OBESITY

What type of fat predominates during childhood and adulthood?

-During childhood and into adulthood, either white fat or beige fat predominate

What happens if an individual is deficient in leptin or is deficient in the leptin receptor?

-Family kindred with either deficiency of leptin protein or the leptin receptor were noted to have severe obesity. -Affected individuals were noted to consume excessive calories and have a low basal metabolic rate.

For all adults with BMIs in the 25 to 30 range, what further measurement should be calculated?

-For all adults with BMIs in the 25 to 30 range, waist and hip circumferences should be measured to calculate waist-to-hip ratios. -BMI may miss individuals with significant risk for comorbidities or classify individual at risk who remain healthy (those with significant muscle mass).

VERTICAL SLEEVE GASTRECTOMY What happens to the levels of GLP-1 and PYY?

-GLP-1 and PYY levels are increased

What is the function of GLP-1?

-GLP-1 stimulates glucose-dependent insulin secretion, inhibits glucagon release and inhibits gastric emptying.

In the fasting state, stomach cells release what hormone?

-Ghrelin

ROUX-EN-Y GASTRIC BYPASS What happens to ghrelin levels?

-Ghrelin levels decrease

VERTICAL SLEEVE GASTRECTOMY What happens to ghrelin levels?

-Ghrelin levels decrease

ROUX-EN-Y GASTRIC BYPASS What is dumping syndrome?

-Given the anatomy after the Roux-en-Y procedure, patients have accelerated emptying of the stomach (lack of mechanical mixing and a pylorus) resulting in the abrupt delivery of a hyperosmolar load into the small bowel.

Deficiency in what hormone is associated with increases in central adipose tissue?

-Growth Hormone

What are the side-effects of locarserin?

-However, concern still exists regarding the risk of valvulopathy, because of the relatively limited use of the drug thus far. -Most known side effects remain mild (nausea, headaches, nasopharyngitis)

Why might hypothyroidism be associated with weight gain?

-Hypothyroidism may be associated with weight gain because of the slowing of metabolism. -However, modest weight gain typically occurs, and weight loss is minimal after thyroid hormone replacement.

VERTICAL SLEEVE GASTRECTOMY What is it?

-In contrast, the sleeve gastrectomy is a permanent procedure, which removes most the greater curvature of the stomach to produce a stomach in the shape of a tube (or sleeve)

Individuals with what kind of obesity are at highest risk for developing the conditions listed above?

-Individuals with abdominal obesity, termed metabolic syndrome, seem to have the most significant risk of these health diseases.

Carbohydrate intake stimulates the pancreatic release of?

-Insulin

FFAs stimulate the pancreas to increase the release of what hormone?

-Insulin

ROUX-EN-Y GASTRIC BYPASS What is the risk of cholelithiasis?

-It also has the highest risk of cholelithiasis, occurring in 40% of patients within a few years of surgery.

What are the side-effects and contraindications of phentermine and topiramate?

-It has the same side effects as the two individual medications, and is contraindicated during pregnancy and with cardiovascular disease.

Brown fat is characterized by an abundance of what type of organelle?

-It is characterized by an abundance of mitochondria in cells

Why doesn't lorcaserin cause heart problems?

-It is purported not to cause heart disease (thought to be mediated through the 5-HT2B receptor), because it is a selective agonist for the 5-HT2C receptor

What is the MOA of orlistat?

-It prevents the complete hydrolysis of fat, so increases the excretion of fecal fat to as much as 30% of the amount ingested

What is the side-effect profile of Bupropion+Naltrexone?

-Its side effect profile is identical to bupropion's with the addition of nausea, headache and constipation related to naltrexone

LAPAROSCOPIC ADJUSTABLE GASTRIC BANDING How does it work?

-Laparoscopic adjustable gastric banding restricts the size of the stomach inducing a sensation of fullness and limiting food intake at a single setting.

ROUX-EN-Y GASTRIC BYPASS When is Dumping Syndrome seen?

-Last, approximately half of all surgical patients experience dumping syndrome with the consumption of carbohydrates.

POMC and CART promote satiety by acting on what receptor?

-MC4R

What happens if mutations in MC4R prevent α-melanocyte stimulating hormone (α-MSH) from binding?

-MC4R gene mutations prevent the effective binding of α-melanocyte stimulating hormone (α-MSH), a derivative of POMC. -These mutations are noted in approximately 5% of individuals with severe obesity.

What do the FFAs do to the muscle?

