7. Obesity.pdf

MODULE 3 6 DIETARY LIPIDS AND LIPOPROTEINS 7 OBESITY 8 ATHEROSCLEROSIS 1 7 OBESITY 2  7. OBESITY – CONTENTS – I. ADIPOSE TISSUE I...

MODULE 3 6 DIETARY LIPIDS AND LIPOPROTEINS 7 OBESITY 8 ATHEROSCLEROSIS 1 7 OBESITY 2  7. OBESITY – CONTENTS – I. ADIPOSE TISSUE III. DRUGS FOR TREATMENT OF OBESITY Hormones Lifestyle Modifications Cytokines Pharmacotherapy: Hypertrophy and differentiation Anorexiants Lipase inhibitors II. OBESITY Serotonin agonists Definition Combination therapy Incidence Health benefits of intermittent fasting Cost and Consequences Factors determining energy balance IV. AEROBIC AND ANAEROBIC EXERCISE and storage 1. Dietary (Metabolic Factors) Diet saturated fats and VLDL Fructose metabolism and VLDL 2. Neural Control 3. Insulin Resistance Decreased number of IR Inhibition of IR by TNFa Activation of HSL 4. Adipokines Leptin Adiponectin 3  7. OBESITY – LEARNING OBJECTIVES – Describe the hormones and cytokines produced by adipose tissue Define BMI and the values applying to underweight, normal, overweight, and obese individuals Discuss the increase in LDL and the consequences of fructose metabolism in obesity Apply knowledge on neural control to obesity Explain the mechanisms of insulin resistance in obesity Discuss the mechanism of action of drugs to treat obesity as a function of the ‘factors contributing to obesity’ (e.g., dietary factors, neural control, etc). 4 I. ADIPOSE TISSUE 5  I. ADIPOSE TISSUE "Adipose tissue is a remarkably complex organ with profound effects on physiology and pathophysiology and it plays a major role in nutrient homeostasis, serving as the site of calorie storage after feeding and as the source of circulating free fatty acids during fasting”. (Rosen, E.D., Spiegelman, B.M. (2014)). Adipose tissue is an endocrine organ (adipose synthesizes adipokines, such as leptin and adiponectin). Adipose tissue produces inflammatory cytokines (such as TNF-a and IL-1b) at the center of energy homeostasis” (Cell 156, 20-44) LEPTIN HORMONES ADIPONECTIN RESISTIN IL-1β CYTOKINES IL-6 TNF-α 6  I. ADIPOSE TISSUE Adipocytes are terminal differentiated cells, they do not divide. Adipocytes store triglycerides by hypertrophic growth (increase in size until a critical size is reached). The increase in adipose tissue is the result of adipocyte hypertrophy and recruitment of precursor cells. Adipose tissue expansion in adulthood is achieved mainly by the proliferation and differentiation of adipocyte precursors to produce new adipocytes. White Adipose Tissue adipocytes derive from mesenchymal precursor cells. Adipocytes secrete numerous matrix proteins that maintain the structure of the depot. Newborn Adult Generates Fat body heat storage 7 II. OBESITY 8  OBESITY Obesity is a major health risk for cardiovascular disease and stroke as well as for diabetes type II and neurodegenerative diseases. There is also some association of obesity with cancer and reduction of lifespan. BMI (Body Mass Index) is a measure of an adult's weight in relation to his or her height, specifically the adult's weight in kilograms divided by the square of his/her height in meters. Although not entirely correct, the BMI is used to define or characterize obesity: having a very high amount of body fat in relation to lean body mass of 30 or higher. Overweight people have a BMI between 25 and 30. The Mayo Clinic publishes the following standards for BMI values ranging from underweight to obese persons: Weight (kg) __________ BMI = Height (m2) underweight normal overweight obese less than 18.5 18.5 to 24.9 25 to 29.9 30 or greater 9  OBESITY Incidence In 1990, states participating in the Behavioral Risk Factor Surveillance System, 10 states had a prevalence of obesity less than 10% and no state had prevalence equal to or greater than 15%. By 2000, no state had a prevalence of obesity less than 10%, 23 states had prevalence between 20 and 24%, and no state had prevalence equal to or greater than 25%. In 2010, no state had a prevalence of obesity less than 20%. 36 states had prevalence ≥ 25%. 12 of these states had prevalence ≥ 30%. 