אסף רודיך M.D., Ph.D. המחלקה לביוכימיה קלינית והמרכז לתזונה הפקולטה למדעי הבריאות אונ' בן-גוריון rudich@bgu.ac.il מאזן האנרגיה וההוצאה האנרגטית - הבסיס

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M.D., Ph.D. ' - rudich@bgu.ac.il - ( ...) Slide 2 : .... : 1. " , " ? 2. () 3. 4. 5. ... ! Slide 3 Simple: The energy balance and the laws of thermodynamics Energy expenditure Energy intake Slide 4 The energy balance: Energy expenditure - Involuntary: - BMR (basal metabolic rate) - TEF (Thermic effect of food) - Voluntary (activity): - NEAT (non-exercise activity thermogenesis) - ET (exercise thermogenesis) Energy intake Food intake (calories): Nutrients: lipids Carbohydrates proteins Slide 5 The control of food intake -Complex process: Metabolic, Neuro-endocrine, Mental (including mood), Social, Cultural factors -Complex afferent signals (orexigenic Vs anorexigenic): -hunger versus satiety (feeding frequency); -fullness signals (meal size); -energy abundance signals (short/long term); -food composition signals (olfaction); -Mood, social, cultural -Mediators: -Neuronal: -Central: Hypothalamus, brain stem, Area Postrema, reward centers, Cortical centers - peripheral: Vagus -Hormonal (pancreas, fat tissue, GI) Slide 6 Hypothalamus = anorexigenic orexigenic = Slide 7 The Arcuate Nucleus of the Hypothalamus : integrator of orexigenic and anorexigenic signals food-seeking behaviour NPY (Orexogenic signal) MSH (Anorexogenic signal) ** ** MC-R4 (melanocortin Receptor 4) Slide 8 The Arcuate Nucleus of the Hypothalamus : integrator of orexigenic and anorexigenic signals food-seeking behaviour NPY (Orexogenic signal) MSH (Anorexogenic signal) - Homozygous POMC mutations cause early onset obesity, adrenal insufficiency, red hair pigmentation - MSH receptor 4 (MC4) mutations account for ~6% of severe early onset obesity, whereas a hyperactive MC4 mutant negatively associates with obesity - Obesity can result from normal POMC transcription and translation, but impaired post- translational processing due to deficient prohormone convertase 1. Genetic evidence for the central role of the POMC-MSH as a major anorexigenic signal: MC4 agonists as appetite suppressants?? Slide 9 Summary: GI, pancreatic and adipose signals for hypothalmic regulation of food intake food-seeking behaviour NPY (Orexogenic signal) MSH (Anorexogenic signal) Slide 10 Adipose tissue Hypothalamus = anorexigenic orexigenic = Slide 11 (Nature 404: 661, 2000) leptin Adipostatic action of Leptin: Leptin signals fat-storage sufficiency Slide 12 (Science 304:63-4, 2004) food-seeking behaviour NPY (Orexogenic signal) MSH (Anorexogenic signal) - - + + Leptin effect in the arcuate nucleus of the hypothalamus: 1. Direct (rapid) effect 2. Neuroplasticity (h) Excitatory synapses + - + Inhibitory synapses - 3. Developmental Slide 13 Adipose tissue Hypothalamus GI tract Pancreas = anorexigenic orexigenic = - Does insulin resistance develop in the brain? - Does it mediate reduced anorexigneic signal? - Can common mechanisms underlie insulin and leptin resistance??? Slide 14 The energy balance: Energy expenditure - Involuntary: - BMR (basal metabolic rate) - TEF (Thermic Effect of Food) - DIT (Diet-Induced Thermogenesis) - Voluntary: - NEAT (non-exercise activity thermogenesis) - ET (exercise thermogenesis) Energy intake Food intake (calories): Nutrients: lipids Carbohydrates proteins Obligatory Vs. Facultative (adaptive) Slide 15 6-12% Exercise thermogenesis ~60% % of TDEE in sedentary persons 30% (20 to>100%) Activity thermogenesis (AT) Components of Total Daily Energy Expenditure (TDEE) Slide 16 Exercise thermogenesis Facultative (adaptive) thermogenesis Obligatory thermogenesis - Essential thermo. - Endothermic thermo. Diet-induced