REGULATION OF BODY WEIGHT
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REGULATION OF BODY WEIGHT THE BIOCHEMISTRY OF APPETITE AND ENERGY EXPENDITURE REGULATION OF BODY WEIGHT OVERVIEW ORGAN SPECIALIZATION METABOLIC PATHWAYS HOMEOSTASIS DYSREGULATION PROTEINS INVOLVED IN WEIGHT REGULATION STARVATION OBESITY DIABETES: TYPES I AND II DIETING ATKINS DIET OVERVIEW 1 NORMAL METABOLISM IS A HIGHLY CONTROLLED AND REGULATED BALANCE BETWEEN ANABOLISM AND CATABOLISM CATABOLIC PROCESSES RELEASE CHEMICAL ENERGY STORED IN COMPLEX MOLECULES ANABOLIC PROCESSES BUILD COMPLEX MOLECULES FROM SIMPLER MOLECULES REQUIRE ENERGY, USUALLY FROM ATP, NADH, NADPH METABOLIC FUELS (STORAGE MOLECULES) ENERGY SAVED AS ATP, NADH, NADPH, FADH2 OR USED AS NEEDED IN VARIOUS PROCESSES PROTEINS POLYSACCHARIDES LIPIDS NUCLEOTIDE METABOLISM :ONLY A VERY SMALL ROLE IN ENERGY BALANCE (AT THE LEVEL OF PYRIMIDINE CATABOLISM) OVERVIEW 2 PATHWAYS INVOLVED IN ENERGY METABOLISM ARE INTERRELATED REVIEW THE MAJOR PATHWAYS INVOLVED IN FUEL METABOLISM AND THEIR REGULATION GLYCOLYTIC/GLUCONEOGENIC GLYCOGEN METABOLISM FATTY ACID METABOLISM CITRIC ACID CYCLE AMINO ACID METABOLISM PENTOSE PHOSPHATE PATHWAY OXIDATIVE PHOSPHORYLATION OVERVIEW 3 : COMPARTMENTALIZATION TWO COMPARTMENTS IN WHICH METABOLISM IS DIVIDED: CYTOSOL MITOCHONDRIA GLYCOLYSIS GLUCONEOGENESIS GLYCOGEN BREAKDOWN AND SYNTHESIS PENTOSE PHOSPHATE PATHWAY FATTY ACID SYNTHESIS AMINO ACID DEGRADATION AND UREA CYCLE CITRIC ACID CYCLE OXIDATIVE PHOSPHORYLATION FATTY ACID OXIDATION AMINO ACID DEGRADATION AND UREA CYCLE MEMBRANE TRANSPORT BETWEEN CYTOSOL AND MITOCHONDRIA OVERVIEW 4 MITOCHONDRIAL-CYTOSOLIC INTERFACE MITOCHONDRIAL MEMBRANE TRANSPORTERS: PYRUVATE TRANSPORTER CARNITINE/ACYLCARNITINE TRANSPORTER CITRATE TRANSPORTER ASPARTATE TRANSPORTER MALATE TRANSPORTER CITRULLINE TRANSPORTER ORNITHINE TRANSPORTER OTHERS OVERVIEW 5 ORGANS ARE SPECIALIZED WITH REGARD TO METABOLISM DIFFERENT METABOLIC NEEDS AND FUNCTIONS INTER-ORGAN COORDINATION WE WILL LOOK AT HOW SPECIFIC METABOLIC FUNCTIONS ARE DISTRIBUTED AMONG THE FOLLOWING ORGANS: BRAIN MUSCLE (SKELETAL AND HEART) LIVER KIDNEY ADIPOSE TISSUE ORGAN SPECIALIZATION: MUSCLE MUSCLE FUELS: GLUCOSE FROM GLYCOGEN FATTY ACIDS KETONE BODIES GLYCOGEN GLYCOGEN GLUCOSE-6-PHOSPHATE G-6-P ENTERS GLYCOLYTIC PATHWAY MUSCLE LACKS G-6-PHOSPHATASE SO CANNOT GENERATE GLUCOSE FOR EXPORT MUSCLE CAN SYNTHESIZE GLYCOGEN FROM GLUCOSE 1% - 2% OF MASS IN RESTED MUSCLE GLYCOGEN MOBILIZED FASTER THAN FAT GLUCOSE METABOLISM BOTH AEROBIC AND ANAEROBIC FAT METABOLISM ONLY AEROBIC MUSCLE CANNOT CARRY OUT GLUCONEOGENESIS MUSCLE CONTRACTION DRIVEN BY ATP HYDROLYSIS AEROBIC OR ANAEROBIC NEEDS ATP REGENERATION ATP RESUPPLY INITIALLY FROM PHOSPHOCREATINE (1st 4s OF MAX. EXERTION) PHOSPHOCREATINE + ADP CREATINE + ATP RESPIRATION (GLYCOLYSIS OF G-6-P) ANAEROBIC DEGRADATION TO LACTATE WHEN GLYCOLYTIC FLUX > KREBS, OXPHOS FLUXES MUSCLE LACTATE pH MUSCLE FATIGUE TRANSFERRED TO LIVER VIA BLOOD HEART MUSCLE AEROBIC PRIMARILY FATTY ACIDS AS FUEL CAN ALSO USE GLUCOSE (FROM SMALL GLYCOGEN STORE) KETONE BODIES PYRUVATE, LACTATE MUSCLE CARBOHYDRATE METABOLISM IN MUSCLE SOLELY SERVES MUSCLE CAN’T EXPORT GLUCOSE CAN’T PARTICIPATE IN GLUCONEOGENESIS IN STARVATION PROTEOLYTIC DEGRADATION OF MUSCLE TO AMINO ACIDS MUSCLE METABOLISM TO LIVER ALANINE TO LIVER LACTATE INTO AMINO ACIDS PYRUVATE H2O + CO2 BLOOD PROTEINS GLUCOSE FATTY ACIDS GLYCOGEN + FROM LIVER KETONE BODIES INTERORGAN PATHWAYS IN-CLASS EXERCISE *** DURING MAXIMUM EXERTION, MUSCLES GENERATE LACTATE, WHICH IS RELEASED INTO THE BLOODSTREAM. (1) SHOW THE PATHWAY BY WHICH GLUCOSE IS SYNTHESIZED FROM LACTATE IN THE LIVER. (2) WHY ARE SEPARATE COMPARTMENTS NEEDED FOR THIS. (3) WHY DOESN’T MUSCLE RELEASE PYRUVATE DIRECTLY FOR UPTAKE BY THE LIVER TO REGENERATE GLUCOSE, INSTEAD OF CONVERTING IT TO LACTATE? (4) WHAT IS THE NET COST, IN TERMS OF NUCLEOSIDE TRIPHOSPHATES, OF ONE SYNTHETIC CYCLE? ADIPOSE TISSUE STORES AND RELEASES FATTY ACIDS STORAGE SUBCUTANEOUS INTRA-ABDOMINAL SKELETAL MUSCLE FATTY ACIDS TRANSPORT: AS LIPOPROTEINS LIPOPROTEINS: NONCOVALENT PROTEIN-LIPID COMPLEX CHYLOMICRONS (INTESTINAL MUCOSA) DIETARY TG, CHOL TISSUES VLDLS (SYNTHESIZED IN LIVER) : LIVER TISSUE; TG, CHOL HDLS (PLASMA) : TISSUELIVER CHOL. TRANSPORT STORED AS TRIGLYCERIDES TRIACYLGLYCEROLS FATTY ACID ACYLATION TO ACYL-CoA FATTY ACYL-CoA + GLYCEROL-3-PHOSPHATE STORED TRIACYLGLYCEROLS GLUCOSE DHAP (GLYCOLYSIS) DHAP + NADH + H+ G-3-P + NAD+ HYDROLYSIS OF TRIACYLGLYCEROLS FOR