10  OBESITY Cost and Consequences 11 Obesity (2012) 20, 214-220 12  OBESITY THE FIRST LAW OF THERMODYNAMICS The energy within a closed system remains constant If you eat it (energy intake), you must burn it (energy expenditure), or you will store it (weight gain) Robert H. Lustig Nature Clinical Practice Endocrinology & Metabolism 2, 447-458 (2006) 13  OBESITY Factors determining the energy balance and storage Fat is the major mechanism to store energy in the body. When energy intake exceeds energy expenditure, fatty acid synthesis will occur. Ingestion of 5% or more calories than expended can result in the accumulation of ~5 kg of adipose tissue in 1 year. There are two mechanisms for fat formation in the body: dietary intake- and de novo synthesis of fatty acids. Genetic and environmental factors help determine the energy balance and storage, i.e., the balance between energy expenditure and energy intake Fuel Input O2 Storage ADP Metabolic Demand ATP CO2 + H2O + urea 14  OBESITY GENETIC AND ENVIRONMENT GENETICS ENVIRONMENT physiology behavior resting active time spent thermic effect assimilation macronutrient where and metabolic rate metabolic rate active of food efficiency selection when to eat energy energy expenditure intake ENERGY BALANCE AND STORAGE 15  OBESITY Factors determining energy balance and storage The most serious and frequent nutritional problem is excessive energy consumption. The resulting obesity has dietary (metabolic) and genetic components. 1. Dietary (metabolic) factors 2. Neural Control 3. Insulin Resistance 4. Adipokines Fuel Input O2 Storage ADP Metabolic Demand ENERGY ATP EXPENDITURE FOOD INTAKE CO2 + H2O + urea 16  OBESITY 1. Dietary (metabolic) factors The major mechanism of weight gain is consumption of calories in excess of daily energy requirements. The most effective treatment of obesity is reduction in the ingestion or increase in the use of calories (dieting + exercise). Fuel Input O2 Storage ADP Metabolic Demand ENERGY ATP EXPENDITURE FOOD INTAKE CO2 + H2O + urea 17  OBESITY 1. Dietary (metabolic) factors One striking clinical feature of overweight individuals is a marked elevation of serum free fatty acids, cholesterol, and triacylglycerols irrespective of the dietary intake of fat. The mechanism would be that saturated fatty acids in the diet increase serum cholesterol by decreasing the expression of LDL Increased VLDL formation receptors, thus leading to an increased 100 CII TG duration of LDL circulation in plasma. VLDL synthesis E C CE Also saturated fatty acids can cause an VLDL increase in VLDL (ultimately LDL) lipoprotein LDL lipase receptor Decreased formation. Trans-fatty acids behave number of Increased LDL receptors conversion similarly to saturated fatty acids. to LDL 100 Increased TG E C LDL levels CE LDL 18  O fatty acid || III. METABOLISM OF TRIACYLGLYCERIDES R–C–OH ATP + CoASH glycerol-P acyl-CoA synthetase CH2OH PPi + AMP | HO– C –H glycolysis glucose O | || C H2–O–Pi O fatty acyl CoA R–C–SCoA fatty acid || R–C–OH acyltransferase ATP + CoASH HSCoA O glycerol-P acyl-CoA || synthetase CH2OH O–C–R PPi + AMP | HO– C –H glycolysis glucose O | || C H2–O–Pi fatty acyl CoA R–C–SCoA acyltransferase HSCoA O O |||| O C H O–C–R || O C| H22O–C–R O CH2O–C–R ||HO– C| –H phosphatase || | R–C–O– C| –H R–C–O– C –H O | –O–Pi | || C CH H22–O–Pi CH2–OH phosphatidic acid Pi O diacylglycerol || R–C–SCoA HSCoA O O || acyltransferase || O CH2O–C–R HSCoAO CH2O–C–R || | phosphatase || | R–C–O– C –H R–C–O– C –H O || | O | H O–C–R C CH2–O–Pi || C| H22–OH phosphatidic acid Pi O R–C–O– C –H diacylglycerol O || | || triacylglycerol CH2–O–C–R R–C–SCoA 19 acyltransferase  SUCROSE OBESITY sucrase 1. Dietary (metabolic) factors Hepatic metabolism of glucose and fruct- GLUCOSE FRUCTOSE ose generates glyceraldehyde-3P, dihydroxy- fructose-6P fructokinase acetone-P, and glyceraldehyde. The conver- fructose-1,6-bisP fructose-1P sion of dihydroxyacetone-P to glycerol-P leads to triacylglycerol forma- aldolase glyceraldehyde-3P dihydroxyacetone-P glyceraldehyde tion after esterification with activated fatty acids (acyl-CoA) pyruvate glycerol-3P HIGH fatty FAT acyl-CoA derived from a high fat diet. acids DIET β-oxidation acetyl-CoA triglyceride ApoB100, C, E TCA CO2 lipoprotein + (VLDL) ATP 20  OBESITY 2. Neural Control The neural control of caloric intake to balance energy expenditure is abnormal in obese hunger saciety patients. Two hormones, released signal Hunger signal signal Satiety signal by stomach (ghrelin) and adipose ­Appetite, Feeding ¯Appetite, Feeding tissue (leptin) act on specific neurons on hypothalamus: ghrelin NPY/AgRP neurons on Agouti-Related Protein-express- POMC neurons ing neurons that generate the ghrelin receptor leptin neuropeptide Y (NPY/AgR neurons) receptor and leptin on Pro-Opio Melano Ghrelin Leptin Cortin-expressing neurons (POMC Ghrelin Leptin neurons). AgRP neurons induce feeding whereas POMC neurons inhibit feeding. stomach adipose tissue adipose 21 adipose stomach stomach tissue  OBESITY 2. Neural Control hunger satiety VENTRICULAR NUCLEUS PARA- Y1R MC4R HYPOTHALAMUS hunger saciety signal signal