thermogenesis Muscle Brown Adipose Tissue White Adipose Tissue GI, liver, WAT, muscle BAT, WAT? Muscle? All organs Most organs Acetylcholine (central) Norepinephrin (central) Thyroid hormone Insulin Norepinephrin (central) none Thyroid hormone 30% (20 to >100) ~ 60% 6-12 % Slide 17 6-12% Exercise thermogenesis ~60% % of TDEE in sedentary persons 30% (20 to>100%) Activity thermogenesis (AT) Components of Total Daily Energy Expenditure (TDEE) Slide 38 Obesity: energy imbalance Energy expenditure Energy intake Food intake (calories): Nutrients: lipids Carbohydrates proteins Processes: Eating initiation (frequency) Satiety sensation / appetite regulation (meal size) Diet composition - Involuntary: - BMR (basal metabolic rate) - TEF (Thermic effect of food) - Voluntary (activity): - NEAT (non-exercise activity thermogenesis) - ET (exercise thermogenesis) The global obesity epidemic: increased energy intake or decreased energy expenditure ? Slide 39 Leptin in human obesity -Circulating leptin levels are regulated by fat mass, gender, fed-fasted state. -Although loss-of-function mutations in the leptin or leptin-receptor genes have been described, this is likely a very rare cause of human obesity. -Common human obesity is associated with elevated circulating leptin levels, which are believed to represent a state of leptin resistance. Leptin therapy trials are largely ineffective in common human obesity Slide 40 Leptin-induced signal transduction pathways * * * * ** (Cell Biol. Int. 28: 159, 2004) Signal termination? Leptin resistance? Overexpression of SOCS3 could be a mechanisms for leptin resistance (Nat. Med. 10: 734, 2004) Slide 41 Copyright 2006 BMJ Publishing Group Ltd. Druce, M et al. Arch Dis Child 2006;91:183-187 Figure 3 Summary of main gut hormones involved in appetite regulation and their sites of production. CCK, cholecystokinin; PYY, peptide YY; GLP1, glucagon-like peptide 1; GLP2, glucagon-like peptide 2. Slide 42 Changes in GI hormones in obesity: pathophysiological relevance and potential for therapy?, 2005 Anorexigenic/ orexigenic OAAAAAOAAAAA AAAAAAAA Weight loss restores levels role in the low rate of wieght loss maintenance? Food-induced ghrelin supression is decreased in obese role in low satiety signal over-eating? Slide 43 The Incretin Glucagon-like peptide 1 (GLP-1) Lancet, 368: 1696, 2006 -Secreted by L-cells in the distal illeum and colon in response to food intake. - Circulating levels rise from 5-10 pM to 15-50 pM within minutes neural input? - Levels decrease rapidly due to proteolytic cleavage by dipeptidyl peptidase 4 (DPP- 4). - Signals through distinct G- couples receptor, GLP-1R, expressed in islet and cells, nerves, heart, kidney. Slide 44 Summary: GI, pancreatic and adipose signals for hypothalmic regulation of food intake Slide 45 The endocannabinoid system in energy balance Metabolic effects of cannabis are mediated through the GPCR cannabinoid receptors (CB1 and CB2), and include : Brain: - Hypothalamus: increase orixogenic, inhibit anorexigenic signals - Mesolimbic system: increased reward and palatability of food - hindbrain: inhibition of nausea and satiety signals (Afferent Vagus) GI: - potentiation of hunger signals, inhibition of satiety, - increase nutrient absorption Fat and liver: increase lipogenesis Muscle: Impair glucose uptake A CB1 antagonist, Rimonabant, is a novel anti-obesity, anti-obesity-related morbidity drug Slide 46 Copyright 2006 The Endocrine Society Pagotto, U. et al. Endocr Rev 2006;27:73-100 FIG. 3. Actions of CB1 antagonists on the target organs involved in food intake and metabolic control Slide 47 Slide 48 , 2005 Slide 49 Slide 50 Fuel flux regulators: pancreatic hormones: Insulin, Glucagon, Somatostatin Other