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Title: REGULATION%20OF%20BODY%20WEIGHT


1
REGULATION OF BODY WEIGHT
  • THE BIOCHEMISTRY OF APPETITE AND ENERGY
    EXPENDITURE

2
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

3
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)

4
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

5
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

6
OVERVIEW 4
  • MITOCHONDRIAL-CYTOSOLIC INTERFACE
  • MITOCHONDRIAL MEMBRANE TRANSPORTERS
  • PYRUVATE TRANSPORTER
  • CARNITINE/ACYLCARNITINE TRANSPORTER
  • CITRATE TRANSPORTER
  • ASPARTATE TRANSPORTER
  • MALATE TRANSPORTER
  • CITRULLINE TRANSPORTER
  • ORNITHINE TRANSPORTER
  • OTHERS

7
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

8
ORGAN SPECIALIZATION MUSCLE
  • MUSCLE FUELS
  • GLUCOSE
  • FROM GLYCOGEN
  • FATTY ACIDS
  • KETONE BODIES

9
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

10
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 gt KREBS, OXPHOS FLUXES

11
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

12
MUSCLE
  • CARBOHYDRATE METABOLISM IN MUSCLE SOLELY SERVES
    MUSCLE
  • CANT EXPORT GLUCOSE
  • CANT PARTICIPATE IN GLUCONEOGENESIS
  • IN STARVATION
  • PROTEOLYTIC DEGRADATION OF MUSCLE TO AMINO ACIDS

13
MUSCLE METABOLISM
TO LIVER
TO LIVER
ALANINE ?
LACTATE ? PYRUVATE ? H2O CO2 ?
INTO BLOOD
AMINO ACIDS ? ? PROTEINS
GLUCOSE ?? GLYCOGEN
FATTY ACIDS KETONE BODIES
FROM LIVER
14
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 DOESNT 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?

15
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) TISSUE?LIVER CHOL. TRANSPORT
  • STORED AS TRIGLYCERIDES

16
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

17
ADIPOSE TISSUE
TRIACYLGLYCEROLS FROM LIVER
TO LIVER
FATTY ACIDS GLYCEROL
WELL-FED
TRIACYLGLYCEROLS
WELL-FED
WELL-FED STATE
FROM LIVER
GLUCOSE
18
BRAIN
  • 20 OF RESTING O2 CONSUMPTION
  • FUEL FOR PLASMA MEMBRANE Na- K ATPase
  • MAINTAINS NEURONAL MEMBRANE POTENTIAL
  • GLUCOSE IS PRIMARY FUEL
  • BRAIN DOESNT STORE MUCH GLYCOGEN
  • ? REQUIRES STEADY SUPPLY OF GLUCOSE
  • DURING FASTING, STARVATION
  • KETONE BODIES

19
BRAIN
KETONE BODIES
H2O CO2
FROM LIVER
TO BLOOD
GLUCOSE
20
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

21
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22
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

23
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 DOESNT EXPLAIN KINETICS
  • OTHER ABSORBED SUGARS ? G-6-P IN LIVER

24
CENTRAL ROLE OF GLUCOSE-6-PHOSPHATE IN CHO
METABOLISM
  • ITS FATE DEPENDS ON DEMAND FOR GLUCOSE
  • G6P ? GLUCOSE (G-6-PHOSPHATASE)
  • WHEN BLOOD GLUCOSE lt 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

25
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 ALANINES AMINO GROUP FROM
    ITS ENTRY INTO THE LIVER TO ITS EXIT AS UREA.
    START WITH 2 MOLECULES OF ALA.

26
IN-CLASS STUDY QUESTION
  • EXPLAIN WHY ALCOHOL CONSUMPTION AFTER STRENUOUS
    EXERCISE, OR ACCIDENTALLY BY A FASTING CHILD,
    CAUSES HYPOGLYCEMIA (A LOW BLOOD GLUCOSE LEVEL)

27
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 BABYS 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.

28
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?