ARCUATE NUCLEUS hunger saciety signal signal Appetite, Feeding Appetite, Feeding Appetite, Feeding Appetite, Feeding NPY/AgRP neurons NPY/AgRPAgRP/NPY neurons POMC POMC POMC neurons ghrelin neurons ghrelin receptor receptor ghrelin leptin leptin leptin receptor receptor receptor receptor Ghrelin Ghrelin Leptin Leptin Ghrelin Leptin Ghrelin Leptin ghrelin leptin stomach adipose stomach adipose tissue stomach adipose 22 tissue stomach adipose tissue tissue 2. Neural Control OBESITY ¯ FOOD INTAKE ­ FOOD INTAKE POMC AgR/NYP LR GR IR IR leptin Insulin ghrelin Insulin binds to IRs on POMC neurons to increase the expression of anorexigenic peptides (POMC and CaRT). Conversely, insulin acts on AgRP neurons to inhibit the expression of orexigenic peptides (AgRP and NPY). 23  OBESITY a. Decreased number of insulin receptors (IR) 3. Insulin Resistance b. TNFa inhibits IR and IRS c. Increased HSL activity and fatty acid release a. Obesity almost always causes some decreased number Ins of insulin receptors degree of insulin resistance: tissues fail to TNF-" IR respond to insulin because the number or affinity of the insulin receptors is reduced or abnormal post-receptor responses. The IRS PIP2 greater the quantity of body fat, the post-receptor PI3K post-receptor responses decrease PTEN greater the resistance of normally insulin- responses sensitive cells to the action of insulin. As PIP3 decrease PDK1 a consequence of insulin resistance, GSK3! plasma insulin levels are greatly elevated Akt in the blood of obese individuals. The insulin resistance of obesity can lead to P GSK3! the development of type 2 diabetes. 24  OBESITY a. Decreased number of insulin receptors (IR) 3. Insulin Resistance b. TNFa inhibits IR and IRS c. Increased HSL activity and fatty acid release Ins b. Obesity is associated with an increased number TNF-α IR and size of adipose tissue cells. These cells over- produce inflammatory chemokines such as tumor PIP2 necrosis factor a (TNF-a), which cause cellular IRS resistance to insulin by interfering with the autophos- PI3K PTEN phorylation of the insulin receptor and the subsequent PIP3 phosphorylation of the insulin receptor substrate 1 (IRS-1). PDK1 LEAN OBESE INSULIN-SENSITIVE INSULIN-RESISTANT GSK3β Akt GSK3β P 25  OBESITY a. Decreased number of insulin receptors glucose transport (IR) glucagon into the cell prostaglandin E1 3. Insulin Resistance b. TNFa inhibits IR and IRS epinephrine Ins c. IncreasedGlucose HSL activity and fatty acidACTH release nicotinic acid IR TNF-" glucose glucagon TSH phosphorylation glycogenesis receptor c. Failing of insulin to inhibit Glucose–6–P Pentose HSL in adipose glycogen Phosphates PIP2 Pentose AC IRS Phosphate tissue results in increased activity of glycogenolysis Pathway the HSL PI3K glycolysis cAMP and increase in circulating free fatty acids, Pyruvate pyruvate PIP3 PDK1 CO2 decarboxylation HSL inactive which are carried to the liver and converted Acetyl-CoA GSK3! Akt HSL lipogenesis PKA inactivephosphatase X INSULIN into triglycerides and cholesterol. Their excess PKA phosphataseP GSK3! insulin Fat ADIPOSE TISSUE CELLS active P HSL is released as VLDL, thus leading to higher HSL P active TG circulating levels of both triacylglycerol and TG fatty acids fatty acids cholesterol. 80% of adult-onset (type II) glycerol fatty acids diabetics are overweight. TG acetyl-CoA VLDL cholesterol Apo B-100 26 Apo C-II Apo E  OBESITY leptin 4. Adipokines adiponectin Adipokines: Leptin Genetic factors: The ob gene in mice (and humans) encodes a hormone known as leptin polypeptide (166 amino acids) that is expressed in adipose tissue in proportion to the severity of obesity. A strain of mice homozygous for defects in the obese (ob) gene (known as ob/ob mice) are over twice the weight of normal (OB/OB) mice and over-eat when provided with unlimited quantities of food. These mice were found to have a single mutation in the protein leptin. When fat cells become filled with high amounts of fat, leptin is secreted into circulation. 27  OBESITY leptin 4. Adipokines Satiety Signal ↓Appetite, Feeding adiponectin Adipokines: Leptin Binding of leptin to the leptin receptors in POMC neurons hypothalamus neurons causes signaling changes that decrease eating (feeling satiated) and stimulate Leptin receptor metabolic rate in adipose tissue. When obese mice lack the adipocyte-produced leptin are injected with leptin, they eat less and lose weight. This does not appear to apply to obese humans. Leptin levels in Leptin humans increase with the percentage of body fat, consistent with the synthesis of leptin by adipocytes. Obesity in humans is the result not of faulty leptin production but of leptin resistance, perhaps due to a decrease in the level of a leptin receptor in the 28 brain.  