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					                         Obesity: An expanding epidemic [Slide 23]

                                       Gavin Bart, MD



   Birth of an epidemic [slides1-22 auto-animation 2 second transition]

            Last 20 years [1]

            Spread across country

from < 15% in 1985 [slide 1]

to > 25% in 2006 [slide 22]

   Introduction [slide 24]

            Obesity

Major public health issue

Has physical, environmental, and genetic influences

            Is

Related to consumption

Result from high caloric intake

            This lecture reviews the following [slide 25]

Definition and epidemiology

Comorbid illness

Mechanism of disease

Treatment



   Obesity

            Defined [slide 26]
Measured through the body mass index (BMI)

BMI defined as weight in kilograms / height in meters squared

Normal weight - BMI 18.5-24.9

Overweight - BMI 25.0-29.9

Obesity - BMI ≥ 30.0 [2]

                           Class I BMI 30.0-34.9

                           Class II BMI 35.0-39.9

                           Class III (extreme) BMI ≥ 40.0

           Obesity epidemiology [3] [slide 27]

66% US population ≥ 20 yrs overweight or obese

                           32% obese

                           5% extreme obesity

Mexican American 76% overweight or obese

Non-Hispanic Black 76%

Non-Hispanic White 64%

non-Hispanic white women 36%

Mexican American women 50%

Non-Hispanic black women 65%

           We now move from [slide 28]

Definition and epidemiology to

Comorbid illness

           Obesity morbidity and mortality [slide 29]

300,000 obesity-related deaths in US per year [4]
5x ↑ risk for diabetes [5]

5x ↑ risk for gallbladder disease [5]

Mood disorders (depression and bipolar) 18% in non-obese v. 22% in obese [6]

Obese ↑ hospitalization and death from cardiovascular disease[7]

           We now move from [slide 30]

Comorbid illness to

Mechanism of obesity

           Mechanisms of obesity

Environment [slide 31]

                             Types of food available and portion sizes

                                    ~3,500 calories = 1 pound weight gain

                                    When caloric intake > energy expenditure weight ↑

                                    Increased intake due to increased portion size

                             Sedentary lifestyle

                                    Decreased activity (e.g., couch-potato)

                                    Decreased mobility (e.g., disability)

Genetics comprise 50% of risk for obesity[8;9] [slide 32]

                             Obesity runs in families

                                    75% monozygotic v 60% dizygotic twins

                                    Body weight of adoptees relate to biological more than

                                        adoptive parents

                             Specific human gene mutations have been identified

                                    Leptin
Picture child with leptin deficiency

Picture after leptin replacement

                                     Proopiomelanocortin (POMC)

                          Obesity can be bred in or out of mice

Many feedback pathways involved [slide 33]

                          Adipocytes, or fat cells, produce the hormone leptin

                                     ↓ feeding by acting in arcuate nuc. of hypothalamus

                                     ↑ expenditure by acting in the brain and muscles

                          Stomach produces the hormone ghrelin

                                     ↑ feeding by acting in arcuate nuc. and vagus nerve

                                     ↓ energy expenditure by acting in brain and adipocytes

                          Both leptin and ghrelin modulate brain activity related to

                              emotion and behavior (e.g., in the hypothalamus/amygdala)

                          Feeding modulates/is modulated by neuropathways[10]

                                     ↑ Dopamine when liked food presented and eaten

                                     ↑ Endogenous opioids ↑ feeding

                                     ↓ in glutamate will initiate feeding

                                     ↑ GABA will ↑ feeding

                                     ↑ Serotonin ↓ feeding

           Stress eating and opioids [slide 34]

Stress increases sugar intake [11]

Opiates increase sugar intake [12]

Common link: proopiomelanocortin which is precursor for
                           Endogenous opioid beta-endorphin

                           Stress hormone adrenocorticotropin (ACTH)

                           Feeding hormone alpha-melanocyte-stimulating hormone

                                 (alpha-MSH)

            Control of feeding [slide 35]

Emotion

                           Stress

                           Boredom

Environment

                           Portion size

                           Availability

Intrinsic

                           Hormonal regulation

                           Dopamine

            Dopamine and reward [slide 36] [13]

Pleasurable things increase dopamine

                           Drugs

                           Sex

                           Food

Prolonged exposure decreases dopamine

                           Drugs

                           Food

            BMI and dopamine receptor [slide 37] [14]
Non-obese no relation between D2 and BMI

Obese D2 and BMI inverse correlation

           Dopamine and reward [slide 37]

Early exposure

                         Increased dopamine release

                         Increased dopamine receptors (esp. D2)

