obesity final

DEFINITIONLatin word “OBESUS” meaning stout, fat, plump.It is defined as a state of excess adipose tissue.BMI ≥ 30

Obesity Vs OverweightOverweight – Fat Fluid Muscle mass Bone TumoursObesity – Fat ( adipose tissue )

epidemiology>1.6 billion overweight of which 400 million are obeseWomen > menMore common even in poor

Regulation of appetiteAppetite – lateral hypothalamusSatiety – ventromedial hypothalamusDestruction of LHA leads to starvation and death.Destruction of VMA leads to obesity.

Other centres in regulation of appetite :Arcuate Nuclei- primary site for action of leptin and insulin.Para Ventricular Nuclei- AMP kinase mediated appetite regulationDorsomedial Hypothalamic Nuclei- destruction leads to hyperphagia and obesity

Neurohumoral factors in ObesityAdipokines– Leptin, Resistin, Adiponectin, Retinol binding Protein 4, VisfatinPancreatic hormones – Insulin, Pancreatic Polypeptide (PP/PYY/NPY)Gut Hormones - Incretins

LeptinLeptin acts on receptors in the hypothalamus of the brain where it: counteracts the effects of neuropeptide Y (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus); counteracts the effects of anandamide (another potent feeding stimulant that binds to the same receptors as THC, the active ingredient of marijuana) promotes the synthesis of α-MSH, an appetite suppressant; RESULT- inhibition of food intake.

LeptinIncrease leptinIncreased POMCPC 1Increased alpha-MSHIncreased Melanocortin receptor signalDecreased Appetite

LeptinThis inhibition is long-term, in contrast to Cholecystokinin(CCK)- the rapid inhibition

PPY- the slower suppression of hunger between meals Leptin also acts on hypothalamic neurons responsible for :the secretion of gonadotropin-releasing hormone (GnRH).

stimulating the sympathetic nervous system to modulate the balance between the formation and breakdown of bone. LeptinIn addition to its effect on the hypothalamus, leptin acts directly on: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). T cells where it enhances the production of Th1 cells promoting inflammation.

ResistinIn humans, Resistin is primarily a product of macrophages, not fat cells. Resistin causes insulin resistanceThere is a strong association in humans between elevated levels of Resistin, Obesity, and Type 2 diabetes over 80% of the people with NIDDM are obese

AdiponectinIts circulating levels are 1000 fold higher than leptin or insulin.It plays a role in increasing energy expenditure and decreasing body weight also increases insulin sensitivityThiazolidinediones increase this hormone via PPAR-gammaIts level are increased after starvation.

Retinol binding protein 4When it is secreted in elevated amounts by fat cells, it :Suppresses glucose uptake by skeletal muscle; Enhances glucose release by the liver. These actions counteract those of insulin. Elevated levels of RBP4 occur in humans with Type 2 diabetes mellitus.

VisfatinProduced by visceral fatIncrease in response to fatty dietRole in adipose differentiation

Pancreatic HormonesPlasma PP are inversely co related with adipocityPatients with PraderWilli have decrease amount of PP

Gut Hormones PYY- Secreted from L cells of GI tract Reduces food intake Ghrelin-mainly secreted from stomachA potent OrexigenicCholecystokininMainly secreted in duodenum Decreasing meal size and duration both.

Adipose tissueTnf alphaIL 6PAI 1Impaired signal transduction of insulinDecrease NO mediated vaso dilatationDecrease GLUT 4atherosclerosisINSULIN RESISTANCEImpaired insulin signalling

Etiology of obesityA heterogeneous group of disordersComplexity of neuroendocrine and metabolic syndromes regulate energy intake, storage and expenditure.Obesity is caused by imbalance between energy intake and expenditure.Obesity runs in familiesInheritance is not mendelian.

Etiology of obesity- twin studiesIdentical twins have similar BMIsHigh concordance between monozygotic twins compared to dizygotic twins correlations did not differ significantly between twins reared apart and twins reared together

Etiology of obesity- adoption studiesStrong relationship between the BMI of adoptees and biological parents.

PLEIOTROPIC OBESITY SYNDROMESAutosomal dominantUlnar Mammary Syndrome: 12q24 Other features- Ulnar defects, delayed puberty, hypoplastic nipples.

