.Appel LJ, Moore TJ, Obarzanek E, et al., DASH Collaborative Research Group. A clinical trial of the effects of dietary patterns on blood pressure.

N Engl J Med 1997;336:1117–24.

78.Estruch R, Ros E, Salas-Salvadó J, et al. Pri- mary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:

1279–90.

79.Gadde KM. Current pharmacotherapy for obesity: extrapolation of clinical trials data to practice. Expert Opin Pharmacother 2014;15:

809–22.

80.Gadde KM, Raj YP. Pharmacotherapy of obesity: clinical trials to clinical practice. Curr Diab Rep 2017;17:34.81.Kim KK, Cho HJ, Kang HC, Youn BB, et al. Ef- fects on weight reduction and safety of short-term phentermine administration in Korean obese peo- ple. Yonsei Med J 2006;47:614–25.

82.Kang JG, Park CY, Kang JH, et al. Randomized controlled trial to investigate the effects of a newly developed formulation of phentermine diffuse-controlled release for obesity. Diabetes Obes Metab 2010;12:876–82.

83.Aronne LJ, Wadden TA, Peterson C, et al.

Evaluation of phentermine and topiramate versus phentermine/topiramate extended-release in obese adults. Obesity 2013;21:2163–71.

84.Leblanc ES, O’Connor E, Whitlock EP, et al.

Effectiveness of primary care-relevant treatments for obesity in adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2011;155:434–47.

85.Yanovski SZ, Yanovski JA. Long-term drug treatment of obesity. A systematic and clinical review. JAMA 2014;311:74–86.

86.Torgerson JS, Hauptman J, Boldrin M, et al.

XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.

Diabetes Care 2004;27:155–61.

87.Smith SR, Weissman NJ, Anderson CM, et al.

Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363:

245–56.

88.Fidler MC, Sanchez M, Raether B, et al. A one- year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab 2011;96:3067–77.

89.O’Neil PM, Smith SR, Weissman NJ, et al.

Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mel- litus: the BLOOM-DM study. Obesity 2012;20:

1426–36.

90.Smith SR, Garvey WT, Greenway FL, et al.

Coadministration of lorcaserin and phentermine for weight management: a 12-week, randomized, pilot safety study. Obesity 2017;25:857–65.

91.Pi-Sunyer X, Astrup A, Fujioka K, et al.

A randomized, controlled trial of 3.0 mg of lir- aglutide in weight management. N Engl J Med 2015;373:11–22. 92.Davies MJ, Bergenstal R, Bode B, et al. Effi- cacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE Diabetes ran- domized clinical trial. JAMA 2015;314:687–99.

93.le Roux CW, Astrup A, Fujioka K, et al. 3 Years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in in- dividuals with prediabetes: a randomised, double- blind trial. Lancet 2017;389:1399–409.

94.Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with lir- aglutide after low-calorie-diet induced weight loss: the SCALE Maintenance randomized study.

Int J Obes 2013;37:1443–51.

95.Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22. JACC VOL. 71, NO. 1, 2018 Gaddeet al. JANUARY 2/9, 2018:69–84 Pathophysiology and Management of Obesity 83 96.Allison DB, Gadde KM, Garvey WT, et al.

Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity 2012;20:330–42.

97.Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377:1341–52.

98.Greenway FL, Fujioka K, Plodkowski RA, et al.

Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-1): a multi- centre, randomised, double-blind, placebo- controlled, phase 3 trial. Lancet 2010;376:

595–605.

99.Wadden TA, Foreyt JP, Foster GD, et al.

Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity 2011; 19:110–20.

100.Hollander P, Gupta AK, Plodkowski R, et al.

Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care 2013;36:4022–9.

101.Nissen SE, Wolski KE, Prcela L, et al. Effect of naltrexone-bupropion on major adverse car- diovascular events in overweight and obesepatients with cardiovascular risk factors: a randomized clinical trial. JAMA 2016;315:

990–1004.

102.Khera R, Murad MH, Chandar A, et al. Asso- ciation of pharmacological treatments for obesity with weight loss and adverse effects: a systematic review and meta-analysis. JAMA 2016;315:

2424–34.

103.Ikramuddin S, Blackstone RP, Brancatisano A, et al. Effect of reversible intermittent intra- abdominal vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial.

JAMA 2014;312:915–22.

104.Lee PC, Dixon J. Medical devices for the treatment of obesity. Nat Rev Gastroenterol Hepatol 2017;14:553–64.

105.Angrisani L, Santonicola A, Iovino P, et al.

Bariatric surgery worldwide 2013. Obes Surg 2015; 25:1822–32.

106.Khorgami Z, Shoar S, Andalib A, et al. Trends in utilization of bariatric surgery, 2010-2014:

sleeve gastrectomy dominates. Surg Obes Relat Dis 2017;13:774–8.

107.Maciejewski ML, Arterburn DE, Scoyoc Van, et al. Bariatric surgery and long-term durability of weight loss. JAMA Surg 2016;151:1046–55.

108.Piché ME, Auclair A, Harvey J, et al. How to choose and use bariatric surgery in 2015. Can J Cardiol 2015;31:153–66.109.Schauer PR, Bhatt DL, Kirwan JP, et al. Bar- iatric surgery versus intensive medical therapy for diabetes: 3-year outcomes. N Engl J Med 2014; 370:2002–13.

110.Ikramuddin S, Korner J, Lee WJ, et al.

Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA 2013;309:2240–9.

111.Rubino F, Nathan DM, Eckel RH, et al. Meta- bolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international dia- betes organizations. Diabetes Care 2016;39:

861–77.

112.Beamish AJ, Olbers T, Kelly AS, et al. Car- diovascular effects of bariatric surgery. Nat Rev Cardiol 2016;13:730–43.

113.Schauer PR, Mingrone G, Ikramuddin S, et al.

Clinical outcomes of metabolic surgery: efficacy of glycemic control, weight loss, and remission of diabetes. Diabetes Care 2016;39:902–11.

114.Nguyen NT, Varela JE. Bariatric surgery for obesity and metabolic disorders: state of the art.

Nat Rev Gastroenterol Hepatol 2017;14:160–9.

KEY WORDSadipose tissue, antiobesity drugs, bariatric surgery, obesity, overweight, weight loss Gaddeet al. JACC VOL. 71, NO. 1, 2018 Pathophysiology and Management of Obesity JANUARY 2/9, 2018:69–84 84