36 Overweight, Obesity, and Co-Morbidities

Question 1

Obesity

• prevalence
• etiologically linked with/
• The treatment and prevention of obesity is of particular relevance for the following reasons:

Answer 1

• a chronic and stigmatizing condition prevalent among both children and adults in the United States and throughout the developed world.
• etiologically linked with serious illnesses and functional limitations, in addition to having a significant economic impact.
• The treatment and prevention of obesity is of particular relevance for the following reasons:
  
  • Obesity is an abnormal nutritional state related to food intake and processing
  • Obesity is linked with several GI diseases (GERD, cholelithiasis, pancreatitis, and liver disease)
  • The GI tract a major target for current and future obesity treatments (Orlistat, bariatric surgery, recombinant human leptin, etc.)
  • Obese patients who undergo bariatric surgery require GI/nutrition specialists to evaluate and treat post-operative complications and manage their diet.

Question 2

Body fat / body mass index (BMI)

• Obesity is defined as/
• Accurate assessment of body fat: simple measures
• The ultimate determination of “healthy” and “unhealthy” amounts of fat mass is complicated and may relate to multiple factors including:
• BMI-Associated Disease Risk (BMI and Health Risk for each)
  
  • Underweight
  • Normal
  • Overweight
  • Obesity Class I
  • Obesity Class II
  • Extreme Obesity Class III

Answer 2

• Obesity is defined as an excessive amount of body fat (>20% of total body mass).
• Accurate assessment of body fat: simple measures
  
  • waist circumference; waist/hip ratio can often suffice to identify abnormal fat depots.
• The ultimate determination of “healthy” and “unhealthy” amounts of fat mass is complicated and may relate to multiple factors including:
  
  • Gender
  • Age
  • Fat distribution
  • Weight (fat) gain since early adulthood
  • Level of physical activity/fitness
  • Genetic factors
  • Concomitant disease risk factors
• BMI-Associated Disease Risk
  
  • Underweight
    
    • BMI: <18.5
    • Health Risk: Increased
  • Normal
    
    • BMI: 18.5-24.9
    • Health Risk: Normal
  • Overweight
    
    • BMI: 25.0-29.9
    • Health Risk: Increased
  • Obesity Class I
    
    • BMI: 30.0-34.9
    • Health Risk: High
  • Obesity Class II
    
    • BMI: 35.0-39.9
    • Health Risk: Very high
  • Extreme Obesity Class III
    
    • BMI: >40.0
    • Health Risk: Extremely high

Question 3

General Concepts

• Men and women considered obese
• Fat Distribution:
  
  • obese persons with excess upper body fat/
  • Measurement of abdominal fat content requires/
  • men and women waist circumferences
• Weight gain during adulthood (as little as ≥ 5 kg since the age of 18 to 20 years) is associated with an increase in the risk of developing
• Aerobic fitness

Answer 3

• Men and women with BMI ≥ 30kg/m2 are considered obese and are at higher risk for adverse health events than those who are overweight (BMI 25.0 – 29.9 kg/m2).
  
  • increases in BMI over 30 are associated with increasing risk of obesity-related morbidity and premature mortality.
• Fat Distribution:
  
  • Compared with obese persons with predominantly increased lower body fat (gluteal and femoral fat), obese persons with excess upper body fat (abdominal and visceral fat) are at a greater risk for diabetes, hypertension, dyslipidemia, fatty liver, ischemic heart disease, and stroke.
  • Measurement of abdominal fat content requires expensive radiologic techniques (i.e. CT scan), so waist circumference is used as a surrogate marker.
  • Men with waist circumference greater than 102 cm (40 inches) and women with a waist circumference of greater than 88 cm (35 inches) are at increased risk of numerous metabolic diseases.
• Weight gain during adulthood (as little as ≥ 5 kg since the age of 18 to 20 years) is associated with an increase in the risk of developing cholelithiasis, diabetes, hypertension and coronary artery disease in both men and women.
• Aerobic fitness
  
  • defined by maximal O2 consumption during exercise
  • a “protective factor” that lowers the incidence of diabetes and heart disease associated with obesity.

