OBESITY

Currently, obesity is epidemic generally as: What is obesity ? a disorder of body weight regulatory systems characterized by an accumulation of excess body fat Currently, obesity is epidemic generally as: abundance of food reduced activity

Why obesity is major problem ? The risk of associated diseases has increased: - DM - hypertension - cardiovascular diseases Childhood obesity ( 3 fold increase in prevalence over the last decades )

Assessment of obesity BMI = ______________ 2 (height in meters) Aim is to measure amount of body fat Direct measurement is difficult Indirect measurement: body Mass Index (BMI): correlate with amount of body fat in most individuals exceptions: athletes : large amounts of lean muscle mass Weight in kg BMI = ______________ 2 (height in meters) 19.5 – 25 : healthy 25 – 29.9 : overweight 30 or more : obese

Anatomic differences in fat deposition Anatomic distribution of body fat has a major influence on associated health risks Android, apple-shaped or upper body obesity excess fat in central abdominal area waist to hip > 1 in men 0.8 in women common in males associated with a greater risk of hypertension, insulin resistance, DM, dyslipidemia & coronary heart diseases Gynoid, pear-shaped or lower body obesity excess fat in lower extremities around the hips or gluteal region waist to hip < 1 in men relatively benign healthwise common in females

Biochemical differences in regional fat depots Abdominal fat cells: much larger than lower body fat cells higher rate of fat turnover hormonally more responsive more in men: lose weight readily than women Substances released from abdominal fat (as free fatty acids) are absorbed via portal vein with direct access to the liver Free fatty acids from abdominal fat & taken up by the liver may lead to: - insulin resistance - increased synthesis of triacylglycerol , released from liver as VLDL --- LDL Fatty acids from gluteal fat enter the general circulation - with no preferential action on liver metabolism

Number of fat cells Obesity = increase in size + increase of number of adipocytes

Body weight regulation Each individual has a biologically predetermined natural set point for body weight around which body weight drifts (within 10%) reflects a balance between factors that influence food intake & energy expenditure The body attempts to: - gain weight when the body weight falls below the set point - lose weight when the body weight is higher than the set point So, body weight is stable as long as the behavioural & environmental factors that influence energy balance are constant

Genetic contributions to obesity Genetic mechanisms play a major role in determining body weight Obesity is observed clustered in families If both parents are obese : 70-80% chance of the children being obese If both parents are lean : 9% chance Inheritance of obesity: - complex polygenic interaction between multiple genes & environment - NOT simple Mendelian genetics (not single gene disorder) Identical twins: have a very similar BMI (more similar than nonidentical dizygotic twins)

Environmental & behavioural contributions to obesity explain the epidemic of obesity over the last decade (as genetic factor are stable on this short time scale) Environmental factors: - ready availability of palatable energy-dense foods - sedentary life-style : TV watching for a long time wide dependency on cars computer using energy-sparing devices at home & at work decrease physical activity Eating behavioural factors: snacking portion size individual`s unique food preferences number of people with whom one eats

Molecules that influence obesity afferent signals reach the hypothalamus: - neural signals - circulating hormones - metabolites Hypothalamus releases efferent signals (peptides) that influence appetite & energy expenditure

LEPTIN RESISTIN ADIPONECTIN Adipose tissue (adipocytes) LEPTIN RESISTIN ADIPONECTIN Stomach GHRELIN

Hormones of adipose tissue Fat cells (adipocytes): store fats function as endocrine cells release many regulatory molecules as leptin, adiponectin & resistin

Leptin is the hormone product of the gene ob secreted by fat cells (adipocytes) produced proportionally to adipose mass Acts on the hypothalamus of the brain to regulate the amount of body fat through the control of appetite & energy expenditure Leptin secretion is : suppressed by starvation enhanced by well-fed state

Leptin (cont.)

