OBESITY<br />
DEFINITION<br />Latin word “OBESUS” meaning stout, fat, plump.<br />It is defined as a state of excess adipose tissue.<br ...
Obesity Vs Overweight<br />Overweight – Fat<br />                        Fluid<br />                       Muscle mass<br ...
epidemiology<br />>1.6 billion overweight of which 400 million are obese<br />Women > men<br />More common even in poor<br />
Regulation of appetite<br />Appetite – lateral hypothalamus<br />Satiety – ventromedial hypothalamus<br />Destruction of L...
Other centres in regulation of appetite :<br />Arcuate Nuclei-                                          primary site for a...
Neurohumoral factors in Obesity<br />Adipokines– Leptin, Resistin, Adiponectin, Retinol binding Protein 4, Visfatin<br />P...
Leptin<br />Leptin acts on receptors in the hypothalamus of the brain where it: <br />counteracts the effects of neuropept...
Leptin<br />Increase leptin<br />Increased POMC<br />PC 1<br />Increased alpha-MSH<br />Increased Melanocortin receptor si...
Leptin<br />This inhibition is long-term, in contrast to <br /><ul><li>Cholecystokinin(CCK)- the rapid inhibition
PPY- the slower suppression of hunger between meals </li></ul>Leptin also acts on hypothalamic neurons responsible for :<b...
stimulating the sympathetic nervous system to modulate the balance between the formation and breakdown of bone. </li></li>...
Leptin<br />
Resistin<br />In humans, Resistin is primarily a product of macrophages, not fat cells. <br />Resistin causes insulin resi...
Adiponectin<br />Its circulating levels are 1000 fold higher than leptin or insulin.<br />It plays a role in increasing en...
Retinol binding protein 4<br />When it is secreted in elevated amounts by fat cells, it :<br />Suppresses glucose uptake b...
Visfatin<br />Produced by visceral fat<br />Increase in response to fatty diet<br />Role in adipose differentiation<br />
Pancreatic Hormones<br />Plasma PP are inversely co related with adipocity<br />Patients with PraderWilli have decrease am...
Gut Hormones <br />PYY- <br />Secreted from L cells of GI tract <br />Reduces food intake     <br />Ghrelin-<br />mainly s...
Adipose tissue<br />Tnf alpha<br />IL 6<br />PAI 1<br />Impaired signal transduction of insulin<br />Decrease NO mediated ...
Etiology of obesity<br />A heterogeneous group of disorders<br />Complexity of neuroendocrine and metabolic syndromes regu...
Etiology of obesity- twin studies<br />Identical twins have similar BMIs<br />High concordance between monozygotic twins c...
Etiology of obesity- adoption studies<br />Strong relationship between the BMI of adoptees and biological parents.<br />
PLEIOTROPIC OBESITY SYNDROMES<br />Autosomal dominant<br />Ulnar Mammary Syndrome:  12q24<br /> Other features- Ulnar defe...
PLEIOTROPIC OBESITY SYNDROMES<br />Autosomal Recessive<br /><ul><li>Alstrom syndrome : 2p13 </li></ul> Other features-.  R...
PLEIOTROPIC OBESITY SYNDROMES<br />Autosomal Recessive<br /><ul><li>Carpenter syndrome : (Acrocephalopolysyndactyly)</li><...
PLEIOTROPIC OBESITY SYNDROMES<br />X linked <br /><ul><li>Borjeson-Forssman-Lehmann syndrome : Xq26</li></ul>Other feature...
PLEIOTROPIC OBESITY SYNDROMES<br />X linked<br /><ul><li>Simpson-Golabi-Behmel - type 2 : Xp22 </li></ul>Other features- C...
PraderWilli Syndrome<br />Most common syndromal cause of human obesity <br />Prevalence of about 1 in 25,000<br />uniparen...
PraderWilli Syndrome<br />diminished growth<br />reduced muscle mass (lean body mass) <br /> increased fat mass - body com...
Albright hereditary osteodystrophy<br />AHO is an autosomal dominant disorder <br />Germline mutations in GNAS1<br />Decre...
Fragile X syndrome<br />extreme obesity (no hypotonia = pws)<br />a full, round face<br />small, broad hands and feet<br /...
BardetBiedl Syndrome<br />Autosomal Recessive disease<br />Obesity<br />Mental retardation<br />Dysphormic extremities (sy...
MONOGENIC HUMAN OBESITY<br />In the past five years several human disorders of energy balance that arise from genetic defe...
Increase leptin<br />leptin receptor<br />Increased POMC<br />Decreased AgRP<br />PC 1<br />Increased alpha-MSH<br />Incre...
Congenital leptin deficiency<br />The first monogenic human obesity syndrome.<br />Homozygous for a frameshift mutation in...
Congenital leptin deficiency<br />
Congenital leptin deficiency<br />The administration of leptin to leptin-deficient ob/ob mice results in a decrease in foo...
Leptin receptor deficiency<br />consanguineous family<br />loss of the leptin receptor results in a more diverse phenotype...
Increase leptin<br />leptin receptor<br />Increased POMC<br />Decreased AgRP<br />PC 1<br />Increased alpha-MSH<br />Incre...
POMC deficiency<br />Pro-opiomelanocortin (POMC) is produced by hypothalamic neurones of the arcuate nucleus<br />presente...
Increase leptin<br />leptin receptor<br />Increased POMC<br />Decreased AgRP<br />PC 1<br />Increased alpha-MSH<br />Incre...
ProhormoneConvertase 1 deficiency<br />childhood obesity<br />abnormal glucose homeostasis<br />very low plasma insulin<br...
Increase leptin<br />leptin receptor<br />Increased POMC<br />Decreased AgRP<br />PC 1<br />Increased alpha-MSH<br />Incre...
Melanocortin 4 Receptor deficiency<br />Mutations in the MC4R appear to be the commonest monogenic cause of obesity<br />i...
Increase leptin<br />leptin receptor<br />Increased POMC<br />Decreased AgRP<br />PC 1<br />Increased alpha-MSH<br />Incre...
AgRP deficiency<br />AgRP antagonizes alpha MSH action<br />So deficiency leads to overexpression of MC4R receptor.<br />
Other molecular defects<br />TUB gene – late onset Obesity<br />FAT gene – obesity by disruption of neuropeptides.<br />
Endocrinal Abnormalities-Cushing syndrome<br />Increased cortisol production<br />Hypertension<br />Glucose intolerance<br...
Endocrinal Abnormalities-Hypothyroidism<br />Uncommon cause of obesity<br />Much of weight gain is due to Myxedema<br />Ru...
Endocrinal Abnormalities-Insulinoma<br />In order to avoid hypoglycemia patients often eat more leading to weight gain.<br...
Endocrinal Abnormalities-Syndrome X<br />Central obesity<br />Glucose intolerance<br />Dyslipidemia<br />hypertension<br />
Endocrinal Abnormalities-PCOD<br />2 out 3 criteria for diagnosis<br />Menstruation irregularities due oligo/an ovulation(...
Craniopharyngioma-other disorders of Hypothalamus<br />Tumours<br />inflammation<br />trauma<br />GH decreases but Somatom...
Viral Etiology ??<br />Virus SMAM-1 – in chicken.<br />Virus Ad-36 found almost exclusively in obese human beings<br />The...
Measurement Of Obesity<br />BMI<br />Waist hip ratio<br />Skin fold thickness<br />Biometric impedance<br />Ultrasound<br ...
Body Mass Index (BMI)<br />Calculated as Weight(kg)/Height(m^2)<br />Correlation between rise in BMI and Complications.<br...