Question 4

General Concepts

• Ethnicity:
  
  • BMI-associated risks/
  • Southeast Asians
  • Polynesians
• Healthcare costs:
• Childhood obesity
• Mortality:
• Obesity is a complex disorder ultimately resulting from the interaction of several factors:

Answer 4

• Ethnicity:
  
  • BMI-associated risks vary by ethnic group.
  • Southeast Asians have higher risks of diabetes and heart disease than Caucasians,
  • Polynesians typically have more muscle mass and less body fat that Caucasians at the same BMI level.
• Healthcare costs:
  
  • annual obesity-related health care costs in the $100-200 billion range.
• Childhood obesity:
  
  • Rates of childhood obesity have tripled over the past 30 years
  • ‘Childhood obesity is one of the most serious public health challenges of the 21st century.
  • rates are “stabilizing”, implying that fewer children are becoming obese in the past year or two.
• Mortality:
  
  • Increases as the degree of overweight/obesity increases
  • When the impact of a sedentary lifestyle is coupled with poor diet, the CDC estimates annual mortality to reach ~400,000
  • Obesity is second only to cigarette smoking as a preventable cause of death in the US
  • The absolute mortality risk associated with an increased BMI actually increases with age, up to age 75. In elderly persons over the age of 75, BMI has less of an impact on mortality but possibly a greater effect on quality of life (QOL).
• Obesity is a complex disorder ultimately resulting from the interaction of several factors:
  
  • increased energy intake,
  • decreased energy expenditure,
  • genetic factors,
  • psychological factors,
  • combinations of any of these 4 factors.

Question 5

Pathogenesis of Obesity:
Neurobiological Models:
Body weight homeostatic “set point” concept and eating behavior

• Based on/
• Supported by/
• When fat stores are depleted/
• When fat stores are replete/
• Ob gene and its product leptin

Answer 5

• Based on a traditional view of homeostasis and peripheral and central feedback loops.
• Supported by physiologic mechanisms including a “sensing system” in adipose tissue which reflects fat stores and receptors or “adipostats” in the hypothalamus.
• When fat stores are depleted, the adipostat signal is low and hypothalamic circuits respond by stimulating hunger and decreasing energy expenditure to conserve energy.
• When fat stores are replete, the adipose signal is increased and the hypothalamus responds by decreasing hunger and increasing energy expenditure.
• Ob gene and its product leptin, is one example of a molecular signal consistent with “set point” theory that accounts for long-term patterns of the regulation of eating

Question 6

Pathogenesis of Obesity:
Neurobiological Models:
Body weight homeostatic “set point” concept and eating behavior:
How does leptin affect weight gain/maintenance in overweight and obesity?

• leptin
• circulating plasma leptin concentration correlates with/
• Leptin binds to/
• Humans without an ability to secrete leptin or with defective leptin receptors/

Answer 6

• leptin is a signaling protein produced by adipose tissue;
• circulating plasma leptin concentration correlates with overall body fat
• Leptin binds to receptors in hypothalamic nuclei that then reduce food intake and enhance thermogenesis
• Humans without an ability to secrete leptin or with defective leptin receptors are severely obese
  
  • Vast minority of obese humans have a demonstrable lack of leptin production or leptin receptors.
  • Rather, many obese individuals could be deemed as having an acquired ‘leptin resistance’

Question 7

Pathogenesis of Obesity:
Neurobiological Models:
Body weight homeostatic “set point” concept and eating behavior:
Monoamines and peptides that are important for both long and short-term regulation of feeding behavior:

• Stimulatory (“hunger”)
• Inhibitory (“satiety”)

Answer 7

• Stimulatory (“hunger”)
  
  • Neuropeptide Y
  • Opioids
  • Melanin-concentrating hormone
  • Ghrelin
  • Growth hormone releasing hormone
  • Endocannabinoids
• Inhibitory (“satiety”)
  
  • Leptin
  • Peptide YY (PYY)
  • Cholecystokinin
  • Serotonin
  • Enterostatin (cleavage product of pancreatic lipase)
  • Corticotropin releasing hormone
  • Alpha MSH (melanocyte stimulating hormone)
  • Glucagon-like peptide 1

Question 8

Pathogenesis of Obesity:
Neurobiological Models:
Body weight homeostatic “set point” concept and eating behavior:
Examples of short-term signals

• Neuropeptide YY (PYY)
• Ghrelin

Answer 8

• Neuropeptide YY (PYY)
  
  • a “satiety signal” secreted postprandially, in proportion to the calories ingested, by endocrine L cells lining the distal small bowel and proximal colon.
  • The initial release of PYY occurs shortly after food intake (driven by cephalic phase of digestion), before ingested nutrients arrive in the distal portion of the small intestine and the colon.
  • Subsequent PYY release is stimulated by exposure of L cells to nutrients, particularly carbohydrates and lipids.
• Ghrelin
  
  • a “hunger signal” secreted by P/D1 cells in the stomach fundus.
  • Its concentration increases preprandially and decreases postprandially.
  • drives meal initiation and increases food intake through the stimulation of ghrelin receptors in the hypothalamus.
  • acts to increase growth hormone release and may be important for energy homeostasis.

