Pathophysiology of nutrition and obesity

1. Pathophysiology of nutrition and obesity Prof. Jana Plevkova, MD PhD 2017

2. OUTLINE OF THE LECTURE • Metabolism and regulations • Hyponutrition (kwashiorkor, marasmus) • Obesity

3. Metabolism Appropriate amount of energy in cells affects the activity of all the body, it's performance, resistance against overload /diseases, stress reactions/ - metabolism is also a source of substrates necessary for the structure and function of the individual compartments and subunits within the human organism qualitative vs quantitative approach • optimal energy content • appropriate composition of nutrients and essential molecules Metabolic disorders could lead to the depletion of energy and/or substrates and also to the accumulation of molecules with potential hazards for the body /ketonbodies/

4. anabolism vs catabolism resistance against diseases abilitiy to recover

5. Regulation of metabolic processes • Insulin – predominantly anabolic effect,  transport of glucose into the muscle and fatty tissue cells, stimulates proteosynthesis, inhibits lipolysis, also causes the transport of K together with glucose into the cells, increases appetite • Glucagon –  plasma glucose level /glycogenolysis a gluconeogenesis in liver cells/,  lipolysis, it´s level increases during fasting • STH – proteoanabolic action, some effects are mediated via IGF– 1, increases plasma glucose level, high level of STH may lead to insulin resistance /acromegalia + impaired glucose tolerance/

6. Regulation of metabolic processes • Cortisol - plasma glucose /gluconeogenesis/, proteocatabolic effect in peripheral tissues, stimulates proteosynthesis in liver, stress hormone responsible for metabolic effects such as hyperglycaemia and insulin resistance, has mineralocorticoid effect • T3 a T4 –  basal metabolism,  oxygen consumption and heat production, sensitize tissues for CA effects, increase glucose absorbtion from he GIT, normal concentration has proteoanabolic effect, while increased level has proteocatabolic effect – the most dangerous is proteocatabolism in the heart • Reproductive hormones – anabolic effect – androgens /muscles, positive nitrogen balance, estrogens – subcutaneous distribution of fat, Na retention, interfere with metabolism of cholesterol, progesterone  thermogenesis

7. The role of different organs in metabolism • Liver – unique anatomic position - portal circulation – contact with substrates reabsorbed in the GIT, regulation of plasma glucose level, synthesis of proteins, origin of urea, lipid particles stock, synthesis of lipoproteins, bile acids, vitamins stock .... • Muscles mass – approx. 40% body weight, important tissue with respect to energy consumption, reservoir of proteins • Fatty tissue – storage of energy, lipolysis and subsequent transportation of FA into the muscles, liver, metabolism of steroid hormones

8. The role of different organs in metabolism • GIT – processes of digestion and absorbtion of nutrients, synthesis of chylomicrones, strong proliferative activity of intestinal mucosa – enterocytes turnover • Bones – calcium storage, buffer activity • Skin – change of the vit. D, thermoregulation, deposition of subcutaneous fat • Kidneys – activation of vit D, absorbtion of glucose, AA, tubular transportsystems require a lot of energy • RS and CVS – the main role of these systems is to provide optimal oxygen and substrates supply to the tissues that matches to their metabolic rate – to produce energy but both systems need energy for function as well.

9. Sources of energy in the human body • There is a hierarchy in the substrate utilization • Glucose – promptly available source, precise regulation, replenished with the glucose from the food and gluconeogenesis, its level is well balanced even during longer fasting • Depletion of the glucose, or inability to utilize glucose /not available glucose/ IR leads to the changes in the energy pathways – energy is predominantly obtained from fat and proteins • Lipolysis due to lack of glucose or if glucose is not available f leads to the production of keton bodies, which may replace the energy sources for the myocardium, muscles, while glucose is saved for the CNS, production of keton bodies, and their utilization protects proteins against excessive breakdown

10. Disorders of nutrition and their consequences • Water, proteins, carbohydrates, fat, micronutrients – all of these food components have to follow the guidelines for „normal – determined“ requirementswith respect to qualitative and quantitative standpoints • Serious, long lasting starvation could lead to – malnutrition, catabolism, hypovitaminosis, or avitaminosis • Increased intake of some food components could lead to disease caused by accumulation of these components in the body – hypervitaminosis A, D • Increased imbalanced intake of food /energy – obesity or hyponutrition • Long lasting inappropriate nutrition - civilization diseases - ATS, cancer