PLEIOTROPIC OBESITY SYNDROMESAutosomal RecessiveAlstrom syndrome : 2p13 Other features-. Retinal dystrophy, neurosensory deafness, diabetes Cohen syndrome : 8q22 Other features- Prominent central incisors, opthalmopathy, microcephaly

PLEIOTROPIC OBESITY SYNDROMESAutosomal RecessiveCarpenter syndrome : (Acrocephalopolysyndactyly)Other features- acrocephaly, polydactyly, genuvalgum, secondary hypogonadism.Laurence Moon Biedl syndrome:Other features-short stature with primary hypogonadism and onset at 1 – 2 years

PLEIOTROPIC OBESITY SYNDROMESX linked Borjeson-Forssman-Lehmann syndrome : Xq26Other features- Mental retardation, hypogonadism, large ears Mehmo syndrome : Xp22Other features- Mental retardation, epilepsy, hypogonadism, microcephaly

PLEIOTROPIC OBESITY SYNDROMESX linkedSimpson-Golabi-Behmel - type 2 : Xp22 Other features- Craniofacial defects, skeletal and visceral abnormalities Wilson-Turner syndrome : Xp21Other features- Mental retardation, tapering fingers, gynaecomastia

PraderWilli SyndromeMost common syndromal cause of human obesity Prevalence of about 1 in 25,000uniparental maternal disomy(15q11.2-q12 )Caused by deletion or disruption of a paternally imprinted gene on the proximal long arm of chromosome 15.Characterized by diminished foetal activity, obesity, hypotonia, mental retardation, short stature, hypogonadotropichypogonadism, and small hands and feet Hyperphagia is a dominant feature in PWS

PraderWilli Syndromediminished growthreduced muscle mass (lean body mass) increased fat mass - body compositionhypogonadotrophichypogonadismFasting plasma ghrelin levels are 4.5-fold higher in PWS subjects

Albright hereditary osteodystrophyAHO is an autosomal dominant disorder Germline mutations in GNAS1Decrease expression/function of G alpha s protein.short stature, obesity, skeletal defects, and impaired olfaction.

Fragile X syndromeextreme obesity (no hypotonia = pws)a full, round facesmall, broad hands and feetregional skin hyperpigmentationsevere mental retardationmacro-orchidismlarge earsprominent jawand high-pitched jocular speech

BardetBiedl SyndromeAutosomal Recessive diseaseObesityMental retardationDysphormic extremities (syndactyly, brachydactyly or polydactyly)Retinal dystrophy or pigmentary retinopathyHypogonadism or hypogenitalism (limited to male patients)Structural abnormalities of the kidney or functional renal impairment.

MONOGENIC HUMAN OBESITYIn the past five years several human disorders of energy balance that arise from genetic defects have been described.Mutations all result in morbid obesity in childhood without the developmental pleiotropic features characteristic of the recognised syndromes of childhood obesity.

Increase leptinleptin receptorIncreased POMCDecreased AgRPPC 1Increased alpha-MSHIncreased Melanocortin receptor signalDecreased Appetite

Congenital leptin deficiencyThe first monogenic human obesity syndrome.Homozygous for a frameshift mutation in the ob gene (ob/ob)Hyperphagic-constantly demanding foodAn intense drive to eat-never satisfied.They developed severe disabling obesity (an 8yr old girl weighing 86kg and a 2yr old boy weighing 29kg)Advanced skeletal maturationImpaired T cell mediated immunityHypogonadotropichypogonadism

Congenital leptin deficiencyThe 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.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.

Leptin receptor deficiencyconsanguineous familyloss of the leptin receptor results in a more diverse phenotype than loss of its ligand leptin.normal birthweightexhibited rapid weight gain in the first few months of lifeaggressive behaviour when denied fooddecreased IGF-1 and IGF-BP3 levels hypothalamic hypothyroidism

POMC deficiencyPro-opiomelanocortin (POMC) is produced by hypothalamic neurones of the arcuate nucleuspresented in neonatal life with adrenal crisis due to isolated ACTH deficiencyhyperphagic, developing early-onset obesitypale skin and red hair due to the lack of MSH function

ProhormoneConvertase 1 deficiencychildhood obesityabnormal glucose homeostasisvery low plasma insulinelevated levels of pro insulinhypogonadotropichypogonadismhypocortisolaemiaelevated levels of POMC

Melanocortin 4 Receptor deficiencyMutations in the MC4R appear to be the commonest monogenic cause of obesityincrease in lean body massIncreased bone mineral densityincreased linear growth throughout childhoodhyperphagiasevere hyperinsulinaemia

AgRP deficiencyAgRP antagonizes alpha MSH actionSo deficiency leads to overexpression of MC4R receptor.