counter-regulatory hormones: GH, glucocorticoides Metabolite hormones: FFA (PPAR) Energy expenditure Energy intake Food intake (calories): - lipids - Carbohydrates - proteins Basal Metabolic rate: - obligatory energy expenditure - Thermogenesis Physical activity Metabolic rate regulators: Thyroid hormones: Thyroxin Beta-adrenergic hormones: adrenalin Fat tissue hormones: leptin Metabolite hormones: FFA Food intake regulator (orexigneic, anorexigenic hormones): Fat tissue derived hormones: Leptin, adiponectin CNS neuropeptides: NPY, MSH, ACRP, POMC GI-peptides: CCK, ghrelin, PYY Pancreatic hormones: insulin Diabetes and Obesity are by far the most prevalent edndocrine disorders, involving an increasing array of hormones involved in complex regulatory circuits. Leonardo daVinci (1452-1519) Fernando Botero (1932 - ) Slide 51 6-12% Exercise thermogenesis ~60% % of TDEE in sedentary persons 30% (20 to>100%) Activity thermogenesis (AT) Components of Total Daily Energy Expenditure (TDEE) Slide 52 Obligatory thermogenesis Facultative (adaptive) thermogenesis Exercise thermogenesis - Essential thermo. - Endothermic thermo. Diet-induced thermogenesis Muscle efficiency thermo Cold-induced shivering thermo Cold-induced non-shivering thermo GI, liver, WAT, muscle BAT, WAT? Muscle? All organs Most organs Insulin Norepinephrin (central) none Thyroid hormone Muscle Thyroid hormone? Muscle Acetylcholine (central) BAT, WAT? Muscle? norepinephrin (central) Slide 53 Components of Total Daily Energy Expenditure (TDEE) Obligatory thermogenesis Facultative (adaptive) thermogenesis Exercise thermogenesis - Essential thermo. - Endothermic thermo. Diet-induced thermogenesis Muscle efficiency thermo Cold-induced shivering thermo Cold-induced non-shivering thermo GI, liver, WAT, muscle BAT, WAT? Muscle? All organs Most organs Insulin Norepinephrin (central) none Thyroid hormone Muscle Thyroid hormone? Muscle Acetylcholine (central) BAT, WAT? Muscle? norepinephrin (central) Slide 54 Where is heat generated? Two organs of thermogenic potential: 1.Fat tissue - Brown fat (BAT) - White fat (WAT) - atypical brown adipocytes in WAT 2. Skeletal muscle - UCP2 and UCP3 - Fiber type: muscle efficiency thermogenesis BATWAT Energy dissipation Multilocular, small TG droplets Energy storage: Unilocular TG droplet Multiple mitochondriaFew mitochondria UCP1Some UCP2, no UCP1 Type I fiberType II fiber Oxidative: slow twitch, low fatigue Glycolytic: fast twitch, high fatigue Multiple mitochondria High capillary density Few mitochondria SERCA2 (High efficiency Ca pump) SERCA1 (Low efficiency Ca pump) Slide 55 Can thermogenesis be manipulated to prevent and treat obesity? Obligatory thermogenesis Facultative (adaptive) thermogenesis Exercise thermogenesis - Essential thermo. - Endothermic thermo. Diet-induced thermogenesis Muscle efficiency thermo Cold-induced shivering thermo Cold-induced non-shivering thermo GI, liver, WAT, muscle BAT, WAT? Muscle? All organs Most organs Insulin Norepinephrin (central) none Thyroid hormone Muscle Thyroid hormone? Muscle Acetylcholine (central) BAT, WAT? Muscle? norepinephrin (central) voluntary Involuntary (fidgeting, restlessness) ? Slide 56 Mechanisms of cold-induced thermogenesis in mice 1 AR: BAT hyperplasia 3 AR: BAT hypertrophy, Mt biogenesis Slide 57 Slide 58 Any relevance to humans? (exercise in a pill) 1.Adipose tissue: - some evidence for generation capacity of BAT, or atypical BA in WAT human 3 Adrenergic receptor agonist? 2. Skeletal muscle: - DII is expressed in humans in skeletal muscle - participates in type I to type II fiber conversion (resistance training in a pill) obesity already associated with tendency to type II > type I fiber DII is not specific to skeletal muscle side effects?