11. Decreased nutrition Hyponutrition – reduced food intake (reduced nutritioin – all components) Malnutrition– inappropriate composition of food regarding QUALITY – enough energy with lack of some essential factors (essential AA, proteins) which depletion could lead to a serious health problems Kwashiorkor– specific type of proteinmalnutrition, deficit of proteins,  hypoalbuminaemia  decrease of oncotic pressure  disorders of Starling balance on the capillary wall  edema - steatosis of the liver – due to excessive metabolism of lipids - changes in the nourishment of the skin - anemia, hypothermia, neurologic disorders, bradycardia, changes of the homeostasis

14. Decreased nutrition • Deficiency diseases– decreased intake of particular food components, which could lead to health problems – deficiency of iron – anemia, in young girls (menstrual bleeding, diets, not eating meat etc.), deficiency of calcium – osteoporosis • Marasmus – type of hyponutrition caused by the lack of all food components – proportional lack of nutrients (carbohydrates, lipids, proteins) (starvation, mental anorexia) - reduction of subcutaneous fat, decrease of metabolic rate • The difference between marasmus and kwashiorkor – lack of quality protein, better prognosis is for marasmus - after the supplementation of food the patients clinical course gets better soon, it depends also on the type of marasmus – simple fasting has better prognosis comparing to marasmus e.g. in terminally ill patients

16. Simple fasting - limitedbutnotcompletefasting - general idea is the most economic use of energy - long lasting fastingleads to depletion of energy and substrates, as well as depletion of vitamins and micronutrients - thefirst - glycogen storage is utilized /12 – 24 hours/ • thesecond- the plasma glucose level is optimized via gluconeogenesis, this stage is linked with  level of insulin and  level of contra regulatory hormones • this processes are followed with  lipolysis and B oxidation of FA • productionof Keton bodies • after the beginning of ketogenesis the processes of gluconeogenesis and proteocatabolism are suppressed – adaptation – this is a protection against excessive proteinbrakdown • manifestation -  body weight

17. Secondary malnutrition The difference between secondarymalnutrition and simple fasting is that secondary malnutrition is caused by serious conditions/diseases which leads to malnutrition via different mechanisms • Decreased food intake – anorexia, nausea, disease of GIT, disorders of digestion, absorption, intestinal inflammation, pancreas, disorders of bile secretion etc. • Increased loss of nutrients – exudative gastro and enteropathy, bleeding, diarrhoea • Increased requirements – fever, infections, tumors, surgical procedures In this type of malnutrition the regulatory mechanisms are disturbed with the presence of proteocatabolism (very likely doe to the high cortisol and low STH) - proteins are not protected and are taken as a possible substrates for the gluconeogenesis

18. Catabolic processes • Caused by disturbances in processes which regulates metabolism • Negative protein and energy balance develops quickly • Pathomechanisms: • effects of inflammatory mediators • effects of activated axis hypothalamusx pit. gland x adrenal gland • Cancer – long lasting catabolic process –lipids, proteins with gluconeogenesis in liver, tumor is producing molecules strongly affecting metabolism /TNF  - kachectin/ • Extensive trauma, burns, SIRS, FUO, extreme stress (two types of responses !)

19. Systemic changes caused by hyponutrition • weight loss – reduction of the adipocytes size, tissue atrophy • ECF – volume is relatively stabile, protein loss leads to decrease of oncotic pressure of plasma • myocardium –  stroke volume,  contractility,  glycogen content with atrophy of myofibrils, changes are reversible • RS – minimal changes, reduced strength of respiratory muscles, VC, abnormal finding in spirometry,  min. ventilation • GIT – decrease of motility and secretion, atrophy of the mucosa, loss of the intestinal microvilli and decreased turnover of enterocytes • pancreas– exocrine function is  , while endocrine function is not affected

20. Systemic changes caused by hyponutrition • kidneys – reduction of capsaula adiposa renis, atrophy,  possibility to concentrate urine due to decrease of the osmotic medullar gradients • liver – atrophy of hepatocytes,  reduction of the cell volume,  glycogen content, suppressed proteosynthesis in kwash., but hepatomegalia due to steatosis • endocrine system –  of hormone production, testosterone, FSH/LH in women, disturbed conversion of T3 to T4 • immune system – all components of immune system are affected, both cellular and humoral processes • barrier impairment – atrophy of skin, GIT mucosa • worse, long lasting healing of wounds

21. Can be fasting beneficial? • Intermittent fasting • A method which uses either fasting days or fasting intervals during the day (typically 16/8) – 16 hours fasting period (overnight till the next lunch time) is interrupted by period in which a person eats normally • According to some literature data this approach reduced body weight and restores insulin sensitivity in subjects with overweight and obesity • Normalizes levels of cholesterol and TAG in the blood • Not for everyone !!!! People with problems to control their glucose (e.g. B blocker medication – decreases the rate of adrenergic lipolysis)

