This supplement was sponsored by PrimaryCare Education Consortium and Primary CareMetabolic Group and is supported by fundingfrom Novo Nordisk Inc. It was edited and peerreviewed by The Journal of Family Practice.SUPPLEMENT TOCopyright 2014Frontline Medical Communications Inc.WWW.PCECONSORTIUM.ORG WWW.PCMG-US.ORGVOL 63, NO 7 JULY 2014 www.jfponline.comManagement ofObesity in AdultsS1 IntroductionStephen A. Brunton, MD, FAAFPS3 Pathophysiology, Epidemiology, andAssessment of Obesity in AdultsNeil S. Skolnik, MD; and Donna H. Ryan, MDS11 Tips for Communicating With Overweightand Obese Patients Carlos Campos, MD, MPH, CDES15 Principles and NonpharmacologicManagement of Obesity in Adults Robert F. Kushner, MD, MS, FACP; and Denise K. Sur, MDS21 The Pharmacological and SurgicalManagement of Adults With Obesity Donna H. Ryan, MDS27 Evolving Directions in ObesityManagement Louis J. Aronne, MD, FACP

Management of Obesity in AdultsFACULTYStephen A. Brunton, MD, FAAFPAdjunct Clinical ProfessorDepartment of Family MedicineUniversity of North CarolinaChapel Hill, North CarolinaExecutive Vice President for EducationPrimary Care Education ConsortiumCharlotte, North CarolinaNeil S. Skolnik, MDAssociate Director, Family Medicine Residency ProgramAbington Memorial HospitalAbington, PennsylvaniaProfessor of Family and Community MedicineTemple University School of MedicinePhiladelphia, PennsylvaniaDonna H. Ryan, MDProfessor EmeritaPennington Biomedical Research CenterBaton Rouge, LouisianaCarlos Campos, MD, MPH, CDEClinical Adjunct ProfessorDepartment of Family MedicineUniversity of Texas Health Science CenterSan Antonio, TexasRobert F. Kushner, MD, MS, FACPProfessor of MedicineClinical DirectorNorthwestern Comprehensive Center on ObesityNorthwestern UniversityFeinberg School of MedicineChicago, IllinoisDenise K. Sur, MDResidency DirectorProfessor and Vice Chair for EducationDepartment of Family MedicineDavid Geffen School of Medicine at UCLALos Angeles, CaliforniaChief of StaffUCLA – Santa Monica Medical CenterSanta Monica, CaliforniaLouis J. Aronne, MD, FACPWeill Cornell Medical College Medical Director, Center for Weight Management andMetabolic Clinical ResearchNew York, New YorkFACULTY DISCLOSURESStephen A. Brunton, MD, FAAFP discloses that he is on the advisoryboards for Abbott Laboratories; AstraZeneca; Boehringer-IngelheimGmbH; Bristol-Myers Squibb Company; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; NovoNordisk, Inc.; sanofi-aventis U.S. LLC; and Teva Pharmaceuticals USA,Inc. He is on the speakers’ bureaus for Boehringer-Ingelheim GmbH; EliLilly and Company; Forest Laboratories; Janssen Pharmaceuticals, Inc.;Meda Pharmaceuticals; Novo Nordisk, Inc.; and Teva PharmaceuticalsUSA, Inc.Neil S. Skolnik, MD discloses that he is on the advisory boards forAstraZeneca, Boehringer Ingelheim GmbH; Eli Lilly and Company;Sucampo Pharmaceuticals, Inc.; Teva Pharmaceuticals USA, Inc.; andVIVUS, Inc. He is on the speakers’ bureau for AstraZeneca.Donna H. Ryan, MD discloses that she is on the advisory boards forEisai Inc.; Janssen Pharmaceuticals, Inc.; Novo Nordisk, Inc.; TakedaPharmaceuticals U.S.A., Inc.; and VIVUS, Inc. Dr. Ryan has ownershipinterest in Scientific Intake.Carlos Campos, MD, MPH, CDE discloses that he is on the advisoryboards and speakers’ bureaus for Bristol-Myers Squibb Company;Eli Lilly and Company; Novo Nordisk, Inc.; and Janssen Pharmaceuticals, Inc.Robert F. Kushner, MD, MS, FACP discloses that he is on the advisory boards for Novo Nordisk, Inc.; Retrofit, Inc.; Takeda Pharmaceuticals U.S.A., Inc.; and VIVUS, Inc. He has intellectual property rights inRetrofit, Inc., and does contracted research for Aspire Bariatrics andWeight Watchers International, Inc.Denise K. Sur, MD discloses that she has no real or apparent conflicts of interest to report.Louis J. Aronne, MD, FACP discloses that he is a contract researcherfor Aspire Bariatrics; GI Dynamics, Inc.; Medical University of SouthCarolina (MUSC); and Novo Nordisk, Inc. He is a consultant for EisaiInc.; Ethicon Endo-Surgery Inc.; Novo Nordisk, Inc.; VIVUS, Inc.; andZafgen Inc. He has ownership interest in Cardiometabolic SupportNetwork, LLC; Myos Corporation; and Zafgen, Inc. He is on the boardof directors