Adobe Systems Eating disorders ZLA - spring 2020 Prof. Anna Vašků 1 Image Energy homeostasis Prof. Anna Vašků 2 Adobe Systems History ̶Lipostatic hypothesis (Kennedy 1953) – adipose tissue products specific „lipostatic“ factor ̶ ̶Glukostatic hypothesis (Mayer and Thomas 1967) – changes in glycemia lead to stimulation /inhibition of food intake (brain and liver) ̶Combination of both hypotheses??? Prof. Anna Vašků 3 It is necessary to distinguish common homeostatic regulations of food intake and hedonic regulations hedonic versus homeostatic valence.jpg Prof. Anna Vašků 4 Adobe Systems These factors are produced by adipocytes, but also by macrophages, fibroblasts, endothelial cells and other cells in adipose tissue [USEMAP] They are usually: 1. Proinflammatory (TNF-a, IL-6, resistin) 2. Anti-inflammatory (adiponektin) They are very important in metabolic regulations WAT produces adipokines To date, a lot of adipose tissue-derived factors has been described. These factors with pleiotropic functions in many processes including regulation of energy metabolism, inflammation, food intake, insulin sensitivity etc. Markedly contribute to metabolic regulations and its pathologies. Prof. Anna Vašků 5 Adobe Systems Gut hormones and the regulation of energy homeostasis Kevin G. Murphy and Stephen R. Bloom Nature 444, 854-859(14 December 2006) CENTRAL AND PERIPHERAL CIRCUITS IN REGULATION OF FOOD INTAKE Prof. Anna Vašků 6 Image86 Drug Insight: the functions of ghrelin and its potential as a multitherapeutic hormone Masayasu Kojima and Kenji Kangawa Nature Clinical Practice Endocrinology & Metabolism (2006) 2, 80-88 REGULATION OF FOOD INTAKE Prof. Anna Vašků 7 Adobe Systems Image85 Prof. Anna Vašků 8 BASIC COMMUNICATION AMONG NEURONS CRH NPY GHRELIN POMC Prof. Anna Vašků 9 LEPTIN INSULIN BLOOD VESSEL NPY AgRP α-MSH MORE FOOD INTAKE LESS FOOD INTAKE α-MSH RECEPTORS OREXIGENIC- ANOREXIGENIX PATHWAYS Prof. Anna Vašků 10 HYPOTHALAMUS ARC ARC VMN DMN PVN VMN DMN PVN LHA MCH CART RETINA LHA DYNORPHIN OREXINS CEREBRAL CORTEX LIMBIC SYSTEM THALAMUS PITUITARY GLAND GLUCOCORTICOIDS IL-6 INSULIN LEPTIN/ ADIPONECTIN/ TNFα, IL-6 GHRELIN ENDOCRINE GLANDS MUSCLE PANCREAS ADIPOSE TISSUE STOMACH/GUT Prof. Anna Vašků 11 NRG403 PATHWAYS OF TRANSCRIPTION FACTORS PARTICIPATING IN NUTRITION BASED INTERACTIONS Prof. Anna Vašků 12 An external file that holds a picture, illustration, etc. Object name is nihms284822f2.jpg The loss of universal helminth infection as occurred in earlier human evolution may alter the numbers or types of bacterial and fungal commensals and thus affect normal mucosal tissue homeostasis. In susceptible or highly exposed individuals, such alterations might alter the balance between immunotolerance, immunosurveillance and nutrient extraction. This imbalance may contribute to the appearance of inflammatory systemic dysregulation at mucosal surfaces, resulting in increases in asthma and allergic diseases, particularly in the setting of environmental changes that have increased exposure to indoor allergens and pollutants, and even to increases in obesity, which can be a risk factor for severe asthma. Immunosurveillance is a term used to describe the processes by which cells of the immune system look for and recognise foreign pathogens, such as bacteria and viruses, or pre-cancerous and cancerous cells in the body. Prof. Anna Vašků 13 Adobe Systems Effect of Interactions of Bacteria, Viruses, and Eukaryotes in Health and ... 