Professional Documents
Culture Documents
Understand the classifications for obesity.
A. MEASUREMENTS OF BODY FAT
● BMI (height, weight)
2
○ Classification underweight <18.5 kg/m ; normal 18.524.9; overweight >25; preobese 2529.9; obese (Class I
3034.9, Class II 3539.9, Class III >40)
○ BMI and % body fat increase with age from 20YO, then level off at 80YO
■ Fat mass in healthy pts, markers were sensitive to gains, but failed to identify losses starting at 47YO
■ Fatfree mass ( eg.
muscle) increases slightly 2047YO, then declines after
■ Aerobic exercise can decrease fat mass, but only delays loss of fatfree mass in >65YO (requires strength
training to preserve)
■ In elderly pts, stable BMI can mask replacement of lost muscle with fat
○ BMI fails to identify 50% pts w/ excess body fat (measured by hydrostatic weighing or skinfolds)
■ Increased BF% in ≥25% men, ≥3035% women
● Skinfold thickness (biceps, triceps, subscapular, suprailiac) better for measuring BF% in Caucasians, African Americans,
Hispanics, and Asians (must use ethnic/genderspecific modifications) than DEXA (dualenergy Xray absorptiometry
accounts for bone density, lean mass, fat mass)
● Surrogate markers for visceral adiposity (better MI predictor than BMI in overweight/obese individuals)
○ Waist circumference (measured at top of iliac crest; ∞ MI risk)
○ Waist/hip ratio (better marker in most ethnicities, except African
Americans and Chinese)
● CT scan
visceral fat ∞ waist circumference (r = 0.80); in men, >25% BF → >40”;
in women, >30% BF → >35”
● MRI
● Hydrodensitometry (underwater weight)
B. SOUTH ASIANS
● South Asians = highest CVD risk group in USA (CA 19%, NY 15%, NJ 11%, TX/IL 8%) d
espite no overt obesity → ↑ HTN, ↑ DM, ↑
obesity, ↑ metabolic syndrome; ↑ PA1, ↑ Lp(a), ↑ TG, ↓ HDL; higher ApoB100/ApoA1 ratio
● Markers ↓ adipocytes, ↑ adipocyte size, ↑ visceral fat, ↑ circulating FAs, ↑ leptin, ↑ CRP, ↓ antiinflammatory (adiponectin)
● Relative risk India, Pakistan > Malaysia > Japan, Korea, China
● Statistics
○ South Asian Americans have 2x mortality rate than other ethnic groups
○ 25% of world population, but 60% of world CVD burden
○ Asian Canadians have 4x CVD risk compared to European Canadians
C. TYPES OF OBESITY
● MONW (metabolically obese, normal weight) increased %BF or waist circumference, but BMI <25; occurs in 23.5% of
normalweight Americans
○ Explains obesity paradox normalweight, CVDfree pts had higher mortality than overweight/obese pts
○ Includes hyperinsulinemia ± insulin resistance; ↑ TG ± ↓ HDL; predisposed to CHD
● NWO (normalweight obesity) >25% BF in men or >31% BF in women, but BMI <25
○ A/W metabolic dysregulation, ↑ BMIindependent CV mortality risk
○ If pt also has central obesity (W/H >1.0), they show 1.87x greater risk, and worse longterm survival
● Sarcopenic obesity high BF in the presence of reduced lean body mass (A/W reduction in cardiorespiratory fitness and
physical function) → disabled mobility and premature death
○ Larger waist A/W increased mortality, ESPECIALLY when BMI is normal
1.2. Understand the inherent bias against obesity.
● Weight bias (<= negative stereotypes, eg.
lazy, unmotivated, no selfdiscipline, incompetent, noncompliant, sloppy) →
inequities in employment settings, healthcare facilities, educational institutions
○ Stereotypes are prevalent in Western society but rarely challenged → overweight/obese ppl are vulnerable to social
injustice, unfair treatment, impaired quality of life
● Healthcare professionals viewed obese pts as awkward, unattractive, lazy, weakwilled, and noncompliant (according to fat
phobia scale) → barrier to Tx
● Obesity education in healthcare professionals
○ Selfefficacy of family physicians to treat obesity increased after interactive course enriching their knowledge of
obesity mgmt (epidemiology, pathogenesis, metabolic factors, nutrition, diet, selfcontrol & behavior modification,
physical activity, drugs, surgery, metabolic syndrome, HTN mechanism, obese diabetic pts, infertility in obese F)
○ AAMC obesity curriculum epidemiology, physiologic aspects of diet/hunger, physical activity & energy balance,
metabolic & immunologic consequences, pharmacology, BMI/WC calculation, obesity classification,
psychosocial/environmental aspects, 2° causes, comorbidities, current guidelines/policies
○ Medical students currently receive inadequate training in obesity and counseling, and not much effort to research and
change this disparity
1.3. Understand the epidemiology and societal costs of obesity and why it now considered an epidemic.
● Obesity often underdiagnosed, eg.
in 55,858 adults, obesity only reported in 38% obese pts, and only 35% of those were
counseled about weight reduction
A. OBESITY TRENDS
1985 1991 1997
2001 2005 2012
● Healthy People 2010 target goal of 15% obesity
○ 20002006 USA life expectancy increased 1.2%
(from birth) and 5.1% (from 65YO), mostly due to 33%
decrease in CHDassociated death (ageadjusted)
○ Newer data suggests that Asians actually met the
2010 goal (only 11% obesity)
○ However, obesity and diabetes rates have increased;
also, adult obesity prevalence increased 19882008
and continues to increase slowly
● Healthy People 2020 target goal of 10% reduction in
prevalence of adult obesity from 34% (2010) to 30%, and child
obesity from 17.4% to 15.7%
● Adult waist circumference has been high, but prevalence has dropped over the past 10 yrs
○ Data shows that BMI didn’t change much in 20032012, while prevalence of abdominal obesity is still increasing
B. OBESITY TRENDS IN CHILDREN (019YO)
● Global burden of obesity
○ 2010 overweight/obesity → 3.4 mil deaths
○ Adults w/ BMI >25 increased from 28.8% (1980) to 36.9% (2013) in men, and 29.8% to 38% in women
○ Children w/ BMI >25 in 2013
■ Developed countries 23.8% boys, 22.6% girls
■ Developing countries increased from 8.1% to 12.9% boys, and 8.4% to 13.4% girls
● Prevalence of obesity in children 219YO
NonHispanic white children NonHispanic black children
NonHispanic Asian children
● Prevalence of obesity in children 02YO (20112012)
● Incidence of childhood obesity in USA
○ Followed kindergarten → 8th grade... obesity 12.4% → 20.8%; overweight 14.9% → 17%; total 27.3% → 37.8%
○ Obese 414YO nearly 50% were overweight since entering kindergarten!
○ Obese 611YO 4.2% (1963) → 15.3% (19992000) → 18% (201112), also 8.1% infants/toddlers, 16.9% 219YO)
● Risk factors predicting childhood obesity
○ Infant rapid weight gain in first 36 mo; breastfeeding <1 yr; introducing solid foods to formulafed infants before 4
mo; <12 hrs sleep per day
○ Mother antepartum depression, gestational diabetes, excessive weight gain or smoking during pregnancy, Csection
○ Socioeconomic status in overweight and normal kids (514YO) is inversely proportional to obesity risk
● Childhood obesity increases risk of adult obesity, as well as risk of
diabetes, high BP, dyslipidemia, and carotid atherosclerosis
○ Obese children who became nonobese adults had similar
results to neverobese adults
○ Adult obesity only occurred in 15% normalweight kids vs.
