Obesity Pathology

More than 66% of U.S. adults are categorized as overweight or obese, and the prevalence of obesity is increasing rapidly in most of the industrialized world.
Children and adolescents also are becoming more obese, indicating that the current trends will accelerate over time.
Obesity is associated with an increased risk of multiple health problems, including hypertension, type 2 diabetes, dyslipidemia, obstructive sleep apnea, nonalcoholic fatty liver disease, degenerative joint disease, and some malignancies.
Thus, it is important for physicians to identify, evaluate, and treat patients for obesity and associated comorbid conditions.

1. Obesity Dr Pranav N Shirbhate

2. Obesity Definition Classification Epidemiology Etiology Pathophysiology General Consequences/ complications Role of obesity in cancer Management of obesity

3. Introduction More than 66% of U.S. adults are categorized as overweight or obese, and the prevalence of obesity is increasing rapidly in most of the industrialized world. Children and adolescents also are becoming more obese, indicating that the current trends will accelerate over time . Obesity is associated with an increased risk of multiple health problems , including hypertension, type 2 diabetes, dyslipidemia, obstructive sleep apnea, nonalcoholic fatty liver disease, degenerative joint disease, and some malignancies. Thus , it is important for physicians to identify, evaluate, and treat patients for obesity and associated comorbid conditions.

4. Def ini t ion : O b e s i t y is a stat e o f e xce s s a dip o s e t i ss ue m ass . 2 2) Obesity is a disease of caloric imbalance that results from an excess intake of calories that exceeds their consumption by the body. 1  T h e W HO de f inition is:  a BMI grea t er t h a n or e q u a l to 25 is o ver w eight  a BMI grea t er t h a n or e q u a l to 30 is o b es it y .

5. BMI / Quetlet index  it is a c lassification of we i ght status NOT b y mere  it is emphasized here that, m us c ularity & he i ght also affect weight . weight  So, BMI or Quetlet index u sed to C lassify obesity  Body Mass Index (BMI)  Most wide l y us e d BMI= W eig h t(kg) Height(mt r ) 2

6. BMI/ Quetelet index This index is a classification of weight status and not merely weight. It is emphasized here that, Muscularity and height also affect weight. Most widely used used Body mass Index/ Quetelet index is calculated as- BMI= W eig h t(kg) Height(mt r ) 2

7.  V alues of BMI are a g e independe n t & same for b o th  At sim i lar BMI, fat c o ntent i n women > m en  BMI 30 is threshold for obe s it y . se x es.  BMI 2 5 - 3 medically significant & req u ires inte r v e ntion • Mo r bidity and mortal i ty incr e ase with BMI simila r ly for men and women • Risk at a given B MI c an v ary between po p ulations.

8. Oth e r I n dices  Bro c a ’ s index = H e i g ht ( cms ) – 100  Cor p ul a nce index = Ac t u a l w e i g ht / D esi r a b le  P onde r al index = Height ( cms ) W e i g ht (Should not exceed 1.2 for normal) Cu b e ro o t of b ody weight ( kg )  Lorent z ’ s f o rmula = ( H e ight ( cms ) – 1 ) - H e ight ( cms ) – 150 2( w omen) or 4( m en)

9. Other methods  W aist hip r at i o - > .9 for w omen is obese - > 1 for m e n is obese  Anthropometry ( skin fo l d thic k n e ss  Ha r penden skin c aliper to measure skin fold thickness in lumber area  < 40 mm in males, < 50 mm in females )  D e nsitometry ( u n d er w a ter w e i ghi n g )  CT Sc a n, MRI, Ele c tric imp e d a n c e

10. Prevalence Obesity is perhaps the most prevalent form of malnutrition . As a chronic disease, prevalent in both developed and developing countries, and affecting children as well as adults, it is now so common that it is replacing the more traditional public health concerns including undernutrition . It is one of the most significant contributors to ill health. For industrialized countries, it has been suggested that such increase in body weight have been caused primarily by reduced levels of physical activity, rather than by changes in food intake or by other factors. It is extremely difficult to assess the size of the problem and compare the prevalence rates in different countries as no exact figures are available. 3