for Myos Corporation.LEARNING OBJECTIVES1. I dentify adults who are overweight or obese2. D escribe the benefits of weight loss in the obese3. D escribe terminology and strategies for discussing weight withpatients4. L ist key considerations for managing adults with obesity5. O utline nutrition and physical activity goals and options6. Identify the role of medications and bariatric surgery7. C ompare the safety and efficacy of medications approved forlong-term use8. D escribe the safety and efficacy of medications in late stagedevelopment for obesity9. Describe future directions in medical therapies for obesitySTATEMENT OF SPONSORSHIP AND SUPPORTThis program is sponsored by Primary Care Education Consortiumand Primary Care Metabolic Group and is supported by fundingfrom Novo Nordisk, Inc.EDITORIAL ASSISTANCE AND FACULTYHONORARIUM DISCLOSUREEditorial support for this supplement was provided to the authors byGregory Scott, PharmD, RPh. Faculty authors re ceived no honoraria.JULY 2014 Volume 63, No 7 Supplement to The Journal of Family Practice

INTRODUCTIONManagement of Obesity in AdultsStephen A. Brunton, MD, FAAFPMore than one-third of adults and one-sixthof children and adolescents in the UnitedStates are obese (ie, body mass index [BMI] 30 kg/m2).1 This is more than double theprevalence in 1994 (FIGURE).2 Also of great concern, is thatthe prevalence of extreme obesity (BMI 40 kg/m2) rose from3.9% to 6.6% in the United States from 2000 to 2010, a 70%increase.3 As primary care providers, family physicians contend on a daily basis with cardiovascular and other healthconsequences of this burgeoning epidemic.However, despite the gloom that is associated with obesity there is good news. After a steady increase in the dailyenergy intake from 1955 kcal during 1971-1975 to 2269 kcalduring 2003-2004, the daily energy intake has declined to2195 kcal during 2009-2010.4 After debate and discussion thatspanned more than 2 decades, obesity is now recognized as adisease by most organizations.5 In 2000, a National Institutesof Health panel was one of the first to describe obesity as achronic disease.6 More recently, the American Medical Association adopted a policy in June 2013 recognizing obesity as adisease, with the hope that doing so will help change how themedical community tackles this complex issue.7To help tackle obesity, physicians now have more toolsand support than ever before. In late 2011, the US Centersfor Medicare and Medicaid Services (CMS) approved Medicare coverage for intensive behavioral therapy for obesity asa stand-alone billable service in the primary care setting.8Recognizing the need for long-term management, this actionStephen A. Brunton, MD, FAAFP, Adjunct Clinical Professor,Department of Family Medicine, University of North Carolina,Chapel Hill, NC; Executive Vice President for Education, PrimaryCare Education Consortium, Charlotte, NCDISCLOSURESDr. Brunton discloses that he is on the advisory boards forAbbott Laboratories; AstraZeneca; Boehringer-Ingelheim GmbH;Bristol-Myers Squibb Company; Eli Lilly and Company;Janssen Pharmaceuticals, Inc.; Novartis PharmaceuticalsCorporation; Novo Nordisk, Inc.; sanofi-aventis U.S. LLC; andTeva Pharmaceuticals USA, Inc. He is on the speakers’ bureausfor Boehringer-Ingelheim GmbH; Eli Lilly and Company; ForestLaboratories; Janssen Pharmaceuticals, Inc.; Meda Pharmaceuticals; Novo Nordisk, Inc.; and Teva Pharmaceuticals USA, the CMS is intended to promote sustained weight lossthrough intensive interventions of diet and exercise.In 2012, after more than a decade without an approval,the US Food and Drug Administration (FDA) approved2 medications as adjuncts to a reduced-calorie diet andincreased physical activity for chronic weight management.Lorcaserin (Belviq) and phentermine/topiramate extendedrelease (Qsymia) are approved for use in adults with an initialBMI of 30 kg/m2 or 27 kg/m2 in the presence of at least 1weight-related comorbid condition (eg, hypertension, dyslipidemia, type 2 diabetes mellitus).9,10In 2013, the American Heart Association/AmericanCollege of Cardiology/The Obesity Society released guidelines and an algorithm to guide primary care providers inmanaging patients that are overweight or obese.11 