-Make the muscle more insulin resistant -The resultant increases in serum glucose induce further insulin resistance

Does white fat contain as much mitochondria as brown fat?

-No -White fat contains very few mitochondria

What factors increase the release of leptin?

-Overeating or excessive insulin release increases the release of leptin

PHARMACOLOGIC AGENTS When is pharmacotherapy recommended to be used?

-Pharmacotherapy for obese patients or overweight patients with medical comorbidities is an adjunct to lifestyle changes, particularly for those who have not had an adequate response to diet and exercise modification -Most agents are associated with a modest (3-5%) weight loss by themselves, but also have significant adverse effects that require careful monitoring.

What is the function of MC4R?

-Promotes satiety

LAPAROSCOPIC ADJUSTABLE GASTRIC BANDING Why are GERD and esophagitis common side-effects?

-Restriction of the stomach pouch also increase the pressure of the proximal stomach and distal esophagus, so esophageal reflux and esophagitis are more common

ROUX-EN-Y GASTRIC BYPASS The most commonly performed bariatric procedure remains the?

-Roux-en-Y gastric bypass

ENVIRONMENTAL INFLUENCES What has sleep restriction been known to do to leptin levels?

-Sleep restriction has been noted to decrease serum leptin

ENVIRONMENTAL INFLUENCES What has sleep restriction been known to do to ghrelin levels?

-Sleep restriction has been noted to increase serum ghrelin

ROUX-EN-Y GASTRIC BYPASS

-Surgeons divide the stomach, creating a small (< 30 mL) proximal gastric pouch, and create a Roux limb of small bowel to anastomose with the gastric pouch

What class of drugs have been the most widely used agents for weight loss?

-Sympathomimetics

What is the function of the FTO gene?

-The FTO gene (named "Fatso" because of the massive size of the gene) produces an enzyme that removes methyl groups from DNA

ROUX-EN-Y GASTRIC BYPASS Complications

-The Roux-en-Y gastric bypass also has the most side effects of any of the currently performed procedures. -Procedure complications, including stomal stenosis, marginal ulcers and internal ulcers are common. -Most patients have nausea and vomiting similar to other restrictive procedures.

LAPAROSCOPIC ADJUSTABLE GASTRIC BANDING What does it consist of?

-The adjustable gastric band consists of a ring, which encircles the upper stomach, connected to a subcutaneous reservoir where the injection of saline increases the degree of restriction.

ROUX-EN-Y GASTRIC BYPASS How much weight loss is seen?

-The gastric bypass induces the greatest amount of weight loss, with a 25-30% long-term reduction in body weight

Methylation of AgPR gene does what to it?

-The normal methylated state results in decreased gene expression

PHARMACOLOGIC AGENTS What is the safest weight loss medication?

-The safest medication is the lipase inhibitor, orlistat

MANAGEMENT When is the use of pharmacotherapy and bariatric surgery recommended in adolescents?

-The use of pharmacotherapy and bariatric surgery are controversial during adolescence, and are generally limited to obese adolescents who are already fully mature (pubertal development and adult height) and who have failed an intensive lifestyle program.

What is the MOA of the Sympathomimetics?

-They stimulate the release and/or re-uptake of norepinephrine to induce satiety

ROUX-EN-Y GASTRIC BYPASS What are the effects of the procedure?

-This combination restricts the quantity of food to be eaten, and induces some malabsorption because the mixing of digestive enzymes and food does not occur until after the anastomosis.

Weight loss of 7-10% has even greater health benefits, such as?

-This provides even greater reductions in triglycerides and blood glucose, along with decreases in LDL and increases in HDL. -Further, this degree of weight loss is associated with a decrease in blood pressure.

COMPLICATIONS Central (abdominal) adipose tissue has a greater propensity to release what into circulation?

-free fatty acids (FFAs) into circulation

What is the function of white fat?

-functions almost exclusively for energy storage and cells contain few mitochondria

In the arcuate nucleus of the hypothalamus, what is the function of the lateral hypothalamic area?

-functions as the feeding center stimulating food intake

What does CCK do to gastric emptying?

-further inhibits gastric emptying

As food enters the small intestine, what hormone is released from intestinal enteroendocrine cells?

-glucagon-like peptide 1 (GLP-1)

COMPLICATIONS The accumulation of FFAs in the liver leads to the liver increasing the release of what substances?

-glucose -triglycerides -very low dense lipoproteins (VLDL)

Increased activity of the FTO gene does what to fat cell differentiation?