BMI Prime<br />BMI Prime - A simple modification of the BMI.<br />The ratio of actual BMI to upper limit BMI (currently de...
Waist To Hip Ratio<br />Central or abdominal obesity is associated with more co morbid conditions.<br />So measuring centr...
Disease Risk (Relative to Normal Weight and Waist Circumference)<br />
Skin fold thickness<br />Harpenderscallipers / MRNL callipers<br />It is measured at biceps/triceps/illiac and interscapul...
Biometric Impedance<br />Radio frequency current is introduced in body through electrodes<br />Fat has less number of elec...
CT/MRI<br />They can differentiate subcutaneous from visceral fat and so are important in research purposes.<br />
DEXA (Dual Energy XrayAbsorptiometry)<br />
Air displacement Plethysmography<br />
Total body electrical conductivity<br />
Hydrometry (most accurate)<br />
Classification of Obesity (BMI)<br />Underweight-  BMI < 18.5<br />Normal weight- BMI between 18.5 to 24.9<br />Overweight...
Classification of Obesity (BMI)<br />Starvation                   Less than 14.9<br />Underweight               From 15 to...
Classification of Obesity (clinical)<br />Stage 0: no apparent obesity-related risk factors <br />Stage 1: presence of obe...
Classification of Obesity (FAT)<br />82% lean <br />18% body fat body mass<br />Body fat 25% in men -obese<br />Body fat 3...
Classification of Obesity (shape)<br />Apples- Android <br />It is characterized by central abdominal obesity<br />It is c...
Co morbidities of Obesity<br />Insulin resistance<br />Type II diabetes mellitus<br />Reproductive disorders<br />Cardiova...
Obesity and Insulin Resistance<br />Mainly associated with Intra abdominal fat<br />Mainly muscle and adipose are resistan...
Insulin Resistance-complications<br />Muscle – hyperglycemia and DM II<br />Kidneys – Salt retention and Hypertension<br /...
Obesity and Diabetes<br />Though patients develop IR not all develop Diabetes.<br />Though it’s a major risk factor for DM...
Obesity and Dyslipidaemia<br />Increase LDL, TG<br />Decrease HDL<br />All this is because of decrease activity of Lipopro...
Obesity and hypertension<br />Increased blood volume<br />Increase cardiac output<br />Increase sympathetic tone<br />Incr...
Obesity and metabolic Syndrome<br />Insulin resistance<br />obesity<br />dyslipidemia<br />hypertension<br />DEADLY QUARTE...
Obesity and Gastro Intestinal diseases<br />Esophagus – GERD<br />Stomach – gastroparesis ( DM )<br />Gall stones<br />NAS...
Obesity and Reproductive disorders<br />Men<br />Plasma Testosterone and SHBG are reduced<br />Increase Estrogen<br />Gyna...
Obesity and atherosclerosis<br />Leptin causes ROS production from monocytes<br />Low Adiponectin reduces protection from ...
Obesity and Cardiovascular disease<br />Hypertension<br />Dyslipidaemias<br />Endothelial damage<br />Diabetes<br />OSA<br...
Obesity and LVH<br />It is eccentric as well concentric hypertrophy<br />Causes<br />Hypertension ( eccentric )<br />Incre...
Obesity and Cardiomyopathy<br />Fat accumulates in cords of cells leadin to a variety of conduction disturbances.<br />All...
Obesity and Stroke<br />Abdominal Obesity is an independent risk factor<br />Others include<br />Hypertension<br />Dyslipi...
Obesity and Pulmonary disease<br />SDB – Sleep Disordered Breathing ( AHI )<br />OSAS – Obstructive Sleep Apnoea Syndrome<...
OSAS – Obstructive Sleep Apnoea Syndrome<br />> 30 episodes<br />Apnoea > 10 sec (SDB – Sleep Disordered Breathing )<br />...
OSAS – Obstructive Sleep Apnoea Syndrome<br />Complications<br />Pulmonary hypertension<br />RVF<br />HT<br />Stroke<br />...
OHS – Obesity Hypoventilation Syndrome<br />Old name – PICKWICKIAN SYNDROME<br />Chronic alveolar hypoventilation in Obese...
Obesity and Asthma<br />Cause<br />Reduced TLC<br />Reduced RV and FRC<br />Relation between obesity and asthma is because...
Obesity and Renal disease<br />Increase glomerularremodelling<br />Increase kidney weight-increased cellular proliferation...
Obesity and Cancers<br />Obesity is the biggest preventable cause of Cancer after smoking.<br />Accounts for 14% of cancer...
Obesity and Skin diseases<br />AcanthosisNigricans:<br />Thickening of skin folds of neck, elbows,<br />Dorsal interphalyn...
Obesity and Orthopaedic Disease<br />Osteoarthritis<br />Hyperuricemia<br />Gout<br />Accidental injury- decrased mobility...
Obesity and retinal disease<br />Overweight diabetics are twice more likely to develop retinopathy than non obese.<br />Wa...
Obesity and Psychological problems<br />Are obese people more jolly?<br />NO<br />Obesity  psychological problems<br />Ps...
Obesity and Psychological problems<br />50% overweight lack self confidence<br />Depression<br />Obesity has more risk of ...
Management of Obesity<br />It is a chronic medical condition<br />Definition of successful treatment:<br />Attainment of n...
Management of Obesity<br />
Life Style Modification<br />
Diet<br />Low calorie diet<br />Low in saturated fats<br />Normal protein intake<br />Increased fibers in diet<br />Low de...
Self Limiting<br />No matter what the calorie intake is the constituents remain in same proportion<br />i.e<br />Carbohydr...
Fixed Energy Diet<br />Intake is limited by controlling portion sizes, menu choice and composition<br />Minimal self monit...
Low Calorie Diet<br />800-1000 Kcal<br />Applicable to most of the patients<br />Fewer restrictions than VLCD.<br />Supple...
Very Low Calorie Diet<br />400 – 600 calorie diet.<br />Even below one’s basal metabolic rate<br />Used for period of 1 to...
Very Low Calorie Diet<br />Complications -fatigue, hair loss, dry skin, dizziness difficulty concentrating, cholelithiasis...
Total Fasting<br />Not recommended<br />There is diuresis, natriuresis<br />All deficiencies<br />Re Feeding Syndrome-seve...
Liquid Protein Diet<br />Banned<br />Used in 1970’s<br />Life threatening Arrythmias.<br />
High Protein Diets<br />High protein<br />Increase ketones<br />Increase purines and urea<br />diuresis<br />Gout<br />Wig...
Fat Intake<br />Decreased fat intake without decreased calories is of no use<br />Because if fat is replaced by carbohydra...
Physical Activity<br />
ScienceDaily (Dec. 12, 2008) — Severely obese patients who have lost significant amounts of weight by changing their diet ...
Pharmacotherapy<br />Indications -<br />BMI > 30<br />BMI > 27 with risk factors like HT, DM, CHD, Sleep Apnoea, Dyslipide...
Pharmacotherapy<br />Phenteramine<br />Phenylpropanolamine<br />Fenfluramine<br />Fen-phen<br />Sibutramine<br />Orlistat<...
Pharmacotherapy<br />Tesofensine<br />Betahistine<br />Amylin<br /> Melanocortin-4 receptor agonist<br />Neuropeptide Y an...
Amphetamine<br />Dextro amphetamine was used as anti obesity drug<br />Tachycardia, HT, Abuse potential<br />
Phenteramine<br />Amphetamine like drug<br />Act centrally to reduce appetite<br />Low addictive potential<br />Modest eff...