Althoughthese guidelines do not include recommendations regardingpharmacotherapy, they provide specific recommendationsregarding assessment, lifestyle intervention, and bariatricsurgery that are applicable to the primary care setting.These resources are important because they support thekey role that family physicians can play in the managementof overweight and obese patients. A recent systematic reviewand meta-analysis involving 207,226 people in the UnitedStates showed the positive impact of primary care physicianadvice on patient engagement in weight loss efforts (oddsratio, 3.85; P .01) and weight loss.12 Furthermore, the greaterthe support provided by physicians, and the health care teamin general, and the better patients rated provider communication, the greater the weight lost.12This supplement is intended to serve as an additionalresource for family physicians to manage overweight andobese patients. In the first of 5 articles, Drs. Neil Skolnik andDonna Ryan provide a concise background of the pathophysiology and epidemiology of obesity in adults. Recommendations are also provided for patient assessment in a respectfuland discrete manner. The importance of good communication with overweight and obese patients is emphasized by Dr.Carlos Campos. Tips are provided regarding how to initiate adiscussion about weight with a patient, including the specificwords preferred, as well as those found offensive, by patients.Suggestions are also made for assessing patient readinessSupplement to The Journal of Family Practice Vol 63, No 7 JULY 2014S1

[INTRODUCTION]Age-adjusted prevalence of obesity (BMI 30 kg/m2) among USadults ages 18 years2FIGUREIt is hoped that you find thissupplement helpful as you provide care to the increasing number of overweight and obesepatients in your practice. lREFERENCES1. O gden CL, Carroll MD, Kit BK, Flegal KM.Prevalence of obesity in the United States,2009-2010. NCHS Data Brief. 2012;82:1-8.2. Centers for Disease Control and Prevention.Maps of Trends in Diagnosed Diabetes andObesity. CDC’s Division of Diabetes Translation. National Diabetes Surveillance Systemavailable at diabetesobesitytrends.pdf. December 2011. Accessed June6, 2014.3. Sturm R, Hattori A. Morbid obesity rates continue to rise rapidly in the United States. Int JAdapted from CDC's Division of Diabetes Translation National Diabetes Surveillance System, available at: http://www.Obes (Lond). 2013;37(6) Ford ES, Dietz WH. Trends in energy intakeAbbreviation: BMI, body mass index.among adults in the United States: findingsfrom NHANES. Am J Clin Nutr. 2013;97(4):848-853.5. A llison DB, Downey M, Atkinson RL, et change and motivating patients, as well as setting up the Obesity as a disease: a white paper on evidence and arguments commissioned bythe Council of the Obesity Society. Obesity (Silver Spring). 2008;16(6) environment to better manage overweight and obese6. Pi-Sunyer FX, Becker DM, Bouchard C et al. National Institutes of Health. The Pracpatients.tical Guide. Identification, Evaluation, and Treatment of Overweight and Obesityin Adults. c.pdf. PublishedThe principles and general considerations for managing2000. Accessed June 6, 2014.overweight and obese patients are summarized by Drs. Rob7. American Medical Association. AMA adopts new policies on second day of votingat annual meeting. Obesity as a disease. Kushner and Denise Sur. Using a case-based approach, Published 2013.Accessed June 6, 2014.nonpharmacologic management of patients is described, with8. Centers for Medicare & Medicaid Services. US Department of Health and Humandetails given about nutrition, physical activity, and behavioralServices. Intensive behavioral therapy for obesity. The role of medications and the principles of NProducts/downloads/ICN907800.pdf. Published 2012. Accessed June 6, 2014.macologic management are provided by Dr. Donna Ryan,9. Belviq [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012.with a focus on the 3 medications approved for long-term use.10. Qsymia [package insert]. Mountain View, CA: Vivus, Inc.; 2013.11. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB,The role and factors to be considered for bariatric surgery areHubbard VS, Jakicic JM, Kushner RF, Loria C, Millen BE, Nonas CA, Pi-Sunyer FX,also described. In the final article, Dr. Louis Aronne providesStevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ. 