REGULATION OF BODY

WEIGHT
THE 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

TO LIVER

TO LIVER
ALANINE


LACTATE
 INTO
AMINO ACIDS  PYRUVATE  H2O + CO2 BLOOD
 
PROTEINS
GLUCOSE

GLYCOGEN FATTY ACIDS
+
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) : TISSUELIVER 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 TO LIVER
FROM LIVER

WELL-FED FATTY ACIDS

+
TRIACYLGLYCEROLS
WELL-FED GLYCEROL

WELL-FED STATE

FROM LIVER GLUCOSE

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

FROM H2O + CO2

LIVER

TO BLOOD
GLUCOSE
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 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
 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 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
 HORMONE
EXTRACELLULAR

L B
I I
RECEPTOR P L
I A
DY
ADENYLATE E
 CYCLASE
 R

GDP

GTP INTRACELLULAR

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
 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
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

GTP ATP ALANINE

FROM
CITRIC LIVER
ACID OXALOACETATE
CYCLE
PYRUVATE
ACTIVATES
ACETYL-CoA
ADP + Pi ATP + CO2
PYRUVATE CARBOXYLASE
CITRIC
ACTIVATES
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
  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
DIRECT EFFECTS OF PROTEINS ON NEURONS IN ARCUATE NUCLEUS

HYPOTHALAMUS

ARCUATE NUCLEUS
INSULIN OR
GHRELIN
LEPTIN
RECEPTOR -
RECEPTOR
OTHER
+ NEURONS

GHRELIN MSH
- NPY/ POMC/ RECEPTOR

AgRP CART

PYY3-36 - +

Y2R
(AN NPY RECEPTOR LEPTIN AND INSULIN
SUBTYPE)
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 CNSBIOLOGICAL 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)
 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
HAS Y-KINASE ACTIVITY
P Y1162 P Y
IRS-1 Y1163 P Y
INSULIN RECEPTOR SUBSTRATE-1 ACTIVATION
LOOP
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.