Fenfluramine<br />Inhibit serotonin uptake<br />Modest efficacy as single agent<br />
Fen Phen<br />Combination fenfluramine and phentermine<br />drugs exerted independent actions on brain satiety mechanisms<...
Sibutramine<br />Originally an anti depressant<br />Mechanism of action –<br />Mono amine reuptake inhibitor ( primarily s...
Sibutramine<br />Time to peak concentration – 1-2 Hrs.<br />Metabolism – Hepatic enzymes, Cytochrome 3A4 to active metabol...
Sibutramine<br />Dose – 10 to 15 once daily.<br />FDA Approval – for adults and adolescents.<br />Side Effects – hypertens...
Sibutramine<br />Advantages<br />It causes sympathetic stimulation and thereby. prevent decrease in BMR.<br />There is imp...
Orlistat<br />Mechanism of action – non systemic reversible inhibitor of gastric and pancreatic lipases by forming a coval...
Orlistat<br />Time to peak concentration – 8 Hrs.<br />Metabolism – In GI Tract to inactive metabolites.<br />Excretion – ...
Orlistat<br />Dose – 120 mg BD or TID with meals<br />FDA Approval – for adults and adolescents as well as children.<br />...
Orlistat<br />Precautions – <br />Patient should take 3 main meals into which dietary constituents are equally divided.<br...
Orlistat<br />Advantages – <br /> Weight loss observed within 2 weeks of starting therapy<br />6 kg weight loss in a year<...
Rimonabant<br />Mechanism of action – Endocannabinoid (CB1) receptor blocker.<br />Site of action – CNS<br />Absorption – ...
Rimonabant<br />Metabolism – hepatic enzymes<br />Excretion – fecal via biliary route<br />FDA approval – BANNED<br />Side...
Metformin<br />Decreases appetite and thereby reduces weight<br />Since most DM II patients are Obese this is a good choic...
Olestra<br />Normal fats consist of a glycerol molecule with three fatty acid tails attached.<br />Olestra is synthesized ...
Olestra<br />Decline in blood cholesterol levels<br />Failed to demonstrate the 15% reduction required by the FDA to be ap...
Amylinpramlintide (brand name Symlin)<br />Part of the endocrine pancreas and contributes to glycemic control<br />Functio...
Tesofensine<br />Tesofensine (TE) is a norepinephrine, dopamine, and serotonin reuptake inhibitor<br />Originally research...
Tesofensine<br />Dry mouth<br />Insomnia<br />Tachycardia<br />Constipation<br />Nausea<br />Diarrhoea<br />high blood pre...
Betahistine<br />Blocking the brain's histamine-1 receptor causes weight gain<br />Stimulating the histamine-1 receptor ap...
Melanocortin-4 Receptor Agonist <br />Suppresses food intake when administered  to db/db mice that lack functional leptin ...
NPY receptor antagonist (1229U91 )<br />reduced spontaneous food intake<br />suppressed water intake<br />no abnormal chan...
Beta(3) adrenergic agonists<br />Amibegron<br />Solabegron<br />Enhancement of lipolysis in adipose tissue<br />
Glucagon-like peptide-1 agonists (Boc5)<br />(GLP)-1 is produced by the intestine<br />stimulates insulin secretion <br />...
Bariatric surgical techniques<br />Divided into two groups<br />Malabsorptiveprocedures - Induce decreased absorption of n...
Bariatric surgical techniques<br />Indications -<br />BMI greater than 40, or 100 pounds overweight <br />BMI 35-39.9 and ...
Malabsorptiveprocedures<br />Jejunoileal bypass<br />Biliopancreatic diversion<br />Biliopancreatic diversion with duodena...
The jejunoileal bypass<br />One of the first bariatric operations<br /> It is associated withsubstantial long-term complic...
Biliopancreatic diversion<br />A partial gastrectomy is performed, creating a 100–150ml gastric pouch<br />gastro-jejunost...
Biliopancreatic diversion with duodenal switch<br />A pylorus-sparing sleeve gastrectomy with duodeno-ileostomyis performe...
Restrictive procedures<br />Vertical banded gastroplasty<br />Laparoscopic adjustable gastric band<br />
Restrictive procedures<br />simpler to perform<br />less procedural complications<br />Represent the currentmost frequentl...
Complications<br />Vomiting <br />Leak into the abdomen <br />Slipping or wearing away of the band <br />Enlargement of th...
Combined procedure<br />Roux-en-Y gastric bypass<br />It is (atleast in the United States) the most frequently performed b...
Success of Bariatric Procedures<br /> 20–40 kg of weight loss<br />10–15kg/m2 reduction in BMI<br />
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obesity final

  1. 1. OBESITY<br />
  2. 2. DEFINITION<br />Latin word “OBESUS” meaning stout, fat, plump.<br />It is defined as a state of excess adipose tissue.<br />BMI ≥ 30<br />
  3. 3. Obesity Vs Overweight<br />Overweight – Fat<br /> Fluid<br /> Muscle mass<br /> Bone<br /> Tumours<br />Obesity – Fat ( adipose tissue )<br />
  4. 4. epidemiology<br />>1.6 billion overweight of which 400 million are obese<br />Women > men<br />More common even in poor<br />
  5. 5.
  6. 6. Regulation of appetite<br />Appetite – lateral hypothalamus<br />Satiety – ventromedial hypothalamus<br />Destruction of LHA leads to starvation and death.<br />Destruction of VMA leads to obesity. <br />
  7. 7. Other centres in regulation of appetite :<br />Arcuate Nuclei- primary site for action of leptin and insulin.<br />Para Ventricular Nuclei- AMP kinase mediated appetite regulation<br />Dorsomedial Hypothalamic Nuclei- destruction leads to hyperphagia and obesity<br />
  8. 8. Neurohumoral factors in Obesity<br />Adipokines– Leptin, Resistin, Adiponectin, Retinol binding Protein 4, Visfatin<br />Pancreatic hormones – Insulin, Pancreatic Polypeptide (PP/PYY/NPY)<br />Gut Hormones - Incretins<br />
  9. 9. Leptin<br />Leptin acts on receptors in the hypothalamus of the brain where it: <br />counteracts the effects of neuropeptide Y (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus); <br />counteracts the effects of anandamide (another potent feeding stimulant that binds to the same receptors as THC, the active ingredient of marijuana) <br />promotes the synthesis of α-MSH, an appetite suppressant; <br />RESULT- inhibition of food intake. <br />
  10. 10. Leptin<br />Increase leptin<br />Increased POMC<br />PC 1<br />Increased alpha-MSH<br />Increased Melanocortin receptor signal<br />Decreased Appetite<br />
  11. 11. Leptin<br />This inhibition is long-term, in contrast to <br /><ul><li>Cholecystokinin(CCK)- the rapid inhibition
  12. 12. PPY- the slower suppression of hunger between meals </li></ul>Leptin also acts on hypothalamic neurons responsible for :<br /><ul><li>the secretion of gonadotropin-releasing hormone (GnRH).