2013 AHA/ACC/TOSguideline for the management of overweight and obesity in adults: a report of thea look into the near future with a discussion of medicationsAmerican College of Cardiology/American Heart Association Task Force on Pracunder review by the FDA or in phase III clinical trials for obetice Guidelines and The Obesity Society. Circulation. November 2013:1–69.12. Rose SA, Poynter PS, Anderson JW, Noar SM, Conigliaro J. Physician weight losssity. Also described are evolving approaches to treatmentadvice and patient weight loss behavior change: a literature review and metaanalysis of survey data. Int J Obes (Lond). 2013;37(1):118-128.based on a greater understanding of obesity and its causes.S2JULY 2014 Vol 63, No 7 Supplement to The Journal of Family Practice

Pathophysiology, Epidemiology, andAssessment of Obesity in AdultsNeil S. Skolnik, MD; and Donna H. Ryan, MDINTRODUCTIONTABLE 1The rising prevalence of obesity has generated extensiveinvestigation into the consequences of, and diseases associated with, obesity. Much has also been learned abouthow food intake and satiety are regulated in humans andthe pathophysiology associated with obesity. Both involvea complex network of central and peripheral pathways andmediators.Before discussing these topics, as well as the assessmentof obesity in adults in primary care, it is necessary to understand how obesity is defined. The accepted definition of overweight and obesity, worldwide, is based on body mass index(BMI), which is a better correlate of total body fat than bodyweight alone, especially on a population basis.1 However, therelationship between BMI and percent body fat is less exacton an individual basis, particularly in men (especially thosewho are very muscular) and with increasing age.2,3 “Overweight” is defined as having a BMI of 25.0 to 29.9 kg/m2 and“obesity” applies to patients with a BMI 30.0 kg/m2 (Table 1).REGULATION OF FOOD INTAKEObesity results from a chronic imbalance between energyintake and energy expenditure leading to storage of excessenergy as fat, primarily in white adipose tissue.4,5 This seemingly simple fact belies the complex underpinnings of theincreasing obesity prevalence observed since 1980. In addition to environmental and behavioral factors, biologic factorsNeil S. Skolnik, MD, Associate Director, Family MedicineResidency Program, Abington Memorial Hospital, Abington, PA;Professor of Family and Community Medicine, Temple UniversitySchool of Medicine, Philadelphia, PADonna H. Ryan, MD, Professor Emerita, Pennington BiomedicalResearch Center, Baton Rouge, LADisclosuresDr. Skolnik discloses that he is on the advisory boards forAstraZeneca; Boehringer Ingelheim, GmbH; Eli Lilly and Company;Sucampo Pharmaceuticals, Inc; Teva Pharmaceuticals USA, Inc.;and VIVUS, Inc. He is on the speakers’ bureau for AstraZeneca.Dr. Ryan discloses that she is on the advisory boards for EisaiInc.; Janssen Pharmaceuticals, Inc.; Novo Nordisk, Inc.; TakedaPharmaceuticals U.S.A., Inc.; and VIVUS, Inc. Dr. Ryan hasownership interest in Scientific Intake.Classifications for body mass index1Body mass index (kg/m2)Underweight 18.5Normal weight18.5-24.9Overweight25.0-29.9Obesity (class 1)30.0-34.9Obesity (class 2)35.0-39.9Extreme obesity (class 3) 40.0influence both the amount and nutritional composition (ie,high-fat, high-sugar) of food ingested. Conventional wisdomascribes the widespread availability of calorie-dense (ie,high-fat) food and sugary beverages as a major factor contributing to excess energy intake.4,6Why then can’t patients who need to lose weight just eata little less and be a bit more active? Reducing food intake andincreasing physical activity have served as the core management strategies for weight loss, but it is clear that instructionin eating less and exercising more is insufficient to produceand sustain weight loss in many patients. Patients strugglebecause of problems with appetite and metabolic adaptations to weight loss. Most currently available and many evolving treatments have, or are focused on, controlling appetiteas a way to