Other molecular defectsTUB gene – late onset ObesityFAT gene – obesity by disruption of neuropeptides.

Endocrinal Abnormalities-Cushing syndromeIncreased cortisol productionHypertensionGlucose intoleranceCushingoidfacies

Endocrinal Abnormalities-HypothyroidismUncommon cause of obesityMuch of weight gain is due to MyxedemaRuled out by serum TSH.

Endocrinal Abnormalities-InsulinomaIn order to avoid hypoglycemia patients often eat more leading to weight gain.High insulin promote fat genesis.

Endocrinal Abnormalities-Syndrome XCentral obesityGlucose intoleranceDyslipidemiahypertension

Endocrinal Abnormalities-PCOD2 out 3 criteria for diagnosisMenstruation irregularities due oligo/an ovulation(progesterone level at 21st day of cylcle)Clinical or biochemical evidence of hyperandrogenism.USG s/o ovarian cysts.

Craniopharyngioma-other disorders of HypothalamusTumoursinflammationtraumaGH decreases but Somatomedin is normal.

Viral Etiology ??Virus SMAM-1 – in chicken.Virus Ad-36 found almost exclusively in obese human beingsThe mechanism by which Ad-36 causes obesity is unclear. It can be hypothesized that hypothalamic damage caused by viruses might be a cause.

Measurement Of ObesityBMIWaist hip ratioSkin fold thicknessBiometric impedanceUltrasoundDEXA (Dual Energy XrayAbsorptiometryCT / MRIAir displacement PlethysmographyTotal body electrical conductivityHydrometry (most accurate)

Body Mass Index (BMI)Calculated as Weight(kg)/Height(m^2)Correlation between rise in BMI and Complications.BMI measures individual’s total weight relative to its height.BMI may be high in a vey muscular personFor similar BMIs women have greater fat mass than their male counterpartsSo BMI may be misleading in certain cases

BMI PrimeBMI Prime - A simple modification of the BMI.The ratio of actual BMI to upper limit BMI (currently defined at BMI 25).Individuals can tell, what percentage they deviate from normal.BMI Prime < 0.74 – underweightbetween 0.74 and 0.99 - optimal weight>/=1.00 overweight

Waist To Hip RatioCentral or abdominal obesity is associated with more co morbid conditions.So measuring central obesity is of greater significanceW/H ratio is taken by a simple measure tape in men > 102 cm/90 in women > 88 cm/80

Disease Risk (Relative to Normal Weight and Waist Circumference)

Skin fold thicknessHarpenderscallipers / MRNL callipersIt is measured at biceps/triceps/illiac and interscapular. Total of all four sites is considered15-45 mm – 8-22 % of total body fat46-75 mm – 23-30 % of total body fat76-150 mm – 31-40 % of total body fat151-170 mm – 41-45 % of total body fatUpto 22% it is normal (males)Upto 30% it is normal (females)

Biometric ImpedanceRadio frequency current is introduced in body through electrodesFat has less number of electrolytes Water is less conductive

CT/MRIThey can differentiate subcutaneous from visceral fat and so are important in research purposes.

DEXA (Dual Energy XrayAbsorptiometry)

Air displacement Plethysmography

Total body electrical conductivity

Classification of Obesity (BMI)Underweight- BMI < 18.5Normal weight- BMI between 18.5 to 24.9Overweight- BMI between 25.0 to 29.9Obese grade I- BMI between 30.0 to 34.9Obese grade II- BMI between 35.0 to 39.0Obese grade III ( morbid obese)- BMI ≥ 40

Classification of Obesity (BMI)Starvation Less than 14.9Underweight From 15 to 18.4Normal From 18.5 to 22.9Overweight From 23 to 27.5Obese From 27.6 to 40Morbidly Obese Greater than 40It is used in SINGAPORE.It is to applied in INDIA.

Classification of Obesity (clinical)Stage 0: no apparent obesity-related risk factors Stage 1: presence of obesity-related sub-clinical risk factors, mild physical symptoms.Stage 2: presence of established obesity-related chronic disordersStage 3: established end-organ damage Stage 4: severe (end-stage?) disabilities

Classification of Obesity (FAT)82% lean 18% body fat body massBody fat 25% in men -obeseBody fat 30% in women – obeseThis method is used in JAPAN.