OBESITY leptin 4. Adipokines adiponectin Adipokines: Adiponectin Adiponectin is a protein produced and secreted exclusively by adipocytes; it circulates in high concentrations in healthy adults, accounting for 0.01% of total plasma protein and its plasma levels are a 1,000 times that of leptin. Circulating levels of adiponectin range between 2- and 30 µg/ml in humans and are generally higher in females than males. The plasma levels of adiponectin are decreased in obesity. 29  OBESITY leptin 4. Adipokines adiponectin Adiponectin controls glucose homeostasis by decreasing gluconeogenesis and increasing glucose uptake. Adiponectin increases lipid oxidation and clearance of triacylglycerides. Mechanisms related to glucose homeostasis depend on two types of receptors: AdipoR1 is ubiquitously distributed but most AdipoR1 abundantly expressed in skeletal muscle and it is linked AMPK to the activation of the AMPK pathway that results in !!! increased skeletal muscle fatty acid oxidation and !!! fatty acid oxidation lactate production lactate production. AdipoR2 AdipoR2, abundantly expressed in liver, is associated with the activation of peroxisome proliferator-activated PPARα receptor (PPAR)-a pathways that results in increased ↓!! fatty acid oxidation hepatic fatty acid oxidation, decreased gluconeogene- ↓!! glucose uptake sis, increased cellular glucose uptake, and inhibition of gluconeogenesis ↓!! inflammation and oxidative stress. ↓!! inflammation 30 III. DRUGS FOR OBESITY TREATMENT 31  III. DRUGS FOR OBESITY TREATMENT The TYPS website: http://typs.acadoinformatics.com/ includes several educational modules linked to various courses; you can practice basic drug information with practice questions on brand/generic, therapeutic category, indication and dosing of drugs. The content is based on the Top 300 drug list. 32  III. DRUGS FOR OBESITY TREATMENT There are two excellent articles addressing different therapies to combat obesity: Lifestyle modification to treat obesity is effective in inducing and maintaining losses of approximately 7-10% of initial weight that can prevent or ameliorate obesity-related health complications, including type 2 diabetes and hypertension. Lifestyle modification incorporates both cognitive and behavioral techniques, including self-monitoring, stimulus control, and cognitive restructuring. Pharmacotherapy is recommended in some patients as an adjunct to lifestyle modification to improve the induction and maintenance of weight loss. Advances in pharmacologic treatment of obesity must be accompanied by determination of which individuals with obesity will benefit the most for treatment. Vetter et al (2010) Nature 6, 578-588 Medications approved for long-term obesity treatment (Pharmacotherapy), when used as an adjunct to lifestyle intervention, lead to greater mean weight loss and an increased likelihood of achieving clinically meaningful 1-year weight loss relative to placebo. By discontinuing medication in patients who do not respond with weight loss of at least 5%, clinicians can decrease their patients’ exposure to the risks and costs of drug treatment when there is little prospect of long-term benefit. Yanovski & Yanovski (2014) JAMA 311, 74-86 33  III. DRUGS FOR OBESITY TREATMENT A guide to selecting treatment of obesity: Committees of the WHO and NIH encourage individuals with obesity to lose approximately 10% of their initial weight through consumption of a calorie-restricted diet and an increase in physical activity. This lifestyle modification approach is considered the cornerstone of treatment for overweight and obese individuals. If lifestyle modification alone is ineffective, pharmacotherapy may be considered for individuals with BMI ≥ 30 kg/m2 or for those with a BMI ≥ 27 kg/m2 when comorbidities (such as hypertension or type 2 diabetes mellitus) are present. _________________________ BMI category (kg/m2) _________________________ Treatment 25.0-26.9 27.0-29.9 30.0-34.0 35.0-39.9 ≥40.0 _______________________________________________________________________________________________________________________ Diet, physical with with + + + activity, and comorbidities comorbidities behavior therapy Pharmacotherapy N/A with + + + comorbidities Surgery N/A N/A with comorbidities 34  III. DRUGS FOR OBESITY TREATMENT Under Molecular Mechanisms of Obesity, four factors can be recognized: dietary (metabolic) factors neural control insulin resistance