produce more weight loss and to sustain reducedweight. (See The Pharmacological and Surgical Managementof Adults With Obesity and Evolving Directions in ObesityManagement in this supplement.)The physician’s understanding of regulation of bodyweight is a critical first step to helping patients lose weightand sustain a reduced weight over the long term. Success atweight loss is determined not solely by motivation and willpower, but also by strategies to affect appetite and the reduction in the metabolic rate that accompanies weight loss. Thisdiscussion on energy balance regulation serves as a foundation for clinical decision-making in helping patients withweight management.Energy homeostasis is largely regulated by the brain,with input from the gastrointestinal (GI) tract, other organsystems, and adipose tissue to control food intake, satiety,and energy expenditure (Figure 1).7 Current understandingSupplementTheJournalFamilyPractice Vol Vol 63,63,NoNo7 7 JULY2014S3S3

[PATHOPHYSIOLOGY, EPIDEMIOLOGY, AND ASSESSMENT]The gut-brain axis regulation of food intake7types of peptides are directly anddifferentially sensitive to hormones such as leptin, insulin, andghrelin, but also to metabolites,including glucose, fatty acids, andamino acids.8The nonhomeostatic (ie,reward or hedonic) system alsoplays a major role in feedingbehavior. In obesity, hedonicresponses generated in mesolimbic dopamine structures overridehomeostatic regulation to alleviate deficits in reward signaling,resulting in sustained and escalated overeating. Consequently,despite normal or excessiveenergy storage, palatable foodsare over consumed for their pleaNutrients created by the digestion of food are proposed to activate G protein-coupled receptors on the luminal sidesurableeffects.8,10of enteroendocrine cells (eg, the L-cell). This stimulates the release of gut hormones which may influence food intakeat three sites: the vagus nerve, brainstem, and hypothalamus. Within the arcuate nucleus of the hypothalamus, twoObesity appears to shareneuronal populations are thought to be critical conduits through which peripheral signals are integrated to alter the drivesome properties observed withto eat, the orexigenic NPY/AgRP neurons, and the anorexigenic POMC neurons. Further connections between hypothalamic nuclei and higher brain centers may exist, which control the hedonic aspects of food ingestion.drug addiction. Among theseAbbreviations: ARC, arcuate nucleus; AgRP, agouti related peptide; GLP-1, glucagon like peptide-1; NPY, neuropeptide Y;properties, impairment in dopaPOMC, propiomelanocortin; PVN, paraventricular nucleus; PYY, peptide YY.minergic pathways appears to beReprinted from Neuropharmacology, volume 63, Sam AH, Troke RC, Tan TM, Bewick GA, The Role of the Gut/Brain Axisin Modulating Food Intake, pages 46-56, copyright 2012, with permission from Elsevier.involved, although it is unclear ifthe homeostatic or reward system—or both—is affected. Altersuggests that this complex and highly redundant neurobioations in self-control, conditioning, stress reactivity, andlogic circuitry involves a variety of chemical mediators (eg,interoceptive awareness have been observed.11,12adipokines) and neurochemical pathways (eg, negative feedPeripheral Signalsback regulation).4,5,8 The way to conceptualize energy balanceAdipose tissue is extensively involved in bodily functionsregulation is to consider peripheral signals (eg, leptin, ghreby exerting endocrine, paracrine, and autocrine actionslin, and glucagon-like peptide-1 [GLP-1]) as informational to(Figure 2).13 While brown adipose tissue is mainly involvedthe brain on the status of food intake and energy stores. Thein thermogenesis, white adipose tissue serves diverse funcbrain receives these signals and through various neural cirtions.13 Among these is the production of numerous adipocuits and neurotransmitters adjusts metabolic rate and appekines such as leptin and adiponectin, both of which playtitive behaviors to eat or stop eating.roles in obesity, as well as having important cardiometaCentral Regulationbolic effects (Table 2).13-15While several areas of the brain are important in regulatingLeptin is synthesized and secreted in direct proportionfeeding, current