14 Cell 2012; 148: 1258–1270 Prof. Anna Vašků Adobe Systems Stages of Metabolism Figure 24.3 Prof. Anna Vašků 15 Metabolic pathways 04-21_1b Prof. Anna Vašků 16 Adobe Systems Glycolysis Prof. Anna Vašků 17 Major enzymes and substrates involved in the regulation of gluconeogenesis. Red arrows and text represent the major enzymes and pathways involved in the regulation of gluconeogenesis. Direct glucose release from glycogen via the debranching enzyme accounts for <10% of the total glucose made via gluconeogenesis. AAT, alanine aminotransferase; fruc-1,6-bisphosphatase, fructose-1,6-bisphosphatase; glu-6-phosphatase, glucose-6-phosphatase; glyceraldehyde-3-P, glyceraldehyde-3-phosphate; glycerol-3-P, glycerol-3-phosphate; LDH, lactate dehydrogenase; OAA, oxaloacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase phosphoenolpyruvate carboxykinase (PEPCK) Gluconeogenesis Prof. Anna Vašků 18 RELATIONS TO GLUCOCORTICOIDS LEPTIN ADIPOSE TISSUE ADRENAL GLAND THIRD VENTRICLE ARC PVN/LHA POMC NPY/AgRP OREXIN CRH CRH ACTH CORTISOL Prof. Anna Vašků 19 Obesity is associated with local inflammatory response in FAT JCI0320514 Prof. Anna Vašků 20 Obesity is accompanied by local subclinical inflammatory response in adipose tissue that probably contributes to insulin resistance and the development of metabolic sysndrome Adobe Systems Prof. Anna Vašků 21 Vitamins soluble in lipids ̶Vitamins A, D and K directly modify state of the bone. ̶Their levels are dependent on composition of food (sufficient amount of fat is necessary for their absorption) ̶State of the bone is related fo functional state of insulin and leptin (insulin and leptin sensitivity and rezistance) Copyright ©2006 American Society for Clinical Investigation Holick, M. F. J. Clin. Invest. 2006;116:2062-2072 Prof. Anna Vašků 22 Regulation of gene expresssion by VDR Prof. Anna Vašků 23 oVitamin K2 is substantial cofactor for γ-carboxylase, enzyme which catalyses conversion of specific residuals of glutamic acid to Gla residuals oVitamin K2 is necessary for γ-carboxylation of proteins of bone matrix which contain Gla as MGP (= matrix Gla protein) a osteokalcin. oUncompleted γ-carboxylation of osteocalcin and MGP during vitamin K decrease lead to osteoporosis and high risk of fractures. Vitamin K2 stimulates synthesis of osteoblastic markers and bone deposition. oVitamin K2 decreases bone reabsorbtion by inhibition of osteclasts formation and by decrease of their resorbtion activity. oVitamin K2 treatment induces osteoclast apoptosis, but inhibits osteoblasts apoptosis which is leading to increased bone formation. oVitamin K2 supports osteocalcin expression ( increases its mRNA) which can be further modulated by 1, 25-(OH)2 vitamin D3. Vitamin K and bones Prof. Anna Vašků 24 C:\Users\prof. Vasku\plocha_stara\Výuka-obrázky\Vitamin K-2.jpg Vitamin K2 is transcription regulator od specific bone genes, functioning using SXR which will lead to increase of osteoblastic markers expression. SXR originally identifies as xenobiotic sensor… Prof. Anna Vašků 25 Adobe Systems Osteoporosis ̶is a skeletal disease characterised by low bone mass and microarchitectural deterioration with a resulting increase in bone fragility and hence susceptibility to fracture. ̶It is an important public health issue because of the potentially devastating results and high cumulative rate of fractures; in white populations, about 50% of women and 20% of men older than 50 years will have a fragility fracture in their remaining lifetime. Prof. Anna Vašků 26 osteoporosis_symptom Osteoporosis Prof. Anna Vašků 27 Adobe Systems Osteoporosis ̶Oestrogen has a central role in normal physiological remodelling, and oestrogen deficiency after the menopause results in a remodelling imbalance with a substantial increase in bone turnover. ̶This imbalance leads to a progressive loss of trabecular bone, partly because of increased osteoclastogenesis. ̶Enhanced formation of functional osteoclasts seems to be the result of increased elaboration of