11. Prevalence Obesity is a major public health problem in developed countries and an emerging health problem in developing nations , such as India. Globally, the World Health Organization estimated that by 2015, 700 million adults would be obese. In India, the non-communicable risk factor survey phase 2 was carried out in the year 2007-2008, in the states of Andhra Pradesh, Kerala, Madhya Pradesh, Maharashtra, Tamil Nadu, Uttarakhand and Mizoram. The survey shows high prevalence of overweight in all age groups except in 15-24 years group. Overweight prevalence was higher among females than males and in urban areas than in rural areas.

12. Prevalence Low prevalence was recorded among lower level of education (ill-literate and primary level), and in people whose occupation was connected with agriculture or manual work. 3 In India, 1.3 per cent males and 2.5 per cent females aged more than 20 years were obese in the year 2008. Compared to U.S. where 66% of adults are categorized in overweight and obese in 2014, it is also expected that Indian data too raise a lot. 3

13. A n d r o i d =Ab d o m in a l=C e nt r al= A pp le sh ap ed G ynec o i d = P eripheral= P ear sh ap ed Types of Obesity

14. Obesity can be due to ad i p o c y te h y pertro p hy a n d/or h y per p l as i a…

15. What causes obesity? Lack of energy balance. Genes and family history. Endocrine: Hypothyroidism, Cushing’s Syndrome, and PCOD. Drugs : Corticosteroids, antidepressants and seizure medications. Emotional factors. Alcoholism. Smoking cessation.

16. What causes obesity? Pregnancy. Lack of sleep. An inactive lifestyle. Lack of access to healthy foods. Lack of neighborhood sidewalks and safe places for recreation.

17. What causes obesity? Even though genetic influences play an important role in weight control, but obesity is a disease that depends on the interaction between multiple factors. After all, regardless of genetic makeup, obesity would not occur without intake of food.

18. Control of Appetite

19. En e rgy bala n ce 3 c o mponents 1 . Af f e r ent/pe r ipheral system - Generates sig n als f r om va r ious sites - Comp o sed of L eptin , A diponectin - by F at c e lls, G hrelin f r om S toma c h, P eptide YY ( PYY ) f r om I leum, C o lon, I n sul i n f r om P a n c r eas

20.  2.Arcuate nucleus in hyp o thalamus  - P rocesses & inte g rates neuro h umoral peri p heral  - Generates efferent sign a ls  - Comp o sed of 2 su b sets of first or d er neuro n s  1 . POMC ( p ro - o p io m e l an o c or t i n ) & C A R T ( c o caine amp h etamin e - regula t e d transcripts ) neuro n s sign a ls  2 . Neuron containing Neurope p tide Y & Ag R P (a g ou t i - rela t ed pe p tid e ) T h ese f irst or d er ne u ro n s c o mm u nica t e with sec o nd or d er neuro n s in hypothalamus

21.  3 . Ef f e r ent system  Car r ies signals f r om se c ond o rd e r neur o ns of hy p othalamus to c o ntrol fo o d i n take and ene r gy expenditure

22. Neurohumoral circuits in Hypothalamus POMC/CART neurons enhance energy expenditure and weight loss through the production of the anorexigenic α- melanocyte-stimulating hormone (MSH), and the activation of the melanocortin receptors 3 and 4 (MC3/4R) in second-order neurons. These second order neurons are in turn responsible for producing factors such as thyroid releasing hormone (TSH) and corticotropin releasing hormone (CRH) that increase the BMR and catabolic metabolism, thus favoring weight loss. By contrast, the NeuropeptideY / AgRP neurons promote food intake ( orexigenic effect) and weight gain, through the activation of Y1/5 receptors in secondary neurons. These secondary neurons then release factors such as melanin-concentrating hormone (MCH) and orexin , which stimulate appetite.

23. Vagal Afferent ie . Neuronal Signa l s Vagal efferent are stimulated by the nutrient and stretch receptors from stomach after food intake. These signal goes to Nucleus tractus solitaries in hind brain and accordingly decreases feeding, causes gastric emptying and increase metabolic rate.