concepts consider circuitry as being theto body fat mass, while the level of adiponectin is decreasedproper way to conceive appetite regulation. These circuitsin obese individuals.14,15 Leptin is involved in the regulationof food intake and energy expenditure, partly in concertinclude the homeostatic systems regulating hunger and satiwith insulin. Leptin suppresses insulin secretion in a negaety, the reward system, and addiction.tive feedback loop, whereas insulin stimulates the release ofThe hypothalamus is the regulating center of appetiteleptin.15 Deficiency of, and/or resistance to, insulin or leptin isand energy homeostasis and receives input from all periphassociated with severe obesity, while administration of eithereral organs, as well as neural pathways from mainly thedirectly into the arcuate nucleus suppresses appetite andbrainstem.8,9 Orexigenic and anorexigenic peptides are theprimary integrators of various nutritional information. Bothreduces food intake.16 Because leptin levels correlate withFIGURE 1S4S4JULY 2014 Vol 63, No 7 Supplement to The Journal of Family Practice

[PATHOPHYSIOLOGY, EPIDEMIOLOGY, AND ASSESSMENT]FIGURE 2The major physiological functions of adipose tissue secretory products13Lipid metabolism and energy storage-lipoprotein lipase-acylation stimulating protein-angiopoietin like protein 4Energy homeostasis and metabolism-leptin-adiponectin-visfatin-interleukin 6-tumor necrosis factor-aHematopoiesis-leptinModulation of immune system-interleukin 6 and 8-monocyte chemoatractant protein-1-migration inhibitory factor-leptin-resistin-adipsinBone metabolism-leptin-adiponectin-interleukin 1 and 6-tumor necrosis factor-aAdiposetissueCoagulation and fibrinolysis-plasminogen activator inhibitor-1-leptinAngiogenesis-vascular endothelial growth factor-leptin-angiopoetin-2-adiponectinKidney function-leptin-adiponectinSteroid hormones conversion-11b-hydroxysteroid dehydrogenase type 1Sexual itrix oxide-prostaglandin E2-angiotensin II-asymetric ene sulfide-angiotensin 1-7-omentin-visfatin-leptin-resistinReprinted from Seminars in Nephrology, volume 33, number 1, Adamczak M and Wiecek A, The Adipose Tissue as an Endocrine Organ, pages 2-13, copyright 2013, withpermission from Elsevier.body fat stores, and obese individuals have very high levels ofleptin as well as hyposensitivity to leptin, clinical trials withleptin did not demonstrate efficacy, even at extremely highdoses because of tolerance/resistance.9,15-18 The leptin levelfluctuates throughout the day, with a decreased level correlating with food intake.The role of adiponectin in obesity is unclear, but appearsto involve feedback loops with insulin and pro-inflammatorycytokines. Adiponectin exerts beneficial effects on insulinaction in peripheral tissues and promotes pancreatic b-cellfunction and survival.14,15 Gut microbiota also appear to playa direct role in regulating weight; they may also act indirectlythrough GI peptides.Several hormones secreted in the gut have anorexigeniceffects, including cholecystokinin (CCK), pancreatic polypeptide, peptide tyrosine-tyrosine (PYY), GLP-1, and oxyntomodulin, whereas ghrelin has an orexigenic effect.9 Theclinically relevant example of the impact of these hormoneson appetite and body weight is with surgical bypass, associated with reduction in ghrelin and increases in GLP-1 andother gut anorexigenic peptides. Cholecystokinin serves as asatiation signal as it is released in response to luminal fat andprotein, but not glucose.8 Indeed, obese women have beenshown to have a low fasting CCK level and blunted postprandial response suggesting that CCK may play a role in thepathogenesis of obesity.10Glucagon-like peptide-1 and PYY are secreted throughdirect luminal stimulation by all 3 macronutrients as well asSupplement to The Journal of Family Practice Vol 63, No 7 JULY 2014S5