29
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30
HORMONAL INFLUENCES ON METABOLISM
  • EPINEPHRINE
  • CYCLIC AMP AS SECONDARY MESSENGER
  • GLUCAGON
  • CYCLIC AMP AS SECONDARY MESSENGER
  • INSULIN

31
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

32
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

33
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

34
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

35
HETEROTRIMERIC G PROTEINS
  • MEDIATE SIGNAL TRANSDUCTION
  • LIGANDRECEPTOR ? 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

36
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

37
EXTRACELLULAR
HORMONE
RECEPTOR
L B
I I
P L
I A
ADENYLATE CYCLASE
D Y
?
E
?
R
?
GDP
INTRACELLULAR
GTP
INACTIVE HETEROTRIMERIC G PROTEIN
38
HORMONE-RECEPTOR COMPLEX
RECEPTOR
ADENYLATE CYCLASE
?
?
?
GTP
GDP
GTP-GDP EXCHANGE REACTION ? ACTIVATED G PROTEIN
39
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
40
HORMONE
RECEPTOR
ADENYLATE CYCLASE
?
?
?
GDP
PPi
BOUND GTP IS HYDROLYZED AND AC IS DEACTIVATED
41
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)

42
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

43
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

44
THE ADENYLATE CYCLASE SIGNALING
SYSTEM
  • REFER TO THE MECHANISM OF RECEPTOR-MEDIATED
    ACTIVATION/INHIBITION OF AC ON PAGE 676 OF THE
    VOETVOET TEXT

45
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

46
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

47
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?

48
GLUCONEOGENESIS
PHOSPHOENOLPYRUVATE
ADP
CO2 GDP
PYRUVATE KINASE
PEP CARBOXYKINASE
ATP
GTP
ALANINE FROM LIVER
CITRIC ACID CYCLE
OXALOACETATE
PYRUVATE
ACTIVATES
ACETYL-CoA
ATP CO2
ADP Pi
PYRUVATE CARBOXYLASE
CITRIC ACID CYCLE
ACTIVATES
49
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

50
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

51
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

52
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

53
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

54
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

55
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

56
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)

57
APPETITE CONTROL AT HYPOTHALAMIC LEVEL
DIRECT EFFECTS OF PROTEINS ON NEURONS IN ARCUATE
NUCLEUS
HYPOTHALAMUS
ARCUATE NUCLEUS
INSULIN OR LEPTIN RECEPTOR
GHRELIN RECEPTOR
-
OTHER NEURONS

GHRELIN
MSH RECEPTOR
POMC/ CART
NPY/ AgRP
-

-
PYY3-36
Y2R (AN NPY RECEPTOR
SUBTYPE)
LEPTIN AND INSULIN
58
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

59
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

60
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 CNS?BIOLOGICAL ACTIVITY

61
LEPTIN
  • SUMMARY
  • WEIGHT-CONTROL IN NON-OBESE
  • ? CONCENTRATION WITHOUT EFFECT IN OBESE
  • LEPTIN RESISTANCE
  • RESPONSIBLE FOR LONG-TERM WEIGHT PROBLEMS

62
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

63
(No Transcript)
64
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 ?

65
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

66
(No Transcript)
67
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

68
GASTRIC BYPASS SURGERY
69
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

70
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

71
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

72
APPETITE CONTROL AT HYPOTHALAMIC LEVEL SUMMARY
(2)
  • NEUROPEPTIDE SECRETION REGULATED BY
  • LEPTIN
  • GHRELIN
  • INSULIN
  • PYY3-36

73
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

74
OBESITY
75
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 gt 1 BILLION OVERWEIGHT
  • WORLDWIDE gt 300 MILLION OBESE
  • PROJECTING TO 2008 OBESITY RATE OF 38

76
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

77
OBESITY
  • DEFINITIONS
  • OVERWEIGHT BMI gt 25 KG / M2
  • OBESITY BMI gt 30 KG / M2
  • CALCULATE YOUR OWN BMI AND WRITE THE VALUE ON A
    SHEET OF PAPER. WELL COLLECT THESE AND DETERMINE
    THE CLASS DISTRIBUTION OF BMIs
  • http//nhlbisupport.com/bmi/

78
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

79
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

80
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

81
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

82
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

83
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?