FUEL ATP-DEPENDENT ACYL-CoA SYNTHETASES FATTY ACIDS + GLYCEROL WHEN GLUCOSE IS PLENTIFUL, GLYCOLYSIS PREDOMINATES DHAP G-3-P FATTY ACIDS STORED AS TRIACYLGLYCEROLS ADIPOSE TISSUE TRIACYLGLYCEROLS FROM LIVER WELL-FED TRIACYLGLYCEROLS TO LIVER FATTY ACIDS + WELL-FED GLYCEROL WELL-FED STATE FROM LIVER GLUCOSE BRAIN 20 % OF RESTING O2 CONSUMPTION FUEL FOR PLASMA MEMBRANE Na+- K+ ATPase GLUCOSE IS PRIMARY FUEL BRAIN DOESN’T STORE MUCH GLYCOGEN MAINTAINS NEURONAL MEMBRANE POTENTIAL REQUIRES STEADY SUPPLY OF GLUCOSE DURING FASTING, STARVATION KETONE BODIES BRAIN KETONE BODIES H2O + CO2 FROM LIVER GLUCOSE TO BLOOD LIVER A “CENTRAL CLEARINGHOUSE” FOR METABOLITES ALL NUTRIENTS ABSORBED BY INTESTINES DRAIN DIRECTLY INTO THE LIVER VIA THE PORTAL VEIN EXCEPT FATTY ACIDS REGULATES BLOOD GLUCOSE LEVEL RESPONDS TO: INSULIN GLUCAGON EPINEPHRINE BLOOD GLUCOSE LEVEL LIVER WHAT HAPPENS AFTER CHO INGESTION? LIVER CELLS ARE PERMEABLE TO GLUCOSE INSULIN HAS NO DIRECT EFFECT ON UPTAKE WHEN [GLUCOSE] ~ 6 mM LIVER CONVERTS IT TO G-6-P GLUCOKINASE IS THE ENZYME AN ISOZYME OF HEXOKINASE REVIEW ENZYME KINETICS OF BOTH KM = 0.1 mM FOR HEXOKINASE; 5 mM FOR GLUCOKINASE HYPERBOLIC VS SIGMOIDAL KINETICS LIVER EARLY SATURATION OF HEXOKINASE GLUCOKINASE ACTIVITY LINEAR AT HIGHER [GLUCOSE] NOT INHIBITED BY G-6-P GLUCOKINASE IS MONOMERIC INHIBITION BY G-6-P ALLOSTERISM DOESN’T EXPLAIN KINETICS OTHER ABSORBED SUGARS G-6-P IN LIVER CENTRAL ROLE OF GLUCOSE-6PHOSPHATE IN CHO METABOLISM ITS FATE DEPENDS ON DEMAND FOR GLUCOSE G6P GLUCOSE (G-6-PHOSPHATASE) WHEN BLOOD [GLUCOSE] < 5 mM TRANSPORT TO PERIPHERAL ORGANS G6P GLYCOGEN WHEN GLUCOSE DEMAND IS LOW WHEN GLUCAGON AND/OR EPINEPHRINE LEVELS G-6-P PYRUVATE (GLYCOLYSIS) ACETYL CoA INDICATES GLUCOSE DEMAND GLYCOGEN G-6-P GLUCOSE OXIDIZED BY C.A. CYCLE AND OXPHOS OR USED FOR FATTY ACID SYNTHESIS ALSO PHOSPHOLIPIDS, CHOLESTEROL PYRUVATE DEHYDROGENASE G-6-P HEXOSE-MONOPHOSPHATE SHUNT INTERORGAN PATHWAYS IN-CLASS STUDY QUESTION *** AMINO ACIDS CAN BE TRANSAMINATED TO ALANINE IN MUSCLE BY USING PYRUVATE AS THE -KETOACID SUBSTRATE. ALANINE IS RELEASED INTO THE BLOODSTREAM AND CIRCULATES TO THE LIVER. (1) SHOW HOW ALANINE IS CONVERTED TO GLUCOSE IN THE LIVER. (2) SHOW THE FATE(S) OF THE AMINO GROUPS TRANSFERRED BY THE AMINO ACIDS METABOLIZED THIS WAY IN MUSCLE (3) SHOW THE FLUX OF ALANINE’S AMINO GROUP FROM ITS ENTRY INTO THE LIVER TO ITS EXIT AS UREA. START WITH 2 MOLECULES OF ALA. IN-CLASS STUDY QUESTION EXPLAIN WHY ALCOHOL CONSUMPTION AFTER STRENUOUS EXERCISE, OR ACCIDENTALLY BY A FASTING CHILD, CAUSES HYPOGLYCEMIA (A LOW BLOOD GLUCOSE LEVEL) CLINICAL CASE STUDY A THREE MONTH OLD BABY IS REFERRED TO A DEVELOPMENTAL PEDIATRICIAN BECAUSE SHE HAS POOR HEAD CONTROL, IS HYPOTONIC, AND IS NOT DEVELOPING IN A TYPICAL FASHION. ON EXAMINATION, SHE SHOWS GLOBAL DEVELOPMENTAL DELAY (AT THE LEVEL OF A ONE MONTH OLD) AND IS FEELS LIKE A “RAG DOLL” WHEN PICKED UP. SHE HAS DECREASED MUSCLE MASS AND IS NOT FEEDING WELL. SHE HAD A NORMAL EXAMINATION AT BIRTH, BUT WAS “SMALL FOR GESTATIONAL AGE”. HEAD CIRCUMFERENCE IS NOW IN THE “MICROCEPHALIC” RANGE. THE PEDIATRICIAN CONSIDERED A METABOLIC CAUSE FOR THE BABY’S SYMPTOMS, AMONG OTHER CAUSES, AND DID AN EXTENSIVE “METABOLIC WORKUP”. ABNORMAL RESULTS INCLUDED: INCREASED SERUM [PYRUVATE], [LACTATE], [AMMONIA] INCREASED LEVELS OF SERUM ALANINE AND CITRULLINE LOW SERUM [ASPARTATE] LOW FASTING BLOOD GLUCOSE LEVEL BORDERLINE LOW BLOOD pH *NOTE: THE PHLEBOTOMIST WAS INSTRUCTED TO TRANSPORT THE LACTATE AND PYRUVATE IMMEDIATELY TO THE LAB ON ICE. CLINICAL CASE STUDY: CONTINUED THE REMAINDER OF THE BLOOD STUDIES WERE NORMAL. AFTER THE LABS RETURN, A FIBROBLAST CULTURE IS OBTAINED AND A PYRUVATE CARBOXYLASE DEFICIENCY IS DIAGNOSED. BEFORE THE RESULTS OF THE FIBROBLAST CULTURE ARE AVAILABLE, THE INFANT DEVELOPS A VIRAL SYNDROME WITH FEVER, DEVELOPS SEIZURES AND DIES. QUESTIONS: EXPLAIN THE BIOCHEMICAL BASIS FOR EACH OF THE ABNORMAL LAB FINDINGS “PSYCHOMOTOR RETARDATION” IS THE RESULT OF A LACK OF THE NEUROTRANSMITTERS GLU, ASP AND GABA. WHY DOES PYRUVATE CARBOXYLASE DEFICIENCY RESULT IN DEFICIENCIES OF THESE? IF THIS INFANT HAD NOT DIED, WHAT WOULD HAVE BEEN SOME POTENTIAL TREATMENTS? HORMONAL INFLUENCES ON METABOLISM EPINEPHRINE GLUCAGON CYCLIC AMP AS SECONDARY MESSENGER CYCLIC AMP AS SECONDARY MESSENGER INSULIN ACTIONS OF EPINEPHRINE AS AN INSULIN ANTAGONIST ACTIVATES MUSCLE GLYCOGEN PHOSPHORYLASE GLUCOSE-6-P USED IN GLYCOLYSIS TRIGGERS PHOSPHORYLATION (ACTIVATION) OF HORMONE-SENSITIVE