[PATHOPHYSIOLOGY, EPIDEMIOLOGY, AND ASSESSMENT]Selected metabolic effectsof leptin and adiponectin13-15TABLE 2MediatorMetabolic effectsLeptini Food intakei Adipose tissue massh Insulin sensitivity and improvement oftype 2 diabetesh Energy expenditureAdiponectini Plasma free fatty acids and muscletriglyceridesi Hepatic triglycerides and fatty liverh Hepatic insulin actionh Glucose-stimulated insulin secretioni Visceral adipose tissuei Inflammationhunger and reduced satiety.21-23 Significant differences frombaseline to 1 year in the mean levels of other mediators ofappetite have also been observed, including PYY, CCK, andpancreatic polypeptide.22 In fact, most measures of appetiteappear to be enhanced and measures of satiety reduced inthe weight-reduced state.23,24Changes in substrate metabolism also occur. For example, weight-stable formerly obese people have lower fastingor 24-hour rate of fat oxidation compared with controls. Theymay also have an altered ability to appropriately increase fatoxidation in response to a high-fat diet.24 These changes maystimulate feeding to restore glycogen reserves. These andother adaptations explain the difficulty many persons havein maintaining weight loss long-term. Knowledge of themhelps inform a strategy for maintenance of reduced weight,with emphasis on physical activity, vigilance, and reinitiatingsuccessful strategies when gain is documented.Socioecological factorsneural reflexes originating in the upper small intestine.8,10Whereas satiety appears to be the most important action ofPYY, GLP-1 has potent effects on suppression of food intake,gastric emptying and motility, and regulation of blood glucoselevels by stimulating insulin secretion. Suppression of foodintake by GLP-1 occurs locally through vagal afferents andcentrally through brain neurons arising from the hindbrainthat maintain synaptic connections with the hypothalamus.8,10GLP-1 also acts directly on the hypothalamus resulting inreduced food intake.19 Serving as a signal to initiate food intake,levels of the orexigenic hormone ghrelin rise before the onsetof a meal, but are rapidly suppressed upon food ingestion.10Gut microbiota also appear to play a direct role in regulatingweight; they may also act indirectly through GI peptides.10Many of the hormones and pathways discussed earlier,as well as others, are being investigated as possible targets fortherapeutic intervention for either weight loss and/or maintenance (see Evolving Directions in Obesity Management inthis supplement).Adaptations in intake regulation to weight lossOnce weight is lost, a variety of compensatory changes occurin several biological pathways involved in the utilizationand storage of energy and the regulation of appetite, whichtogether predispose to weight regain.20 A reduction in resting energy expenditure is observed, perhaps as an adaptivemechanism to protect lean body mass.21 Adiposity-relatedsignals, such as leptin and insulin, fall during weight lossand remain significantly reduced after 1 year comparedwith baseline. Conversely, ghrelin levels rise and remain elevated.17,22 These changes appear to contribute to enhancedS6Many socioecological factors contribute to obesity with afinal common pathway of an increase in energy intake relative to energy expenditure. These range from individualfactors (age, sex, socioeconomic status, race) to behavioralsettings (communities, work, health care, home) to other factors, such as education, media, food-and-beverage industry,and entertainment, and evolving social norms and values.25From 1971-1974 to 2005-2008, total caloric intake increasedfrom 2450 kcal/day to 2656 kcal/day in males ages 20 yearsand from 1542 kcal/day to 1811 kcal/day in females ages 20 years. The increases were due to 10% increase in percent of energy from carbohydrates.26 Factors contributingto the increase in caloric intake in adults are an increase inportion size—particularly of soft drinks, fruit drinks, and fastfood—as well as excess availability of calorie-dense food andincreased consumption of food outside the home.25On the other side of the energy balance equation, insufficient physical activity remains an issue. Although participation in leisure-time aerobic and muscle-strengthening activities that meet th

David Geffen School of Medicine at UCLA Los Angeles, California Chief of Staff UCLA - Santa Monica Medical Center Santa Monica, California Louis J. Aronne, MD, FACP . Identify the role of medications and bariatric surgery 7. Compare the safety and efficacy of medications approved for long-term use 8. Describe the safety and efficacy of .