  13. 13. stimulating the sympathetic nervous system to modulate the balance between the formation and breakdown of bone. </li></li></ul><li>Leptin<br />In addition to its effect on the hypothalamus, leptin acts directly on:<br />the cells of the liver and skeletal muscle where it stimulates the oxidation of fatty acids in the mitochondria. This reduces the storage of fat in those tissues (but not in adipose tissue). <br />T cells where it enhances the production of Th1 cells promoting inflammation.<br />
  14. 14. Leptin<br />
  15. 15. Resistin<br />In humans, Resistin is primarily a product of macrophages, not fat cells. <br />Resistin causes insulin resistance<br />There is a strong association in humans between elevated levels of Resistin, Obesity, and Type 2 diabetes <br />over 80% of the people with NIDDM are obese <br />
  16. 16. Adiponectin<br />Its circulating levels are 1000 fold higher than leptin or insulin.<br />It plays a role in increasing energy expenditure and decreasing body weight also increases insulin sensitivity<br />Thiazolidinediones increase this hormone via PPAR-gamma<br />Its level are increased after starvation.<br />
  17. 17. Retinol binding protein 4<br />When it is secreted in elevated amounts by fat cells, it :<br />Suppresses glucose uptake by skeletal muscle; <br />Enhances glucose release by the liver. <br />These actions counteract those of insulin. <br />Elevated levels of RBP4 occur in humans with Type 2 diabetes mellitus. <br />
  18. 18. Visfatin<br />Produced by visceral fat<br />Increase in response to fatty diet<br />Role in adipose differentiation<br />
  19. 19. Pancreatic Hormones<br />Plasma PP are inversely co related with adipocity<br />Patients with PraderWilli have decrease amount of PP <br />
  20. 20. Gut Hormones <br />PYY- <br />Secreted from L cells of GI tract <br />Reduces food intake <br />Ghrelin-<br />mainly secreted from stomach<br />A potent Orexigenic<br />Cholecystokinin<br />Mainly secreted in duodenum <br />Decreasing meal size and duration both.<br />
  21. 21. Adipose tissue<br />Tnf alpha<br />IL 6<br />PAI 1<br />Impaired signal transduction of insulin<br />Decrease NO mediated vaso dilatation<br />Decrease GLUT 4<br />atherosclerosis<br />INSULIN RESISTANCE<br />Impaired insulin signalling<br />
  22. 22. Etiology of obesity<br />A heterogeneous group of disorders<br />Complexity of neuroendocrine and metabolic syndromes regulate energy intake, storage and expenditure.<br />Obesity is caused by imbalance between energy intake and expenditure.<br />Obesity runs in families<br />Inheritance is not mendelian.<br />
  23. 23. Etiology of obesity- twin studies<br />Identical twins have similar BMIs<br />High concordance between monozygotic twins compared to dizygotic twins <br />correlations did not differ significantly between twins reared apart and twins reared together<br />
  24. 24. Etiology of obesity- adoption studies<br />Strong relationship between the BMI of adoptees and biological parents.<br />
  25. 25. PLEIOTROPIC OBESITY SYNDROMES<br />Autosomal dominant<br />Ulnar Mammary Syndrome: 12q24<br /> Other features- Ulnar defects, delayed puberty, hypoplastic nipples. <br />
  26. 26.
  27. 27. PLEIOTROPIC OBESITY SYNDROMES<br />Autosomal Recessive<br /><ul><li>Alstrom syndrome : 2p13 </li></ul> Other features-.  Retinal dystrophy, neurosensory deafness, diabetes <br /><ul><li>Cohen syndrome : 8q22 </li></ul> Other features- Prominent central incisors, opthalmopathy, microcephaly <br />
  28. 28. PLEIOTROPIC OBESITY SYNDROMES<br />Autosomal Recessive<br /><ul><li>Carpenter syndrome : (Acrocephalopolysyndactyly)</li></ul>Other features- acrocephaly, polydactyly, genuvalgum, secondary hypogonadism.<br /><ul><li>Laurence Moon Biedl syndrome:</li></ul>Other features-short stature with primary hypogonadism and onset at 1 – 2 years<br />
  29. 29.
  30. 30. PLEIOTROPIC OBESITY SYNDROMES<br />X linked <br /><ul><li>Borjeson-Forssman-Lehmann syndrome : Xq26</li></ul>Other features- Mental retardation, hypogonadism, large ears <br /><ul><li>Mehmo syndrome : Xp22</li></ul>Other features- Mental retardation, epilepsy, hypogonadism, microcephaly <br />
  31. 31. PLEIOTROPIC OBESITY SYNDROMES<br />X linked<br /><ul><li>Simpson-Golabi-Behmel - type 2 : Xp22 </li></ul>Other features- Craniofacial defects, skeletal and visceral abnormalities <br /><ul><li>Wilson-Turner syndrome : Xp21</li></ul>Other features- Mental retardation, tapering fingers, gynaecomastia <br />
  32. 32. PraderWilli Syndrome<br />Most common syndromal cause of human obesity <br />Prevalence of about 1 in 25,000<br />uniparental maternal disomy(15q11.2-q12 )<br />Caused by deletion or disruption of a paternally imprinted gene on the proximal long arm of chromosome 15.<br />Characterized by diminished foetal activity, obesity, hypotonia, mental retardation, short stature, hypogonadotropichypogonadism, and small hands and feet <br />Hyperphagia is a dominant feature in PWS<br />
  33. 33.
  34. 34. PraderWilli Syndrome<br />diminished growth<br />reduced muscle mass (lean body mass) <br /> increased fat mass - body composition<br />hypogonadotrophichypogonadism<br />Fasting plasma ghrelin levels are 4.5-fold higher in PWS subjects <br />
  35. 35.
  36. 36. Albright hereditary osteodystrophy<br />AHO is an autosomal dominant disorder <br />Germline mutations in GNAS1<br />Decrease expression/function of G alpha s protein.<br />short stature, obesity, skeletal defects, and impaired olfaction. <br />
  37. 37.
  38. 38. Fragile X syndrome<br />extreme obesity (no hypotonia = pws)<br />a full, round face<br />small, broad hands and feet<br />regional skin hyperpigmentation<br />severe mental retardation<br />macro-orchidism<br />large ears<br />prominent jaw<br />and high-pitched jocular speech<br />
  39. 39. BardetBiedl Syndrome<br />Autosomal Recessive disease<br />Obesity<br />Mental retardation<br />Dysphormic extremities (syndactyly, brachydactyly or polydactyly)<br />Retinal dystrophy or pigmentary retinopathy<br />Hypogonadism or hypogenitalism (limited to male patients)<br />Structural abnormalities of the kidney or functional renal impairment.<br />
  40. 40. MONOGENIC HUMAN OBESITY<br />In the past five years several human disorders of energy balance that arise from genetic defects have been described.<br />Mutations all result in morbid obesity in childhood without the developmental pleiotropic features characteristic of the recognised syndromes of childhood obesity.<br />
  41. 41. Increase leptin<br />leptin receptor<br />Increased POMC<br />Decreased AgRP<br />PC 1<br />Increased alpha-MSH<br />Increased Melanocortin receptor signal<br />Decreased Appetite<br />
  42. 42. Congenital leptin deficiency<br />The first monogenic human obesity syndrome.<br />Homozygous for a frameshift mutation in the ob gene (ob/ob)<br />Hyperphagic-constantly demanding food<br />An intense drive to eat-never satisfied.<br />They developed severe disabling obesity (an 8yr old girl weighing 86kg and a 2yr old boy weighing 29kg)<br />Advanced skeletal maturation<br />Impaired T cell mediated immunity<br />Hypogonadotropichypogonadism<br />
  43. 43. Congenital leptin deficiency<br />
  44. 44.
  45. 45. Congenital leptin deficiency<br />The administration of leptin to leptin-deficient ob/ob mice results in a decrease in food intake, weight loss and restoration of fertility and T cell mediated immune function.<br />Leptin-deficient children have been treated with daily subcutaneous injections of recombinant human leptin for up to four years with sustained, beneficial effects on appetite, fat mass, hyperinsulinaemia and hyperlipidaemia.<br />
  46. 46.