Question 9

Pathogenesis of Obesity:
Neurobiological Models:
“Non-homeostatic” eating / societal factors

• Psychology of Eating
• Eating behavior is influenced by/
• Reinforced, learned behaviors can/
• Obese individuals share many similar impairments in the function of these central neural stuctures as seen in individuals with/
• Socioeconomic status and food availability

Answer 9

• Psychology of Eating – food typically is hedonic (i.e. “pleasurable”), leading to a sense of reward
• Eating behavior is influenced by associational and reinforcement learning (cerebral cortex, basal ganglia, and cerebellum) and stress reactivity (amygdala), in many ways similar to drug taking behavior
  
  • Examples: snacking while watching TV, increased eating when stressed or worried, and feeling hungry when presented with food cues (“Golden arches”)
• Reinforced, learned behaviors can easily “override” hypothalamic-based signals
• Obese individuals share many similar impairments in the function of these central neural stuctures as seen in individuals with drug addiction:
  
  • Impairments in neural pathways that regulate reward sensitivity, incentive motivation, self-control, stress reactivity, and interoceptive awareness, among others.
• Socioeconomic status and food availability –
  
  • lower SES individuals often have poor access and/or lack resources to consume fresh, healthy foods.
  • Inexpensive, widely available and calorically dense food consumption in this population likely drives high obesity rates.

Question 10

Energy Intake and Expenditure in Obesity

• Do obese individuals eat more?
• Component of energy expenditure: % of total 24 hour energy expenditure
  
  • Resting metabolic rate (RMR): most of the energy expenditure in sedentary individuals
  • Thermic effect of food
  • Physical activity

Answer 10

• Do obese individuals eat more?
  
  • Yes – the average energy expenditure increases with increasing BMI, primarily related to an increase in metabolically active lean body mass and increased energy required for movement.
  • an obese person must consume more calories to maintain their increased weight and increased lean body mass.
• Component of energy expenditure: % of total 24 hour energy expenditure
  
  • Resting metabolic rate (RMR): most of the energy expenditure in sedentary individuals: 60-75%
  • Thermic effect of food: 5-10%
  • Physical activity: 15-30%

Question 11

Average total energy expenditure

• Average total energy expenditure is higher in/
• As weight is lost, energy expenditure/
• Non-exercise activity thermogenesis (NEAT)

Answer 11

• Average total energy expenditure is higher in obese than lean persons when measured at stable weight
• As weight is lost, energy expenditure falls secondary to:
  
  • loss of lean body mass
  • decreased sympathetic activity
• Non-exercise activity thermogenesis (NEAT) is a newly recognized component of total thermogenesis driven by non-aerobic / resistance exercise.
  
  • This includes activities of daily living, fidgeting, spontaneous muscle contraction, and maintaining posture and can account for a significant amount of daily energy expenditure.
  • Body weight-adjusted NEAT is generally lower in obese individuals.
  • Molecular basis and regulation of NEAT are unclear.
  • Increasing NEAT could be an important therapeutic target to increase caloric expenditure and facilitate weight loss.

Question 12

Obesity as a Chronic Inflammatory Syndrome

• Old thought: adipose tissue/
• New thought: adipose tissue/
• Diseases associated with obesity can be divided into two (over-simplified) forms

Answer 12

• Old thought: adipose tissue is simply an inert depot of fat
• New thought: adipose tissue is a metabolically-active endocrine organ and the adipocyte is an endocrine cell
  
  • Adipose tissue plays a central role in lipid and glucose metabolism and produces a variety of hormones.
  • Adipose tissue also secretes cytokines (adiponectin, TNF-α) that drive and amplify systemic inflammation
  • Increased adiposity is also associated with increased sympathetic nervous system activity, which contributes to a proinflammatory state via increased IL-6 production
• ​Diseases associated with obesity can be divided into two (over-simplified) forms:
  
  • those that impact health due to fat mass,
  • those that impact health due to factors secreted from enlarged fat cells