Leptin (cont.) In mice, daily injection of leptin causes non-obese & overweight mice to lose weight In humans, leptin increases metabolic rate & decreases appetite In obese persons, plasma leptin is normal for their fat mass indicating the resistance to leptin Hypothamic receptors for leptin is produced by db gene Mutations of db gene produces leptin resistance (in rodents) BUT not in most human obesity

Ghrelin A peptide secreted primarily in the stomach Peptide-stimulating hormone In rodents, injection of ghrelin: increases food intake decreases energy expenditure decreases fat catabolism

Glucose intolerance (& DM) Dyslipidemia (low HDL & elevated VLDL) Metabolic effects of obesity: Metabolic Syndrome (insulin resistance syndrome or syndrome X) Insulin resistance Hyperinsulinemia Glucose intolerance (& DM) Dyslipidemia (low HDL & elevated VLDL) Hypertension WITH SIGNIFICANTLY INCREASED RISK OF DEVELOPING DM & CARDIOVASCULAR DISORDERS men with the syndrome are 3 – 4 times more likely to die from cardiovascular disease

Metabolic effects of obesity: Insulin Resistance Insulin resistance is the decreased ability of target tissues, such as liver, adipose tissue & muscle to respond properly to normal circulating insulin Insulin resistance increases with weight gain (overweight & obesity) & diminishes with weight loss (controlling overweight & obesity) So, fat accumulation (OBESITY) causes insulin resistance as: - substances produced by fat cells as leptin & resistin may contribute to development of insulin resistance - Free fatty acids elevated in obesity is involved in insulin resistance

In early stages of insulin resistance Metabolic effects of obesity: Insulin Resistance & Hyperglycemia (cont.) In early stages of insulin resistance with the absence of defect in b-cell function obese individuals can compensate for insulin resistance by increasing levels of secretion of insulin from b-cells So, glucose levels in blood remain within normal range With time (late stages) b-cells become dysfunctional (due to fat cells substances , FFA & hyperglycemia) So, b-cells fail to secrete enough insulin leading to Increased blood glucose levels (hyperglycemia)

Metabolic effects of obesity: Dyslipidemia insulin resistance in adipose tissues causes increased activity of hormone-sensitive lipase (deactivated with insulin) resulting in increased free fatty acids released in blood In the liver, free fatty acids are converted to cholesterol & triacylglycerol Excess cholesterol & triacylglycerol are released as VLDL resulting in increased serum triacylglycerol & hyperchlosterolemia with increased risk of Coronary Heart Diseases (CHD)

Obesity & Health 1- Obesity is associated with increased risk of death 2- Obesity is a risk factor for many chronic diseases: type 2 DM hyperchlosterolemia high plasma level of triacylglycerol hypertension coronary heart diseases some cancers gallstones arthritis gout

Weight Reduction GOALS of weight management in obese patients: To induce negative energy balance to reduce body weight decrease caloric intake and/or increase energy expenditure To maintain a lower body weight over a longer term

Weight reduction: 1- Physical activity increases cardiopulmonary fitness & reduces risk of cardiovascular diseases (independent on weight loss) Combination of caloric restriction & exercise with behavioural treatment may be expected to reduce 5 – 10 % of weight over a period of 4-6 months Essential for maintaining weight reduction

Weight reduction: 1- Caloric restriction 1 pound of adipose tissue (~ 0.5 kg) corresponds to about 3500 Kcal Ineffective for a long term for many obese individuals More than 90% regain the lost weight after suspension of dieting Weight losses of 10% of body weight over a 6-month period often reduces blood pressure reduces lipid levels enhance control of type 2 DM

Weight reduction: 1- Pharmacological treatment For BMI 30 or more: 1- sibutramine: appetite suppressant inhibits serotonin & norepinephrine reuptake 2- orlistat: lipase inhibitor that inhibits gastric & pancreatic lipases It inhibits digestion & hence absorption of about 30% of diet fat.

Weight reduction: 1- Surgical treatment To reduce food consumption For severely obese patients