  47. 47. Leptin receptor deficiency<br />consanguineous family<br />loss of the leptin receptor results in a more diverse phenotype than loss of its ligand leptin.<br />normal birthweight<br />exhibited rapid weight gain in the first few months of life<br />aggressive behaviour when denied food<br />decreased IGF-1 and IGF-BP3 levels <br />hypothalamic hypothyroidism<br />
  48. 48. Increase leptin<br />leptin receptor<br />Increased POMC<br />Decreased AgRP<br />PC 1<br />Increased alpha-MSH<br />Increased Melanocortin receptor signal<br />Decreased Appetite<br />
  49. 49. POMC deficiency<br />Pro-opiomelanocortin (POMC) is produced by hypothalamic neurones of the arcuate nucleus<br />presented in neonatal life with adrenal crisis due to isolated ACTH deficiency<br />hyperphagic, developing early-onset obesity<br />pale skin and red hair due to the lack of MSH function <br />
  50. 50.
  51. 51. Increase leptin<br />leptin receptor<br />Increased POMC<br />Decreased AgRP<br />PC 1<br />Increased alpha-MSH<br />Increased Melanocortin receptor signal<br />Decreased Appetite<br />
  52. 52. ProhormoneConvertase 1 deficiency<br />childhood obesity<br />abnormal glucose homeostasis<br />very low plasma insulin<br />elevated levels of pro insulin<br />hypogonadotropichypogonadism<br />hypocortisolaemia<br />elevated levels of POMC <br />
  53. 53. Increase leptin<br />leptin receptor<br />Increased POMC<br />Decreased AgRP<br />PC 1<br />Increased alpha-MSH<br />Increased Melanocortin receptor signal<br />Decreased Appetite<br />
  54. 54. Melanocortin 4 Receptor deficiency<br />Mutations in the MC4R appear to be the commonest monogenic cause of obesity<br />increase in lean body mass<br />Increased bone mineral density<br />increased linear growth throughout childhood<br />hyperphagia<br />severe hyperinsulinaemia<br />
  55. 55.
  56. 56. Increase leptin<br />leptin receptor<br />Increased POMC<br />Decreased AgRP<br />PC 1<br />Increased alpha-MSH<br />Increased Melanocortin receptor signal<br />Decreased Appetite<br />
  57. 57. AgRP deficiency<br />AgRP antagonizes alpha MSH action<br />So deficiency leads to overexpression of MC4R receptor.<br />
  58. 58. Other molecular defects<br />TUB gene – late onset Obesity<br />FAT gene – obesity by disruption of neuropeptides.<br />
  59. 59. Endocrinal Abnormalities-Cushing syndrome<br />Increased cortisol production<br />Hypertension<br />Glucose intolerance<br />Cushingoidfacies<br />
  60. 60. Endocrinal Abnormalities-Hypothyroidism<br />Uncommon cause of obesity<br />Much of weight gain is due to Myxedema<br />Ruled out by serum TSH.<br />
  61. 61. Endocrinal Abnormalities-Insulinoma<br />In order to avoid hypoglycemia patients often eat more leading to weight gain.<br />High insulin promote fat genesis.<br />
  62. 62. Endocrinal Abnormalities-Syndrome X<br />Central obesity<br />Glucose intolerance<br />Dyslipidemia<br />hypertension<br />
  63. 63. Endocrinal Abnormalities-PCOD<br />2 out 3 criteria for diagnosis<br />Menstruation irregularities due oligo/an ovulation(progesterone level at 21st day of cylcle)<br />Clinical or biochemical evidence of hyperandrogenism.<br />USG s/o ovarian cysts.<br />
  64. 64. Craniopharyngioma-other disorders of Hypothalamus<br />Tumours<br />inflammation<br />trauma<br />GH decreases but Somatomedin is normal.<br />
  65. 65. Viral Etiology ??<br />Virus SMAM-1 – in chicken.<br />Virus Ad-36 found almost exclusively in obese human beings<br />The mechanism by which Ad-36 causes obesity is unclear.<br /> It can be hypothesized that hypothalamic damage caused by viruses might be a cause.<br />
  66. 66. Measurement Of Obesity<br />BMI<br />Waist hip ratio<br />Skin fold thickness<br />Biometric impedance<br />Ultrasound<br />DEXA (Dual Energy XrayAbsorptiometry<br />CT / MRI<br />Air displacement Plethysmography<br />Total body electrical conductivity<br />Hydrometry (most accurate)<br />
  67. 67. Body Mass Index (BMI)<br />Calculated as Weight(kg)/Height(m^2)<br />Correlation between rise in BMI and Complications.<br />BMI measures individual’s total weight relative to its height.<br />BMI may be high in a vey muscular person<br />For similar BMIs women have greater fat mass than their male counterparts<br />So BMI may be misleading in certain cases<br />
  68. 68. BMI Prime<br />BMI Prime - A simple modification of the BMI.<br />The ratio of actual BMI to upper limit BMI (currently defined at BMI 25).<br />Individuals can tell, what percentage they deviate from normal.<br />BMI Prime<br /> < 0.74 – underweight<br />between 0.74 and 0.99 - optimal weight<br />>/=1.00 overweight<br />
  69. 69.
  70. 70. Waist To Hip Ratio<br />Central or abdominal obesity is associated with more co morbid conditions.<br />So measuring central obesity is of greater significance<br />W/H ratio is taken by a simple measure tape<br /> in men > 102 cm/90<br /> in women > 88 cm/80<br />
  71. 71. Disease Risk (Relative to Normal Weight and Waist Circumference)<br />
  72. 72. Skin fold thickness<br />Harpenderscallipers / MRNL callipers<br />It is measured at biceps/triceps/illiac and interscapular. <br />Total of all four sites is considered<br />15-45 mm – 8-22 % of total body fat<br />46-75 mm – 23-30 % of total body fat<br />76-150 mm – 31-40 % of total body fat<br />151-170 mm – 41-45 % of total body fat<br />Upto 22% it is normal (males)<br />Upto 30% it is normal (females)<br />
  73. 73.
  74. 74. Biometric Impedance<br />Radio frequency current is introduced in body through electrodes<br />Fat has less number of electrolytes <br />Water is less conductive<br />
  75. 75. CT/MRI<br />They can differentiate subcutaneous from visceral fat and so are important in research purposes.<br />
  76. 76. DEXA (Dual Energy XrayAbsorptiometry)<br />
  77. 77. Air displacement Plethysmography<br />
  78. 78. Total body electrical conductivity<br />
  79. 79. Hydrometry (most accurate)<br />
  80. 80. Classification of Obesity (BMI)<br />Underweight- BMI < 18.5<br />Normal weight- BMI between 18.5 to 24.9<br />Overweight- BMI between 25.0 to 29.9<br />Obese grade I- BMI between 30.0 to 34.9<br />Obese grade II- BMI between 35.0 to 39.0<br />Obese grade III ( morbid obese)- BMI ≥ 40<br />
  81. 81. Classification of Obesity (BMI)<br />Starvation Less than 14.9<br />Underweight From 15 to 18.4<br />Normal From 18.5 to 22.9<br />Overweight From 23 to 27.5<br />Obese From 27.6 to 40<br />Morbidly Obese Greater than 40<br />It is used in SINGAPORE.<br />It is to applied in INDIA.<br />
  82. 82. Classification of Obesity (clinical)<br />Stage 0: no apparent obesity-related risk factors <br />Stage 1: presence of obesity-related sub-clinical risk factors, mild physical symptoms.<br />Stage 2: presence of established obesity-related chronic disorders<br />Stage 3: established end-organ damage <br />Stage 4: severe (end-stage?) disabilities<br />
  83. 83. Classification of Obesity (FAT)<br />82% lean <br />18% body fat body mass<br />Body fat 25% in men -obese<br />Body fat 30% in women – obese<br />This method is used in JAPAN.<br />
  84. 84. Classification of Obesity (shape)<br />Apples- Android <br />It is characterized by central abdominal obesity<br />It is clinically more important as disease are more correlated with this abdominal fat<br />Pears – Gynecoid<br />It is characterized by accumulation of fat around hip and buttocks.<br />
  85. 85.