adipokines Drugs approved by the Food and Drug Administration (FDA) for long-term weight management in adults with body mass index of 30 or body mass index of at least 27 with comorbid conditions: Noradrenergic activators, compounds that partly act on the neural control of feeding (e.g., Phentermine (Adipex-P) Combination Therapy, Phentermine plus topiramate-extended release, is the first FDA-approved combination with a nonstandard dose of topiramate. Gastrointestinal lipase inhibition: the compounds act on the dietary (metabolic) component (e.g., Orlistat (Xenical)) CNS acting drugs (e.g., Serotonin receptor agonists (cause appetite suppression (e.g., Lorcaserin); Naltrexone/Bupropion. GLP-1 receptor agonists (e.g., Liraglutide, Semaglutide) 35 III. DRUGS FOR OBESITY TREATMENT Yanovski, S.Z. and Yanovski, J.A. (2014) JAMA 311, 74-86 36  O || O—S—N III. DRUGS FOR OBESITY TREATMENT NH2 O | || O — ANOREXIANTS — O O O NH2 O || OO—S—N Noradrenergic activators: Phentermine phentermine O | O topiramate || NH2 (Adipex-P) acts on the neural control of Phentermine O O (phenyl-t-butylamine) feeding and promotes catecholamine Adipex-P®, Ionamin®O O phentermine topiramate GABA Noradrenaline release from the nerve terminals and inhibiting reuptake. Phentermine acts Noradrenaline POMC GABA NPY/AGRP on the hypothalamus, it stimulates the release of norepinephrine or noradrenal- POMC Increases NPY/AGRP Reduces ine from the dopaminergic neurons. Satiety Hunger Noradrenaline activates the POMC neurons leading to satiety. Increases Satiety Reduces Hunger 37  III. DRUGS FOR OBESITY TREATMENT — COMBINATION THERAPY — Combination therapies are designed to target multiple receptor subtypes in the hypothalamus, an area of the brain critical for the control of energy homeostasis and their mechanism of action falls within the neural control of energy homeostasis. The combination of phentermine and controlled-release topiramate (an antiepileptic agent) (Qsymia®) has been found to induce weight loss by neural control. This combination has been approved for long-term use in the treatment of obesity. O || O—S—NH2 O | || NH2 O O O O O phentermine topiramate 38  O || O—S—NH2 III. DRUGS FOR OBESITY TREATMENT O | || NH2 O — COMBINATION THERAPY — O O O || O OO—S—NH2 phentermine || NH2 O | O topiramate Topiramate stimulates GABA release, O O which has an inhibitory effect of NYP, O O phentermine topiramate GABA Noradrenaline thus reducing feelings of hunger. Phentermine stimulates release of Noradrenaline POMC GABA NPY/AGRP noradrenaline from the dopamine neurons in the hypothalamus; noradre- POMC NPY/AGRP Reduces naline stimulates POMC neurons lead- Increases Satiety Hunger ing to satiety. Increases Reduces Satiety Hunger 39  III. DRUGS FOR OBESITY TREATMENT — LIPASE INHIBITORS — Gastrointestinal lipase inhibitors like Orlistat –a specific pancreatic lipase inhibitor– prevents the hydrolysis and absorption of approximately 30% of dietary fat contained in a meal. The fats loss of calories from decreased ingested fat absorption is the main cause of weight fats ingested in the diet in the diet loss. However, the drug's mechanism 8 fatty of acidsaction are oxidizedoften results in8 fatty several gastrointestinal acids are oxidized as fuel or esterified for as fuel or esterified for adverse effects, including abdominal pain, bloating, and even ga cholestatic llb storage hepatitis. fa t i si ga llb storage in fa ts i lad de th nge lad n th nge gallbladder gallbladder e di sted d e d ste r et er INTESTINAL LUMEN adipocyte H iet d adipocyte | N—C=O 1 1 bi orlistat b O O le LIPASE d sm ieta salt LIPASE di ile s O O s e m tar lts a m al ry s e small m a ix l i fa m 2 iintestine ed nt ts ul 2 iintestine ix ll i y fa em small nt e in s 7 e nt ts ul de es m st n if i i i t s y tes a m nt fattyd acids m est enter in scellsify in sm t8es a 7 fatty acids enter cells gr tin ce ne he ti l l d e e s i c i n t Orlistat l ad al lls fo , n e g t ra ina e e lls , f e h ti fa ne l 8 1 bile salts emulsify e t lip rm delipoprotein l o a tt fa r a i 1 bile salts emulsify t lip lipase rm s sf ya lipoprotein lipase as tty dietary fats3 fin the iac se n r 6 lipoprotein iac ase lipase,ingactivated to ue ci sto fu ac g dietary fats3 fin the 6 lipoprotein lipase, activated a small intestine, th tty forming yl s gl a by yl s in the capillary rag l or ds a ApoC-II ra el o ids ge r a y small intestine, th y tt forming g ly triacylglycerols to e e r by ApoC-II in the capillary co e in ac mixed micells ce mixedcapillary co e in ac micells converts ce MUCOSAL CELL ste e o converts triacylglycerols to es re nv te ids