REGULATION OF BODY WEIGHTTHE BIOCHEMISTRY OF APPETITE AND ENERGY EXPENDITURE
REGULATION OF BODY WEIGHT
OVERVIEW ORGAN SPECIALIZATION METABOLIC PATHWAYS HOMEOSTASIS
PROTEINS INVOLVED IN WEIGHT REGULATION DYSREGULATION
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 ENERGY SAVED AS ATP, NADH, NADPH, FADH2 OR USED AS NEEDED IN VARIOUS PROCESSES
ANABOLIC PROCESSES BUILD COMPLEX MOLECULES FROM SIMPLER MOLECULES REQUIRE ENERGY, USUALLY FROM ATP, NADH, NADPH
METABOLIC FUELS (STORAGE MOLECULES) 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
GLYCOLYSIS GLUCONEOGENESIS GLYCOGEN BREAKDOWN AND SYNTHESIS PENTOSE PHOSPHATE PATHWAY FATTY ACID SYNTHESIS AMINO ACID DEGRADATION AND UREA CYCLE
MITOCHONDRIA 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
GLUCOSE GLYCOGEN
LACTATE PYRUVATE H2O + CO2
TO LIVER
AMINO ACIDS PROTEINS
ALANINE
TO LIVER
FATTY ACIDS +KETONE BODIES
INTOBLOOD
FROM LIVER
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
ATP-DEPENDENT ACYL-CoA SYNTHETASES
FATTY ACYL-CoA + GLYCEROL-3-PHOSPHATE STORED TRIACYLGLYCEROLS
GLUCOSE DHAP (GLYCOLYSIS) DHAP + NADH + H+ G-3-P + NAD+
HYDROLYSIS OF TRIACYLGLYCEROLS FOR FUEL FATTY ACIDS + GLYCEROL
WHEN GLUCOSE IS PLENTIFUL, GLYCOLYSIS PREDOMINATES DHAP G-3-P FATTY ACIDS STORED AS TRIACYLGLYCEROLS
ADIPOSE TISSUE
TRIACYLGLYCEROLS WELL-FED
FATTY ACIDS
+
GLYCEROL
GLUCOSE
WELL-FED STATE
FROM LIVER
TO LIVERTRIACYLGLYCEROLS FROM LIVER
WELL-FED
BRAIN
20 % OF RESTING O2 CONSUMPTION FUEL FOR PLASMA MEMBRANE Na+- K+ ATPase
MAINTAINS NEURONAL MEMBRANE POTENTIAL
GLUCOSE IS PRIMARY FUEL BRAIN DOESN’T STORE MUCH GLYCOGEN
REQUIRES STEADY SUPPLY OF GLUCOSE
DURING FASTING, STARVATION KETONE BODIES
BRAIN
KETONE BODIES
GLUCOSE
H2O + CO2
TO BLOOD
FROMLIVER
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 INHIBITION BY G-6-P
GLUCOKINASE ACTIVITY LINEAR AT HIGHER [GLUCOSE] NOT INHIBITED BY G-6-P
GLUCOKINASE IS MONOMERIC ALLOSTERISM DOESN’T EXPLAIN KINETICS
OTHER ABSORBED SUGARS G-6-P IN LIVER
CENTRAL ROLE OF GLUCOSE-6-PHOSPHATE 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
INDICATES GLUCOSE DEMAND GLYCOGEN G-6-P GLUCOSE
G-6-P PYRUVATE (GLYCOLYSIS) ACETYL CoA 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 PATHWAYSIN-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 CYCLIC AMP AS SECONDARY MESSENGER
GLUCAGON 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
PHOSPHORYLATION
CONTROL AT LEVEL OF PROTEIN PHOSPHORYLN’ 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 G-6-PHOSPHATE GLUCOSE + Pi
RATES OF GLYCOGEN SYNTHESIS RATE OF GLYCOLYSIS IN LIVER
CONSERVE GLUCOSE FOR OTHER ORGANS RATES OF GLUCONEOGENESIS
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 G- HETEROTRIMERIC 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 SIGNALL-R COMPLEX ACTIVATES MANY HET G PROTEINS
HET G PROTEINS BIND GTP AND GDPINACTIVE FORM: HET G PROTEIN + GDPACTIVE 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 PROTEINA 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 GTPG PROTEINS HAVE GTPase ACTIVITYAMONG THEIR FUNCTIONS ARE:
SIGNAL TRANSDUCTION VESICLE TRAFFICKINGTRANSLATIONTARGETING (SIGNAL RECOGNITION)
(NOTE THAT THE GTPase ACTS AS AN “ENERGASE” AND NOT A HYDROLASE IN THESE)
HETEROTRIMERIC G PROTEINS INCREASE CYCLIC AMPI.E., A SIGNAL TRANSDUCTION FUNCTION
RECEPTOR
ADENYLATECYCLASE
GDP
HORMONE
INACTIVE HETEROTRIMERIC G PROTEIN
GTP
L B
I IP LI AD Y
ER
EXTRACELLULAR
INTRACELLULAR
RECEPTOR
ADENYLATECYCLASE
GTP
GTP-GDP EXCHANGE REACTION ACTIVATED G PROTEIN
HORMONE-RECEPTOR COMPLEX
GDP
RECEPTOR
ADENYLATECYCLASE
ADENYLATE CYCLASE IS ACTIVATED AND CYCLIC AMP IS PRODUCED IF THE RECEPTOR IS A “STIMULATORY” ONE
HORMONE-RECEPTOR COMPLEX
GTP
4 ATP 4 cAMP + 4 PPi
RECEPTOR
ADENYLATECYCLASE
GDP
HORMONE
BOUND GTP IS HYDROLYZED AND AC IS DEACTIVATED
+ PPi
G PROTEIN-COUPLED RECEPTORS
INTEGRAL MEMBRANE PROTEINS 7 TRANSMEMBRANE HELICES
1 % OF HUMAN GENOME CODES FOR THESE RECEPTORS FOR
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 ALSO KNOWN AS cAMP-DEPENDENT PKA, OR cAPK