  86. 86. Co morbidities of Obesity<br />Insulin resistance<br />Type II diabetes mellitus<br />Reproductive disorders<br />Cardiovascular disorders<br />Pulmonary disorders<br />Gastrointestinal diseases<br />Renal diseases<br />Cancers<br />Bone, joint and cutaneous diseases<br />Retinal diseases<br />Psychological problems<br />
  87. 87. Obesity and Insulin Resistance<br />Mainly associated with Intra abdominal fat<br />Mainly muscle and adipose are resistant.<br />Factors that play a role are<br />Insulin <br />FFA  decreased mitochondria  decrease action of insulin.<br />Intracellular lipid accumulation<br />Adipokines (resistin) decreases mRNA expression<br /> TNF-alpha, IL-6  inflammatory process<br />Reduced activity of Leptin, Adiponectin<br />
  88. 88. Insulin Resistance-complications<br />Muscle – hyperglycemia and DM II<br />Kidneys – Salt retention and Hypertension<br />Ovaries – Increase testosterone and PCOS<br />Heart – Increase plasminogen activator inhibitor ( PAI 1) and ACS<br />Cancers – Colon, Prostrate, Breast<br />Sympathetic system – Increase Cytokines and increase Blood Pressure. <br />
  89. 89. Obesity and Diabetes<br />Though patients develop IR not all develop Diabetes.<br />Though it’s a major risk factor for DM.( 85% of type II DM are Obese)<br />If BMI > 35 - 93 times more likely to develop DM.<br />There is direct correlation between BMI and DM.<br />
  90. 90. Obesity and Dyslipidaemia<br />Increase LDL, TG<br />Decrease HDL<br />All this is because of decrease activity of Lipoprotein Lipase.<br />10% wt gain  12 mg/dl increase in cholesterol.<br />With treatment there is improvement in dyslipidemias<br />
  91. 91. Obesity and hypertension<br />Increased blood volume<br />Increase cardiac output<br />Increase sympathetic tone<br />Increase Salt sensitivity<br />Salt retention by insulin<br />Increase angiotensinogen<br />HYPERTENSION<br />
  92. 92. Obesity and metabolic Syndrome<br />Insulin resistance<br />obesity<br />dyslipidemia<br />hypertension<br />DEADLY QUARTET<br />METABOLIC SYNDROME<br />
  93. 93. Obesity and Gastro Intestinal diseases<br />Esophagus – GERD<br />Stomach – gastroparesis ( DM )<br />Gall stones<br />NASH<br /> NAFLD<br />
  94. 94. Obesity and Reproductive disorders<br />Men<br />Plasma Testosterone and SHBG are reduced<br />Increase Estrogen<br />Gynaecomastia seen<br />Secondary sexual characters preserved.<br />Women<br />Increased Androgen<br />Decrease SHBG<br />PCOS<br />Uterine cancer (lower body obesity )<br />Not only fertility but their chances of IVF success reduces<br />
  95. 95. Obesity and atherosclerosis<br />Leptin causes ROS production from monocytes<br />Low Adiponectin reduces protection from monocyte adhesion<br />TNF alpha, IL6, ICAM1 and VCAM1 affect endothelium via Transcription Factor KB<br />PAI1 increased by TF-KB<br />Angiotensinogen increases<br />
  96. 96. Obesity and Cardiovascular disease<br />Hypertension<br />Dyslipidaemias<br />Endothelial damage<br />Diabetes<br />OSA<br />W/H ratio may be the best predictor<br />BMI > 29…..3 fold rise in MI<br />Obesity is responsible for 17% of all CVD<br />Angina increases by 1.8 times<br />MI increases by 3.2 and 1.5 fold in woman and men respectively. .<br />Cardi vascular complications<br />
  97. 97. Obesity and LVH<br />It is eccentric as well concentric hypertrophy<br />Causes<br />Hypertension ( eccentric )<br />Increased blood volume  Starling principle<br />There is fatty infiltration of myocytes<br />
  98. 98. Obesity and Cardiomyopathy<br />Fat accumulates in cords of cells leadin to a variety of conduction disturbances.<br />All kinds of ARRYTHMIAS<br />AF in presence of LVH poorly tolerated.<br />QT prolongation in 10% cases.<br />Fatty infiltration of conducting system.<br />Hypercapnia<br />Hypoxia<br />CAD<br />Sleep Apnoea<br />
  99. 99. Obesity and Stroke<br />Abdominal Obesity is an independent risk factor<br />Others include<br />Hypertension<br />Dyslipidaemis<br />
  100. 100. Obesity and Pulmonary disease<br />SDB – Sleep Disordered Breathing ( AHI )<br />OSAS – Obstructive Sleep Apnoea Syndrome<br />OHS – Obesity Hypoventilation Syndrome<br />Asthma<br />
  101. 101. OSAS – Obstructive Sleep Apnoea Syndrome<br />> 30 episodes<br />Apnoea > 10 sec (SDB – Sleep Disordered Breathing )<br />Daytime drowsiness<br />Snoring at night<br />Memory loss<br />Mood swings<br />Cause<br />REM atonia<br />Increase soft tissue infiltration around neck<br />Decreased chest wall compliance<br />Diaphragmatic displacement in supine<br />
  102. 102. OSAS – Obstructive Sleep Apnoea Syndrome<br />Complications<br />Pulmonary hypertension<br />RVF<br />HT<br />Stroke<br />Arrythmias (flutter,bradycardia)<br />VT<br />Car accidents<br />
  103. 103. OHS – Obesity Hypoventilation Syndrome<br />Old name – PICKWICKIAN SYNDROME<br />Chronic alveolar hypoventilation in Obese with BMI > 30 (PaO2 <70 PaCO2 >45 )<br />Cause<br />High work of breathing<br />Dysfunction of respiratory centre<br />Repeated nocturnal sleep apnoea<br />
  104. 104. Obesity and Asthma<br />Cause<br />Reduced TLC<br />Reduced RV and FRC<br />Relation between obesity and asthma is because<br />Common etiologies<br />Co morbidities<br />Adipokines<br />Mechanical factors<br />
  105. 105. Obesity and Renal disease<br />Increase glomerularremodelling<br />Increase kidney weight-increased cellular proliferation.<br />This changes in long term lead to glomerular sclerosis and DM nephropathy.<br />
  106. 106. Obesity and Cancers<br />Obesity is the biggest preventable cause of Cancer after smoking.<br />Accounts for 14% of cancer deaths in Men and 20% in women.<br />
  107. 107. Obesity and Skin diseases<br />AcanthosisNigricans:<br />Thickening of skin folds of neck, elbows,<br />Dorsal interphalyngeal spaces<br />Reflects severity of IR<br />Friability of skin and varicosities.<br />Aggravation of other conditions caused by DM<br />Necrobiosislipoidica<br />Ulcers<br />Infections<br />
  108. 108. Obesity and Orthopaedic Disease<br />Osteoarthritis<br />Hyperuricemia<br />Gout<br />Accidental injury- decrased mobility, daytime somnolence<br />
  109. 109. Obesity and retinal disease<br />Overweight diabetics are twice more likely to develop retinopathy than non obese.<br />Waist to hip ratio was only second to glycaemic control in its importance in preventing retinopathy.<br />
  110. 110. Obesity and Psychological problems<br />Are obese people more jolly?<br />NO<br />Obesity  psychological problems<br />Psychological problems  obesity<br />
  111. 111. Obesity and Psychological problems<br />50% overweight lack self confidence<br />Depression<br />Obesity has more risk of depression in Women<br />More physical and sexual abuse<br />Lack of attention<br />Low education<br />Low self esteem <br />