ro n i r r i x i ter o er sti a ls TG ve es st d fatty acids and o l glycerol capillary fie iz d fatty acids and glycerol ifi t 2 intestinal lipases r ed na e tLIPASE intestinal a rte tin re 5 chylomicrons move s d ed e i l m a 2 intestinal mucosa lipases d a l t intestinal f o r 5 chylomicrons move nt u ke degrade triacylglycerols degrade triacylglycerols in m akthrough the lymphatic mucosa o c n to uc en TG through the lymphatic tri os up tri os system up to tissues ac a a b a a ad system to tissues ad yl n y cy an by ip ip gl d lg chylomicron d o c oc yc ly yte chylomicron yte er c er 3 fatty acids are taken up by ols fatty acids 3 fatty acids 4 in triacylglycerols are oincorporated 4in triacylglycerols are incorporated mu tes arecataken up by ls 7fatty acids mu tes ca the intestinal mucosa and the intestinal cowith cholesterol tin mucosa pi and and apoproteins 7 converted into triacylglycerols lla sa al chylomicrons into f att cowithtin cholesterol a pi l and apoproteins fa converted into triacylglycerols r y y s into a chylomicrons l l a tty ry 6lLehninger, lip a cid2nd Edition ac nd i op s 6l l Lehninger, ip id2 Edition LIPASE p by op rot en ipo pro o se co A ro in e ter b y p t nt t co A ro in e er 4 f n p e l c fa nv po ein lipa t tri 5 c atty ver oC in l pas i ell 4 5 t C ce lls 40 wi acy h a ts -II ip e s tr i c ty ert -I li se y th lo ci tr in as w a c th h y a s c t i a I p in th lg to ch ly sy rou m ds iac th e, in ith ylg sy rou lom ids riac n th se, c ch y st g ic an yl e ac to c ly c s i a y e a  III. DRUGS FOR OBESITY TREATMENT — SEROTONIN AGONISTS — Serotonin receptor agonists: Lorcaserin binds to a Satiety Signal ↓Appetite, Feeding sub-type of serotonin (5-hydroxytryptamine) receptor, the 5-HT2C receptor, which is present in the POMC neurons. Their activation leads to POMC neurons 5-HT2CR melanocortin receptor activation and appetite Leptin receptor suppression. Lorcaserin lorcaserin Decreased appetite NH Melanocortin Cl receptor Leptin activation Increased POMC 5-HT2C receptor activation 41 III. DRUGS FOR OBESITY TREATMENT — SEROTONIN AGONISTS — 42  NALTREXONE PLUS BUPROPION The mechanism of action of the combination Bupropion/Naltrexone is stimulation of POMC neurons by Bupropion and blocking the auto-inhibitory mechanism of POMC by Naltrexone. POMC neurons –stimulated by bupropion– co-release a-MSH (a-Melanocyte Stimulated Hormone) and b-endorphin. a-MSH stimulates the melanocortin-4 receptor (MC4R) which leads to decreased food intake and weigh loss. b-endorphin binds to the inhibitory µ-Opioid Receptor (MOP-R) on POMC cells and acts like a brake to reduce activity of POMC cells. Naltrexone blocks the MOP-R and prevents the b-endorphin-mediated feedback autoinhibition of POMC cells. Together, the naltrexone/bupropion combination results in greater activity of POMC activity. Decreased appetite bupropion + Increased energy expenditure = Weight Loss MC4-R α-MSH x POMC β-endorphin MOP-R naltrexone 43  LIRAGLUTIDE AND SEMAGLUTIDE Liraglutide (Saxenda®) and Semaglutide POMC (Ozempic®,Wegovy®) (recently approved GLP1R by FDA for weight loss) have a hypo- Liraglutide Semaglutide phagic effect, which depends on the direct activation of POMC neurons: both stimulate the Glucagon-Like Peptide-1 Receptors (GLP1R) located in the NPY/AgRP POMC neurons in hypothalamus, thus resulting in satiety. GABA Liraglutide indirectly suppresses NPY/ AgRP neurons through GABA-depend- ing signaling. 44  LIRAGLUTIDE AND SEMAGLUTIDE Liraglutide (Saxenda®) and Semaglutide POMC (Ozempic®,Wegovy®) stimulate the Glucagon- GLP1R Like Peptide-1 Receptors (GLP1R) located in Liraglutide the POMC neurons in hypothalamus, thus Semaglutide resulting in satiety. Current preclinical studies support the notion that GLP1R can be a target for reward system NPY/AgRP related disorders, e.g., drugs of abuse, alcoholism, palatable foods. Semaglutide and liraglutide may have new functions by GABA mechanisms involving a reward behavior. Eren-Yazicioglu CY et al (2021) Front. Behav. Neurosci. 14:614884. 45  FDA APPROVES NEW DRUG TREATMENT FOR CHRONIC WEIGHT MANAGEMENT, FIRST SINCE 2014 Today, the U.S. Food and Drug Administration approved Wegovy (semaglutide) injection (2.4 mg once weekly) for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure, type 2 diabetes, or high cholesterol), for use in addition to a reduced calorie diet and increased physical activity. This under-the-skin injection is the first approved drug for chronic weight management in adults with general obesity or overweight since 2014. The drug is indicated for chronic weight management in patients with a body mass index (BMI) of 27 kg/m2 or greater who have at least one weight-related ailment or in patients with a BMI of 30 kg/m2 or greater. 