84
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

85
GENETIC OR ENVIRONMENTAL?
86
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

87
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

88
BIOCHEMISTRY OF OBESITY
  • PANCREAS MUST ? INSULIN PRODUCTION
  • CAUSES ? APPETITE (HYPERPHAGIA)
  • INSULIN ? PRODUCTION AND STORAGE OF F.A.s IN
    ADIPOSE TISSUE

89
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.

90
BIOCHEMISTRY OF THE ATKINS DIET
  • ITS 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

91
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?

92
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)

93
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

94
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)
  • ITS UNHEALTHY
  • CAN RESULT IN SIGNIFICANT MORBIDITY
  • CAN RESULT IN PREMATURE DEATH

95
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. ITS
    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.

96
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 HASNT
    BEEN FEELING WELL LATELY. SHE HAS BEEN HAVING
    HEADACHES AND CONSTIPATION FOR A FEW MONTHS AND
    SOMETIMES SHE DOESNT 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.

97
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

98
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 HASNT THE CHOLESTEROL LEVEL CHANGED MUCH,
    DESPITE THE FACT THAT SHES EATING MORE FAT?

99
DRUGS AND DIET
  • XENICAL
  • INTESTINAL LIPASE INHIBITORS
  • MERIDIA (SIBUTRAMINE)
  • AMPHETAMINE-LIKE
  • NE AND SEROTONIN RE-UPTAKE INHIBITION
  • PHENTERMINE (PART OF REDUX)

100
FUTURE ANTI-OBESITY DRUGS
  • RIMBONABANT
  • INHIBITS CANNABINOID RECEPTORS
  • CNTF (CILIARY NEUROTROPHIC FACTOR) (AXOKINE)
  • CNTF AND LEPTIN RECEPTORS VERY MUCH ALIKE
  • CNTF DOESNT GENERATE RESISTANCE
  • MELANOCORTINS AND RECEPTORS
  • ?-MSH

101
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 gt 40 YEAR OLDS
  • NOW SEEN MORE FREQUENTLY IN OBESE YOUTH

102
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

103
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

104
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

105
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

106
GLUCOSE TRANSPORT PROTEINS
  • OTHER GLUCOSE TRANSPORTERS
  • GLUT1 ERYTHROCYTES
  • GLUT2 PANCREATIC ß-CELLS AND LIVER
    CELLS
  • GLUT3 BRAIN, PLACENTA, FETAL
  • MUSCLE

107
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

108
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

109
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

110
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

111
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

112
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

113
PDB EXERCISES
  • EXPLORE THE XRAY STRUCTURE OF THE PTK DOMAIN OF
    InsR
  • PDB ID 1IRK (UNPHOSPHORYLATED)
  • PDB ID 1IR3 (PHOSPHORYLATED)

114
AUTOPHOSPHORYLATION OF PTK DOMAINS OF InsR
INSULIN
?
S-S
?
S-S
S-S
S-S
TRANSMEMBRANE PART OF ?-SUBUNITS
MEMBRANE
?
Y1158
Y
P
PTK DOMAIN
HAS Y-KINASE ACTIVITY
Y
Y1162
P
P
IRS-1
Y
Y1163
P
INSULIN RECEPTOR SUBSTRATE-1
ACTIVATION LOOP

115
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

116
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

117
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

118
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)
119
From Lowell BB, Shulman GI. 2005. Mitochondrial
Dysfunction and Type 2 diabetes. Science. 307
384-387.
120
STUDY QUESTION
  • EXPLAIN HOW INCREASED FREE FATTY ACIDS CAUSES
    INSULIN RESISTANCE.
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