LIPASE IN FAT CELLS MOBILIZES FAT BY HYDROLYZING TGs GLYCOGEN BREAKDOWN IN LIVER ACTIVATES GLUCONEOGENESIS IN LIVER INHIBITS FATTY ACID SYNTHESIS THE ACTIONS OF GLUCAGON ACTIONS RESTRICTED TO THE LIVER BINDS TO A GLUCAGON RECEPTOR cAMP AS A SECONDARY MESSENGER PROTEIN KINASE A IS ACTIVATED CONTROL AT LEVEL OF PROTEIN PHOSPHORYLN’ PHOSPHORYLATION OF GLYCOGEN PHOSPHORYLASE ACTIVITY OF GLYCOGEN SYNTHASE ACTIVITY OF PYRUVATE KINASE GLYCOLYTIC ACTIVITY OF FRUCTOSE -2,6-BIPHOSPHATASE F-2,6-P PFK1 GLYCOLYTIC ACTIVITY AN INSULIN ANTAGONIST THE ACTIONS OF GLUCAGON RATES OF GLYCOGENOLYSIS G-6-PHOSPHATASE IN LIVER RATES OF GLYCOGEN SYNTHESIS RATE OF GLYCOLYSIS IN LIVER CONSERVE GLUCOSE FOR OTHER ORGANS RATES OF GLUCONEOGENESIS G-6-PHOSPHATE GLUCOSE + Pi GENERATES GLUCOSE FOR RELEASE TO BLOOD RATES OF FATTY ACID SYNTHESIS FAT BECOMES ENERGY SOURCE TO PRESERVE BLOOD GLUCOSE LEVELS EPINEPHRINE AND GLUCAGON ARE INSULIN ANTAGONISTS AFTER BINDING TO THEIR RECEPTORS, THEIR INTRACELLULAR SIGNALS ARE MEDIATED BY THE TRANSIENT ACTIVATION OF STIMULATORY GHETEROTRIMERIC PROTEINS ADENYLATE CYCLASE IS ACTIVATED cAMP IS A “SECONDARY MESSENGER” HETEROTRIMERIC G PROTEINS MEDIATE SIGNAL TRANSDUCTION : LIGAND+RECEPTOR HET G PROTEIN TARGET AMPLIFICATION OF EXTRACELLULAR SIGNAL L-R COMPLEX ACTIVATES MANY HET G PROTEINS HET G PROTEINS BIND GTP AND GDP INACTIVE FORM: HET G PROTEIN + GDP ACTIVE FORM : HET G PROTEIN + GTP INACTIVE FORM + GTP ACTIVE FORM + GDP -THIS IS AN EXCHANGE REACTION -REQUIRES LIGAND BOUND TO RECEPTOR HET G PROTEINS HYDROLYZE GTP TO GDP + Pi CAUSES DEACTIVATION OF ACTIVATED G PROTEIN A SLOW PROCESS (2 – 3 MIN-1) ACTIVATED HET G PROTEIN ACTIVATES ADENYLATE CYCLASE HETEROTRIMERIC G PROTEINS ONE OF A LARGER FAMILY OF “G PROTEINS” G PROTEINS BIND GDP AND GTP G PROTEINS HAVE GTPase ACTIVITY AMONG THEIR FUNCTIONS ARE: SIGNAL TRANSDUCTION VESICLE TRAFFICKING TRANSLATION TARGETING (SIGNAL RECOGNITION) (NOTE THAT THE GTPase ACTS AS AN “ENERGASE” AND NOT A HYDROLASE IN THESE) HETEROTRIMERIC G PROTEINS INCREASE CYCLIC AMP I.E., A SIGNAL TRANSDUCTION FUNCTION EXTRACELLULAR HORMONE L B I I P L RECEPTOR ADENYLATE CYCLASE I A DY E R GDP INTRACELLULAR GTP INACTIVE HETEROTRIMERIC G PROTEIN HORMONE-RECEPTOR COMPLEX RECEPTOR ADENYLATE CYCLASE GTP GDP GTP-GDP EXCHANGE REACTION ACTIVATED G PROTEIN HORMONE-RECEPTOR COMPLEX RECEPTOR ADENYLATE CYCLASE GTP 4 ATP 4 cAMP + 4 PPi ADENYLATE CYCLASE IS ACTIVATED AND CYCLIC AMP IS PRODUCED IF THE RECEPTOR IS A “STIMULATORY” ONE HORMONE RECEPTOR ADENYLATE CYCLASE GDP + PPi BOUND GTP IS HYDROLYZED AND AC IS DEACTIVATED G PROTEIN-COUPLED RECEPTORS INTEGRAL MEMBRANE PROTEINS 1 % OF HUMAN GENOME CODES FOR THESE RECEPTORS FOR 7 TRANSMEMBRANE HELICES CATECHOLAMINES EICOSANOIDS MOST PEPTIDE AND PROTEIN HORMONES OLFACTION AND GUSTATION LIGHT SENSING (RHODOPSIN) MOST IMPORTANT CLASS OF DRUG TARGETS (~ 50 % OF NEW DRUG EFFORTS) CYCLIC AMP A “SECONDARY MESSENGER” ATP 3’,5’- cAMP + PPi (ADENYLATE CYCLASE) cAMP + H2O AMP (PHOSPHODIESTERASE) REQUIRED FOR ACTIVITY OF PROTEIN KINASE A cAPK PHOSPHORYLATES SPECIFIC Ser AND/OR Thr ALSO KNOWN AS cAMP-DEPENDENT PKA, OR cAPK PHOSPHORYLASE b KINASE GLYCOGEN SYNTHASE cAMP PHYSIOLOGIC EFFECTS MEDIATED BY ACTIVATION OF SPECIFIC PROTEIN KINASES CYCLIC AMP GLUCAGON AND EPINEPHRINE cAMP LEVELS THIS cAPK ACTIVITY cAPK ACTIVITY PHOSPHORYLATION RATES DEPHOSPHORYLATION RATES PHOSPHORYLATION OF ENZYMES OF GLYCOGEN METABOLISM GET GLYCOGEN BREAKDOWN WHY? ACTIVATION OF GLYCOGEN PHOSPHORYLASE INACTIVATION OF GLYCOGEN SYNTHASE OPPOSITE HAPPENS WHEN [cAMP] DECREASES THE ADENYLATE CYCLASE SIGNALING SYSTEM REFER TO THE MECHANISM OF RECEPTORMEDIATED ACTIVATION/INHIBITION OF AC ON PAGE 676 OF THE VOET&VOET TEXT INSULIN ACTIONS: PERIPHERAL STIMULATES GLUCOSE UPTAKE IN STIMULATES GLUCOSE STORAGE AS GLYCOGEN IN ADIPOSE TISSUE MUSCLE LIVER MUSCLE STIMULATES STORAGE AS FAT IN ADIPOCYTES PROMOTES DIFFERENTIATION OF WHITE FAT CELLS ACTIVATES LIPOPROTEIN LIPASE INHIBITS HORMONE-SENSITIVE LIPASE INHIBITS GLUCONEOGENESIS IN LIVER INHIBITS GROWTH HORMONE RELEASE INHIBITS CATECHOLAMINES STARVATION NORMAL DISTRIBUTION OF NUTRIENTS AFTER A MEAL PROTEINS AMINO ACIDS IN GUT ABSORBED BY INTESTINAL MUCOSA PORTAL VEIN CIRCULATION TO LIVER IF NOT METABOLIZED IN LIVER PROTEIN SYNTHESIS IF EXCESS, OXIDATION FOR ENERGY PERIPHERAL CIRCULATION FOR METABOLISM SERINE FROM RENAL GLY METABOLISM ALANINE FROM INTESTINAL GLN METABOLISM NO DEDICATED STORAGE FOR AMINO ACIDS STARVATION IN-CLASS STUDY QUESTIONS DURING STARVATION, GLUCOSE