65% overweight kids and 82% obese kids
C. OBESITY TRENDS IN ELDERLY (>65YO)
● Mortality risk = 1.0 for overweight, 1.1 for obesity (BMI >30); attenuated by…
○ Survivor effect susceptible pts already died; remaining pts are resistant to consequences ( ie.
less dysmetabolic)
○ Competing mortality ↑ risk + ↓ life expectancy → ↓ followup + ↓ ability to establish obesity/mortality relationship
○ BMI is poorer measure of elderly obesity due to muscle loss + adipose gain (WHR or WHC may be better)
● Statistics
○ 20,975 obese elderly in 19942008; 48% died during 14yr f/u, but obesity only A/W mortality in BMI >35
○ For baseline elderly w/o severe disability, 17% developed new/worsening ADL disability and 26% new/worsening
IADL (instrumental ADL) disability w/i 2 yrs → overweight/obesity (BMI 2535) A/W new/worsening disability →
overweight/obese elderly should be targeted for preventing disability
■ ADL = bathing/showering, dressing, eating, getting in/out of chairs, walking, toileting
■ IADL = using telephone, doing light/heavy housework, making meals, shopping, managing money
D. COST OF OBESITY
● US healthcare spending is the most costly in the world
○ Per capita cost increased from $2738 (1990) to $4637 (2000) to $8608 (2011)
○ Following historical trend, healthcare spending will be 19.5% by 2017
● Societal costs
○ Leading cost of preventable death (400,000 annual deaths)
○ 39 mil lost work days ≈ $65 bil in lost productivity
○ Annual costs for obese pts are $1429 (42%) higher on average than normalweight pts
○ $150 bil of healthcare resources spent on comorbidities related to metabolic syndrome (in addition to $116 bil for
diabetes and $200 bil for CVD + obesityrelated malignancies)
○ 30% of increased healthcare spending over past 20 yrs attributed to soaring obesity rate
○ US hospital costs increased 63% from 1997 to 2011, eg.
special wheelchairs; widening revolving doors
○ 25% male/40% female military applicants are too obese to qualify
○ Other triplewide coffins, airplane fuel costs (due to increased passenger weight), replacing ballpark seats
● Prevalence of overweight/obesity by insurance category
● Obesity as a global issue
○ In 2011, UN declared that chronic noncommunicable diseases ( eg.
heart disease, cancer, diabetes) posed a greater
health burden worldwide than infectious diseases → 35 mil annual deaths
○ In 2012, obesity declared as a disease
○ Currently, 30% more obese people than undernourished
2.1. Understand the pathogenesis behind the growing prevalence of obesity.
2.1.a. Understand the genetic influence in obesity.
● Thrifty genotype theory thrifty gene enables individuals to produce quick insulin trigger, allowing for storage of Glc in the form
of TGs in fat cells, which can be drawn from in times of food scarcity
● Twin studies normal healthy twins ate 1000 extra calories and limited exercise
○ Weight gain and fat distribution matched amongst brothers, but varied widely among twins due to biological
determinism via variety of central and peripheral mechanisms
○ If one twin is obese, there is 77% chance that the other twin will also be obese
● >100 genes may predispose to obesity, and result in current obesity epidemic when combined w/ environmental factors
○ eg. FTO (fat mass & obesity) gene variant on Chr 16
■ Heterozygotes have 30% higher obesity risk (found in 65% Europeans/Africans, 2744% Asians);
homozygotes have 60% higher risk
■ Kids w/ FTO variant were more likely to eat highcalorie/fat foods and thus accumulate more body fat
○ Genomewide association analysis for obesity show that effects of obesity susceptibility loci are additive, but this
does not actually explain variance in obesity and BMI
○ Genetic screen
■ Negative test may predict less risk, but there may be unidentified genes causing false negative
■ Positive test may increase likelihood of highcalorie/fat diet since obesity is inevitable!
● However, environmental influences play a key role in the epidemic, eg.
greater intake of sweetened beverages attenuated by
genetic association w/ adiposity
○ Combined genetic effects on BMI among daily drinkers of sweetened
drinks were 2x as large as monthly drinkers, ie.
pts w/ greater genetic
predisposition to obesity appeared to be more susceptible to
deleterious effects of sweetened beverages on BMI
2.1.b. Understand the influence of different nutrients.
● Only 12% obesity can be attributed to disease (hypothyroidism, Cushing’s, insulinoma, craniopharyngioma & other
hypothalamic disorders) and drugs (antidepressants, steroids)
● Weight loss attempted by 25% American men and 43% American women, but only 5% successfully keep the weight off
● Correlation of fat and CHD
○ CAD incidence correlated w/ sucrose calories (due to intercorrelation of sucrose w/ saturated fat), which may explain
why Italy and Japan (lowsucrose diets) have lower CHD rates
● 30yr lipid trends show improvement, but CVD remains #1 killer in America (69% LDL >100; 19% HDL <40) despite advances
in coronary artery bypass, percutaneous intervention, and Tx for MI, unstable angina, and heart failure
○ Population weighs 25 lb more than 30 yrs ago despite efforts to decrease fat intake from 40% to 30%, due to 3x
increase in sugar consumption (
eg. highfructose corn syrup in processed food makes sugar much easier for the
body to obtain)
○ Increased caloric intake
■ Teen boys eat 275 more calories than 30 yrs ago (5g fat = 45 cal; 57g carbs = 228 cal)
■ Men consume 2656 kcal/d (vs. 2450) and women consume 1811 (vs. 1542)
● Toxic environment due to prevalence of fast food (commercials, less time to prepare food), prevalence of highfructose corn
syrup (commercials, increased portions, addition to most foods), and energysaving devices (reduce physical activity)
2.1.c. Understand differences between Glc and Frc, and shared biochemical properties from trans FAs, Frc, EtOH.
● Glycemic index
○ Carbs w/ higher glycemic index are rapidly digested and produce more marked glycemic/insulinemic response, while
lowerindex foods may have more soluble fiber and thus get digested slower
○ Accounts for net carbs (sugar/starch that is rapidly absorbed, converted to Glc, and stimulates insulin release) AND
amt consumed
○ Rule of thumb for any meal, keep net carbs <20 g (enough to stimulate insulin surge)
● Carbohydrates
○ Monosaccharides (simple sugars), eg.
6C (hexose) = Glc, Frc, Gal
○ Disaccharides (2 monosaccharides linked together), eg.
maltose (Glc + Glc), sucrose (aka cane sugar; Glc + Frc),
lactose (aka milk sugar; Glc + Gal)
○ Polysaccharides (series of mono/disaccharides), eg.
starch, glycogen (animal starch), dextrin, cellulose
■ Dietary starch and glycogen (stored in liver and muscle) metabolized to Glc, then CO and H
2 O
2
○ Complex carbs, eg.
grainderived foods
● Glc metabolism
○ 80% Glc used by cells for energy
○ 20% Glc transported to liver via GLUT2 → glucokinase converts Glc to G6P → G6P converted to glycogen (nontoxic
Glc storage)
● Mechanism of regional adipose distribution
○ Subcutaneous adipose (SA) is more sensitive to insulininduced LPL activation than visceral adipose (VA)
○ ↑ postprandial insulin exposure w/ Glc → ↑ LPL activation → ↑ TG uptake in SA → ↓ TG uptake in VA
● Frc metabolism completely transported to liver via GLUT5 →
metabolized by fructokinase into F1P (in the process, ATP → ADP)
○ Frc not metabolized by brain, thus has no acute symptoms
and doesn’t directly stimulate insulin
○ Frc (NOT Glc) → ↑ de novo lipogenesis → dyslipidemia (↑ TG,
↑ FFA, hepatic steatosis)
■ Comparison to EtOH consumption
● 10% firstpass effect in stomach/intestines
● 10% kidney/brain
● 80% liver → acetaldehyde → acetate →
VLDL (dyslipidemia) + FFA in muscle (→
insulin resistance) + lipid droplets in liver
○ ↓ postprandial insulin exposure w/ Frc → ↓ LPL activation in SA → ↓ TG uptake in SA → ↑ TG uptake in VA
○ Donut syndrome highFrc + fat diet may have more adverse effects than highFrc + complex carb diet
■ Dietary fat increases postprandial chylomicrons, which compete w/ VLDL for LPL, thus prolonging VLDL
circulation time and creating sdLDL.