Classification of Obesity (shape)Apples- Android It is characterized by central abdominal obesityIt is clinically more important as disease are more correlated with this abdominal fatPears – GynecoidIt is characterized by accumulation of fat around hip and buttocks.

Co morbidities of ObesityInsulin resistanceType II diabetes mellitusReproductive disordersCardiovascular disordersPulmonary disordersGastrointestinal diseasesRenal diseasesCancersBone, joint and cutaneous diseasesRetinal diseasesPsychological problems

Obesity and Insulin ResistanceMainly associated with Intra abdominal fatMainly muscle and adipose are resistant.Factors that play a role areInsulin FFA  decreased mitochondria  decrease action of insulin.Intracellular lipid accumulationAdipokines (resistin) decreases mRNA expression TNF-alpha, IL-6  inflammatory processReduced activity of Leptin, Adiponectin

Insulin Resistance-complicationsMuscle – hyperglycemia and DM IIKidneys – Salt retention and HypertensionOvaries – Increase testosterone and PCOSHeart – Increase plasminogen activator inhibitor ( PAI 1) and ACSCancers – Colon, Prostrate, BreastSympathetic system – Increase Cytokines and increase Blood Pressure.

Obesity and DiabetesThough patients develop IR not all develop Diabetes.Though it’s a major risk factor for DM.( 85% of type II DM are Obese)If BMI > 35 - 93 times more likely to develop DM.There is direct correlation between BMI and DM.

Obesity and DyslipidaemiaIncrease LDL, TGDecrease HDLAll this is because of decrease activity of Lipoprotein Lipase.10% wt gain  12 mg/dl increase in cholesterol.With treatment there is improvement in dyslipidemias

Obesity and hypertensionIncreased blood volumeIncrease cardiac outputIncrease sympathetic toneIncrease Salt sensitivitySalt retention by insulinIncrease angiotensinogenHYPERTENSION

Obesity and metabolic SyndromeInsulin resistanceobesitydyslipidemiahypertensionDEADLY QUARTETMETABOLIC SYNDROME

Obesity and Gastro Intestinal diseasesEsophagus – GERDStomach – gastroparesis ( DM )Gall stonesNASH NAFLD

Obesity and Reproductive disordersMenPlasma Testosterone and SHBG are reducedIncrease EstrogenGynaecomastia seenSecondary sexual characters preserved.WomenIncreased AndrogenDecrease SHBGPCOSUterine cancer (lower body obesity )Not only fertility but their chances of IVF success reduces

Obesity and atherosclerosisLeptin causes ROS production from monocytesLow Adiponectin reduces protection from monocyte adhesionTNF alpha, IL6, ICAM1 and VCAM1 affect endothelium via Transcription Factor KBPAI1 increased by TF-KBAngiotensinogen increases

Obesity and Cardiovascular diseaseHypertensionDyslipidaemiasEndothelial damageDiabetesOSAW/H ratio may be the best predictorBMI > 29…..3 fold rise in MIObesity is responsible for 17% of all CVDAngina increases by 1.8 timesMI increases by 3.2 and 1.5 fold in woman and men respectively. .Cardi vascular complications

Obesity and LVHIt is eccentric as well concentric hypertrophyCausesHypertension ( eccentric )Increased blood volume  Starling principleThere is fatty infiltration of myocytes

Obesity and CardiomyopathyFat accumulates in cords of cells leadin to a variety of conduction disturbances.All kinds of ARRYTHMIASAF in presence of LVH poorly tolerated.QT prolongation in 10% cases.Fatty infiltration of conducting system.HypercapniaHypoxiaCADSleep Apnoea

Obesity and StrokeAbdominal Obesity is an independent risk factorOthers includeHypertensionDyslipidaemis

Obesity and Pulmonary diseaseSDB – Sleep Disordered Breathing ( AHI )OSAS – Obstructive Sleep Apnoea SyndromeOHS – Obesity Hypoventilation SyndromeAsthma

OSAS – Obstructive Sleep Apnoea Syndrome> 30 episodesApnoea > 10 sec (SDB – Sleep Disordered Breathing )Daytime drowsinessSnoring at nightMemory lossMood swingsCauseREM atoniaIncrease soft tissue infiltration around neckDecreased chest wall complianceDiaphragmatic displacement in supine