24. Humoral components in detail Adipocytes Leptine Adiponectine Cytokines (TNF, IL 6, IL 1, IL 18, chemokine, steroid hormones) Ghrelin –From stomach and arcuate nucleus of Hypothalamus Peptide YY – from ileum and Colon. Pancreatic Polypeptide , Insulin and Amylin.

25. Is a 16kD hormone produced by adipocytes P roduct of " o b " gene P r o vides sign a l for “energy suffi c ien c y”. Abundant fat  L e p t in secreti o n R egula t ed by insulin stimula t ed glu c ose me t abolism It is absent in mice (so they eat voraciously) Le p tin h as OB-R receptor (type 1 CK-R family)   N P Y / A g RP neur o ns  + POM C / C A R T N eur o ns  A no r exic neur o p e ptid es - (M S H)  Not to produce o re x iner g ic neur o p e p tid e s It stimulates thermogen e sis , ac t ivi t y , ene rgy e x pendi t ure - Increase energy expenditure Not to take food

26.  MC 4 R ( Melanoc o rtin r e c e ptor 4 (on 2 nd order neuron activated by MSH) ) mutation s are more f r equent , cause of 5 % massive ob e sity  No sensing of satiety ( anorex i ner g ic) si g nal generated  Patient b ehave s as if undernouris h ed , eat voraciously  In suffici e ncy of B rai n - deri v ed ne u r o tr o ph i c fact o r ( BDN F ) – (a c o mponent of MC 4 R do w ns t r e am signaling in hypothalamus ) A/w ob e sity in W AGR sy n dr o me

27. Ad i pone c t i n P roduced mainly by adipocytes le v els are low obesity , more in lean. Stimulat e s fa t ty a c id oxidation So it is also called as “Fa t - burning molec u le” “Guard i an angel aga i nst obesity”      Ad i poR 1 (in skeletal mu s cle ) , Ad i poR2 ( in live r , bra i n ) + cAMP acti v ated pr o tein kinase Inactivates acetyl c o enzyme A carbo x ylase ( K ey enzyme in Fatty acid synthesis ) - No obesity It reduces fatty acid influx in liver, and gluconeogenesis from liver  It p rote c ts against Me t abolic S yndr o me , by increasing insulin sensitivity 

28.  Adipocytes also produce TN F , I L-6, I L - 1, I L - 18, c hemokine , Steroi d s l eading to Chro n ic sub - clini c al /pro- infl a mma t ory sta t e (^ CRP ) So these are acted upon by macrophages and accordingly macrophages are considered to be regulating adipocyte function.  This shows that adipocytes acts as link b e t ween lipid metab o lism, nu t ritio n , inflammati o n .

29.  These are s ho r t te r m m e al init i ato r s and ter m i n atop r s  G h r e li n ( stoma c h, ar c uate n u cl e us ) - only o r exenergic gut hormone  It s ti m ulates N P Y / AgRP neur o ns of hypothalamus and Ghrelin acts by binding the growth hormone secretagogue receptor , which is abundant in the hypothalamus and the pituitary.

30.  P eptide YY ( secreted by endocrine cells of ileum, and c o lon)  Level of PYY are found reduced in Prader willi syndrome. These observations have led to ongoing work to produce PYYs for the treatment of obesity.

31.  Amyli n secreted along with insulin by pa n c r eat i c ß c e lls), it reduces food intake and weight gain. Both PYY and amylin act centrally by stimulating POMC/CART neurons and inhibiting NPY/ AgRP in the hypothalamus, causing a decrease in food intake .

32. WHY is it HARD to mai n tain the wei g ht lo s s for th o se who lose after die t ary restriction?

33. WHY is it HARD to mai n tain the wei g ht lo s s for th o se who lose after die t ary restriction? On dieting, adipocytes number never reduces. Adipocyte numbers are tightly controlled and loss of fat mass in an adult person occurs through shrinkage of existing adipocytes . Adipocytes number remain constant.