-increased activity resulting in higher body weights -Certain risk alleles have been identified that increase the risk for obesity, and seem to be the strongest genetic signal for determining an individual's BMI

What happens when 11-β-hydroxysteroid dehydrogenase is induced by corticosteroids?

-increasing lipogenesis

As a result of the muscle becoming more insulin resistant, what happens?

-increasing the accumulation of triglyceride within skeletal muscle

What is the function of peptide YY?

-inhibits food intake, gastric emptying and intestinal motility

VERTICAL SLEEVE GASTRECTOMY Because of restriction of food intake and gastric acid loss, nutritional deficiencies are more common than with gastric banding, particularly?

-iron, vitamin B12 and calcium

ROUX-EN-Y GASTRIC BYPASS What nutritional deficiencies are common?

-iron, vitamin B12, vitamin B1 (thiamine), vitamin D, folate and calcium

What are the side-effects of orlistat?

-it has the troublesome consequences of increasing fecal fat, including -abdominal cramps -fecal urgency -fecal incontinence -oily spotting -discharge with flatus -It can induce fat-soluble vitamin deficiencies with extensive use.

What are the contraindications for the use of Sympathomimetics?

-known coronary artery disease, hypertension or hyperthyroidism

Adipocytes have a constant release of what hormone that is proportional to fat mass?

-leptin

What is the function of leptin?

-leptin directly binds to cells in the lateral and ventromedial hypothalamus to inhibit food intake

COMPLICATIONS The FFAs released into circulation induce changes in what organs?

-liver, muscle, and the pancreas

What appears to be more accurate predictors of comorbidities and early mortality compared to BMI?

-measures of centripetal obesity

NPY and AgRP are released in other areas of the hypothalamus to either directly stimulate food intake or to antagonize what receptors?

-melanocorticotropin 4 receptors (MC4R)

What are the side-effects of topiramate?

-metabolic acidosis -paresthesias -somnolence -difficulty concentrating

What are the main molecules that stimulate food intake?

-neuropeptide Y (NPY) -Agouti-related peptide (AgRP)

Obstructive sleep apnea and obesity hypoventilation syndrome are the result of what?

-obstruction of the upper airway, often secondary to adipose tissue

Last, as incompletely digested nutrients enter the ileum and colon, enteroendocrine cells release what peptide?

-peptide YY (PYY)

What combination medication has the greatest efficacy for weight loss?

-phentermine and topiramate -Prescribing is currently restricted under the Risk Evaluation and Mitigation Strategy (REMS), which requires special training for physicians and pharmacies.

What are the Sympathomimetics used for weight loss?

-phentermine, -diethylpropion -benzphetamine -phendimetrazine

What are the main stimuli that promote satiety?

-proopionmelanocortin (POMC) -cocaine/amphetamine regulated transcript (CART)

BARIATRIC SURGERY Many procedures have been used over the last several decades, but most functioned as?

-restrictive (decreasing the size of the stomach pouch) -malabsorptive (inducing nutrient malabsorption) -or a combination of the two effects

What are the side-effects of the Sympathomimetics?

-result in the multitude of effects from sympathetic stimulation (insomnia, dry mouth, constipation, and nervousness). -Most concerning, patients typically have increases in their heart rate and blood pressure, and have a higher risk of cardiovascular events.

What were the therapeutic effects of fenfluramine?

-resulted in a central reduction in appetite

Potential contributors to obesity consist mainly as?

-sedentary lifestyle, increased caloric intake and contributing medications

In the arcuate nucleus of the hypothalamus, what is the ventromedial hypothalamic area?

-serves as the satiety center, inhibiting food intake

What does insulin do to food intake?

-serves to inhibit food intake

VERTICAL SLEEVE GASTRECTOMY Complications

-significant bleeding -stomal stenosis leading to gastric outlet obstruction -gastric leak leading to peritonitis

In adolescence, obesity is associated with what condition?

-slipped capital femoral epiphysis (SCFE), presumably because of increased mechanical strain on the physis

COMPLICATIONS FFAs accumulate within the liver leading to?

-steatosis (nonalcoholic fatty liver disease)

ENVIRONMENTAL INFLUENCES The effects of sugar and fat consumption seem to be most significant in individuals with alterations in what gene?

-the FTO gene

What is the main cerebral center controlling food intake?

-the arcuate nucleus in the hypothalamus

Hypothalamic obesity is a rare condition associated with damage to what portion of the hypothalamus?