OSAS – Obstructive Sleep Apnoea SyndromeComplicationsPulmonary hypertensionRVFHTStrokeArrythmias (flutter,bradycardia)VTCar accidents

OHS – Obesity Hypoventilation SyndromeOld name – PICKWICKIAN SYNDROMEChronic alveolar hypoventilation in Obese with BMI > 30 (PaO2 <70 PaCO2 >45 )CauseHigh work of breathingDysfunction of respiratory centreRepeated nocturnal sleep apnoea

Obesity and AsthmaCauseReduced TLCReduced RV and FRCRelation between obesity and asthma is becauseCommon etiologiesCo morbiditiesAdipokinesMechanical factors

Obesity and Renal diseaseIncrease glomerularremodellingIncrease kidney weight-increased cellular proliferation.This changes in long term lead to glomerular sclerosis and DM nephropathy.

Obesity and CancersObesity is the biggest preventable cause of Cancer after smoking.Accounts for 14% of cancer deaths in Men and 20% in women.

Obesity and Skin diseasesAcanthosisNigricans:Thickening of skin folds of neck, elbows,Dorsal interphalyngeal spacesReflects severity of IRFriability of skin and varicosities.Aggravation of other conditions caused by DMNecrobiosislipoidicaUlcersInfections

Obesity and Orthopaedic DiseaseOsteoarthritisHyperuricemiaGoutAccidental injury- decrased mobility, daytime somnolence

Obesity and retinal diseaseOverweight diabetics are twice more likely to develop retinopathy than non obese.Waist to hip ratio was only second to glycaemic control in its importance in preventing retinopathy.

Obesity and Psychological problemsAre obese people more jolly?NOObesity  psychological problemsPsychological problems  obesity

Obesity and Psychological problems50% overweight lack self confidenceDepressionObesity has more risk of depression in WomenMore physical and sexual abuseLack of attentionLow educationLow self esteem

Management of ObesityIt is a chronic medical conditionDefinition of successful treatment:Attainment of normal weightNo treatment induced morbidityThis is rarely achieved in clinical practice.

DietLow calorie dietLow in saturated fatsNormal protein intakeIncreased fibers in dietLow density foods1000 K cal deficit produces 1 kg wt loss per week

Self LimitingNo matter what the calorie intake is the constituents remain in same proportioni.eCarbohydrates 55%Fat 30%Protein 15%Results in wt loss 2-6 kg over1 year

Fixed Energy DietIntake is limited by controlling portion sizes, menu choice and compositionMinimal self monitoring1200 to 1800 kcalLack of compliance to this rigid pattern

Low Calorie Diet800-1000 KcalApplicable to most of the patientsFewer restrictions than VLCD.Supplementation of vitamins and minerals is requiredOver a year there is reduction of 6 to 7 kgs.

Very Low Calorie Diet400 – 600 calorie diet.Even below one’s basal metabolic rateUsed for period of 1 to 2 months under medical supervision45 to 70 % protein30 to 50 % carbohydrates2g fat Supplemented with vitamins, minerals and trace elementsGreater wt loss compared to restrictive diets

Very Low Calorie DietComplications -fatigue, hair loss, dry skin, dizziness difficulty concentrating, cholelithiasis, pancreatitis, gall stones.Contraindications – pregnancy, cancer, MI, hepatic disease, CV Stroke.

Total FastingNot recommendedThere is diuresis, natriuresisAll deficienciesRe Feeding Syndrome-severe an potentially fatal electrolyte, fluid and metabolic abnormalities when feeding is resumed.

Liquid Protein DietBannedUsed in 1970’sLife threatening Arrythmias.

High Protein DietsHigh proteinIncrease ketonesIncrease purines and ureadiuresisGoutWight loss

Fat IntakeDecreased fat intake without decreased calories is of no useBecause if fat is replaced by carbohydrates there is rise in triglycerides.Instead saturated fats should be replaced by MUFA or PUFA

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

PharmacotherapyIndications -BMI > 30BMI > 27 with risk factors like HT, DM, CHD, Sleep Apnoea, Dyslipidemia.