■ Effects also due to ↓ TG uptake in SA + ↑ TG uptake in VA, which increases central obesity
○ 7x more likely than Glc to form AGE (advanced glycation end) products, or browning agents → ↑ atherosclerosis, ↓
GFR (↑ glycemia), ↑ endothelial dysfunction, ↓ NO
○ Drives formation of reactive oxygen species (100x vs. Glc)
■ Nonenzymatic fructosylation is 7x more rapid than protein glycation
○ No ghrelin suppression → excessive sugar consumption
○ Stimulates nucleus accumbens → ↑ reward + continued ingestion
○ Trans FAs used to be added as hardening agent to increase shelf life, but they were removed due to
↑
CVD risk
● Highfructose corn syrup = 55% Frc + 42% Glc (≈ sucrose, where 50% Frc is connected to Glc by ether linkage)
○ 20% sweeter than sucrose (used in soft drinks)
○ Cheaper → 40% added caloric sweeteners
○ Mostly responsible for increasing Frc intake in Americans, eg.
8% of diet (1978) → 10.2% (1992) → 12% (2010,
where 25% adolescents get >15% from Frc), or 63 lb/person/yr (>55 g/d)
○ Also responsible for decreasing consumption of fruits/vegetables (24 → <15 g/d) and fiber (100 → 15 g)
○ Consumption produces linear doseresponse increase in CV risk factors (TG, LDL, uric acid, apoB, apoC3) w/i 2 wks
● Portion distortion is also a contributing factor to the obesity epidemic
● Soft drinks = 7% daily calories = #1 food in American diet (41% increase in soft
drinks, also 35% increase in fruit drinks)
○ Avg can of soda (150 cal) x 365 days / 3500 cal/lb = 15.6 lb gained per
yr from drinking 1 can of soda per day
○ Additionally, 55 mg Na per can + caffeine → ↑ free water clearance →
↑ Na → ↓ H O → ↑ thirst
2
■ Increased Na masked by sugar, allowing us to take in more
○ Each additional sweetened beverage increases BMI by 0.24, as well as odds for obesity; however, removing these
drinks from schools didn’t decrease prevalence of obesity, while leaving them in schools increased it
■ Other studies showed that diet modification (Netherland replacement w/ noncaloric drinks; Harvard
decrease consumption of sweetened beverages) reduced weight gain and/or fat accumulation
● Sugar consumption in infants
○ Similar ingredients in baby formula (50% HFCS + sucrose) contribute to infant obesity!
■ Breastfed infants stop when full, while bottlefed infants stop
when bottle is empty! However, breastfeeding isn’t necessarily
protective against obesity
○ Early exposure to sugar (eaten by mom during pregnancy) →
developmental programming → altered adiposity before birth
2.1.d. Understand the influence of inflammation in obesity and related clinical outcomes.
● Adiposopathy in environmentally/genetically susceptible pts,
positive caloric balance → adipocyte hypertrophy +
accumulation in nonSA areas
○ Increased VA + accumulation in
perivascular/pericardial adipose → outsidetoinside
inflammatory signaling → atherosclerosis + arterial
inflammation (adiposopathy or dysfunctional sick fat)
● Fat cells
11 10
○ Obese pts have 10 fat cells (born w/ 10 ), but only
5% have genetic propensity for fat cell accumulation
○ You can gain 30 lb by increasing fat cell size w/o
increasing cell number (similarly, weight loss involves
shrinking cells rather than decreasing cell number);
thus, cell number is stable even with weight gain/loss
○ When fat cells reach maximum size by overeating,
they signal precursor cells to mature
■ Large cells can hold up to 10x more fat per
cell, but they are at increased risk of dying,
which would leave behind insoluble fat that is
taken up by macrophages → fatengorged
macrophages induce inflammatory state that
releases cytokines into blood
● Obesity linked to metabolism and immunity
○ Bacterial infections → Th1 response → energy demand (due to macrophages and T cells using circulating nutrients)
→ promotes inflammation, insulin resistance, energy mobilization
■ Hypertrophic adipocytes in VA develop hypoxemia, oxidative stress, and endoplasmic reticulum stress →
dysfunction + Th1 response → TNF release → adipocyte apoptosis → recruitment of lymphocytes (adaptive
immunity) and macrophages (innate immunity)
● Thus, obesity ≈ continuous bacterial infection → chronic inflammation → → CVD
● Metaflammation immune system reacts at lower level to proinflammatory environmental inducers
(central fat, inactivity, diet, etc.) than to acute injury (no time to react)
○ Parasitic infections → Th2 response (requires deprivation of circulating nutrients) → prevents inflammation & insulin
resistance; preserves host nutrient requirements (energy sequestration)
■ Lean adipocytes secrete IL4, IL13, IL10, and adiponectin, which promote Th2 response
● Western diet modified intestinal barrier → induced development of Glc intolerance and atherosclerosis
● Human Microbiome Project collective genomes of microbes (bacteria, fungi, protozoa, virus) living inside the human body
○ Humans possess 2023,000 genes and 3.3 mil nonredundant microbiota genes → 150x more microbial genes (we
are <1% human!)
● Antibiotics highly prescribed to humans and farm animals → infiltrates into food, soil, and water
○ Started at same time as obesity epidemic, and is practiced most prevalently in southeast/central US where obesity
rates are greatest
● Kids <6MO treated w/ antibiotics are more likely to be overweight at 3YO, and kids <2YO treated w/ antibiotics had increased
risk of childhood obesity
○ Gut flora returns quickly after 1 round of antibiotics, but can change longterm w/i months after 2nd round
○ ⅓ babies delivered by Csection may have different microbiota due to not being exposed to microbes w/i mother’s
birth canal (require microbe supplement, everyday contact, etc.), and this shift can persist for weeks to years
■ However, risk of childhood obesity at 3YO is similar to naturalborn kids
3.1. Understand the adipokines and hormones associated with obesity.
● Ghrelin
○ Influences gastric satiety signaling by altering
sensitivity of vagal afferents, which send gastric
distention info to CNS
○ Secreted from gastric endocrine cells to signal
hypothalamus via vagus nerve to stimulate
appetite (≈ antileptin)
● Adipokines (adiposederived factors) = adiponectin,
TNFα, leptin, IL6, resistin
● Adiponectin peptide predominantly secreted by adipocytes, accounts for 0.05% total serum protein
○ Small fat cells produce high amounts, but not as much when
enlarged → decreasing cell size improves adiponectin levels!
○ Expression downregulated in obesity, insulin resistance, and
T2DM → adiponectin improves insulin sensitivity!