34. WHY is it HARD to mai n tain the wei g ht lo s s for th o se who lose after die t ary restriction? On dieting, adipocytes number never reduces. Adipocyte numbers are tightly controlled and loss of fat mass in an adult person occurs through shrinkage of existing adipocytes . Adipocytes number remain constant. Adipocyte number is already higher in o b ese.

35. .. SO maintaining and not allowing it to increase in number in childhood is important.

36. Pathogenesis of complications:

37. Type 2 Diabetes Obesity is associated with insulin resistance and hyperinsulinemia , which are the important features of type 2 diabetes, and weight loss is associated with improvements in these abnormalities. 80% type 2 DM are found to be obese. Excess insulin, play a role in the retention of sodium, expansion of blood volume , production of excess norepinephrine, and smooth muscle proliferation that are the hallmarks of hypertension . Regardless of the nature of the pathogenic mechanisms , the risk of developing hypertension among previously normotensive persons increases proportionately with weight.

38. Type 2 Diabetes

39. Type 2 Diabetes

40. Cardio v ascular system Obesity  Obesity is a in dependent r i sk factor for CAD, CHF Insulin R esistance  W ai s t – H i p rat i o P r e dictor for CVS complication be s t ↑ Insulin  Abd o minal as s ociated obesity with ath e rogen i c l i pid  Excess glucose causes retention of sodium- water leading to Hypertension. profi l e ↑ F F A ↑ T riglyceride , HDL

41. ↑ Adipose tis s ue ↑ Leptin H y pothalamu s - ↑ M S H, ↓ A g R P , ↓ NPY Increas e d SNS activity Hyp e rten s i on

42.  Abdo m inal obes i ty (visceral and intra abdominal adipocyte deposition)  Insulin re s istance  H y pe r triglyc e ridem i a  Low s e rum H D L  ↑ ri s k of CAD  Seen more in Indian s , proba b ly due to low levels of adi p onectin Syndrome X or Metabolic syndrome

43. Syndrome X or Metabolic syndrome

44.  In m ale  H y pog o nadism  ↓ Plas m a testo s terone & sex hor m one bind i ng globulin  E str o gen levels ↑  Mas c ulizati o n, lib i do, potenc y , sper m at o ge n esis preser v ed

45.  Females –  Me n strual irre g ularit i e s , oli g o m enorrh e a  ↑ andro g en product i on, ↓ sex hor m one bind i ng globulin  PCOD – ie anovulation , obes i t y , hirsutism

46.  Apnoe i c pauses during s leep  Hypers o m n olen c e at both day  P olycythe m ia & n i ght  Event u ally right sided heart falure Obesity hypoventilation syndrome ( Pickwikian syndrome)

47. Role of Sleep in Obesity

48. Role of Sleep in Obesity

49.  Obesity predisposes to Gall sto n es, Pa n creat i t i s, Abdom i n a l h e rnia, N A F L D  Gall stones  F asting  enhanced mobilization cholesterol from fat depots  ↑ chole s tero l  Enha n ced billiary excretion of chole s terol  Super sa t urated bile  C h oleli t h i a s is  local inflammatory state  risk for GB Cancer  Gall stones are six times more common in obese than in lean subject. GIT

50.  This condition is s trongly as s oc i ated w i th Obes i t y , Dyslip i dem i a, T ype 2 DM .  P resents like – Stea t os i s & Stea t ohepat it is  10 – 20 % develop s to Cirrhos i s and fibrosis

51.  Stroke  Due to ↑ Bl o od pres s ure and also due to pulomonary embolism, particularly in those with decreased mobility.  T ype 2 DM  E levated chole s terol levels  Dep r ession –  Is more commonly due to S l eep di s turbances

52. Bones, Joints, C u taneous disorders  Osteoarthritis and G o ut : results from increased weight-bearing on joints due to increased adiposity and the injurious effects that inflammatory adipokines such as resistin - have on joint synovia and muscle function.  Skin –  Aca n th o sis ni g ran s ,  Friability of skin, enha n cing the risk of fungal and yeast infection