PharmacotherapyPhenteraminePhenylpropanolamineFenfluramineFen-phenSibutramineOrlistatRibonabantMetforminOlestraLeptin

PharmacotherapyTesofensineBetahistineAmylin Melanocortin-4 receptor agonistNeuropeptide Y antagonists Beta(3) adrenergic agonistsGlucagon-like peptide-1 agonists.

AmphetamineDextro amphetamine was used as anti obesity drugTachycardia, HT, Abuse potential

PhenteramineAmphetamine like drugAct centrally to reduce appetiteLow addictive potentialModest efficacyCVS side effects

FenfluramineInhibit serotonin uptakeModest efficacy as single agent

Fen PhenCombination fenfluramine and phenterminedrugs exerted independent actions on brain satiety mechanismsPrimary Pulmonary hypertension increases 20 fold in this patients.Drug was withdrawn in 1997.

SibutramineOriginally an anti depressantMechanism of action –Mono amine reuptake inhibitor ( primarily serotonin and norepinephrine )Site of action - Central nervous systemAbsorption – 77 %Protein binding – 94 %

SibutramineTime to peak concentration – 1-2 Hrs.Metabolism – Hepatic enzymes, Cytochrome 3A4 to active metabolites M1 and M2Excretion – Urine ( 77 % )Half Life– M1 – 14 hrs, M2 – 16 hrs

SibutramineDose – 10 to 15 once daily.FDA Approval – for adults and adolescents.Side Effects – hypertension ( DBP increases by 2 to 3 mm ) and tachycardia ( 3/ min), sweating, dizziness and headache.Contraindications – coronary artery disease, cardiac arrythmias, uncontrolled HTEffects – 20 % decrease in calorie intake.

SibutramineAdvantagesIt causes sympathetic stimulation and thereby. prevent decrease in BMR.There is improvement in FBS.Decrease in TG and cholesterol.About 7 % wt loss.

OrlistatMechanism of action – non systemic reversible inhibitor of gastric and pancreatic lipases by forming a covalent bond with serine residueSite of action - stomach and intestineAbsorption – minimalProtein binding – > 99 %

OrlistatTime to peak concentration – 8 Hrs.Metabolism – In GI Tract to inactive metabolites.Excretion – Faeces ( 97 % ). 83 % is unchanged.Half Life – 14 – 19 hrs.

OrlistatDose – 120 mg BD or TID with mealsFDA Approval – for adults and adolescents as well as children.Side Effects – flatulence, defecation increases, oily evacuation, rectal leakage, steatorrhoea.Contraindications – cholestasis, hypersensitivity, pregnancy, nursing mothers,

OrlistatPrecautions – Patient should take 3 main meals into which dietary constituents are equally divided.Multivitamins are to be addedHigh fat diet should be avoided as it will lead to fatty large stools.Overdose – it is safe as significant overdoses are seen without any harmful effects.Pellets – pelletized formulations increasing surface area of the drugs are also available.

OrlistatAdvantages – Weight loss observed within 2 weeks of starting therapy6 kg weight loss in a yearDecrease LDL cholesterol, and raises HDL cholesterol.Reduces Systolic and Diastolic blood pressure.Reduces waist and hip circumferanceWeight regain is also less significant.

RimonabantMechanism of action – Endocannabinoid (CB1) receptor blocker.Site of action – CNSAbsorption – not knownPlasma protein binding – 99.9 %Time to peak concentration – 2 hrs

RimonabantMetabolism – hepatic enzymesExcretion – fecal via biliary routeFDA approval – BANNEDSide effects – depression, anxiety, suicidal tendencies.

MetforminDecreases appetite and thereby reduces weightSince most DM II patients are Obese this is a good choice in DM II.

OlestraNormal fats consist of a glycerol molecule with three fatty acid tails attached.Olestra is synthesized using a sucrose molecule, which can support from six to eight fatty acid chains arranged radially like an octopusToo large to move through the intestinal wall and be absorbed.Same taste and mouth feel as fatApproval as a food additive upto 35% replacement of fats in home cooking and 75% in commercial uses.