○ Antidiabetic/atherogenic properties make adiponectin inversely
predictive for risk of DM, CVD (BP, HR, LDL, TG, CAC score;
directly predictive of HDL levels), atherosclerotic plaque burden,
coronary plaque vulnerability
● TNFα (cachexin)
○ Secreted by activated macrophages (major) and visceral adipocytes
■ Additionally, adipose tissue produces ↑ NEFA (nonesterified fatty acids) → ↑ ROS in endothelial cells and
monocytes → ↑ TNFα → ↓ adiponectin + ↑ leptin resistance → ↑ leptin
○ Effects
■ ↓ insulin signaling → ↑ insulin resistance
■ Binds to TNFR1 & R2 → 1) release IL1/6/8 and resistin; 2) upregulate endothelial adhesion molecules;
3) coordinate migration of leukocytes to targeted organs
● Leptin
○ Produced from white adipose tissue proportional to total body fat mass
○ Functions
■ Regulates food intake, energy expenditure, and Glc homeostasis, eg.
↓ food intake, ↓ adipose tissue mass,
↑ energy expenditure, ↑ insulin sensitivity, ↑ atherogenic vascular remodeling, ↑ BP
■ Satiety signal to hypothalamus that inhibits feeding by reducing hunger
○ Levels often high in obesity (<= TNF, CRP) → leptin resistance (Tx w/ leptin reduces hunger in thin pts, but proves
ineffective in obese pts since levels are already elevated)
○ Frc intake → 2030% reduction in leptin → ↑ hunger + ↓ satiety
● Resistin protein expressed primarily in macrophages and monocytes; exacerbates insulin resistance
○ A/W adiposity and decreased insulin signaling
○ Induced by inflammatory mediators (liposaccharides, TNFα)
● NPY (neuropeptide Y) potent appetite stimulant
○ Stimulated by highfat/sugar diet, while production inhibited by functional leptin to reduce feeding
● Corticotropinreleasing factor appetite suppressant (↓ feeding + ↑ energy expenditure)
● Short vs. longacting energy balance
○ Shortacting (mealrelated) ghrelin stimulates hunger; gastric distention + GI peptide signal for satiation through
hypothalamic activity
○ Longacting (adiposerelated) leptin augments longacting satiation signals
● Weight loss
○ The body responds to acute weight loss by trying to regain weight via ↓ leptin + ↓ insulin + ↓ cholecystokinin + ↑
ghrelin, but these shifts can persist longterm
○ Dietinduced weight loss did not revert hormones to original levels, and can still stimulate weight regain 1 yr later!
Thus, high relapse rate among obese pts who lost weight has strong physiological basis.
■ Daily caloric intake must average 250400 less calories per day to maintain the same weight
4.1. Understand those diseases directly and indirectly associated with obesity.
● Prevalence of multimorbidities = 23% normalweight M, 28% normalweight F; but if BMI >40, rises to 44% and 51%
● Almost all leading causes of death are A/W obesity, eg.
heart disease, cancer, stroke, chronic lower respiratory disease
● Physical exam findings in obese pts
○ Neck size >17” (M) or >16” (F) A/W increased risk of obstructive sleep apnea
○ BP large cuffs required to encircle 80% upper arm
○ Pulse handheld Doppler
○ Cardiac auscultation pt leans forward to bring heart closer to chest wall
○ May need to ask pt to retract breast/abdominal pannus to facilitate exam, or examine breast in decubitus position
○ Liver size scratch test, ultrasound
○ Gynecological exam longer speculum, transvaginal ultrasound
● Obesity may account for 40% of overall mortality in USA, particularly for #1 mortality CVD (worsens most CV risk factors,
eg.
lipids, Glc, BP, inflammation; increases heart burden → worsens ventricular structure and function)
● Complications of obesity
○ Metabolic = CVD (T2DM, HTN, ↑ TC, ↑ TG/↓ HDL, platelet dysfunction, thromboembolic Dx)
■ HTN mechanisms in obesity
1) ↑ vascular resistance <= ↑ oxidative stress → ↑ ADMA (endogenous NO inhibitor) → ↓ NO
2) ↑ sympathetic tone
3) ↑ angiotensinogen expression by adipose tissue
■ Diabetes prevalence increased by obesity (matching geographic distribution also coincides w/ sleep
disorders and #/McDonald’s restaurants)
● ↑ BMI from 22 to 32 → cumulative 23x ↑ CVD risk <= 1) ↑ SBP by 10 → ↑ risk by 3040%; 2) ↑
nonHDL by 40 → ↑ risk by 4050%; 3) ↓ HDL by 10 → ↑ risk by 3040%
○ Structural = obstructive sleep apnea, GE reflux ± asthma, venous insufficiency, venous thrombosis, pseudotumor
cerebri, skin infections/ulcers, stress incontinence, injuries
○ Effects on cardiac performance
■ Hemodynamics = ↑ blood vol; ↑ stroke vol; ↑ arterial pressure; ↑ LV wall stress; ↑ pulmonary artery pressure
■ Cardiac structure = LV concentric remodeling; LV ± RV hypertrophy; LA enlargement
■ Cardiac function = LV systolic/diastolic dysfunction; RV failure
■ Inflammation = ↑ CRP; ↑ TNF expression
■ Cellular = hypertrophy; apoptosis; fibrosis
■ Neurohumoral = insulin resistance; leptin insensitivity; ↓ adiponectin; SNS activation; RAA activation; ↑
peroxisome proliferatoractivator receptor expression
● Pathophysiology of obesity cardiomyopathy
○ 58% Afib pts had BMI >27, but those who went on to lose
>10% weight had significant reduction in AF burden and
improved sinus rhythm maintenance (46%, vs. 22% in 39%
weight loss vs. 13% in <3% weight loss)
■ However, >5% weight fluctuation → 2x risk of
recurrent Afib
● Obesity also has an impact on #2 US mortality cancer
2
○ 5 kg/m increase in BMI A/W higher risk of cancer in uterus
(HR 1.62); gallbladder (1.31); kidney (1.25); liver (1.19);
colon, cervix (1.10); thyroid, ovary, leukemia (1.09);
postmenopausal breast, pancreas (1.05)
2
■ In UK, estimated that 1 kg/m increase in BMI → 3790 additional cancers annually
○ Obesity accounts for 41% uterine cancers and >10% gallbladder/liver/colon cancers
● Sleep deprivation may compromise efficacy of weight loss via dietary intervention
○ Decreases proportion of weight lost as fat, eg.
↓ fat oxidation, ↑ ghrelin (<= ↓ leptin), ↑ hunger
○ May also increase appetite, due to more awake hours to eat
○ Sleep patterns are disrupted by high sucrose intake, eg.