osteoclastogenic proinflammatory cytokines such as interleukin-1 and tumour necrosis factor, which are negatively regulated by oestrogen. ̶A direct effect of oestrogen in accelerating osteoclast apoptosis has also been attributed to increased production of transforming growth factor β. Prof. Anna Vašků 28 Adobe Systems Osteoporosis - causes ̶Glucocorticoids excess ̶Estrogene deficiency ̶Vitamin K2 deficiency? Prof. Anna Vašků 29 Cortisol generally antagonizes insulin … Prof. Anna Vašků 30 a)Several endogenic factors support osteoblastogenesis against adipogenesis. b)High levels of cortisol prefer adipogenesis to osteoblastogenesis Low [GC] low (physiological) concentrations of glucocorticoids, GH- growth hormone, IGF-1 insulin-like growth factor-1, FGF-2 fibroblast growth factor-2, IL-11 interleukin- 11, CT-1 cardiotrophin-1, OSM oncostatin M, OB osteoblast, AD-adipocyte Equilibrium between osteoblastogenesis (OB) and adipogenesis (AD) Prof. Anna Vašků 31 Adobe Systems Common adverse effects of glucocorticoid therapy ̶There is substantial and accelerated decreases in bone mineral density (BMD) with oral glucocorticoid therapy, most pronounced in the first year, with trabecular bone more quickly affected than cortical bone. ̶Even after only 2 months of high-dose glucocorticoids, studies show markedly decreased BMD at the lumbar spine, femoral neck and whole body, with the greatest loss in the trabecular lumbar vertebrae. ̶In light of the high incidence of glucocorticoid-induced osteoporosis and associated fractures, screening and treatment rates for glucocorticoid-induced osteoporosis has come under substantial scrutiny. ̶Less than 50% of patients receiving long-term glucocorticoids have been evaluated for osteoporosis, and less than 25% have been treated. There is great variability among clinicians in both the awareness of glucocorticoid-induced osteoporosis and the importance of prevention and treatment as the standard of care. ̶The use of antiosteoporotic medication was observed to be most common among postmenopausal women, where it approached 50%. Prof. Anna Vašků 32 Adobe Systems Common adverse effects of glucocorticoid therapy- glucocorticoid-induced osteoporosis ̶Glucocorticoid-induced osteoporosis is the most common type of iatrogenic osteoporosis and a frequent cause of secondary osteoporosis. ̶An estimated 50% of patients taking glucocorticoids for longer than 6 months will develop secondary osteoporosis . ̶The absolute risk for glucocorticoid-induced osteoporosis is higher in patients aged 65 years or older given their baseline age-related fracture risk, although the relative risk of fracture related to glucocorticoid use may be even higher in patients under 65 . Prof. Anna Vašků 33 Adobe Systems Size and endocrine profil of adipocytes is correlated with the whole adiposity MA_HE_200 OBESNI_HE_200 HALU_HE-200 ZASILKA Malnutrition (Anorexia nervosa) Normal state (slight overweight)) Obesity Solny_4JPG Prof. Anna Vašků 34 The number of adipocytes remains widely stable during the life of the subject (there are some exceptions – morbidly obese???), whereas the size of adipocytes is widely variable. The size of adipocyte is probably the key to endocrine function of adipose tissue and its abnormalities. The second one is the infiltration of adipose tissue by immunocompetent cells which produce inflammatory factors. Diagnostic criteria of obesity (BMI) Weight (kg) Height (m2) WHO, 1998 Classification BMI (kg/m2) metabolic rate Normal body weight 18.524.9 average Overweight 2529.9 increased Obesity I 30.034.9 middle Obesity II 35.039.9 high Obesity III 40.0  very high BMI = Prof. Anna Vašků 35 How we can classify that somebody is obese? The most simple is to get its weight