  112. 112. Management of Obesity<br />It is a chronic medical condition<br />Definition of successful treatment:<br />Attainment of normal weight<br />No treatment induced morbidity<br />This is rarely achieved in clinical practice.<br />
  113. 113. Management of Obesity<br />
  114. 114. Life Style Modification<br />
  115. 115. Diet<br />Low calorie diet<br />Low in saturated fats<br />Normal protein intake<br />Increased fibers in diet<br />Low density foods<br />1000 K cal deficit produces 1 kg wt loss per week<br />
  116. 116. Self Limiting<br />No matter what the calorie intake is the constituents remain in same proportion<br />i.e<br />Carbohydrates 55%<br />Fat 30%<br />Protein 15%<br />Results in wt loss 2-6 kg over1 year<br />
  117. 117. Fixed Energy Diet<br />Intake is limited by controlling portion sizes, menu choice and composition<br />Minimal self monitoring<br />1200 to 1800 kcal<br />Lack of compliance to this rigid pattern<br />
  118. 118. Low Calorie Diet<br />800-1000 Kcal<br />Applicable to most of the patients<br />Fewer restrictions than VLCD.<br />Supplementation of vitamins and minerals is required<br />Over a year there is reduction of 6 to 7 kgs.<br />
  119. 119. Very Low Calorie Diet<br />400 – 600 calorie diet.<br />Even below one’s basal metabolic rate<br />Used for period of 1 to 2 months under medical supervision<br />45 to 70 % protein<br />30 to 50 % carbohydrates<br />2g fat <br />Supplemented with vitamins, minerals and trace elements<br />Greater wt loss compared to restrictive diets<br />
  120. 120. Very Low Calorie Diet<br />Complications -fatigue, hair loss, dry skin, dizziness difficulty concentrating, cholelithiasis, pancreatitis, gall stones.<br />Contraindications – pregnancy, cancer, MI, hepatic disease, CV Stroke.<br />
  121. 121. Total Fasting<br />Not recommended<br />There is diuresis, natriuresis<br />All deficiencies<br />Re Feeding Syndrome-severe an potentially fatal electrolyte, fluid and metabolic abnormalities when feeding is resumed.<br />
  122. 122. Liquid Protein Diet<br />Banned<br />Used in 1970’s<br />Life threatening Arrythmias.<br />
  123. 123. High Protein Diets<br />High protein<br />Increase ketones<br />Increase purines and urea<br />diuresis<br />Gout<br />Wight loss<br />
  124. 124. Fat Intake<br />Decreased fat intake without decreased calories is of no use<br />Because if fat is replaced by carbohydrates there is rise in triglycerides.<br />Instead saturated fats should be replaced by MUFA or PUFA<br />
  125. 125. Physical Activity<br />
  126. 126. ScienceDaily (Dec. 12, 2008) — Severely obese patients who have lost significant amounts of weight by changing their diet and exercise habits may be as successful in keeping the weight off long-term as those individuals who lost weight after bariatric surgery, according to a new study published online by the International Journal of Obesity<br />
  127. 127. Pharmacotherapy<br />Indications -<br />BMI > 30<br />BMI > 27 with risk factors like HT, DM, CHD, Sleep Apnoea, Dyslipidemia.<br />
  128. 128. Pharmacotherapy<br />Phenteramine<br />Phenylpropanolamine<br />Fenfluramine<br />Fen-phen<br />Sibutramine<br />Orlistat<br />Ribonabant<br />Metformin<br />Olestra<br />Leptin<br />
  129. 129. Pharmacotherapy<br />Tesofensine<br />Betahistine<br />Amylin<br /> Melanocortin-4 receptor agonist<br />Neuropeptide Y antagonists<br /> Beta(3) adrenergic agonists<br />Glucagon-like peptide-1 agonists.<br />
  130. 130. Amphetamine<br />Dextro amphetamine was used as anti obesity drug<br />Tachycardia, HT, Abuse potential<br />
  131. 131. Phenteramine<br />Amphetamine like drug<br />Act centrally to reduce appetite<br />Low addictive potential<br />Modest efficacy<br />CVS side effects<br />
  132. 132. Fenfluramine<br />Inhibit serotonin uptake<br />Modest efficacy as single agent<br />
  133. 133. Fen Phen<br />Combination fenfluramine and phentermine<br />drugs exerted independent actions on brain satiety mechanisms<br />Primary Pulmonary hypertension increases 20 fold in this patients.<br />Drug was withdrawn in 1997.<br />
  134. 134. Sibutramine<br />Originally an anti depressant<br />Mechanism of action –<br />Mono amine reuptake inhibitor ( primarily serotonin and norepinephrine )<br />Site of action - Central nervous system<br />Absorption – 77 %<br />Protein binding – 94 %<br />
  135. 135. Sibutramine<br />Time to peak concentration – 1-2 Hrs.<br />Metabolism – Hepatic enzymes, Cytochrome 3A4 to active metabolites M1 and M2<br />Excretion – Urine ( 77 % )<br />Half Life– M1 – 14 hrs, M2 – 16 hrs<br />
  136. 136. Sibutramine<br />Dose – 10 to 15 once daily.<br />FDA Approval – for adults and adolescents.<br />Side Effects – hypertension ( DBP increases by 2 to 3 mm ) and tachycardia ( 3/ min), sweating, dizziness and headache.<br />Contraindications – coronary artery disease, cardiac arrythmias, uncontrolled HT<br />Effects – 20 % decrease in calorie intake.<br />
  137. 137. Sibutramine<br />Advantages<br />It causes sympathetic stimulation and thereby. prevent decrease in BMR.<br />There is improvement in FBS.<br />Decrease in TG and cholesterol.<br />About 7 % wt loss.<br />
  138. 138. Orlistat<br />Mechanism of action – non systemic reversible inhibitor of gastric and pancreatic lipases by forming a covalent bond with serine residue<br />Site of action - stomach and intestine<br />Absorption – minimal<br />Protein binding – > 99 %<br />
  139. 139. Orlistat<br />Time to peak concentration – 8 Hrs.<br />Metabolism – In GI Tract to inactive metabolites.<br />Excretion – Faeces ( 97 % ). 83 % is unchanged.<br />Half Life – 14 – 19 hrs.<br />
  140. 140. Orlistat<br />Dose – 120 mg BD or TID with meals<br />FDA Approval – for adults and adolescents as well as children.<br />Side Effects – flatulence, defecation increases, oily evacuation, rectal leakage, steatorrhoea.<br />Contraindications – cholestasis, hypersensitivity, pregnancy, nursing mothers,<br />
  141. 141. Orlistat<br />Precautions – <br />Patient should take 3 main meals into which dietary constituents are equally divided.<br />Multivitamins are to be added<br />High fat diet should be avoided as it will lead to fatty large stools.<br />Overdose – it is safe as significant overdoses are seen without any harmful effects.<br />Pellets – pelletized formulations increasing surface area of the drugs are also available.<br />
  142. 142. Orlistat<br />Advantages – <br /> Weight loss observed within 2 weeks of starting therapy<br />6 kg weight loss in a year<br />Decrease LDL cholesterol, and raises HDL cholesterol.<br />Reduces Systolic and Diastolic blood pressure.<br />Reduces waist and hip circumferance<br />Weight regain is also less significant. <br />