22. Update WHO October 2017 • Worldwide obesity has nearly tripled since 1975. • In 2016, more than 1.9 billion adults, 18 years and older, were overweight. Of these over 650 million were obese. • 39% of adults aged 18 years and over were overweight in 2016, and 13% were obese. • Most of the world's population live in countries where overweight and obesity kills more people than underweight. • 41 million children under the age of 5 were overweight or obese in 2016.Over 340 million children and adolescents aged 5-19 were overweight or obese in 2016. • Obesity is preventable.

23. Obesity Obese person – person with body weight noticeably exceeding the upper interval of physiological values and this weight increase is caused by accumulation of fat, in men more than 25% and in woman more than 30% of total body weight is represented by fat Obesity is a chronic disease leading to multiple organ dysfunction and premature mortality Obesity is caused by a complex action of several factors –multifactorial disease

24. Consequences of obesity • CVS – atherosclerosis, IHD, heart failure, varices, deep venous thrombosis with complications • endocrine – PCO, irregular period, infertility • GIT – GERD, liver statuses, bile stones, hernia, colorectal Ca • genitourinary– erectile dysfunction, hypogonadism in men, Ca of breast and uterus, premature labour, incontinence, • skin and skin adnex – lymphedema, celulitis, skin infection • musculosceletal– gouty arthritis, immobility, osteoarthritis, sacral back pain • neurologic – cerebral ischemia, carpal tunnel syndrome • respiratory– Pickwick syndrome (hypoventilation) OSA • psychologic – depression, low self retting, social stigmatization

25. Methods for assessing obesity 1) body mass index – BMI body weight (kg) BMI = height (m)2 normal value: BMI =19 – 25, overweight: BMI =26 – 30 obesity: BMI > 30 „malignant“ obesity: BMI > 40 2) waist:hip ratio normal value: 0,7 – 0,95 3) measurement of the skin folds 4) waist circumference: men < 95cm; women < 81cm

26. Classification of obesity • Etiopathogenetic 1. Primary 2. Secondary B. Pathological anatomy 1. Hypertrophic 2. Hypertrophic+ hyperplastic C. According to the fat distribution 1. Android type (men) – apple shape - risk of DM, AMI, cerebral ischemia, other CVS diseases 2. Gynoid type (women) – pear shape - risk of disorder of musculosceletal system (hip joins, knees)

27. Main causes and mechanism involved in pathogenesis of obesity Genetic determinants – approx. 33% of obese patients have genetic background monogenic diseases – mutation of the gene coding the synthesis of leptin, or mutation of leptin receptor polygenic disorders – mutation of several genes, which combination and simultaneous effects of external factors leads to onset of obesity These disorders might be related to  receptors with metabolic effects, genes for uncoupling proteins or LDL receptors

28. Main causes and mechanism involved in pathogenesis of obesity The most common factors leading to overweight and obesity are: • genetic predisposition • food containing too much energy • limited body movement and lack of physical exercise • consequence of other disease /hypothyreosis/ • disorders of food intake and its regulation • psychic stress • side effects of some drugs

29. do thephysicalprincipleswork? - lowcalories no obesity • but – highcalories ???? somepeopledonotgetobeseeventheyhavehighcaloryintake(uncouplingporteins, goodmeatabolicspeed) Behavioralchangesobserved in last coupleofyears - Food oncedaily – extremeportion, skippingbreakfast • Fastfood • Alcohol (beer) • Nibbling (TV) • Stress • Nighteating • Bingeeating • Eatingregualtiondisorders – mentalanorexia - bulimia

30. Main causes and mechanism involved in pathogenesis of obesity The most common pathomechanism is  intake of food - energy exceeds the energy requirements or consumption, and this"energy“ is then stored as a fat I. primary increased intake of energy/food, and boby is not able to utilize it eventhough the person has normal metabolic speed /overeating/ II. primary decrease of the energy consumption to the level leading to the increase of the fat in the body in subjects with normal food intake /decreased metabolic speed/ III. combination of both mechanisms

32. Control of food intake and energy balance Food intakeis primarily controlled by hypothalamus • Appetite centre – signals give rise to hunger and promote eating • Satiety centre – signals lead to sensation of fullness and supress eating Arcuate nucleus of hypothalamus • Contains two clusters of appetite regulating neurons • Neurons that secrete neuropeptide Y (NPY) – they increase appetite and food intake • Neurons that secret melanocortin – they supresses appetite and food intake