cAPK PHOSPHORYLATES SPECIFIC Ser AND/OR Thr 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 RECEPTOR-MEDIATED ACTIVATION/INHIBITION OF AC ON PAGE 676 OF THE VOET&VOET TEXT
INSULIN ACTIONS: PERIPHERAL STIMULATES GLUCOSE UPTAKE IN
ADIPOSE TISSUE MUSCLE
STIMULATES GLUCOSE STORAGE AS GLYCOGEN IN 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
PROTEIN SYNTHESIS IF EXCESS, OXIDATION FOR ENERGY
IF NOT METABOLIZED IN LIVER PERIPHERAL CIRCULATION FOR METABOLISM
SERINE FROM RENAL GLY METABOLISM ALANINE FROM INTESTINAL GLN METABOLISM
NO DEDICATED STORAGE FOR AMINO ACIDS
STARVATIONIN-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
PYRUVATE
OXALOACETATE
ADP
ATP
PYRUVATE KINASE
ATP + CO2ADP + PiPYRUVATE CARBOXYLASE
GTP
CO2 + GDP
PEP CARBOXYKINASE
CITRICACID
CYCLE
ACETYL-CoA
CITRICACID
CYCLEACTIVATES
ACTIVATES
ALANINE FROM LIVER
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
CITRIC ACID CYCLE TRANSPORTED TO CYTOSOL
TRICARBOXYLATE TRANSPORT SYSTEM CITRATE + CoA ACETYL-CoA + OXALOACETATE + ADP + Pi
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
RELEASES GLUCOSE
PROMOTES GLUCONEOGENESIS 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 STAR-VATION: 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
HYPOTHALAMUS
ARCUATE NUCLEUS
NPY/AgRP
POMC/CART
LEPTIN AND INSULIN
+-PYY3-36
GHRELIN
+
-
INSULIN OR LEPTIN RECEPTOR
GHRELINRECEPTOR
Y2R(AN NPY RECEPTOR SUBTYPE)
DIRECT EFFECTS OF PROTEINS ON NEURONS IN ARCUATE NUCLEUS
OTHERNEURONS
-
MSHRECEPTOR
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 NON-
ADIPOSE TISSUE INHIBITS LIPID ACCUMULATION IN NON-ADIPOSE
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 PROTECTION FROM INTERMITTENT FAMINES
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 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/AgRP (NEUROPEPTIDE Y/AGOUTI-RELATED
PEPTIDE) POMC/CART (PRO-OPIOMELANOCORTIN/COCAINE AND
AMPHETAMINE-REGULATED TRANSCRIPT) NPY AND AgRP:
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) THIS HAS DOUBLED OVER THE PAST 20 YEARS!
ANOTHER 35 % ARE OVERWEIGHT (NHANES) 15 % OF CHILDREN AND ADOLESCENTS ARE OVERWEIGHT
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
FASTER PACE OF LIFE INCREASED STRESS NOT ENOUGH TIME WALLMARTS : GETTING MORE FOR LESS
CHANGING FAMILY STRUCTURE 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
FAT STORAGE = FAT MOBILIZATION % BODY FAT DIETARY FAT INTAKE LEPTIN RESISTANCE DEVELOPS
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: TISSUE BUILDING AND REPAIR CONVERSION TO GLUCOSE FOR ENERGY
LOW CARBOHYDRATE INTAKE: 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
BLADDER, GI TRACT, PROSTATE
KETOGENESIS IS NEEDED TO PRODUCE ENERGY 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
INHIBITS CANNABINOID RECEPTORS CNTF (CILIARY NEUROTROPHIC
FACTOR) (“AXOKINE”) 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
POLYURIA GLUCOSE ENTRY INTO CELLS IMPAIRED ALTERNATE FUEL NEEDED HYDROLYSIS OF TRIACYLGLYCEROLS
INCREASED FATTY ACID OXIDATION KETONE BODIES
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 “EXOCYTOSIS”
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 “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: ARG-ARG LYS-ARG BOTH ARE COMMON SIGNALS FOR PROTEOLYTIC PROCESSING
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
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
THE “A” CHAIN: 21 AMINO ACIDS THE “B” CHAIN: 30 AMINO ACIDS
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 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
3 SPECIFIC TYR RESIDUES ARE PHOSPHORYLATED “AUTOPHOSPHORYLATION”
ACTIVATED TYRs CAN FURTHER PHOSPHORYLATE AT: 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)
INSULIN
S-S S-S
P
P
P
S-S
S-S
IRS-1P
PTK DOMAIN HAS Y-KINASE ACTIVITY
AUTOPHOSPHORYLATION OF PTK DOMAINS OF InsR
ACTIVATION LOOP
Y
Y
Y
Y1158
MEMBRANE
TRANSMEMBRANE PART OF -SUBUNITS
Y1162
Y1163
INSULIN RECEPTOR SUBSTRATE-1
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
phosShc STIMULATES MAPK Gab-1
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.