HFCS
● Polycystic ovarian syndrome is most common cause of female infertility (5060%), affecting 610% women of childbearing age
○ Most common endocrinopathy in young women (3550% obese
women w/ PCOS develop impaired Glc tolerance or T2DM by 30YO)
○ Clinical consequences
■ Traditional = infertility, hirsutism, alopecia, acne, ↑ risk of
endometrial cancer
● Acanthosis nigricans brown/black plaques w/ accentuated skin markings (velvety appearance)
and skin tags on axilla, neck, groin, knuckles, elbows
○ Suggests Dx in young pts (PCOS, obesity, endocrinopathy) and elderly (GI
adenocarcinoma, often w/ oral/palmar hyperkeratosis)
■ Newer potential risks mimic risks of obesity/metabolic syndrome = Glc intolerance, T2DM, HTN,
dyslipidemia (↓ HDL, ↑ TG), CVD, ↑ OSA risk, ↑ NAFLD risk (30%), endothelial dysfunction
● Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and abnormal LFT levels in US
(30%, equal M/F incidence), and is especially noted in pts w/ obesity, metabolic syndrome, corticosteroid Tx, T2DM,
hypertriglyceridemia (prevalence rises to 70100% in obese diabetics)
○ Nonalcoholic steatohepatitis (NASH) in 21% normal pts, 50% T2DM, 75% >110% IBW, 100% morbidly obese
■ Also, CVD is higher risk and leading cause of death in NASH pts
■ NASH → expanded and inflamed visceral fat mass → ↑ CKs → ↑ insulin resistance + ↑ FFA + chronic
inflammatory state
○ Prognosis 820% steatosis → NASH; 925% NASH → cirrhosis
■ 1% liver TPx due to NASH, and can recur again after TPx
■ Improved obesity (not Glc) tends to improve LFT
○ Waist circumference (and BMI) are good screens for NAFLD, showing 4x increase from lowest to highest quartile
4.2. Understand the differences in obesity as associated with adverse metabolic factors & metabolic syndrome.
● Metabolic syndrome
○ Defined by ATP III as three of the following: waist circumference >40” (M)/35” (F); serum TG ≥150; HDLC <40
(M)/50(F); BP ≥130/85; serum Glc ≥100
■ Components = abdominal obesity, atherogenic dyslipidemia, high BP, insulin resistance ± Glc intolerance,
proinflammation
(obese subjects w/ metabolic syndrome had significantly higher sdLDL and CRP than those w/o metabolic syndrome)
○ Defined by International Diabetes Federation as central obesity (WC) + two of the following: TG >150; HDLC <40
(M)/50 (F); BP >130/85 or HTN Tx; FPG >100
● Prevalence of metabolic syndrome (19992006)
● Parallel prevalence in overweight/obesity, metabolic syndrome, and diabetes
○ In 20002004, 29 of 36 studied countries had lower obesity rates than USA!
● Obesity and metabolic syndrome may independently predict CV risk
○ Metabolic syndrome increases risk of major adverse coronary
events (regardless of Framingham estimated risk)
● Not all obesity is the same… insulin resistance can be found in
normalweight pts and may be absent in obese pts, but it IS related to
atherosclerosis
● Prevalence of metabolic syndrome by weight matches insulin resistance (
ie.
even normalweight pts are at risk)
● Obesity is an inflammatory state! Adipose tissue (and resident macrophages) expresses TNF, IL6, CRP, and Eselectin, all of
which are elevated in obese children and A/W increased carotid IMT and endothelial dysfunction
○ Chronic lowdose inflammation (≈ CRP)
■ In kids, may be independently correlated to BMI
■ Adds predictive value (when >3 mg/L) to LDLC, global risk score, impaired Glc/lipid metabolism
(highsensitivity CRP is better predictor than many other factors)
● Pts shown to benefit clinically from both LDL reduction and inflammation reduction; methods of
CRP reduction include:
○ Best results exercise, weight loss, statins (± ezetimibe, stanols), antiinflammatory meds
(methotrexate, TNFαI, IL6 inhibitor, IL1β inhibitor
○ Mixed results low amts of alcohol, multivitamins, ω3 FAs, fibrates, niacin, PPAR gamma
(TZD), clopidogrel/abciximab, CCB/nitrates, ARB
○ Neutral effect aspirin ± COX1/2, ezetimibe (monotherapy), stanol ester (monotherapy)
■ May be pathogenic for DM, along w/ insulin resistance (both are elevated earlier than FBG and TG)
○ IL6 proinflammatory adipokine that increases levels of other adipokines in peripheral tissues
■ ↓ insulin signaling (≈ insulin resistance)
■ ↑ proatherogenic PAI1
■ ↑ CRP (synthesized by liver as acutephase reactant;
detected 4 hrs after injury, peaks 2472 hrs)
■ ↑ vascular inflammation
● Metabolically healthy obese (MHO) (2030% among obese pts) high BMI + normal insulin sensitivity + no diabetes,
dyslipidemia, HTN (no metabolic syndrome, but some metabolic risk, eg.
2 risk factors)
○ Characteristics ↑ total fat mass; = visceral or ectopic fat; ↓/= TG; ↑/= HDL; ↓ inflammatory markers (CRP); ↑
adiponectin; = carotid IMT
○ 50% MHO pts transition to MUO (metabolically unhealthy obese) over 10 yrs
■ Predictive factors for transitioning to MUO ↑ WC, ↑ WHR
■ Predictive factors for maintaining MHO healthy diet, exercise
○ MHO may have increased risk of mortality and CV events, compared to metabolically health pts of normal weight
■ Metabolically benign overweight/obese women appear to have significantly greater subclinical CVD than
normal weight (35% actually had metabolic syndrome 2 risk factors + weight ± CRP >3)
■ Jshaped relationship b/t BMI and mortality of healthy white adults → mortality lowest at BMI 2025
● Obesitymortality paradox
○ Mortality inversely related to LMI in pts w/ stable CHD
○ Mortality highest (3x) in pts w/ low BF% and low LMI (Lean Mass Index)
■ Nonsurvivors had average BMI, low LMI, dysmetabolism, but not truly low BF% (avg 25.2%) or BMI (25.1)
● High TG/HDL ratio (>3.5) ≈ visceral adiposity, hyperinsulinemia,
sdLDL (80% for >3.8), metabolic syndrome, CHD & DM (partially
mediated by proinflammatory state reflected by CRP)
○ 7% US population has TG >200 and HDL <40 (M)/50 (F);
increases to 15% in diabetics
● Obesity and smoking are equally detrimental to life expectancy,
regardless of gender or BMI
● Inflammation links obesity with metabolic syndrome and T2DM, and
also facilitates MHOMUO transition
● Obesity itself is NOT the cause of this epidemic ; rather, it is a marker for
(2030% obese pts have normal metabolism and lifespan)
metabolic dysfunction that leads to T2DM, HTN, dyslipidemia, CVD, NAFLD, cancer, dementia (occurs in ≤40% normalweight pts)
4.3. Understand psychological issues and behavior modification as it relates to obesity.
● Psychological complications of obesity = depression, anxiety/panic, bingeeating, reactive bulimia
○ Pts must understand that these are not the actual problem, but rather manifestations of the problem
○ Americans are more concerned about weight than family health, higher prices, health maintenance, and busyness
○ Rather than be obese again, 100% formerly severely obese pts preferred to be deaf, dyslexic, diabetic, have heart
disease, or have bad acne; 91.5% preferred leg amputation; 89.4% preferred blindness
■ 100% preferred to be normal weight than a severely obese multimillionaire
● Bingeeating triggered by 1) breaking dietary rule; 2) disinhibition from alcohol, etc.; 3) undereating; 4) external event or
adverse mood, eg.
stress
4.4. Understand the various nutritional and dietary treatment options for obesity.
● Factors in success of behavioral weight loss interventions
○ Personal support, eg.
>5% weight loss over 2 yrs observed in 18.8% selfdirected programs, 38.2% remote support,
and 41.4% inperson + remote support
■ Social networking improves and sustains weight loss
○ Lifestyle counseling, eg.
>5% weight loss over 2 yrs observed in 21.5% usual care (PCP only); 26% brief counseling
(lifestyle coach) → 915 lb.; and 35% enhanced brief counseling (coach + meal replacement + meds orlistat,
sibutramine) → 1122 lb.