IS SYNTHESIZED FROM PROTEOLYTIC DEGRADATION OF PROTEINS (MOSTLY MUSCLE). EXPLAIN HOW THE REACTIONS OF THE GLUCOSE-ALANINE CYCLE OPERATE DURING STARVATION. WHAT KIND OF MOLECULE CAN BE CONSIDERED AS A KIND OF STORAGE DEPOT FOR AMINO ACIDS? HOW DOES IT DIFFER FROM OTHER FUEL-STORAGE MOLECULES? GLUCONEOGENESIS PHOSPHOENOLPYRUVATE ADP CO2 + GDP PYRUVATE KINASE PEP CARBOXYKINASE ATP GTP CITRIC ACID CYCLE OXALOACETATE ALANINE FROM LIVER PYRUVATE ACTIVATES ADP + Pi ATP + CO2 ACETYL-CoA PYRUVATE CARBOXYLASE ACTIVATES CITRIC ACID CYCLE STARVATION NORMAL DISTRIBUTION OF NUTRIENTS AFTER A MEAL CARBOHYDRATES DEGRADED IN GUT PORTAL VEIN CIRCULATION TO LIVER DIETARY GLUCOSE ~1/3 CONVERTED TO GLYCOGEN IN LIVER ~1/3 CONVERTED TO GLYCOGEN IN MUSCLE REMAINDER OXIDIZED FOR IMMEDIATE ENERGY GLUCOSE IN BLOOD INSULIN INSULIN STIMULATES: GLUCOSE UPTAKE GLYCOGEN SYNTHESIS: BODY STORES ~ 24 HR SUPPLY OF CARBOHYDRATE STARVATION NORMAL DISTRIBUTION OF NUTRIENTS AFTER A MEAL FATTY ACIDS PACKAGED AS CHYLOMICRONS CIRCULATED FIRST IN LYMPH AND BLOODSTREAM NOT DIRECTLY DELIVERED TO LIVER UPTAKE BY ADIPOSE TISSUE TRIACYLGLYCEROLS FAT METABOLISM REGULATION F.A. OXIDATION REGULATED BY BLOOD [FATTY ACID] CONTROLLED BY TG HYDROLYSIS IN FAT CELLS MITOCHONDRIAL OXIDN’ ACETYL-CoA KETONE BODIES + OXALOACETATE CITRATE TRICARBOXYLATE TRANSPORT SYSTEM CITRATE + CoA ACETYL-CoA + OXALOACETATE + ADP + Pi CITRIC ACID CYCLE TRANSPORTED TO CYTOSOL ATP-CITRATE LYASE IS THE ENZYME F.A. SYNTHESIS TGS ACETYL-CoA CARBOXYLASE IS 1st COMMITTED STEP THE METABOLIC CONSEQUENCES OF STARVATION WHEN [GLUCOSE] , GLUCAGON RELEASED GLYCOGEN BREAKDOWN IN LIVER PROMOTES GLUCONEOGENESIS RELEASES GLUCOSE FROM AMINO ACIDS, LACTATE AT SAME TIME, INSULIN MOBILIZATION OF FATTY ACIDS FROM FAT INHIBITS GLUCOSE UPTAKE BY MUSCLE MUSCLE USES FATTY ACIDS FOR FUEL LACTATE PRODUCTION STARVATION EVENTUALLY LIVER GLYCOGEN DEPLETED RELIANCE ON GLUCONEOGENESIS CANNOT SYNTHESIZE GLUCOSE FROM F.A.s WHY NOT? SOURCE OF GLUCONEOGENIC INTERMEDIATES AMINO ACIDS FROM MUSCLE BREAKDOWN GLYCEROL FROM TRIACYLGLYCEROL BREAKDOWN AFTER A FEW DAYS OF STARVATION: KETONE BODIES SYNTHESIZED IN LIVER FROM FATTY ACID OXIDATION ALTERNATE FUEL FOR BRAIN STARVATION FATTY ACID BREAKDOWN AFTER PROLONGED STARVATION SPARES MUSCLE BREAKDOWN SURVIVAL TIME ULTIMATELY DEPENDS ON FAT STORES NORMAL ADIPOSE STORE CAN SUSTAIN LIFE FOR ONLY ~ 3 MONTHS STARVATION STUDY QUESTION EXPLAIN THE BIOCHEMICAL CHANGES SEEN AS THE BODY ADAPTS TO STARVATION. LIST THE ORDER IN WHICH THE LIVER USES THE FOLLOWING SUBSTANCES TO PROVIDE THE BODY WITH METABOLIC FUEL DURING STARVATION: GLYCOGEN, FATTY ACIDS, MUSCLE PROTEIN, NON-MUSCLE PROTEIN PROTEINS INVOLVED IN BODY WEIGHT REGULATION LEPTIN INSULIN GHRELIN PYY3-36 NEUROPEPTIDE Y (NPY) AgRP (AGOUTI-RELATED PEPTIDE) PRO-OPIOMELANOCORTIN (POMC) -MELANOCYTE STIMULATING HORMONE (-MSH) COCAINE AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) APPETITE CONTROL AT HYPOTHALAMIC LEVEL DIRECT EFFECTS OF PROTEINS ON NEURONS IN ARCUATE NUCLEUS HYPOTHALAMUS ARCUATE NUCLEUS GHRELIN RECEPTOR INSULIN OR LEPTIN RECEPTOR - OTHER NEURONS + GHRELIN - PYY3-36 Y2R (AN NPY RECEPTOR SUBTYPE) MSH RECEPTOR POMC/ CART NPY/ AgRP - + LEPTIN AND INSULIN LEPTIN A MONOMERIC PROTEIN OF 146 RESIDUES DISCOVERED IN 1994 EXPRESSED ONLY BY FAT CELLS REFLECTS QUANTITY OF BODY FAT FAT LEPTIN APPETITE SIGNAL TRANSDUCTION: LEPTIN BINDS TO OB-R PROTEIN IN HYPOTHALAMUS ALSO CONTROLS ENERGY EXPENDITURE ( METAB. RATE) IN OBESITY, LEPTIN BUT LACK OF EXPECTED IN APPETITE “LEPTIN RESISTANCE” SATURATION EFFECT AT BLOOD-BRAIN BARRIER LEPTIN ***LEPTIN HAS PERIPHERAL EFFECTS AS WELL AS CNS EFFECT PERIPHERAL OB RECEPTORS STIMULATES FATTY ACID OXIDATION IN NONADIPOSE TISSUE INHIBITS LIPID ACCUMULATION IN NONADIPOSE TISSUE ACTIVATION OF AMPK INACTIVATION OF ACETYL-CoA CARBOXYLASE (BY PHOSPHORYLATION) [MALONYL-CoA] INHIBITION OF CARNITINE PALMITOYL TRANSFERASE I TRANSPORT OF FATTY ACYL-CoA INTO MITOCHONDRIA DOES NOT PREVENT OBESITY, THOUGH LEPTIN “THRIFTY GENE” HYPOTHESIS SHORT-TERM FAT STORAGE IN ADIPOSE TISSUE PREVENTION OF ACCUMULATION IN NON-ADIPOSE TISSUES DURING SHORT-TERM OBESITY PROTECTS AGAINST: CAD, INSULIN RESISTANCE, DIABETES LEPTIN INJECTIONS APPETITE OBESITY IN INDIVIDUALS WITH LEPTIN DEFICIENCY PROTECTION FROM INTERMITTENT FAMINES RARE CONDITION G DELETED IN CODON 133 FRAMESHIFT MUTN’ INACTIVE LEPTIN IN OVERFED RODENTS RESISTANT TO LEPTIN, IN-JECTION OF LEPTIN INTO CNSBIOLOGICAL ACTIVITY LEPTIN SUMMARY WEIGHT-CONTROL IN