-the ventromedial hypothalamus, which produces hyperphagia

What antiepileptic medication has been associated with weight loss?

-topiramate

Weight loss of 3-5% of body weight has been associated with clinically meaningful reductions in?

-triglycerides and blood glucose, with a reduced risk of developing diabetes mellitus -Greater weight loss of 7-10% has even greater health benefits

What is the MOA of fenfluramine?

-was a 5-HT2B and 5-HT2C receptor agonist

LAPAROSCOPIC ADJUSTABLE GASTRIC BANDING Weight Loss Effects

Long-term weight loss of 15-20% is typical with this procedure, although the amount of weight loss can vary from as little as 5% to as much as 35%

What kind of obesity is seen within Cushing's syndrome?

- is known to cause progressive central obesity, usually involving the face, neck, trunk and abdomen

What enzymes do corticosteroids induce in visceral fat?

-11-β-hydroxysteroid dehydrogenase

ROUX-EN-Y GASTRIC BYPASS What sort of diet can prevent dumping syndrome?

-A strict diet is necessary to limit the osmolality of food delivered to the jejunum. Patients consume a low carbohydrate diet (especially of simple sugars) with increased amounts of fat and protein.

What are some predisposing factors for Hypothalamic obesity?

-Affected individuals usually have had massive trauma or hypothalamic disease requiring surgery.

How does AgPR overexpression affect α-MSH?

-AgRP overexpression inhibits the satiety signal from α-MSH binding at MC4R

What are the side-effects of the GLP-1 agonists?

-Although effective, most patients develop nausea and vomiting at the doses necessary to induce significant weight loss

VERTICAL SLEEVE GASTRECTOMY What happens to gastric acid release?

-Although primarily restrictive, the sleeve gastrectomy decreases the gastric acid release, interfering with the absorption of some nutrients

EPIDEMIOLOGY Childhood obesity is more common in certain ethnicities, such as?

-American Indian, black and Mexican ancestry to a much greater degree than non-Hispanic whites -These changes disappear during adulthood with all ethnicities similarly affected except for Asian Americans, who have a significantly lower prevalence. -Last, obesity is more prevalent among low-income populations

What is the MOA of burpropion?

-As it effects norepinephrine metabolism, it has a similar mechanism as the sympathomimetics

Importance of Waist-to-Hip Ratos

-As stated previously, waist circumference is becoming a key marker of comorbidities, because of its strong relationship to metabolic syndrome. -Thus, individuals with a low BMI but elevated waist circumference or waist-to-hip ratio should be counseled appropriately to avoid complications.

How much mitochondria is contained within beige fat?

-Beige fat contains a moderate number of mitochondria in cells

What are the three types of fat produced by the human body?

-Brown fat -White fat -Beige fat

During what stage of life is brown fat typically found?

-Brown fat is typically only found during infancy

Given the relative limited efficacy of single agents, the FDA has approved two combination products. Which is?

-Bupropion combined with naltrexone

ROUX-EN-Y GASTRIC BYPASS The abrupt delivery of a hyperosmolar load into the small bowel results in a vigorous hormonal response with increased levels of?

-CCK -PYY -vasoactive intestinal peptide -renin-angiotensin-aldosterone

ROUX-EN-Y GASTRIC BYPASS What happens to CCK and GLP-1 levels?

-CCK and GLP-1 levels increase

EFFECTS OF WEIGHT LOSS Traditionally, after a period of months of or following the weight loss, what will happen to the BMR?

-Traditionally, after a period of months, this is followed by a rebound in the metabolic rate closer to the baseline level. -However, in recent studies of weight loss and individuals with severe obesity, the metabolic rate did not rebound after significant weight loss even years later. -In fact, the metabolic rate of most individuals continued to slow, requiring a consistent decrease in caloric intake over time.

What was the major side-effect of fenfluramine?

-Unfortunately, it was also associated with a condition nearly identical to carcinoid heart disease, with 50% of affected patients developing tricuspid regurgitation, and the FDA rescinded its approval.

EFFECTS OF WEIGHT LOSS What does weight loss do to the BMR?

-Weight loss is accompanied by a subsequent decrease in the basal metabolic rate, representing the body's natural survival response to conserve energy

The most common genetic cause for obesity has been linked to a greater propensity to produce what kind of fat?

-White fat

What happens to ghrelin release with food consumption?

-With food consumption, ghrelin release is inhibited and a cascade of digestive hormones are released.