● AHA 2013 Guidelines for Lifestyle Intervention & Counseling
○ Participation >6 mo in comprehensive lifestyle program adhering to lower caloric diet & increase physical activity,
including 1) reduced caloric diet, 2) increased physical activity
(aerobic ≥150 min/wk, but 200300 to maintain loss or
minimize regain) , and 3) behavior therapy
(regular selfmonitoring of foot intake, physical activity, and weight)
○ Prescribe in site, high intensity (i.e. ≥ 14 sessions in 6 months) comprehensive weight loss interventions provided in
individual or group sessions by a trained interventionist
● Selfblame must be avoided, as being overweight/obese is not all about loss of control, but rather a combination of genetic,
environmental, physiological, and behavioral issues
○ Encourage an attitude of selfcompassion
● Stress can lead to obesity
○ Causes cravings for highcalorie foods to feed stress pathway in limbic systems
■ Even playing video games can cause stress, leading to ↑ mental workload + ↑ sympathetic tone → ↑ food
intake (even though hunger sensation remains the same)
○ {+ ↓ sleep quality/duration} → ↑ cortisol + ↑ glycemic instability → obesity
● Hungry brain syndrome inherent directive from brain to eat + defend against fat loss (evolved due to uncertainty of next meal)
○ Heavier pts viewing food pics had ↑ functional MRI activity in putamen (reward center) + ↓ response in satiety areas;
brains of thinner pts had the opposite response
■ This phenomenon was also observed in women viewing pictures of exercise or sedentary behavior
● Also, overweight women viewing exercise had no activity in brain area related to movement
memory, suggesting that they didn’t even know how to exercise, which might contribute to their
negative emotional response
■ However, it is possible to convert the central emotional response to food/exercise from negative to positive
by losing weight and exercising
○ Also related to circadian rhythm; upregulated w/ sleep disturbances and stress, which ↓ metabolism but ↑ desire for
highcalorie food
● Food overconsumption mimics detrimental effects of drug abuse on brain reward system, eg.
decreased striatal activation
○ Compulsive behaviors like these may be predisposed by common genetic vulnerabilities and neuroadaptive
responses in reward system
5.1. Understand the various nutritional and dietary treatment options for obesity.
● Obesityfocused history = What factors contribute to obesity? How does obesity affect your health? What are your risks from
obesity? What are your goals and expectations? Are you motivated to initiate a weight management program? What kind of
help do you need?
● Diet yielded significant weight loss regardless of lowcarb vs. lowfat (both
better than moderate macronutrient), but most important factor was adherence
○ All diets were superior to no diet at 6 mo
○ Weight loss enhanced by behavioral support and exercise
● Commercial weight loss programs
○ Very low calorie diets (8001000/d), HMR, Medifast, OPTIfast
eg. → shortterm results that attenuate after 6 mo
○ Compared to control/education/counseling,, Weight Watchers achieved ≥2.6% and Jenny Craig ≥4.9% greater weight
loss at 1 yr (longterm)
● Longterm weight gain over 20 yrs = 3.35 lb/4 yrs
○ It is more difficult to push away fries or ice cream than fruits and vegetables b/c your brain looks for nutrients not
calories (drives you to eat until satisfied)
● Fiber intake prevents obesity
○ Highfiber foods expand in stomach, slow digestion, and augment satiety → taking in the right calories can help
prevent the need for more calorie intake later
○ ↓ rate of intestinal carbohydrate absorption → ↓ insulin response
○ ↑ speed of transit of intestinal contents to ileum → ↑ satiety hormones
○ ↓ FFA absorption into colon (normally metabolized by colonic bacteria into shortchain FAs, which suppress insulin)
○ eg. nuts vs. French fries
● Typical lowfat diets are often ineffective due to substituting fat for fructose
○ Frc metabolized by like fat, and 30% of its calories are converted to fat
○ Hepatic Frc metabolism → metabolic syndrome (HTN; de novo lipogenesis,
dyslipidemia, steatosis; inflammation; insulin resistance; CNS leptin resistance
→ continuous consumption; obesity)
○ Reducing Frc in highFrc kids even just for 10 days can result in significant
reduction in sugartofat conversion, liver fat deposition, and TGs
● Western diet/lifestyle is being adopted by less educated, physically inactive, single/divorced/separated, and smokers
● Something in the Western diet may work centrally to make ppl crave a less healthy alternative when under stress or actively
pursuing a less healthy lifestyle perhaps artificial sweeteners, eg. artificial sweetened beverages (ASB)
○ Possible mechanism = mismatch of intense appetite stimulation of sweet taste + lack of energy consumption →
dysregulation of appetite control → ↑ consumption of other caloric sources ( ie.
solid foods) → ↑ weight
■ There are also sweet taste receptors in the gut can be stimulated by nutritive and nonnutritive sweeteners
○ However, public health recommendations are equivocal due to conflicting studies, even though most ASB consumers
are obese, DM, or CVD
● Altered composition/function of gut microbiota induces Glc intolerance
○ Noncaloric artificial sweeteners linked to host susceptibility to metabolic disease and Glc intolerance in healthy pts
○ Antibiotics before birth or in early life alter microbiota → ↑ total fat mass + ↑ ectopic fat → weight gain
● Metabolic benefits of weight loss
○ In overweight/obese adults, weight loss of 2.55.5 kg at 2yr mark → ↓ T2DM risk by 3060%
■ 25% weight loss over 14 yrs decreases HbA1C by 0.20.3%, while 510% loss (± orlistat) decreases
HbA1c by 0.61.0%
○ >3 kg weight loss → ↓ TG by 15 mg/dl
○ 58 kg weight loss → ↓ LDL by 5, ↑ HDL by 23
○ 5% weight loss → ↓ BP by 3/2 mmHg
5.2. Understand the implications of physical activity & exercise, lifestyle and energy expenditure for obesity.
● Marked decline in occupationrelated physical activity and women’s household management energy expenditure in past 50 yrs
→ additional 1800 calories/wk retained
● AHA 2013 Guideline for Reduced Caloric Diets for Weight Loss
○ 12001500 kcal/d (F), 15001800 (M), ie.