  143. 143. Rimonabant<br />Mechanism of action – Endocannabinoid (CB1) receptor blocker.<br />Site of action – CNS<br />Absorption – not known<br />Plasma protein binding – 99.9 %<br />Time to peak concentration – 2 hrs<br />
  144. 144. Rimonabant<br />Metabolism – hepatic enzymes<br />Excretion – fecal via biliary route<br />FDA approval – BANNED<br />Side effects – depression, anxiety, suicidal tendencies.<br />
  145. 145. Metformin<br />Decreases appetite and thereby reduces weight<br />Since most DM II patients are Obese this is a good choice in DM II.<br />
  146. 146. Olestra<br />Normal fats consist of a glycerol molecule with three fatty acid tails attached.<br />Olestra is synthesized using a sucrose molecule, which can support from six to eight fatty acid chains arranged radially like an octopus<br />Too large to move through the intestinal wall and be absorbed.<br />Same taste and mouth feel as fat<br />Approval as a food additive upto 35% replacement of fats in home cooking and 75% in commercial uses.<br />
  147. 147. Olestra<br />Decline in blood cholesterol levels<br />Failed to demonstrate the 15% reduction required by the FDA to be approved as a treatment<br />Side effects-<br />abdominal cramping<br />loose stools.<br />Vitamins A, D, E, and K deficiency<br />anal leakage<br />increase in bowel movement frequency<br />
  148. 148. Amylinpramlintide (brand name Symlin)<br />Part of the endocrine pancreas and contributes to glycemic control<br />Functions as a synergistic partner to insulin<br />It is cosecreted from pancreatic beta cells in response to meals<br />Reduction of food intake, slowing of gastric emptying, inhibition of digestive secretion<br />It was recently approved for adult use in patients with both diabetes mellitus type 1 and diabetes mellitus type 2<br />Insulin and pramlintide, injected separately but both before a meal,<br />
  149. 149. Tesofensine<br />Tesofensine (TE) is a norepinephrine, dopamine, and serotonin reuptake inhibitor<br />Originally researched for the treatment of Alzheimer's disease and Parkinson's Disease<br />Primarily as an Appetite suppressant<br />Positive effects on fat oxidation and resting energy expenditure<br />Weight loss of approximately 4% for >14 weeks without any diet and lifestyle therapy<br />Final stage trials are scheduled to begin in early 2009 in which the 0.5mg dose will be tested.<br />
  150. 150. Tesofensine<br />Dry mouth<br />Insomnia<br />Tachycardia<br />Constipation<br />Nausea<br />Diarrhoea<br />high blood pressure<br />
  151. 151. Betahistine<br />Blocking the brain's histamine-1 receptor causes weight gain<br />Stimulating the histamine-1 receptor appears to reduce the craving not only for food in general but for fatty foods in particular<br />Participants lost up to 12 percent of their body weight<br />No side effects<br />Not approved by FDA.<br />
  152. 152. Melanocortin-4 Receptor Agonist <br />Suppresses food intake when administered to db/db mice that lack functional leptin receptors<br />Peptide 1 (BL3020–1), was selected according to its selectivity in activating the MC4R, its favorable transcellular penetration through enterocytes and its enhanced intestinal metabolic stability<br />once daily oral dosing (0.5 mg/kg/day) for 12 days reduced weight gain.<br />
  153. 153. NPY receptor antagonist (1229U91 )<br />reduced spontaneous food intake<br />suppressed water intake<br />no abnormal change in general behavior <br />suppressed spontaneous food intake in lean rats also<br />doses of 10 and30 µg<br />
  154. 154. Beta(3) adrenergic agonists<br />Amibegron<br />Solabegron<br />Enhancement of lipolysis in adipose tissue<br />
  155. 155. Glucagon-like peptide-1 agonists (Boc5)<br />(GLP)-1 is produced by the intestine<br />stimulates insulin secretion <br />Boc5 one of the first non-peptidic agonists at glucagon-like peptide-1<br />dose-dependently inhibited food intake <br />
  156. 156. Bariatric surgical techniques<br />Divided into two groups<br />Malabsorptiveprocedures - Induce decreased absorption of nutrientsby shortening the functional length of the small intestine<br />Restrictive procedures - Reduce the storage capacity of the stomachand as a result early satiety arises, leading to a decreasedcaloric intake <br />
  157. 157. Bariatric surgical techniques<br />Indications -<br />BMI greater than 40, or 100 pounds overweight <br />BMI 35-39.9 and a life-threatening condition, such as heart disease or diabetes.<br />BMI 35-39.9 and severe physical limitations that affect employment, mobility, and family life<br />
  158. 158. Malabsorptiveprocedures<br />Jejunoileal bypass<br />Biliopancreatic diversion<br />Biliopancreatic diversion with duodenal switch<br />
  159. 159. The jejunoileal bypass<br />One of the first bariatric operations<br /> It is associated withsubstantial long-term complications -<br />liver failure<br />Malnutrition<br />electrolyte imbalances<br />vitamin deficiencies<br />renal (oxalate) stones<br />Death<br />This procedure is thereforeno longer performed<br />
  160. 160. Biliopancreatic diversion<br />A partial gastrectomy is performed, creating a 100–150ml gastric pouch<br />gastro-jejunostomyor gastro-ileostomy<br />long (food) limb is anastomosed tothe biliopancreatic (bile,pancreaticjuice) limb <br />
  161. 161. Biliopancreatic diversion with duodenal switch<br />A pylorus-sparing sleeve gastrectomy with duodeno-ileostomyis performed <br />less cases of dumpingand marginal ulcers than a classical biliopancreatic diversion<br />
  162. 162. Restrictive procedures<br />Vertical banded gastroplasty<br />Laparoscopic adjustable gastric band<br />
  163. 163. Restrictive procedures<br />simpler to perform<br />less procedural complications<br />Represent the currentmost frequently performed restrictive procedures<br />Two approaches –<br />Open<br />Laparoscopic<br />
  164. 164. Complications<br />Vomiting <br />Leak into the abdomen <br />Slipping or wearing away of the band <br />Enlargement of the pouch <br />Reflux esophagitis<br />Vitamin deficiencies <br />Wound infection <br />Bleeding <br />Abdominal hernia <br />Gallstones <br />Heart and lung problems <br />Phlebitis, embolism <br />Complications of general anesthesia <br />Death, occurs in less than 1% of patients<br />
  165. 165. Combined procedure<br />Roux-en-Y gastric bypass<br />It is (atleast in the United States) the most frequently performed bariatricprocedure<br />Both restrictive and malabsorptive aspects<br />A (restrictive) gastric pouch is created andseparated from the remainder of the stomach.<br /> The continuityis then restored by a Roux-Y-limb, which is connected to thejejunum <br />
  166. 166. Success of Bariatric Procedures<br /> 20–40 kg of weight loss<br />10–15kg/m2 reduction in BMI<br />
  167. 167. THANK YOU <br />

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