NON-OBESE CONCENTRATION WITHOUT EFFECT IN OBESE LEPTIN RESISTANCE RESPONSIBLE FOR LONG-TERM WEIGHT PROBLEMS LEPTIN E100 (Zhang F, Basinski MB, et al. 1997. “Crystal structure of the obese protein leptin-E-100”. Nature 387(8):206-209.) X-RAY STRUCTURE OF LEPTIN E100 (WILD-TYPE HUMAN LEPTIN IS DIFFICULT TO CRYSTALLIZE BECAUSE IT AGGREGATES EXTENSIVELY. SUBSTITUTION OF Glu FOR Trp AT POSITION 100 RESULTS IN THE PROTEIN LEPTIN-E100 WHICH CRYSTALLIZES READILY AND HAS COMPARABLE BIOLOGIC ACTIVITY TO THE WILD-TYPE. ON A STRUCTURAL BASIS, LEPTIN BELONGS TO THE LONG-CHAIN HELICAL CYTOKINE FAMILY, OF WHICH HUMAN GROWTH HORMONE IS ANOTHER MEMBER.) SEE PDB 1AX8 A MONOMER, 146 RESIDUES, ONE DOMAIN IDENTIFY THE FOUR-HELIX BUNDLE ONE DISULFIDE BOND: IDENTIFY THE CYS RESIDUES INVOLVED IDENTIFY E100 IDENTIFY Tyr 61 WITHIN A HYDROPHOBIC POCKET A BURIED Tyr ON THIS HELIX IS CONSERVED IN LONG-CHAIN HELICAL CYTOKINES WHAT ATOM H-BONDS TO THE –OH GROUP OF Tyr61 PROTEINS: GHRELIN A PEPTIDE SECRETED BY GASTRIC MUCOSA ON AN EMPTY STOMACH (FASTING GHRELIN LEVELS) 28 RESIDUES REQUIRES OCTANOYLATION OF SER3 FOR ACTIVITY ALSO RELEASES GROWTH HORMONE GHRELIN DURING FASTING APPETITE FOOD INTAKE FAT UTILIZATION INJECTIONS OF GHRELIN DO THE SAME THINGS IN OBESITY, GHRELIN LEVELS ARE GHRELIN ACTIVATES NPY/AgRP NEURONS IN ARCUATE NUCLEUS IN HYPOTHALAMUS THESE ARE APPETITE-STIMULATING NEURONS SHORT-TERM APPETITE CONTROL OVERPRODUCTION OBESITY PRADER-WILLI SYNDROME HIGHEST LEVELS OF GHRELIN EVER MEASURED IN HUMANS GHRELIN LEVELS IN MOST OBESE PEOPLE ARE LOWER THAN IN NON-OBESE GHRELIN GHRELIN LEVELS WHEN WEIGHT IS LOST WHILE DIETING OPPOSES EFFECTS OF DIETING IN GASTRIC BYPASS SURGERY, GHRELIN LEVEL AND STAY THAT WAY NOT SURE WHY GASTRIC BYPASS SURGERY PROTEINS: PYY3-36 A PEPTIDE SECRETED BY GI TRACT IN PROPORTION TO CALORIC INTAKE FOOD INTAKE ACTIONS IN ARCUATE NUCLEUS INHIBITS NPY/AgRP NEURONS STIMULATE POMC/CART CELLS POMC RELEASE POMC PROCESSING IN HYPOTHALAMUS RELEASE OF -MSH -MSH INHIBIT FOOD INTAKE; ENERGY USE CART INHIBIT FOOD INTAKE; ENERGY USE INSULIN AS A HORMONAL SIGNAL IN THE BRAIN STIMULATES POMC/CART CELLS SATIETY INCREASES ENERGY EXPENDITURE INHIBITS NPY/AgRP CELLS DECREASES APPETITE (SATIETY) INHIBITS ENERGY EXPENDITURE APPETITE CONTROL AT HYPOTHALAMIC LEVEL: SUMMARY (1) APPETITE CONTROL CENTER IN HYPOTHALAMUS ARCUATE NUCLEUS TWO CELL TYPES: (SECRETE NEUROPEPTIDES) NPY AND AgRP: NPY/AgRP (NEUROPEPTIDE Y/AGOUTI-RELATED PEPTIDE) POMC/CART (PRO-OPIOMELANOCORTIN/COCAINE AND AMPHETAMINE-REGULATED TRANSCRIPT) STIMULATE APPETITE INHIBIT ENERGY EXPENDITURE POMC CONVERTED TO -MSH CART AND -MSH: INHIBIT FOOD INTAKE STIMULATE ENERGY EXPENDITURE APPETITE CONTROL AT HYPOTHALAMIC LEVEL: SUMMARY (2) NEUROPEPTIDE SECRETION REGULATED BY: LEPTIN GHRELIN INSULIN PYY3-36 APPETITE CONTROL AT HYPOTHALAMIC LEVEL: SUMMARY (3) LEPTIN AND INSULIN: (1) STIMULATE POMC/CART NEURONS CART AND -MSH LEVELS (2) INHIBIT NPY/AgRP NEURONS NPY AND AgRP NET EFFECTS: SATIETY AND APPETITE GHRELIN STIMULATES NPY/AgRP NPY AND AgRP SECRETION APPETITE PYY3-36 IS A HOMOLOGUE OF NPY BINDS TO AN INHIBITORY RECEPTOR ON NPY/AgRP SECRETION OF NPY AND AgRP APPETITE OBESITY OBESITY A MAJOR PUBLIC HEALTH PROBLEM 30% OF U.S. ADULTS ARE OBESE (NHANES 1999-2000) ANOTHER 35 % ARE OVERWEIGHT (NHANES) 15 % OF CHILDREN AND ADOLESCENTS ARE OVERWEIGHT THIS HAS DOUBLED OVER THE PAST 20 YEARS! WENT FROM 11 % - 15 % OVER PAST 20 YEARS 300,000 PEOPLE DIE EACH YEAR FROM OBESITY-RELATED DISEASES WORLDWIDE > 1 BILLION OVERWEIGHT WORLDWIDE > 300 MILLION OBESE PROJECTING TO 2008: OBESITY RATE OF 38% OBESITY OBESITY ACCOUNTS FOR 5.5 % - 7.8 % OF ALL HEALTH CARE EXPENDITURES HEALTH RISKS OF OBESITY TYPE II DIABETES ( 10X INCREASE IN PAST 20 YEARS) HEART ATTACK STROKE SOME CANCERS BREAST, COLON DEPRESSION OBESITY DEFINITIONS OVERWEIGHT: BMI > 25 KG / M2 OBESITY: BMI > 30 KG / M2 CALCULATE YOUR OWN BMI AND WRITE THE VALUE ON A SHEET OF PAPER. WE’LL COLLECT THESE AND DETERMINE THE CLASS DISTRIBUTION OF BMIs http://nhlbisupport.com/bmi/ OBESITY MAJOR FACTORS DRIVING THE OBESITY EPIDEMIC: THE PHYSICAL ENVIRONMENT! OVERCONSUMPTION EASY AVAILABILITY OF FOODS ENERGY-DENSE LARGE PORTIONS DECREASING FREQUENCY OF FAMILY MEALS FAST FOOD RESTAURANTS ADVERTISING TO CHILDREN REDUCED PHYSICAL ACTIVITY IN JOBS REQUIRING PHYSICAL ACTIVITY GENERAL CONVENIENCES ENERGY EXPENDITURES SEDENTARY ACTIVITIES TV, VIDEO GAMES, WWW OBESITY FACTORS DRIVING INCREASE IN OBESITY: THE SOCIAL ENVIRONMENT TECHNOLOGY PRODUCTIVITY CHANGING