500 (F)/750 (M) daily energy deficit
○ Evidencebased diet (lowfat, lowcarb, highprotein) → maximal weight loss at 6 mo, then slow weight regain after →
total weight loss in 1 yr = 410 kg, in 2 yr = 34 kg
● Benefits of 30 min daily exercise = ↓ CHD risk by 40%; ↓ stroke risk by 30%; ↓ T2DM risk by 30%; ↓ TC, ↓ LDL, ↓ TG, ↑ HDL; ↓
colon cancer risk; ↓ osteoporosis risk; strengthens bones, joints, muscles; improves anxiety/depression; ↓ stress (→ ↓ cortisol
release → ↓ appetite); improves insulin sensitivity (skeletal muscle; liver → more efficient TCA cycle + Frc detoxification)
○ Increasing to 60 min daily will yield additional benefits w/ lipid subfractions and weight
○ Obese pts w/ good cardiorespiratory fitness generally have lower CV mortality risk, even than lean, poorly fit pts (<=
SA is more sensitive to LPL activation by insulin)
○ These benefits don’t apply to centrally obese pts, as insulin resistance → ↓ LPL activation → ↑ VA + ↓ SA
■ Physical training → more efficient O transfer to muscle → central lipid stores can be utilized (rather than
2
depending on limited carbohydrate reserves)
○ After losing weight, you initially burn 2025% less calories during everyday activity than ppl normally at your weight
due to transformation of muscle fibers into slowtwitch type (burn less calories w/ exertion), such that 812 mo
continuous daily moderate exercise is required to increase metabolism back to baseline efficiency
● Once adjusted for fitness, MHO pts no longer had higher risk than normal metabolism/weight pts
○ MHO pts 13% obese by BMI >30; 29% obese by BF% >25% (M)/30% (F); 46% obese
metabolically normal (better fitness than MUO)
○ Differences in obesity risk in MHO = ↓ VA; ↓ adipocyte size; ↑ expression of adipocyte
differentiation markers; ↓ inflammatory markers (CRP); ↑ cardiorespiratory fitness
■ Graded exercise improves O uptake (exercise tolerance), but no body weight
2
○ Fitness was determined by exercise testing protocols, which showed that minimum
exercise to neutralize CV effects is lower in MHO pts than MUO pts
● Aerobic exercise (even w/o concomitant caloric restriction) after 12 wks leads to significant reduction of
visceral fat (
eg. during dietinduced weight loss), while resistance exercise had no such effect
○ Can also prevent visceral fat regain after weight loss
● Improved cardiorespiratory fitness (≈ functional aerobic capacity ≈ METS)
= improved mortality in all weight classes
○ Ambulatory steps baseline = 6245, and every additional 2000
steps A/W 10% lower CV risk over 1 yr (independent of ΔBMI) in
pts w/ impaired Glc tolerance and CVD or 1+ other risk factors
● If on a statin, improved fitness decreases mortality risk (for fit individuals
>9 METS, hazard ratio = 0.30 vs. least fit <5 METS)
● Actual measured physical activity (according to accelerometer) was
substantially underestimated by pt
● Prolonged sedentary time A/W deleterious health outcomes (CVD, cancer,
death) regardless of physical activity → if seated >1 hr, stand ≥1 min
● Physical activity recommendations from US dietary guidelines
○ ≥30 min/d for CV health benefits
○ Intensity 6085% MHR (conversational dyspnea), or 120140 bpm ≥60 min/d to prevent weight gain; 6090 min/d to
prevent weight regain in formerly obese pts
○ Reasonable goal = 10,000 steps/d (≈5 mi)
■ Pedometers = simplest way to monitor walking (total steps, distance, and burned calories) and cost $1050
● >50% pts Rx’ed w/ physical activity were more active 1 yr later
● Recommendations for lifestyle intervention (maintaining healthy lifestyle in young adulthood → ↓ CV risk profile in middle age)
○ Cut out sugary beverages; only water, milk, coffee, tea
○ Eat carbs w/ fiber (fruit, vegetables)
○ Wait 20 min for 2nd portion
○ Use physical activity to “buy” leisure time
● Myths 1) “Obesity is just a function of lack of willpower,” 2) “A
calorie is just a calorie,” 3) “Fat is just fat,” 4) “Skipping breakfast is
protective against obesity,” 5) “Snacking contributes to weight gain
and obesity,” 6) “Breastfeeding is protective against obesity,” 7)
“Preventing obesity is easier than treating obesity,” 8) “Small,
sustained changes in energy intake or expenditure will produce
large, longterm weight changes that accumulate indefinitely,” 9)
“Slow, steady weight loss is superior to large, rapid weight loss,”
10) “Eating more fruit/vegetables will result in weight loss
regardless of any other behavioral or environmental changes.”
● Diet facts/suggestions
○ Liquids are often responsible for large portion of total calories and produce less satiety
○ Eating is best only at a designated location (dining room, kitchen), and not in the car, family room, etc.
○ 10% reduction in body weight → 33% reduction in abdominal fat cell mass
6.1. Understand the medications used for the short and long term treatment of obesity. Know various classes of medications
that can induce weight changes and what options are available to counter these effects.
● Pharmacotherapy for recommended for 1) BMI ≥27 + diabetes, HTN, hypercholesterolemia; 2) BMI ≥30 w/o comorbidities
○ Other meds (not primarily for obesity) = fluoxetine, exenatide, pramlintide, ephedra, Ma Huang
● Sympathomimetic drugs (phentermine for shortterm use; diethylpropion)
○ Stimulate norepinephrine release or inhibit reuptake into nerve terminals →
early satiety → reduce food intake
○ Rapidly absorbed w/ peak conc 12 hrs
○ Potential abuse only approved for shortterm use (max 12 wks)
● Orlistat nonsystemic lipase inhibitor (blocks absorption of ⅓ fat calories,
but not protein or carbs)
○ Dosage = 120 mg w/ lowfat meal (or ≤1 hr after) TID
○ Adverse effects oily spotting, flatus + discharge, fecal urgency +
frequency, fatty/oily stool, oily evacuation, fecal incontinence
■ Can reduce absorption of fatsoluble vitamins → pts
should supplement w/ multivitamins 2 hrs before/after
○ Combination w/ sibutramine yielded no additional weight loss
● Serotonergic agonists enhance presynaptic serotonin release and block its reuptake → serotonininduced valvulopathy via
5HT receptor agonism on cardiac valves
2B
○ Fenfluramine, dexfenfluramine nonselective
○ Lorcaserin selectivity 15x 5HT > 5HT
2C and 100x > 5HT
2A 2B, but same weight loss effects expected as orlistat
■ Adverse effects headache, dizziness, fatigue, nausea, dry mouth, constipation
■ Safety concerns serotonin syndrome, cognitive impairment, hypoglycemia (in DM), bradycardia, ↑ prolactin
● Qsymia = topiramate + phentermine → 6.68.6% weight loss
○ Risk concerns 1) Category X → cleft lip; 2) CV events <= bradycardia
○ Topiramate central GABA modulator → ↓ caloric intake (taste aversion) + ↑ energy expenditure
■ Approved for epilepsy and migraine
■ Adverse effects paresthesia, hypoesthesia, taste perversion, psychomotor impairment (difficulty
concentrating), A/W metabolic acidosis (carbonic anhydrase inhibitor)
○ Phentermine sympathomimetic amine; stimulates neurons to release/maintain higher levels of norepi and dopamine
■ Approved for shortterm obesity Tx
■ Adverse effects dizziness, dry mouth, insomnia, constipation, doserelated tachycardia
● Contrave = naltrexone SR 8 mg/d + bupropion SR 90 mg/d = longterm obesity Tx
○ Dosing qAM in Wk 1; BID in Wk 2; 2 qAM + 1 qPM in Wk 3; 2 BID in Wk 4
○ Bupropion stimulates hypothalamic proopiomelanocortin (POMC) neurons → ↓ food intake + ↑ energy expenditure
■ Approved for depression and smoking cessation
■ Adverse effects insomnia, headache; drug interactions w/ CYP2B6 inhibitors (↓ dose)/inducers (↓ efficacy)
○ Naltrexone opioid receptor antagonist; blocks POMC autoinhibition → augments POMC synergistically
■ Used for addictive behaviors, but shouldn’t be started prior to 710 days of abstinence from opioids
■ Adverse effects nonspecific GI symptoms (diarrhea, abdominal cramps)
● Liraglutide GLP1R agonist (gut incretin hormone) involved in peripheral AND central
satiety pathways
○ Used as adjunct Tx to reducedcalorie diet + increased physical activity for
longterm obesity Tx in adults w/ BMI >30, or >27 + 1+ comorbidity (high BP,
T2DM, dyslipidemia)
○ Contraindicated for T2DM, insulin, other GLP1R agonist, pregnancy,
medullary thyroid cancer, MEN2 (multiple endocrine neoplasia syn Type 2)
○ Adverse effects nonspecific GI symptoms (diarrhea, abdominal cramps)
● OTC meds = green tea, coffee, conjugated linoleic acid, guarana chromium, bitter orange, garcinia cambogia, ephedra
○ Garcinia cambogia derived from hydroxycitric acid, mainly found in Asian fruits → 1) ↑ serotonin → appetite
suppression (may help w/ emotional eating); 2) prevent formation of new adipocytes; 3) control cortisol levels
● Meds A/W body fat weight gain psychiatric/neurologic (antipsychotics, mood stabilizers, antidepressants, anticonvulsants);
antihistamines; antihypertensives (β and α blockers); HIV protease inhibitors; steroid hormones (corticosteroids,
1
progestational steroids); antidiabetics (insulin, sulfonylureas, thiazolidinediones)
● Meds A/W little/no weight gain antidepressants (bupropion, fluoxetine, venlafaxine); antiepileptics (topiramate, lamotrigine,
zonisamide); antipsychotics (ziprasidone, aripiprazole); antidiabetics (metformin, pramlintide, exenatide, liraglutide)
6.2. Understand the criteria needed for surgical options for obesity and the types of surgical procedures used.
A. CRITERIA FOR BARIATRIC SURGERY
● NIH treatment guidelines
● met by 5% obese population!)