53.  C u sh i ng ‟ s S yn d r o me –  ↑ cor t isol l e ve l s  Pro m ot e s deposi t ion of ad i pose  Upper f a ce – Moon F a c i es  I n ter s c apular area – Bu f felow t i s s ue in p e cu l i a r distr i but i on Hump  Mesenteric bed – T runcal obe s ity  Hypothyrodism –  Wt. gain insp i te of poor appetite  Obesity here is mainly due to flu i d r e tention

54.  Ins u li n oma-  Wt. gain occurs here as a re s ult of over eating by the patient to avoid hypoglycemia s y mpto m s  Craniop h aryngioma –  T um o r a r is i ng from Rathek e ‟ s pouch  P r e ss u re eff e ct on h y pothalamus stimulation anabolic (NPY/ AgRPR ) and reduced catabolic (POMC/CART) - Obesity

55.  Complications in Pregnancy - Obesity is a risk factor for preeclampsia and eclampsia of pregnancy, in which increased adipokines include RAS, prostaglandins, and other fatty-acid derivatives. Adipocytes also secrete these substances, which exacerbates hypertension and fluid retention in this syndrome. Endarteritis within the placenta may also be related to the increased inflammatory adipokines that contribute to preeclampsia.

56.  Both s e xes affect e d equal l y with high mortal i ty rate  In males – Ca. e s ophagus, colon, r e ctum, panc r ea s , l i ver & prost a te  In femal e s – Ca. gall bl a dde r , bile duct , br e ast, endometri u m, ce r vix, ovar i es

57.  How they are re l ated?

58.  How they are re l ated? 1) Elevated insulin levels .

59.  How they are re l ated? 1) Elevated insulin levels . Insulin resistance  hyperinsulinemia  inhibits the production of the IGFBP-1 and IGFBP-2,  rise in levels of free insulin-like growth factor-1 (IGF-1) . (IGF-1 is a mitogen, and its receptor, IGFR-1, is highly expressed in many human cancers.) It binds with high affinity to the IGFR-1 receptor.  Binding activates the RAS and PI3K/AKT pathways , which promote the growth of both normal and neoplastic cells.

60.  How they are re l ated? 2 ) Obesity has effects on steroid hormones that regulate cell growth and differentiation in the breast, uterus, and other tissues. O besity  increased synthesis of estrogen from androgen precursors through an effect of adipose tissue aromatases increases androgen synthesis in ovaries and adrenals, enhances estrogen availability by inhibiting the production of sex-hormone-binding globulin (SHBG) in the liver. .

61. Pathogenesis of Cancer:

62. Manag e ment of obesity  Goal is to re d u c e or p r event mor b idi t ies.  Di e t T h era p y  P hysi c al Activity T h era p y  Behavioral T h era p y  P h a rmacotherap y - c o - Sibutra m i n e, Orli s ta t , Rimon a ba nt  Surger y .

63. A. La p ar o sc o p ic gast r ic b a nd (L A GB) B . The R o u x - e n-Y gast r ic by p a s s.

64. C. Biliop a nc r eatic d iversion w i th d uoden a l s w itch. D. Biliop a nc r eatic d iversion.

65.  Obe s ity is pre v entable.  W orldwi d e o b esity has more than d o ubled since 1980.   In 2008, 1.5 billi o n ad u lt s , 20 yr age and ol d e r , were overweig h t . Of these over 200 million men and nearly 300 milli o n   65% of t he overweig h t women we r e o b ese. world's p o pula t ion live in co u ntries w ere a nd it said that o b esity kills more peo p le than underweight.   Nearly 43 million chil d ren un d er the age of five w ere overweig h t i n 2010.

66. Thank You

67. References Vinay Kumar, Abul K. Abbas, Jon C. Aster-Robbins and Cotran . Pathologic Basis of Disease-Saunders. 9Ed,2015. Harrison. Harrison’s Principles of Internal Medicine. 19Ed,2015. K Park. Park’s text book of preventive and social medicine. 23Ed,2016 Redinger RN. The Pathophysiology of Obesity and Its Clinical Manifestations.  Gastroenterology & Hepatology . 2007;3(11):856-863.