LAPAROSCOPIC ADJUSTABLE GASTRIC BANDING What nutrient deficiencies are commonly seen?

-With the restriction of food intake, both iron and vitamin B12 deficiency can occur

What is α-melanocyte stimulating hormone (α-MSH)?

-a derivative of POMC

EVALUATION Screening for obesity should be performed on all patients, from childhood through adulthood. Most commonly, screening consists of?

-an accurate weight and height to allow the calculation of the BMI

VERTICAL SLEEVE GASTRECTOMY Due to either the procedure or the associated weight loss, approximately 10-15% of patients will develop what?

-approximately 10-15% of patients will develop cholelithiasis in the years after the surgery

The excess of mitochondria found within brown fat are responsible for what?

-are responsible for significant thermogenesis

MEDICATIONS The classes of medications associated with the greatest weight gain are?

-atypical antipsychotics (clozapine, olanzapine and risperidone) -tricyclic antidepressants (amitriptyline, clomipramine and imipramine) -antiepileptics drugs (valproic acid and carbamazepine) -diabetes medications (insulin, sulfonylureas and thiazolidinediones) -exogenous corticosteroids

Traditionally, overweight and obesity have been classified per what?

-body mass index (BMI)

Which antidepressant has been used for weight loss?

-bupropion

How do peripheral hormones Insulin and leptin also trigger satiety?

-by antagonizing NPY and AgRP and stimulating POMC and CART release

How does ghrelin stimulate food intake?

-by stimulating NPY and AgRP release

How does ghrelin stimulate food intake?

-by stimulating the lateral hypothalamus to release NPY and AgRP

Beige fat can undergo thermogenesis in response to what?

-can undergo thermogenesis in response to stress

ROUX-EN-Y GASTRIC BYPASS Within 30 minutes of a meal, affected individuals develop?

-cardiovascular (flushing, diaphoresis, tachycardia, light-headedness) -gastrointestinal symptoms (nausea, abdominal cramps, belching, diarrhea). -A late hypoglycemic response follows 1-3 hours later due to an exaggerated release of insulin.

COMPLICATIONS The physiologic effects of obesity seem to be mediated primarily via what kind of tissue?

-central (abdominal) adipose tissue

What environmental factors can result in hypomethylation of the AgPR gene?

-certain environmental factors (perhaps exposure to plastics) result in hypomethylation and increased gene expression

Consumption of fat also stimulates the release of what hormone?

-cholecystokinin (CCK)

LAPAROSCOPIC ADJUSTABLE GASTRIC BANDING Due to either the procedure or the associated weight loss, approximately 10-15% of patients will develop what?

-cholelithiasis in the years after the surgery

COMPLICATIONS Increases in circulating VLDL does what to HDL and LDL levels?

-decrease the high-density lipoprotein (HDL) and increase low-density lipoproteins (LDL)

Individuals who have the onset of obesity in early childhood or adolescence seem to be of particularly high risk to develop what diseases?

-diabetes mellitus and cardiovascular disease

What is the function of GLP-1?

-directly inhibits food intake -stimulates insulin and glucagon secretion -inhibits gastric emptying

What is Cushing's Syndrome?

-endogenous increases in corticosteroids

What is a major contraindication for bupropion?

-epilepsy is a contraindication because it also lowers the seizure threshold

What GLP-1 (glucagon like-peptide-1) agonists have been shown to result in significant weight loss?

-exenatide -liraglutide

For obesity, most recommend a basic laboratory evaluation consisting of?

-fasting glucose or hemoglobin A1C (screening for diabetes) -liver enzymes (screening for nonalcoholic fatty liver disease) -lipid profile (screening for hyperlipidemia)

EFFECTS OF WEIGHT LOSS Although still in the infancy of understanding, the responses to neurotransmitters and peripheral hormones seem to differ in individuals with obesity. As a result, excessive calories are more likely to be stored as?

-fat mass and weight loss is less likely to be followed by a rebound in metabolic rate

What are the serotonin agonists used for weight loss?

-fenfluramine (part of the Fen-Phen combination with phentermine) -Lorcaserin

Using measures of centripetal obesity, what is a more accurate cut-off for determining what obesity is in men?

Adult Men: waist circumference > 102 cm (40 inches) or waist-to-hip ratio of 0.90 or greater

Using measures of centripetal obesity, what is a more accurate cut-off for determining what obesity is in women?

Adult Women waist circumference > 88 cm (35 inches) or waist-to-hip ratio of 0.85 or greater