46  FDA NEWS RELEASE FDA Approves New Medication for Chronic Weight Management Today, the U.S. Food and Drug Administration approved Zepbound (tirzepatide) injection for chronic weight management in adults with obesity (body mass index of 30 kg per square meter (kg/ m2) or greater) or overweight (body mass index of 27 kg/m2 or greater) with at least one weight-related condition (such as high blood pressure, type 2 diabetes or high cholesterol) for use, in addition to a reduced calorie diet and increased physical activity. Tirzepatide, the active ingredient in Zepbound, is already approved under the trade name Mounjaro to be used along with diet and exercise to help improve blood sugar (glucose) in adults with type 2 diabetes mellitus. “Obesity and overweight are serious conditions that can be associated with some of the leading causes of death such as heart disease, stroke and diabetes,” said John Sharretts, M.D., director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research. “In light of increasing rates of both obesity and overweight in the United States, today’s approval addresses an unmet medical need.” Approximately 70% of American adults have obesity or overweight, and many of those overweight have a weight-related condition. Losing 5% to 10% of body weight through diet and exercise has been associated with a reduced risk of cardiovascular disease in adults with obesity or overweight. 47 USC Study: Exploring Popularity of Commercial Insurance Ozempic, Wegovy Among Privately Pays for Most filled Semaglutide Prescriptions Insured Patients May Worsen Share of prescription paid in 2,203, Disparities by source A USC Study of prescription data shows that people with Medicaid or Medicare Part D may be missing out on powerful new obesity and diabetes drugs. _________________________________________________________________ MECHANISM OF ACTION OF CENTRALLY ACTING ANTI-OBESITY DRUGS LORCASERIN 5-HT2CR POMC GLP1R NALTREXONE MOPR MC4R LIRAGLUTIDE SEMAGLUTIDE BUPROPION 50 Tirzepatide………… MounjaroTM Semaglutide………. OzempicTM WegovyTM GLP-1 RybelsusTM Orforglipron Retatrutide GLP-1 GCG GIP GLP-1: Glucagon-Like Peptide 1 GIP: Glucose-dependent Insulinotropic Polypeptide GCG: Glucagon 51 IV. INTERMITTENT FASTING 52  HEALTH BENEFITS OF INTERMITTENT FASTING Anton SD et al (2017) Obesity 26, 254-268 53  HEALTH BENEFITS OF INTERMITTENT FASTING LIVER BLOOD NEURON transcription BDNF b-hydroxybutyrate b-hydroxybutyrate b-hydroxybutyrate factors acetoacetate acetyl-CoA mitochondrial biogenesis 3-HMG-CoA TCA Synaptic plasticity Enhanced performance acetyl-CoA fatty acyl CoA ATP Disease resistance ADIPOCYTE FFA FFA b-hydroxybutyrate acetoacetate triacylglycerol diacylglycerol glucose 3-HMG-CoA MUSCLE fatty acyl CoA acetyl-CoA ATP TCA acetyl-CoA b-hydroxybutyrate Sustained performance ASTROCYTE and cell growth during recovery (rest and food Anton SD et al (2017) Obesity 26, 254-268 intake) 54  HEALTH BENEFITS OF INTERMITTENT FASTING BRAIN Improved cognition Neurotrophic factor production* Synaptic plasticity* Mitochondrial biogenesis Resistance to injury and disease BLOOD Elevated ketone levels CARDIOVASCULAR SYSTEM Reduce glucose, insulin, leptin level Reduced blood pressure Elevated adiponectin levels Reduced resting heart rate Reduced inflammatory cytokines Increased parasympathetic tone Reduced markers of oxidative stress Stress resistance* LIVER Glycogen depletion ADIPOSE TISSUE Ketone production Lipolysis Increased insulin sensitivity Reduced leptin production Reduced lipid accumulation Reduced inflammation INTESTINES Enhanced motility Reduced inflammation MUSCLE Increased insulin sensitivity Enhanced efficiency/endurance Reduced inflammation Anton SD…Mattson MP (2017) Obesity 26, 254-268 55 V. ANAEROBIC AND AEROBIC EXERCISE 56  IV. ANAEROBIC AND AEROBIC EXERCISE Anaerobic Exercise example: weigh lifting. Storage of immediate “high-energy” phosphate in cardiac and skeletal muscle occurs by transfer of the phosphate group of ATP to creatine. A small percentage of creatine phosphate is excreted in urine daily. During anaerobic exercise muscle relies on its own stored phosphocreatine and glycogen; phosphocreatine serves as a source of high-energy phosphate for ATP synthesis until glycogenolysis and glycolysis are stimulated. The glycogen amount of creatine in the body is related to muscle mass. There is excreted glucose creatine-P creatinine in urine very little inter-organ cooperation during anaerobic