Criteria for bariatric surgery ( 1) BMI >40; 2) BMI =3539 + 1+ comorbidity (diabetes, asthma,
HTN, OSA, GERD, pseudotumor cerebri); 3) BMI = 3034.9 if uncontrolled T2DM or metabolic syndrome
● Major complications = postop mortality 0.12%; PE, respiratory failure, GI leaks from breakdown suture line, stomal
obstruction/stenosis, bleeding
● Bariatric surgery → better weight loss and DM remission than nonsurgical therapy in pts w/ BMI >40, but ⅓ pts who underwent
surgery started w/ BMI >50 and still had BMI >35 postop
● Bariatric surgery in diabetics
○ T2DM remission rate = 0% in medical therapy alone; 75% gastric bypass; 95% biliopancreatic diversion
■ Preop BMI and weight loss didn’t predict glycemic improvement
○ Indicated if medical therapy can’t achieve glycemic target, especially if major coexisting illness,
eg.
HTN, dyslipidemia
○ Insufficient evidence to indicate bariatric surgery for BMI <35, but has
proven effective if pt also has T2DM
○ Gastric bypass had better outcomes than gastric band for longterm weight loss, T2DM, high BP, and dyslipidemia
● Even removing small amounts of intraabdominal adipose (<1 kg) can substantially improve Glc tolerance, insulin sensitivity,
fasting Glc, and fasting insulin
○ In comparison, liposuction has proven ineffective; even though it significantly decreases subcutaneous fat, it has no
effect on insulin levels/sensitivity, CRP, IL6, TNFα, adiponectin, BP, Glc, or lipids
B. TYPES OF BARIATRIC SURGERY
● Laparoscopic rouxenY gastric bypass
○ Higher morbidity and mortality (0.3%)
○ 2% leak rate
○ Risk for malabsorption and internal hernia
● Laparoscopic adjustable gastric band
○ Lowest operative morbidity and mortality
○ Requires frequent adjustments and has 20% reoperative rate
○ Not a good choice for sweeteaters
● Biliopancreatic diversion + duodenal switch reroutes a lengthy portion of small
intestine to create separate pathways for food (short, from stomach) and bile (long, from
liver) that eventually converge into the common channel
○ Potentially greater weight loss, but also greater adverse events
● Laparoscopic sleeve gastrectomy
○ Moderate morbidity and mortality
○ 1% leak rate
○ May be as good as bypass for T2DM based on early studies, but no good
longterm studies proving effectiveness as standalone procedure
○ Currently most popular option
6.3. Understand the rationale for an osteopathic approach to obesity and its possible enhancement to an approach that would
include antiinflammatory therapy.
● Physicians should view pt’s struggle with weight the same way as other diseases
○ Excess body weight isn’t a personal choice, but a result of complex interactions b/t genetics and environment
○ Weight loss is not a matter of willpower, but hard work that requires vigilance against factors that promote regain
● Obesity stigmatization = poor intelligence, sexual unattractiveness, laziness, gluttony
○ Frequent exposure to stigma (most commonly from physicians and family) increases likelihood of higher BMI
● Osteopathic approach can further improve dietary and exercise adherence and compliance, ultimately resulting in improved
health (less metabolic abnormalities and obesityrelated diseases)
6.4. Understand the rationale for the CIRT trial and the potential utility of MTX
and other antiinflammatory meds in reducing CVD in obese individuals.
● CIRT trial investigates how CV events can be reduced by decreasing
inflammation independent of lipid reduction, particularly using anti
inflammatory meds like methotrexate, TNFαI (1), IL6I(2), IL1βI (3)
● Benefits of MTX
○ Inhibits atherogenesis
○ Low doses → ↓ CRP + ↓ IL6 + ↓ TNFα
■ 21% lower CVD risk, 18% lower MI risk
■ Rheumatoid arthritis pts on lowdose MTX had
less CV events despite having worse symptoms
and risk factor profiles
■ Can take ± food (minimally affects absorption)
■ 50% proteinbound + minimal interactions w/
statins, ASA, BB, ARB, ACE
● Obesity and metabolic syndrome can be improved by decreasing sympathetic autonomic activity
○ Visceral obesity correlates w/ muscle sympathetic nerve activity, eg. obese pts have increased Low Frequency/ High
Frequency ratio (∞ sympathovagal balance)
○ Insulin resistance (prior to obesity or diabetes) may show sympathetic overactivity (if genetically predisposed) →
adrenoceptor downregulation + ↓ sensitivity → ↓ sympathetic responsiveness → ↑↑↑ sympathetic activity
■ Postprandial state → ↓ dietinduced thermogenesis + ↑ postprandial fat oxidation → fat accumulation
○ Metabolic syndrome → low HR variability, sympathetic overactivity, low parasympathetic activity = subclinical
inflammation
■ In diabetics w/ metabolic syndrome, cardiac sympathetic overactivity A/W CRP >3 (this was not seen in
diabetics w/o metabolic syndrome, or w/ CRP <2)
■ Subclinical inflammation A/W increased CV event risk, even if pt is clinically asymptomatic
○ OMT can reduce TNFα, but no effect on IL1β/6/8/10 (which correlate w/ osteopathic lesions and low back pain)
■ Rib raising → ↓ salivary αamylase (∞ hypothalamuspituitaryadrenal activity) → ↓ sympathetic activity (but
no changes in parasympathetic activity)
■ Cranial OMT
● Compression of 4th ventricle can alter sleep latency and muscle sympathetic nerve activity
● Transcranial direct current stimulation of temporal lobe → ↑ parasympathetic + ↓ sympathetic + ↓
LF/HF (sympathovagal balance)
■ Need to study effects on inflammatory markers (CRP, fibrinogen, IL1, IL6, TNFα), adipokines (adiponectin,
leptin), HR variability in asymptomatic pts in subclinical inflammatory state (CRP >2) w/ sole manifestation of
obesity or metabolic syndrome
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =
WRAPUP
● All obesity is not the same
● A calorie is not necessarily a calorie
● Fructose is “hazardous” to your health
● Diabetics can lose weight as effectively as nondiabetics
● The best diet is the one you can follow (but lowcarb is generally better)
● Metabolic syndrome & inflammation play a significant role in CV risk
● Exercise improves CV risk, often independent of weight
● Unintended consequences of pharmaceutical treatment for obesity
continues to be a therapeutic conundrum
● Losing weight and improving metabolism may lengthen life as shown in
studies from the bariatric literature