OlestraDecline in blood cholesterol levelsFailed to demonstrate the 15% reduction required by the FDA to be approved as a treatmentSide effects-abdominal crampingloose stools.Vitamins A, D, E, and K deficiencyanal leakageincrease in bowel movement frequency

Amylinpramlintide (brand name Symlin)Part of the endocrine pancreas and contributes to glycemic controlFunctions as a synergistic partner to insulinIt is cosecreted from pancreatic beta cells in response to mealsReduction of food intake, slowing of gastric emptying, inhibition of digestive secretionIt was recently approved for adult use in patients with both diabetes mellitus type 1 and diabetes mellitus type 2Insulin and pramlintide, injected separately but both before a meal,

TesofensineTesofensine (TE) is a norepinephrine, dopamine, and serotonin reuptake inhibitorOriginally researched for the treatment of Alzheimer's disease and Parkinson's DiseasePrimarily as an Appetite suppressantPositive effects on fat oxidation and resting energy expenditureWeight loss of approximately 4% for >14 weeks without any diet and lifestyle therapyFinal stage trials are scheduled to begin in early 2009 in which the 0.5mg dose will be tested.

TesofensineDry mouthInsomniaTachycardiaConstipationNauseaDiarrhoeahigh blood pressure

BetahistineBlocking the brain's histamine-1 receptor causes weight gainStimulating the histamine-1 receptor appears to reduce the craving not only for food in general but for fatty foods in particularParticipants lost up to 12 percent of their body weightNo side effectsNot approved by FDA.

Melanocortin-4 Receptor Agonist Suppresses food intake when administered to db/db mice that lack functional leptin receptorsPeptide 1 (BL3020–1), was selected according to its selectivity in activating the MC4R, its favorable transcellular penetration through enterocytes and its enhanced intestinal metabolic stabilityonce daily oral dosing (0.5 mg/kg/day) for 12 days reduced weight gain.

NPY receptor antagonist (1229U91 )reduced spontaneous food intakesuppressed water intakeno abnormal change in general behavior suppressed spontaneous food intake in lean rats alsodoses of 10 and30 µg

Beta(3) adrenergic agonistsAmibegronSolabegronEnhancement of lipolysis in adipose tissue

Glucagon-like peptide-1 agonists (Boc5)(GLP)-1 is produced by the intestinestimulates insulin secretion Boc5 one of the first non-peptidic agonists at glucagon-like peptide-1dose-dependently inhibited food intake

Bariatric surgical techniquesDivided into two groupsMalabsorptiveprocedures - Induce decreased absorption of nutrientsby shortening the functional length of the small intestineRestrictive procedures - Reduce the storage capacity of the stomachand as a result early satiety arises, leading to a decreasedcaloric intake

Bariatric surgical techniquesIndications -BMI greater than 40, or 100 pounds overweight BMI 35-39.9 and a life-threatening condition, such as heart disease or diabetes.BMI 35-39.9 and severe physical limitations that affect employment, mobility, and family life

MalabsorptiveproceduresJejunoileal bypassBiliopancreatic diversionBiliopancreatic diversion with duodenal switch

The jejunoileal bypassOne of the first bariatric operations It is associated withsubstantial long-term complications -liver failureMalnutritionelectrolyte imbalancesvitamin deficienciesrenal (oxalate) stonesDeathThis procedure is thereforeno longer performed

Biliopancreatic diversionA partial gastrectomy is performed, creating a 100–150ml gastric pouchgastro-jejunostomyor gastro-ileostomylong (food) limb is anastomosed tothe biliopancreatic (bile,pancreaticjuice) limb

Biliopancreatic diversion with duodenal switchA pylorus-sparing sleeve gastrectomy with duodeno-ileostomyis performed less cases of dumpingand marginal ulcers than a classical biliopancreatic diversion

Restrictive proceduresVertical banded gastroplastyLaparoscopic adjustable gastric band

Restrictive proceduressimpler to performless procedural complicationsRepresent the currentmost frequently performed restrictive proceduresTwo approaches –OpenLaparoscopic

ComplicationsVomiting Leak into the abdomen Slipping or wearing away of the band Enlargement of the pouch Reflux esophagitisVitamin deficiencies Wound infection Bleeding Abdominal hernia Gallstones Heart and lung problems Phlebitis, embolism Complications of general anesthesia Death, occurs in less than 1% of patients

Combined procedureRoux-en-Y gastric bypassIt is (atleast in the United States) the most frequently performed bariatricprocedureBoth restrictive and malabsorptive aspectsA (restrictive) gastric pouch is created andseparated from the remainder of the stomach. The continuityis then restored by a Roux-Y-limb, which is connected to thejejunum

Success of Bariatric Procedures 20–40 kg of weight loss10–15kg/m2 reduction in BMI

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