exercise. pyruvate/ lactate creatine ATP 57  IV. ANAEROBIC AND AEROBIC EXERCISE Aerobic Exercise requires inter-organ cooperation: Glycogenolysis and glycolysis are sources of lactic acid, which establishes the Cori cycle with liver. Glucose uptake from blood into muscle is accelerated by the translocation of GLUT-4 to the plasma membrane, a process that occurs independently of insulin during exercise. During distance running there is a progressive switch from degradation of glycogen to fatty acid oxidation. Lipo- lysis increases as glucose glycogen stores are exhausted. In the fasting state, muscle oxidi- zes fatty acids in preference glucose fatty to glucose. There is little ketone acids bodies increase in blood ketone glucose bodies during exercise: this reflects the balance between lactate hepatic ketogenesis and muscle ketolysis. CO2 energy 58  EXERCISE AND EXERKINES Exerkines elicit their effects through endocrine, paracrine, and/or autocrine pathways. The classical cytokines released during acute exercise, as found in humans, include IL-6, IL-8, IL-1 receptor antagonist (IL-1RA) and IL-10, but this depends on the type and intensity of exercise. Exerkines are not merely cytokines, because hormones, neurotransmitters or metabolites associated with exercise, such as catecholamines, lactate, or free fatty acids, casn also serve as exerkines with endocrine signalling potential. Chow LS et al (2022) Nature Endocrinology 18, 273-289 59  EXERCISE AND EXERKINES Exercise’s beneficial effects enhance overall resilience, healthspan and longevity. Muscle releases exerkines –signaling moieties– in response to acute or chronic exercise. Exerkines have potential roles in the treatment of cardiovascular disease, type 2 diabetes, and obesity. Exercise Chow LS et al (2022) Nature Endocrinology 18, 273-289 Cardiovascular Healthspan disease Longevity Cognitive Resillience decline Obesity Cancer T2DM 60  EXERCISE AND EXERKINES Exerkines elicit their effects through endocrine, paracrine, and/or autocrine pathways. The classical cytokines released during acute exercise, as found in humans, include IL-6, IL-8, IL-1 receptor antagonist (IL-1RA) and IL-10, but this depends on the type and intensity of exercise. Acute exercise response is associated with responses focused on maintenance of metabolic homeostasis with acute inflammation balanced by anti-inflammatory mediators. Chronic exercise’s responses are associated with long-term metabolic adaptations and decreased inflammation. Chow LS et al (2022) Nature Endocrinology 18, 273-289 ACUTE OR CHRONIC SIGNALING EFFECT THROUGH EXERCISE MOIETY PATHWAYS endocrine Exerkine paracrine (IL-6, IL-8, IL-1RA, IL-10) autocrine 61  muscle doesn't have Glucose 6 phosphate EXERCISE AND EXERKINES _________________________________________________________________________________________________________ NAME TISSUE TARGET BIOLOGICAL ACTION RESPONSE _____________________ ACUTE CHRONIC _________________________________________________________________________________________________________ IL-6 Skeletal Many sites Multiple effects:enhancing ­ ¯ muscle enhancing WAT lipolysis, lipid oxidation, glucose homeo- tasis, anti-inflammatory response _________________________________________________________________________________________________________ IL-8 Skeletal Endothelium Regulates tissue angiogenesis ­ « and blood flow _________________________________________________________________________________________________________ Lactate Skeletal Many tissues, Provides substrate for hepatic ­ « including gluconeogenesis brain _________________________________________________________________________________________________________ Chow LS et al (2022) Nature Endocrinology 18, 273-289 62  EXERCISE AND THE IMMUNE SYSTEM Monocyte Cytokines Exerkines in the Acute effects Chronic effects systemic ­TGFb1 ¯IL-6 Exercise circulation ­IL-6 ¯ TNF Tissue effects of Exercise ­IL-10 Increased lipid oxidation ­TNF Increased mitochondrial biogenesis ­IL-1RA Increased local injury Chow LS et al (2022) Nature Endocrinology 18, 273-289 63  EFFECTS OF EXERCISE ON THE NERVOUS SYSTEM IL-6 Skeletal muscle Lactate FGF21 Adiponectin ? Exerkines Adipose crossing Exerkines in the the BBB tissue Nervous system systemic circulation ­BDNF production Exercise ­neurogenesis ­cognition ­synaptic plasticity Liver GPLD1 FGF21 Chow LS et al (2022) Nature Endocrinology 18, 273-289 64 EFFECTS OF EXERCISE ON THE SYSTEMIC CIRCULATION IL-6 Skeletal muscle Lactate FGF21 Adiponectin ? Exerkines Adipose crossing Exerkines in the the BBB tissue Nervous system systemic circulation