FAMILY STRUCTURE FASTER PACE OF LIFE INCREASED STRESS NOT ENOUGH TIME WALLMARTS : GETTING MORE FOR LESS INCREASE IN BOTH PARENTS WORKING INCREASE IN SINGLE-PARENT FAMILIES SOCIAL ENVIRONMENT PHYS. ENVT. RECIPROCITY OBESITY BIOLOGICAL FACTORS INVOLVED IN OBESITY INDIVIDUAL DIFFERENCES IN HEIGHT, WEIGHT GENETIC (GIVEN ADEQUATE ACCESS TO FOOD) WEIGHT (BMI), HEIGHT ARE DISTRIBUTED AROUND A MEAN VALUE IN THE POPULATION HEREITABILITY OF OBESITY = THAT OF HEIGHT AND WEIGHT DEFINITION OF OBESITY: A FIXED “THRESEHOLD” VALUE SHIFTING THE POPULATION CURVE TO THE RIGHT LARGE INCREASE IN AREA UNDER THE CURVE BEYOND THRESHOLD OBESITY BIOLOGICAL FACTORS INVOLVED IN OBESITY GENETIC DIFFERENCES IN DRIVE TO EAT 5% - 6% OF SEVERLY OBESE CHILDREN HAVE SINGLE GENE MUTATIONS 10 % OF MORBIDLY OBESE CHILDREN WITHOUT DOCUMENTED GENE DEFECTS COME FROM HIGHLY INBRED FAMILIES “THRIFTY GENE HYPOTHESIS” DRIVE TO EAT IS “HARDWIRED”; DRIVE TO NOT EAT IS WEAKER AND CAN BE OVERRIDDEN OBESITY THE THERMODYNAMICS OF OBESITY THE “FIRST LAW” : LAW OF CONSERVATION OF ENERGY ENERGY STORED = ENERGY INTAKE – ENERGY EXPENDED THERE IS NO WAY AROUND THIS! EXCESS ENERGY STORED PRIMARILY AS TRIGLYCERIDES IN FAT CELLS “POSITIVE ENERGY BALANCE” CENTRAL REGULATORY MECHANISMS A “LIPOSTAT” (IN HYPOTHALAMUS) BODY MAINTAINS FAT RESERVES AT WHATEVER THEY ARE WITHIN ~ 1% OVER YEARS PEOPLE TEND TO “DEFEND” HIGHEST ATTAINED WEIGHT OBESITY A VARIATION ON THE “SECOND LAW” YOU CANNOT GET MORE FOR LESS IMPROVEMENTS IN QUALITY OF LIFE IN ONE AREA WILL OFTEN HAVE UNINTENDED AND UNEXPECTED NEGATIVE CONSEQUENCES IN OTHER AREAS. WILL YOUR GENERATION AND THOSE SUCCEEDING IT HAVE A LESSER LIFE EXPECTANCY THAN MINE? OBESITY SOME “BOTTOM LINE” COMMENTS DESPITE THE GENETICS, THE OBESITY EPIDEMIC IS A CONSEQUENCE OF THE FIRST LAW OF THERMODYNAMICS EVOLUTION HAS BEEN DIRECTED ALONG THE LINES OF ENERGY STORAGE LONG-TERM MAINTENANCE OF WEIGHT LOSS IS DIFFICULT DIETING MAY BRING SHORT-TERM WEIGHT REDUCTIONS BUT NOT LONG-TERM ONES PREVENTION IS THE BEST APPROACH INDIVIDUAL EFFORTS POPULATION EFFORTS GENETIC OR ENVIRONMENTAL? BIOCHEMISTRY OF OBESITY PROTEIN AND GLYCOGEN LEVELS ARE REGULATED NARROWLY FAT STORES ARE NOT, SO: EXCESS FAT INTAKE COMPARED TO FAT OXIDN’ WITH EXCESS FAT INTAKE, CHO-DERIVED ACETYL-CoA IS NOT A SIGNIFICANT SOURCE OF F.A.s ADIPOSE TISSUE MASS INCREASE IN # OF FAT CELLS INCREASE IN SIZE OF FAT CELLS BIOCHEMISTRY OF OBESITY STEADY STATE EVENTUALLY REACHED % BODY FAT DIETARY FAT INTAKE LEPTIN RESISTANCE DEVELOPS FAT STORAGE = FAT MOBILIZATION HYPOTHALAMIC SET-POINT IS RAISED APPETITE NOT SUPPRESSED ENERGY METABOLISM (IN NON-ADIPOSE TISSUE) HIGH CONCENTRATIONS OF F.F.A.s INSULIN RESISTANCE DECREASES FUSION OF GLUT4-CONTAINING VESICLES WITH PLASMA MEMBRANE (MORE ABOUT THIS LATER) GLUCOSE ENTERS CELL BIOCHEMISTRY OF OBESITY PANCREAS MUST INSULIN PRODUCTION CAUSES APPETITE (“HYPERPHAGIA”) INSULIN PRODUCTION AND STORAGE OF F.A.s IN ADIPOSE TISSUE DIETING AMERICAN HEART ASSOCIATION RECOMMENDS: PROTEIN: 10% – 15% CARBOHYDRATES: 55% – 60% FAT: 25% - 30% IN-CLASS EXERCISE: PREDICT THE BIOCHEMICAL RESPONSE TO HAVING A DIET CONSISTING OF NO FAT, 70% CARBOHYDRATES AND 30% PROTEIN. IN-CLASS EXERCISE: DO THE SAME FOR A DIET WITH 0% CARBOHYDRATES, 70% FAT AND 30% PROTEIN. BIOCHEMISTRY OF THE ATKINS DIET IT’S A HIGH FAT, HIGH PROTEIN, LOW CARBOHYDRATE DIET PROTEIN IS USED FOR: LOW CARBOHYDRATE INTAKE: TISSUE BUILDING AND REPAIR CONVERSION TO GLUCOSE FOR ENERGY PROTEIN-DERIVED GLUCOSE CANNOT SUSTAIN ENERGY NEEDS FAT MUST BE BURNED LESS INSULIN PRODUCED BECAUSE LESS GLUCOSE ABSORBED FATS HIGH SATIETY FACTOR INGESTED FAT IS NOT STORED (LOW INSULIN) EXCESS FAT IS CATABOLIZED AND EXCRETED ATKINS DIET: STUDY QUESTIONS*** EXPLAIN WHAT HAPPENS TO THE ACTIVITY OF THE CITRIC ACID CYCLE WHEN SOMEONE IS ON THE ATKINS DIET. WHAT EFFECT DOES THIS HAVE ON FAT METABOLISM? BIOCHEMISTRY OF ATKINS DIET DISADVANTAGES: HIGH SATURATED FAT DIET INCREASES RISK OF HEART DISEASE A DIET LOW IN FRUITS FRUITS ARE PROTECTIVE IN CANCER KETOGENESIS IS NEEDED TO PRODUCE ENERGY BLADDER, GI TRACT, PROSTATE PERPETUAL STATE OF KETOSIS SIMILAR TO LONG-TERM STARVATION SYMPTOMS OF KETOSIS: ABDOMINAL: PAIN, NAUSEA, VOMITING (DEHYDRATION), LIVER FUNCTION ABNORMALITIES NEUROLOGIC: FATIGUE, HEADACHE METABOLIC: K+ LOSS, Ca++ LOSS, RTA HEMATOLOGIC: HEMOLYTIC ANEMIA CARDIAC: CARDIOMYOPATHY (POSSIBLY REVERSIBLE) BIOCHEMISTRY OF THE ATKINS DIET ACID-BASE EFFECTS: KETONE BODIES BLOOD pH A LOW pH GFR RENAL TUBULAR REABSORPTION OF Ca++ CALCIUM IN URINE Ca++ SALTS MOBILIZED FROM BONE PO42- NEEDED TO BUFFER ACID LOAD TO KIDNEY OSTEOPOROSIS CALCIURIA STONE FORMATION BIOCHEMISTRY OF ATKINS DIET ADVANTAGES IT WORKS IN THE SHORT RUN TG AND HDL CHOLESTEROL LEVELS IMPROVED RISK/BENEFIT ANALYSIS: PROBABLY NOT FAVORABLE WEIGHT LOSS NOT SUSTAINED (UNLESS YOU STAY ON THE DIET) IT’S UNHEALTHY CAN RESULT IN SIGNIFICANT MORBIDITY CAN RESULT IN PREMATURE DEATH BIOCHEMISTRY OF THE ATKINS DIET DESPITE ALL OF THE FANCY BIOCHEMISTRY, THE BOTTOM LINE IS THAT INCREASED FAT IN THE DIET CAUSES EARLY AND SUSTAINED SATIETY, WHICH ULTIMATELY RESULTS IN LESS DAILY INTAKE OF CALORIES. IT’S STILL A CONSEQUENCE OF THE “FIRST LAW OF THERMODYNAMICS” (ENERGY IN – ENERGY OUT). THERE ARE NO SAFE FAD DIETS THAT BOTH WORK AND ARE HEALTHY AT THE SAME TIME. YOU WILL ALWAYS GAIN THE WEIGHT BACK AFTER YOU STOP THE DIET. A CLINICAL CASE STUDY A 20 YEAR OLD, 5’ 4”, 180# FEMALE COLLEGE STUDENT WHO HAS BEEN OVERWEIGHT SINCE THE AGE OF 3 YEARS VISITS THE INFIRMARY BECAUSE SHE HASN’T BEEN FEELING WELL LATELY. SHE HAS BEEN HAVING HEADACHES AND CONSTIPATION FOR A FEW MONTHS AND SOMETIMES SHE DOESN’T THINK AS CLEARLY AS SHE USED TO. HER PERIODS HAVE BECOME IRREGULAR AND NOW SHE HAS ABDOMINAL PAIN, BACK PAIN AND RED URINE. HER FRIENDS HAVE TOLD HER THAT HER BREATH SMELLS “FUNNY”. IN TAKING A HISTORY, YOU LEARN THAT SHE HAS BEEN EXPERIMENTING WITH THE ATKINS DIET FOR THE PAST 5 OR 6 MONTHS AND HAS LOST OVER 40 POUNDS. CLINICAL CASE STUDY: CONTINUED HER PHYSICAL EXAM IS GENERALLY NORMAL EXCEPT FOR SOME ABDOMINAL TENDERNESS AND A SWEET SMELL TO HER BREATH. LABORATORY STUDIES SHOWED A LOW INSULIN LEVEL, A BLOOD GLUCOSE OF 60 mg/dL (LOW), AND AN ABNORMALLY LOW BLOOD pH. A URINALYSIS SHOWED RED BLOOD CELLS, A LOW pH, AND A MARKEDLY ELEVATED CALCIUM/CREATININE RATIO. HER CHOLESTEROL LEVEL IS 190 mg/dL. AN ABDOMINAL X-RAY (“KUB”) SHOWED SOME KIDNEY STONES CLINICAL CASE STUDY: CONTINUED QUESTIONS: WHY DOES HER BREATH SMELL SWEET? WHY IS SHE HAVING TROUBLE THINKING? WHY ARE HER INSULIN LEVELS LOW? WHY IS HER BLOOD pH LOW? WHY IS HER URINARY CALCIUM EXCRETION INCREASED? WHY IS HER URINARY pH DECREASED? WHY HASN’T THE CHOLESTEROL LEVEL CHANGED MUCH, DESPITE THE FACT THAT SHE’S EATING MORE FAT? DRUGS AND DIET XENICAL INTESTINAL LIPASE INHIBITORS MERIDIA (SIBUTRAMINE) AMPHETAMINE-LIKE NE AND SEROTONIN RE-UPTAKE INHIBITION PHENTERMINE (PART OF “REDUX”) FUTURE ANTI-OBESITY DRUGS RIMBONABANT CNTF (CILIARY NEUROTROPHIC FACTOR) (“AXOKINE”) INHIBITS CANNABINOID RECEPTORS CNTF AND LEPTIN RECEPTORS VERY MUCH ALIKE CNTF DOESN’T GENERATE RESISTANCE MELANOCORTINS AND RECEPTORS -MSH BIOCHEMISTRY OF DIABETES TYPE I INSULIN ABSENT OR ALMOST ABSENT AUTOIMMUNE GENETIC PREDISPOSITION CLASS II MHC PROTEINS MOSTLY IN CHILDREN TYPE II INSULIN RESISTANCE OBESE GENETIC PREDISPOSITION USUALLY IN > 40 YEAR OLDS NOW SEEN MORE FREQUENTLY IN OBESE YOUTH BIOCHEMISTRY OF DIABETES BLOOD GLUCOSE LEVELS RISE “HYPERGLYCEMIA” OSMOTIC EFFECT DEHYDRATION POLYDYPSIA GYCOSURIA OSMOTIC LOSS OF WATER GLUCOSE ENTRY INTO CELLS IMPAIRED ALTERNATE FUEL NEEDED HYDROLYSIS OF TRIACYLGLYCEROLS INCREASED FATTY ACID OXIDATION KETONE BODIES POLYURIA KETOACIDOSIS GLUCONEOGENESIS BIOCHEMISTRY OF DIABETES KETOACIDOSIS A STRESS ON BUFFER CAPACITY OF BLOOD KIDNEYS EXCRETION OF EXCESS H+ INTO URINE ACCOMPANIED BY EXCRETION OF NH4+ Na+ K+ INORGANIC PHOSPHATE WATER DEHYDRATION AND BLOOD VOLUME SHOCK BIOCHEMISTRY OF DIABETES [K+] IN BLOOD IS MAINTAINED BY LOSS OF K+ FROM CELLS “WHEN pH IS LOW, K+ MUST GO” TOTAL BODY K+ DEPELETION INAPPROPRIATE REHYDRATION AND INSULIN ADMINISTRATION WITHOUT SUPPLEMENTING K+ CAN CARDIAC ARYTHMIAS AND DEATH GLUCOSE TRANSPORT PROTEIN: GLUT4 LOCATED IN MEMBRANES OF INTRACELLULAR VESICLES TRANSLOCATED TO AND FUSED TO CELL MEMBRANE TRIGGERED BY INSULIN BINDING TO INSULIN RECEPTORS RATE OF GLUCOSE ENTRY INTO CELL A PASSIVE TRANSPORT Vmax BECAUSE OF INCREASED # OF GLUT4s MOSTLY IN MUSCLE AND FAT CELLS WHEN INSULIN LEVELS TRANSPORTERS RELOCATE INTO CELL “EXOCYTOSIS” “ENDOCYTOSIS” DEFECTS IN GLUT4 INSULIN RESISTANCE GLUCOSE TRANSPORT PROTEINS OTHER GLUCOSE TRANSPORTERS GLUT1 : ERYTHROCYTES GLUT2 : PANCREATIC β-CELLS AND LIVER CELLS GLUT3 : BRAIN, PLACENTA, FETAL MUSCLE INSULIN ACTIONS AS A NEURAL SIGNAL INSULIN RECEPTORS IN HYPOTHALAMUS NEURONAL REGULATION OF FOOD INTAKE (INCREASES APPETITE) BODY WEIGHT ACTIONS MEDIATED BY INSULIN SIGNALING SYSTEM SIGNAL TRANSDUCTION REQUIRES BINDING OF INSULIN TO INSULIN RECEPTORS INSULIN PROINSULIN INSULIN + C-PEPTIDE SITE SPECIFIC CLEAVAGE AT THE SEQUENCES: 2 INSULIN MONOMERS DIMERIZE ANTIPARALLEL -SHEET ASSOCIATION C-TERMINAL OF B-CHAIN 3 INSULIN DIMERS HEXAMER ASSOCIATION REQUIRES Zn2+ Zn2+ RELEASED WHEN INSULIN SECRETED HEXAMERS ARE STORED IN CELLS OF PANCREAS RECOMBINANT SYNTHESIS OF INSULIN ANALOGS “LISPRO” INSULIN: USUAL INSULIN OF CHOICE IN DIABETICS PRO28 AND LYS29 ON B-CHAIN ARE SWITCHED ARG-ARG LYS-ARG BOTH ARE COMMON SIGNALS FOR PROTEOLYTIC PROCESSING INSULIN MONOMERS DO NOT DIMERIZE FASTER ONSET OF BIOLOGICAL ACTIVITY (15 MINUTES AFTER SC ADMIN.) C-PEPTIDE: NO BIOLOGIC FUNCTION PROTEINS: INSULIN IN PERIPHERAL TISSUES INSULIN HAS 2 CHAINS LINKED BY 2 DISULFIDE BRIDGES GENE PRODUCT IS “PREPROINSULIN” GENE IS ON SHORT ARM OF CHROMOSOME #11 AFTER TRANSLOCATION TO THE E.R. 23 N-TERMINAL AMINO ACIDS ARE REMOVED “PROINSULIN” PROINSULIN: CHAINS “A” AND “B” , 3 –S-S- BONDS, AND “C” PEPTIDE THE “A” CHAIN: 21 AMINO ACIDS THE “B” CHAIN: 30 AMINO ACIDS SINGLE CHAIN OF 86 AMINO ACIDS PROINSULIN PACKAGED IN SECRETORY GRANULES THE INSULIN RECEPTOR A RECEPTOR TYROSINE KINASE A TRANSMEMBRANE GLYCOPROTEIN HAS A CYTOPLASMIC PTK DOMAIN A PERMANENT DIMER (2 AND 2 SUBUNITS) 2 s ARE LINKED BY DISULFIDE BOND EACH LINKED TO A BY –S-S- BOND THE INSULIN RECEPTOR WHEN INSULIN BINDS TO InsR, CONFORMATIONAL CHANGE OCCURS PTK DOMAINS FACE EACH OTHER CROSS PHOSPHORLYATION ACTIVATED TYRs CAN FURTHER PHOSPHORYLATE AT: 3 SPECIFIC TYR RESIDUES ARE PHOSPHORYLATED “AUTOPHOSPHORYLATION” OTHER TYRs OUTSIDE OF PTK DOMAIN CYTOPLASMIC PROTEIN SIMILAR RTKs FOR OTHER PROTEIN GROWTH FACTORS EGF, PDGF, FGF THE INSULIN RECEPTOR THE Y-KINASE ACTIVITY OF THE RTK DEPENDS ON: DEGREE OF PHOSPHORYLATION AT THE 3 Y-SIDE CHAINS FULL ACTIVITY WHEN Y1163 IS PHOSPHORYLATED SIDE CHAINS OF SER AND THR NOT LONG ENOUGH TO REACH ACTIVE SITE MAIN TARGETS OF INSULIN-RTKs “INSULIN RECEPTOR SUBSTRATES” 1 AND 2 WHEN PHSOPHORYLATED, INTERACTIONS WITH PROTEINS THAT HAVE Src HOMOLOGY 2 DOMAINS THESE BIND phospho-Tyr WITH HIGH AFFINITY Phospho-Ser and phospho-Thr NOT BOUND WELL SH2 DOMAINS PDB EXERCISES EXPLORE THE XRAY STRUCTURE OF THE PTK DOMAIN OF InsR: PDB ID 1IRK (UNPHOSPHORYLATED) PDB ID 1IR3 (PHOSPHORYLATED) AUTOPHOSPHORYLATION OF PTK DOMAINS OF InsR INSULIN S-S S-S S-S S-S TRANSMEMBRANE PART OF -SUBUNITS MEMBRANE Y1158 P Y PTK DOMAIN P IRS-1 INSULIN RECEPTOR SUBSTRATE-1 Y1162 P Y Y1163 P Y ACTIVATION LOOP HAS Y-KINASE ACTIVITY INSULIN SIGNALING SYSTEM (1) INSULIN BINDS TO THE INSULIN RECEPTOR AUTOPHOSPHORYLATION AT TYR RESIDUES -SUBUNITS OF IR PROTEINS BOUND AND TYR-PHOSPHORYLATED BY THESE phosTYRs Shc Gab-1 phosShc STIMULATES MAPK phosGab-1 ACTIVATES MAPK ALSO APS/Cbl Complex phosAPS/Cbl STIMULATES TC10 (A G-PROTEIN) ALSO REGULATES GLUCOSE TRANSPORT INDEPENDENT OF PI3K INVOLVES LIPID RAFTS AND CAVEOLAE IRS Proteins phosIRS ACTIVATES PHOSPHOINOSITIDE CASCADE PI3K INTERMEDIATE STIMULATES: GLYCOGEN SYNTHESIS, GLUCOSE TRANSPORT, CELL GROWTH AND DIFFERENTIATION INSULIN SIGNALING SYSTEM (2) OTHER CASCADES ACTIVATED: MAPK (PHOSPHORYLATION) PI3K (PHOSPHORYLATION) MAPK CASCADE REGULATES GENE EXPRESSION CELLULAR GROWTH DIFFERENTIATION Myc, Fos, Jun PROTEINS (TRANSCRIPTION FACTORS) PI3K CASCADE CHANGES PHOSPHORYLATION STATES OF SOME ENZYMES STIMULATES GLYCOGEN SYNTHESIS CONTROL OF VESICLE TRAFFICKING GLUT4 GLUCOSE TRANSPORTER TRANSLOCATED TO CELL SURFACE RATE OF GLUCOSE TRANSPORT INTO CELL INSULIN SIGNALING: SHORT SLIDE PROTEINS THAT BIND TO pY RESIDUES OF IR Shc Gab-1 Aps/Cbl Complex IRS Proteins PHOSPHORYLATION CASCADES ACTIVATED MAPK: PHOSPHORYLATES NUCLEAR TRANSCRIPTION FACTORS (Myc,Fos,Jun) GENE EXPRESSION PI3K: STIMULATES GLYCOGEN SYNTHESIS GLUCOSE TRANSPORT INTO CELL BY STIMULATING TRANSLOCATION OF GLUT4 TRANSPORTERS WHAT IS THE LINK BETWEEN OBESITY AND TYPE II DIABETES? WHAT CAUSES INSULIN RESISTANCE? ONE PROPOSAL BY GERALD SHULMAN (2005) FFAs DIFFUSE INTO MUSCLE CELLS PRODUCTION OF FATTY ACYL-CoA ACTIVATION OF PROTEIN KINASE C (PKC) TRIGGERING OF A SER/THR KINASE CASCADE PHOSPHORYLATION OF IRS-1 INCREASES SER/THR PHOSPHORYLATION DECREASES TYR PHOSPHORYLATION BY INSULIN SIGNAL DECREASE IN TYR PHOS. ACTIVATION OF PI3K RATE OF FUSION OF GLUT4-VESICLES GLUCOSE ENTERING CELL (FATTY ACIDS CAUSE INSULIN RESISTANCE BY DIRECTLY INHIBITING INSULIN-STIMULATED GLUCOSE TRANSPORT ACTIVITY) From: Lowell BB, Shulman GI. 2005. “Mitochondrial Dysfunction and Type 2 diabetes”. Science. 307: 384-387. STUDY QUESTION • EXPLAIN HOW INCREASED FREE FATTY ACIDS CAUSES INSULIN RESISTANCE.