Question 13

Diseases due to Increased Fat Mass

• Psychosocial functioning/depression
• Sleep apnea and hypoventilation

Answer 13

• Psychosocial functioning/depression
  
  • Stigmatization: exposed to the consequences of public disapproval (often not subtle)
    
    • Impact on education, employment, health care, and elsewhere
  • Depression: “I eat because I’m depressed. I’m depressed because I’m heavy.”
  • SF-36 survey: profound abnormalities in health-related QOL associated with obesity
  • Obese women generally have greater psychological dysfunction than men (societal pressures)
  • Enormous disability-related healthcare costs
• Sleep apnea and hypoventilation
  
  • Exact etiology is unclear, but sleep apnea is likely related to increased neck circumference and fatty deposits in pharyngeal area, which contribute to obstruction when prone.
  • Worse in men: obese men have decreased ventilatory capacity
  • Increased snoring index/nocturnal sound index
  • Significantly reduced oxygen saturation
  • Decreased residual lung volume due to increased abdominal pressure on the diaphragm (“obesity hypoventilation syndrome”)

Question 14

Diseases due to Increased Fat Mass (p.36-37)

• Diseases of the bones, joints, connective tissue and skin
  
  • Osteoarthritis
  • Skin changes
• Gastroesophageal Reflux Disease (GERD)

Answer 14

• Diseases of the bones, joints, connective tissue and skin
  
  • Osteoarthritis
    
    • Accounts for significant health costs of overweight
    • Weight-bearing joints (knees, hips) as well as non weight bearing joints—
    • Suggests altered bone and cartilage metabolism
    • Adipokines are capable of promoting synovial inflammation, cartilage degrading enzymes, and bone matrix remodeling
  • Skin changes
    
    • Striae/stretch marks—pressure on the skin from enlarging fat lobules
    • Acanthosis nigricans (physical sign of insulin resistance); unclear pathophysiology
• Gastroesophageal Reflux Disease (GERD)
  
  • Obesity is an independent risk factor for reflux.
  • Increased abdominal weight compresses the stomach in the prone position, leading to increased intragastric pressure with a higher likelihood of overcoming lower esophageal sphincter pressure, leading to reflux.
  • For unclear reasons, obesity is also independently linked with more frequent transient lower esophageal relaxations, which result in a predisposition for reflux.

Question 15

Metabolic Syndrome

• Defined by/
• Increased BMI correlates with/
• Hyperinsulinemia leads to/
• Obesity is associated with/
• Metabolic syndrome (need 3 of the 5 below for diagnosis)

Answer 15

• Defined by increased weight, dysregulated lipid and glucose metabolism, and hypertension.
• Increased BMI correlates with both increased insulin secretion and progressive insulin resistance
• Hyperinsulinemia leads to ↑ hepatic VLDL triglyceride synthesis and secretion (dyslipidemia)
• Obesity is associated with ↑ sympathetic nervous activity, which ↑ renal sodium reabsorption and leads to hypertension
• Metabolic syndrome (need 3 of the 5 below for diagnosis)
  
  • Waist circumference
    
    • Men > 40 inches (102 cm)
    • Women > 35 inches (88 cm)
  • Triglycerides > 150 mg/dL
  • HDL cholesterol
    
    • Men < 40 mg/dL
    • Women < 50 mg/dL
  • Fasting blood glucose ≥ 110 mg/dL
  • Blood pressure ≥ 130/85 mmHg

Question 16

Diabetes and Non-alcohol related fatty liver disease (NAFLD)

• Diabetes
• Non-alcohol related fatty liver disease (NAFLD):

Answer 16

• Diabetes
  
  • Chronic hyperinsulinemia associated with obesity is a major risk factor for the development of Type II Diabetes Mellitus
  • Up to 65% of cases of Type II DM are related to being overweight
  • BMI of 35 or higher had a 40-fold increased risk of Type II DM!
• Non-alcohol related fatty liver disease (NAFLD):
  
  • Triad of hepatomegaly, elevated liver enzymes, and abnormal liver histology driven by inflammation from liver fat deposition
  • Can lead to fibrosis/cirrhosis.
  • now the primary cause of abnormal liver function in the United States

Question 17

Cholelithiasis and Severe acute pancreatitis

• Cholelithiasis:
• Severe acute pancreatitis

Answer 17

• Cholelithiasis:
  
  • The increased risk of gallstones in overweight/obese individuals is due to increased cholesterol turnover related to total body fat-induced dyslipidemia.
  • Cholesterol production is linearly related to body fat;
  • During weight loss, the likelihood of gallstones actually increases because the flux of cholesterol is increased through the biliary system.
  • High fat intake stimulates gallbladder contraction; therefore, continued high fat intake may increase the likelihood of “ejecting” a gallstone into the distal biliary tree and causing pancreatitis and/or cholangitis.
• Severe acute pancreatitis
  
  • individuals who are obese are at increased risk of having a more severe course, with greater pancreatic and systemic complications.
  • The adipokine profile of obese individuals favors a pro-inflammatory state, which combined with the intrapancreatic inflammation, is a major factor in affecting disease severity.