33. Control of food intake and energy balance • Adipocytes • Secrete hormone leptin – one of he most important adipokines, it reduces appetite and decreases food consumption • Insulin – hormone secreted by pancreas in response to rise in glucose concentration • Ghrelin – hunger hormone, appetite stimulator produced by stomach and regulated by feeding status, stimulates the hypothalamic NPY secreting neurons

34. Control of food intake and energy balance • PYY – produced by small and large intestines, at lowest level before meal, rises during meals and signals satiety, believed to be an important meal time regulator • Lateral hypothalamus area - secretes orexin – strong stimulant for food intake • Paraventricular nucleus - releases neuropeptides that decrease food intake

35. Control of food intake and energy balance • NTS – nucleus of the solitary tract in the brainstem • Serves as a satiety centre • Plays key role in short –term control of meals • Psychological and environmental factors can also influence food intake above and beyond internal signals that control feeding behaviour

36. Many pepitides alter food intake

37. Hypothalamus receiving signals Cerebralcortex hypothalamus GIT GIT hormone GITadiposetissue GIT nutrients in blood

38. Factors that regulate appetite through effects on CNS

40. Two theories for regulation of food intake • Glucostatic theory – theory proposes that blood glucose levels ultimately control the feeding and satiety centers • Lipostatic theory – theory proposes that the level of body fat regulates the feeding and satiety centers, recent discovery of several peptides, mainly leptin and NPY seems to support this theory

41. Factors that regulate quantitiy of food intake • Hort term regulation – concerning primarily with preventing over eating at each meal • Long term regulation - concerning primarily with the maintenance of normal quantities of energy stores in the body

43. Ghrelin – the hunger hormone • Identified in 1999 • 28 amino acids, orexigenic peptide hormone • Secreted by gastric mucosa on an empty stomach • Increased during fasting, peak level before meal, fall rapidly after meal

44. Leptin • peptide (167 AMK) • coded by „ob“ gene (7th chormosome) Hormone produced in the fatty tissue – corresponds with the „fat store“ after its transport to the hypothalamus by the blood it supresses appetite It also modulates production of CCK and NPY leading to the satiety feeling – regulates metabolism ´- it reduced food intake and increases energy expenditure Leptin resistance leads to insensitivity to the satiety signal and promotes overeating

45. Content of the fat in food – relation to obesity  amount of fat in food  tendency for the increased intake of energy Mechanisms  feeding effect of the fat is less effective than the feeding effect of carbohydrates and proteins  passive overeating  increased concentration of energy in the food unit  fat has positive effects on the taste receptors –therefore his content in the food perpetuates its intake  late inhibitory effects of the feeding signals after fat intakeenhances intake of the food as a whole

46. Fat paradox Fat induced feeding signals vs overeating of fat Fat in the intestinal system represents strong pre - absorbtion signal mediated - mainly by CCK, glucose, bombesine - enterostatine (pentapeptid from pro-colipasis) - products of the fat ingestion Fat enters the intest. with a delay /long digestion in the stomach/  is mixed with other nutrients – less effective feeding signals due to delay Fat in the mouth  stimulation of the taste receptors  facilitation of fat intake • density of energy in fat food  intake of  amount of energy, because of the delay in satiety signals

47. Short lasting vs long lasting reduction of body weight The total amount of the fat in the body is regulated consequence: any reduction of the fat mass leads to activation of compensatory mechanisms  to get the fat storage into the former status Is there a possibility to reduce body weight in obese people effectively eventhough the mass of fatty tissue is regulated?

48. The mass of fatty tissue which is „protected“ can be effectively reduced, therefore it s not possible to talk about a stabile „set point“ for the fat stores Mass of fatty tissue can be  due to internal factors - changes of emotive status - level of BMR external factors - the taste and availability of the food - increased content of fat in food Mass of fatty tissue can be  due to - intake of low calorie diet at libitum - increased physical activity during long time

49. Visceral obesity Strong link between the visceral obesity and of metabolic complication Example: 2 groups of patients with the same BMI - 1. gr. – fat in subcutaneous location - 2. sk – fat in the abdominal cavity Different metabolic parameters were found in those groups 2. nd group has impaired GTT test and higher level of TAG in the plasma Increased content of visceral fat leads to IR, no matter what ´s the BMI -  level of FFA in blood - insulin resistance - dyslipidaemia -  TAG,  LDL,  HDL cholesterol, predisposition to ATS

50. Visceral obesity