and height and calculate so called body mass index. Its value more than 30 means obesity and less than 18 is one of the diagnostic criterium for anorexia nervosa. Of course the other classification is to measure percent body fat by anthropometry, bioimpedancy etc., but it is more complicated. waist size seems to be the best indicator of visceral obesity Women >88 cm = highly increase risk1 >80 cm = higher risk1 Men >102 cm = highly increased risk1 >94 cm = higher risk1 1Lean MEJ, et al. Lancet;1998:351:853–6 cm Prof. Anna Vašků 36 Waist circumference is a very useful indicator of visceral fat amount, this type of fat triggers the obesity-associated complications such as insulin resistance. We will be talking about this in detail in the next lecture Adobe Systems STANDARDISED PREVALENCE OF OBESITY 2008 Prof. Anna Vašků 37 Adobe Systems Has obesity genetic background? OBESITY Prof. Anna Vašků 38 Adobe Systems ̶Argumenst why yes: ̶Family aggregation ̶Twin studies (higher concordance of obesity incidence in MZ compared to DZ twins) ̶Large family studies ̶ HERITABILITy of OBESITY Family studies 30-50% Adoption studies 10-30% Twin studies 50-90% GENETICS OF OBESITY Prof. Anna Vašků 39 img004 Worm Research To Fight Obesity About 40 percent overweight! A typical obese cat... 28 pounds! People get too fat when they eat too much and don't get enough exercise. IS OBESITY DONE BY CULTURAL EATING HABITS? GENETICS OF OBESITY – ARGUMENTS WHY NOT Prof. Anna Vašků 40 groupimage pleiotropic syndromes with obesity „monogenic“ syndromes with obesity polygenic (complex) syndromes CLASSIFICATION OF OBESITY SYNDROMES Prof. Anna Vašků 41 About 30 syndromes, in which obesity represents constant component PLEIOTROPIC SYNDROMES WITH OBESITY Prof. Anna Vašků 42 Adobe Systems MONOGENIC SYNDROMES WITH OBESITY C:\Users\prof. Vasku\Pictures\2017-03-13 Monogenní obezita 2014\Monogenní obezita 2014 001.jpg N C Med J. 2013; 74(6):530-533 Prof. Anna Vašků 43 Adobe Systems Prof.Stephen O'Rahilly, MD and I. Sadaf Farooqi, MD Heiko Krude, Heike Biebermann, Werner Luck, Rüdiger Horn, Georg Brabant & Annette Grüters Congenital leptin defficiency before and after treatment POMC mutation (cave hair) MONOGENIC OBESITY SYNDROMES Prof. Anna Vašků 44 Adobe Systems Sy Prader- Willi as a clinical example ̶Hypotonic children, mental retardation, small figure, behavioral complacations (hyperphagy as a result of incontrolled appetite – one of the most common causes of children obesity) ̶Loss of expression of paternally imprinted genes at15q11.2-q13 chromosome as a result of microdeletion in the region. PWS8.png Prof. Anna Vašků 45 Adobe Systems ̶Susceptibility genes Genome wide scans Association studies focused on susceptibility (candidates) genes for obesity Metaanalysis of candidate genes identified by different methods QTL (quantitative trait locus) OBESITY AS A COMMON (COMPLEX) DISEASE Prof. Anna Vašků 46 Adobe Systems Future ̶ ̶BMC Med. 2017; 15: 50. ̶Published online 2017 Mar 7. doi: 10.1186/s12916-017-0800-1 ̶PMCID: PMC5340003 ̶Developmental pathways to adiposity begin before birth and are influenced by genotype, prenatal environment and epigenome ̶Xinyi Lin,#1 Ives Yubin Lim,#1,2 Yonghui Wu,1 Ai Ling Teh,1 Li Chen,1 Izzuddin M. Aris,1 Shu E. Soh,1,3 Mya Thway Tint,2,3 Julia L. MacIsaac,4 Alexander M. Morin,4 Fabian Yap,5 Kok Hian Tan,5 Seang Mei Saw,6,7,8 Michael S. Kobor,4 Michael J. Meaney,1,9 Keith M. Godfrey,10 Yap Seng Chong,1,2 Joanna D. Holbrook,1 Yung Seng Lee,1,3,11 Peter D. Gluckman,1,12 Neerja Karnani,1,13 and on behalf of the GUSTO study group ̶ Prof. Anna Vašků 47 Adobe Systems Obesity as a complex disease ̶Genetic, epigenetic and prenatal environmental factors are linked to offspring size and adiposity at