Question 18

Hypertension

• the control of weight would/
• Etiology linking HTN to obesity
  
  • Central adiposity
  • peripheral vascular resistance and nitric oxide (NO) levels
  • Renal sympathetic nerve activity correlates with/

Answer 18

• the control of weight would eliminate 48% of HTN in whites, 28% of HTN in blacks and that, for each decline of 1 mm Hg in diastolic BP, the risk of myocardial infarction would decrease by 2-3%.
• Etiology linking HTN to obesity is complex but believed to be driven by global changes increased hypothalamo-pituatary-adrenal axis activity and in increased sympathetic nerve firing:
  
  • Central adiposity is associated with increased hypothalamo-pituitary-adrenal axis activity; higher cortisol levels are associated with sodium and water reabsorption
  • Obese individuals have greater peripheral vascular resistance and lower nitric oxide (NO) levels
  • Renal sympathetic nerve activity correlates with increased renin production, decreased GFR, and increased sodium reabsorption, all of which predispose to HTN

Question 19

Coronary Artery Disease

Answer 19

• women with BMI > 29 versus BMI < 21 had 3.3 times the risk of developing coronary artery disease.
• Weight gain increases risk of heart disease, regardless of initial BMI.
• Obesity drives dyslipidemia, increased HTN, and general increased sympathetic activity to the heart, all of which correlate with the risk of myocardial infarction.
• HTN alone typically causes concentric cardiac hypertrophy.
• In contrast, HTN in obese individuals is linked with eccentric cardiac dilation, which may relate to changes in chronic sympathetic overdrive.
  
  • This form of cardiac remodeling poses a greater risk of cardiac failure.
  • It also suggests that the mechanism by which obesity increases cardiac risk is not driven solely by HTN.

Question 20

Cancer

• Obesity may be responsible for/
• association between obesity and increased risks of multiple cancers including/
• These associations are likely driven by multiple factors:
  
  • Diabetes
  • The adipokine profile
  • estrogens levels
• Cancer Survival

Answer 20

• Obesity may be responsible for as many as 14% of cancer deaths among men and 20% of cancer deaths among women.
• association between obesity and increased risks of multiple cancers including: renal, colon, esophagus, ovarian, pancreatic, endometrial, post-menopausal breast, gallbladder, stomach, liver, and bladder cancer.
• These associations are likely driven by multiple factors:
  
  • Diabetes may increase the risk of neoplasia via insulin and IGFs stimulation of tyrosine kinase receptors that influence the proliferation rates of tumor cells
  • The adipokine profile in obesity drives chronic systemic inflammation, which is also linked to the development of cancer
  • Obese individuals have higher estrogens levels (produced by adipose stromal cells), which likely links obesity to the development of estrogen-sensitive gynecologic cancers
• Cancer Survival
  
  • obese individuals have decreased disease-free survival following initial treatment, worse prognosis, and greater risk of metastatic disease than lean individuals
  • Higher levels of angiogenic, vascular growth factors
  • Chemotherapy not properly dosed:
    
    • Increased body surface area in the obese
    • Calculate by GFR for accurate dose level adjustment

Question 21

Obesity is linked with (p.39-40)

Answer 21

• Chronic venous insufficiency / varicose veins, particularly in sedentary individuals.
  
  • More common in obese women.
  • Leads to chronic leg pain, lipodematosclerosis and non-healing venous stasis ulcers, leg edema, etc.
• Chronic renal insufficiency (Via increased sympathetic activity to the kidney?)
• Pseudotumor cerebri
• Urinary stress incontinence / pelvic floor disorders
• Gout
• Summary:
  
  • Overweight and obese individuals suffer from significant morbidity and mortalty, and their care is associated with increased healthcare costs compared to lean individuals.
  • The development of increased weight is controlled by a complex network of interactions between the brain, the GI tract, genetic factors, and societal/environmental factors.