Prolonged exposure

                         Decreased dopamine release

                         Down regulation of receptors

                         Seen with PET imaging in obesity

           Liking versus craving? [slide 38]

Increased motivational activity when hungry [15]

                         Caused by stress

                         Caused by food deprivation

Desire is for sweets

           What about carbohydrates? [slide 39]

They increase [16]

                         Dopamine

                         Increase opiates

                         Increase serotonin

Alcohol is carbohydrate rich [17]

                         Is both food and drug

                         Increases dopamine, opiates, serotonin
Indicates some overlapping pathways

           The overlap [slide 40]

Rats that prefer sugar have increased self-administration

                          Cocaine [18]

                          Morphine [19]

                          Alcohol [20]

           Drug withdrawal and sweets [slide 41]

Increased consumption of sweets after

                          Smoking cessation [21]

                          Alcohol abstinence [22]

                          Opiate withdrawal [23]

                          Cocaine withdrawal [24]

Taste perception is not altered [25;26]

           What happens during weight loss? [slide 42]

Case reports of AUD and other SUD after bariatric surgery

Calorie restriction and alcohol

Rats ↑ alcohol when calorie restricted

Standard drink = 100 calories of alcohol

                          12 ounces beer

                          5 ounces wine

                          1.5 ounces spirits

Do dieters seek any kind of calorie?

                          ↑ liquids to overcome surgical reduction of stomach
                          Carbohydrates preferred

Ergo ↑ carbohydrate liquids (soda, milkshakes, alcohol?)

           We now move from [slide 43]

Mechanism of disease to

Treatment of obesity



   Weight loss strategies [slide 44]

           Goals of weight loss

Improve health

Must address behavioral change

Does this mean address neurobiological change?

                          Brain changes persist after weight loss [27]

                          Brain changes with dieting may predict success [28]

Examples of interventions follow

           Bariatric surgery (i.e., weight reduction surgery)[29] [slide 45]

Goal to ↓ appetite and ↓ absorption

Roux-en-Y restricts the size of the stomach and diverts food past much of the duodenum

                       and jejunum

                          Most common bariatric surgery

                          Long-term weight loss 25% body weight

                          Complications: malabsorption, dumping syndrome

Vertical banded gastroplasty and laparoscopic adjustable gastric band

                          Restrict size of stomach
                          Long-term weight loss 15% body weight

                          Complications: reflux, stomal stenosis

           Behavioral [30] [slide 46]

Brief interventions - < 15 minutes advice on:

                          medical aspects of obesity

                          diet change

                          exercise change

Diet and exercise combined 5% ↓ in body weight

12-step (Overeaters Anonymous) [slide 47]

                          Change attitudes and behaviors

                          Get peer network

Cognitive behavioral therapy [slide 47]

                          Help patient change view of role in eating

                          Help change behaviors to ↑ weight loss

                                 Recognize and avoid risky situations

                                  Get peer network

Weight Watchers, Jenny Craig, etc. combine these

Motivational interviewing [slide 48]

                          Emphasize change

                          Discuss patients resistance to change

                          Focus on patient’s perspective

                          Encourage change acceptable to patient

Behavioral therapy alone 5% ↓ in body weight
           Medication [slide 49]

Sibutramine (Meridia): inhibits norepinephrine, serotonin, and dopamine reuptake

                      (approved for obesity)[31]

                            Decreases appetite

                            Increases metabolism

                            5% ↓ in body weight

Rimonabant: cannabinoid receptor antagonist (anticipated approval for obesity)[32]

                            Decreases appetite (opposite of marijuana’s effect)

                            Increases metabolism

                            5% ↓ in body weight

                            Possible depression suicide risk

Orlistat (Xenical) (approved for obesity)[31]

                            Reduces fat absorption

                            5% ↓ in body weight

Naltrexone (ReVia)?: opioid receptor antagonist (not approved for obesity)[33]

                            ↓ pleasantness of sucrose to humans

                            No long-term controlled data for efficacy in obesity

                            Potential hepatotoxicity

   Conclusions [slide 50]

           Obesity Causes Significant Morbidity and Mortality

           Overlapping Neuropathways with Addiction

           Treatment Strategies
Surgical

Behavioral

                            Self-help

                            Motivational interviewing

                            Cognitive behavioral

Pharmacological

             Future studies needed [slide 51]

Behavioral substitution after weight loss?

Elucidate common neuropathways

                            Obesity

                            Addiction

Elucidate common genetics

                            Obesity

                            Addiction

             Until then you should [slide 52]

Screen for overweight/obesity (measure BMI)

Screen for AUD (many screens available)

Advise patients with obesity about impact on health

Treat or refer for treatment

                            Behavioral

                            Pharmacological

                            Surgical
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