birth and in early childhood. ̶Individual prenatal environmental influences on birth weight was identified; some of these prenatal environment variables [maternal ppBMI, GWG („Gestational Weight Gain“) and glucose levels] continued to associate with offspring size and adiposity in early childhood. Prof. Anna Vašků 48 Adobe Systems Obesity as a complex disease ÒGenetic variation, as captured by PRS („Polygenic Risk Score“) , not only influenced birth weight, but also child size and adiposity up to 48 months of age, independent of birth weight. ÒThe PRS was constructed using adiposity-linked genetic risk variants previously reported in an adult population. The association of adult adiposity risk score with size and adiposity in pediatric population indicates that the effects of genetic risk variants can be detected as early as birth. Ò Prof. Anna Vašků 49 Anorexia nervosa (AN) and bulimia nervosa (BN) uare complex psychiatric disorders of great importance for public health policies, as they are associated with a high burden of morbidity and mortality due to their severe medical and psychological consequences. Etiopathogenesis of these eating disorders (EDs) continues to remain elusive, with the result that their treatment is often unsuccessful. uAN is a severe psychiatric disorder leading to life-threatening weight and fat loss. This illness could be characterized by irrational fear of becoming fat, abnormal eating behavior, hyperactivity, GIT complications and wide variety alterations of hormonal and metabolic systems. uThe exact etiopathogenesis is unknown and the way of treatment remain limited. u > AN ZASILKA Prof. Anna Vašků 50 http://www.sciencedirect.com/science?_ob=MiamiCaptionURL&_method=retrieve&_eid=1-s2.0-S027858461630 4882&_image=1-s2.0-S0278584616304882-gr1_lrg.jpg&_cid=271215&_explode=defaultEXP_LIST&_idxType=defa ultREF_WORK_INDEX_TYPE&_alpha=defaultALPHA&_ba=&_rdoc=1&_fmt=FULL&_isHiQual=Y&_issn=02785846&_pii=S 0278584616304882&md5=f985f4c32306c1216d5e24ce7d5ee26f Schematic representation of brain reward circuits. ACC anterior cingulated cortex; Amy amygdala; DS dorsal striatum; Hipp hippocampus; IC insular cortex; LH lateral hypothalamus; mPFC medial prefrontal cortex; NAc nucleus accumbens; OFC orbitofrontal cortex; VTA ventral tegmental area. The brain reward system integrates basic and emotional stimuli, such as hunger, satiety, desire, pleasure and fear, with higher order cognitive processes aimed at modulating further actions or representation of the general experience. These high order processes involve anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and ventromedial prefrontal cortex (PFC), which are necessary for identification of rewarding stimuli, inhibition of emotional responses, and promote behavioral outcomes (Haber and Knutson, 2010; Wittman et al., 2010 ; Sripada et al., 2011). Overall, the PFC provides inhibitory influences on motivation and reward-directed behavior, integrating sensory inputs, memories, goals, and physiological states with the aim to provide an adequate performance (Miller and Cohen, 2001). ACC and dorsolateral prefrontal cortex (DLPFC) may also serve to monitor potential conflict situations induced by reward stimuli (Walton et al., 2003 ; Vogt et al., 2005). Therefore, they have a gating role in action selection following reward cues ( Goldstein and Volkow, 2011). Indeed, by a top-down effect, both OFC and ACC provide a negative feedback to mesolimbic areas regulating reward-seeking motivation (Goldstein and Volkow, 2011). Prof. Anna Vašků 51 Adobe Systems Anorexia nervosa (AN) and bulimia nervosa (BN) ÒFunctional magnetic resonance imaging (fMRI) techniques have been employed to investigate the brain's processing of reward elicited by both food-related and non-food-related stimuli in AN and BN (O'Hara et al., 2015). ÒIt has been shown that, compared to healthy controls, AN patients exhibit abnormal activation of different brain areas, including the parietal, the orbito-frontal, the dorso-lateral prefrontal, the anterior cingulate and the medial prefrontal cortex (Frank, 2015a ; Frank, 2015b) after exposure to visual food cues, especially for highly palatable foods. ÒSimilarly, altered insula, striatum or orbitofrontal responses to sweet stimuli have been found in recovered or symptomatic AN and BN patients. ÒThese findings suggest a dysregulation of brain mechanisms involved in the processing of food-related rewarding stimuli in the pathophysiology of EDs. Prof. Anna Vašků 52 Adobe Systems Pathophysiology of AN ̶An integral pathophysiological scenario that fits to the natural history of AN with the following steps an be porposed: ̶(1) enhanced vulnerability to stress (genetic, epigenetic, or environmental factors); ̶(2) major stressing events activating the stress-axis, increased intestinal permeability, and increased virulence of the microbiota; ̶(3) bacterial proteins (e.g., ClpB) challenge the immune response and due to molecular mimicry, cause increased production of Igs cross-reactive with neuropeptides (e.g., α-MSH); ̶(4) this results in altered food intake, anxiety, gastrointestinal discomfort and other consequences of altered central and peripheral melanocortin signaling; ̶(5) global malnutrition and some specific macro- and micro-nutrient deficiencies contribute to the perpetuation of gut barrier and immune dysfunction as well as behavioral symptoms. Front Neurosci. 2016; 10: 256 Prof. Anna Vašků 53 Adobe Systems Orexigenic neuropeptides ̶Orexigenic neuropeptides including ghrelin, orexins and 26RFa are up-regulated in AN and it is thought that this orexigenic profile reflects an adaptive mechanism of the organism to promote food intake and thus to counteract undernutrition. However, this adaptive mechanism is ineffective in increasing food consumption leading to the concept of a global resistance of AN patients to orexigenic signals. ̶We can speculate that a chronic increase of the activity of LHA orexigenic neurons expressing orexins, MCH, or 26RFa could reinforce dopamine-induced anxiety in the reward system of AN patients and thus the aversion to ingest food. Front Neurosci. 2016; 10: 256 Prof. Anna Vašků 54 https://www.ncbi.nlm.nih.gov/corecgi/tileshop/tileshop.fcgi?p=PMC3&id=491849&s=61&r=1&c=1 Front Neurosci. 2016; 10: 256 Prof. Anna Vašků 55 Loss od adipose tissue is supposed to be the main factor contributing to the body weight loss Normal Weight (n = 50) AN (n = 30) Weight (kg) 62.2 ± 1.54 45.8 ± 1.89* Lean mass (kg) 39.1 ± 0.76 37.8 ± 1.01 BMI (kg/m2) 21.2 ± 0.42 15.7 ± 0.47* Body fat content (%) 24.3 ± 0.79 7.1 ± 0.88* Total fat skinfold (mm) 120.5 ± 12.17 42.1 ± 4.78* Abdominal skinfold (mm) 12.5 ± 2.13 4.8 ± 1.59* Insulin (pmol/l) 28.3 ± 4.53 14.2 ± 3.67* Glucose (mmol/l) 4.7 ± 0.08 4.1 ± 0.11 Menstruation Yes - regular cycle Secondary amenorrhea Means ± SEM Prof. Anna Vašků 56 the loss of adipose tissue and the dysfunction of its function might be critical for endcorine and metabolic complications and weight relapses of AN patients. Adobe Systems ̶AN is 11x more frequent in relatives of probands compared to physiological population. ̶BN is 4-5x more frequent in relative women. ̶~15% risk of eating disorders in relatives of AN and BN vs. 4% risk in healthy population. Strober et al. Am J Psychiatry 2000; 157:393 GENETIC ASSOCIATIONS??? Prof. Anna Vašků 57 BODYSTAT Prof. Anna Vašků 58 Adobe Systems Děkuji vám za pozornost Cheshire_Cat Prof. Anna Vašků 59 Adobe Systems