The Vicious Circle of the

Metabolic Cycle
Ian R. Lanza, Ph.D.
Associate Professor of Medicine
Division of Endocrinology
Mayo Clinic College of Medicine

2014 Prevalence of Self-Reported

Obesity Among U.S. Adults

Human Population Migration

Energy Balance

When engineering fails us

to general
circulation
Hepatic vein

Adi Cohen, Columbia

University

Fat inside muscles

Fat inside muscles

Fat inside muscles

Energetically-demanding
processes in skeletal muscle
Repolarization (Na+/K+
ATPase)
Calcium transport (Ca2+
ATPase)
Crossbridge cycling (Myosin
ATPase)
100x
increase in
ATP demand

yet amazingly, ATP concentrations

remain constant in muscle during high-

How to prevent equilibrium?

Macronutrients:
Carbohydrate
Fat
Protein
Digestion
Fatty acids
Amino acids
Monosaccharide
s
Anabolism
(requires
energy)
Complex compounds
Glycogen
Triglycerides
Proteins

Catabolism
(releases
energy)

Simple compounds
CO2
H2O
NH3

The Mitochondrion

Cardiac muscle

Skeletal muscle

Brain

Oxidative
Phosphorylation
(Cellular Respiration)

Generates 85% of our ATP

ADP phosphorylated as electrons
move from fuels to oxygen
Oxyge
n

H2O
C6H12O6 + 6O2
6CO2 + 6H2O + 36 ATP
RER=6/6=1
(6*2)=3.0
C16H32O2 + 23O2
16CO2 + 16H2O + 129 ATP RER=16/23=0.7
P/O=129/(16*2)=2.8

Electron
sources
CHO
Fatty acids
Ketones
Amino Acids
P/O=36/

Lipid Metabolism
Palmitate
(16:0)

Free fatty acids

Linoleic acid
(18:2)
Eicosapentaenoic acid
(20:5)

Triglyceride

glycerol

esterified fatty
acids

Fat storage

Adipocytes
in adipose
tissue

Droplets in
liver
(ectopic)

Droplets in
muscle
(ectopic)

Goodpaster et al., JCEM, 20

Mohlke, Nature Genetics, 2008

Lipolysis: breaking down triglycerides

Fasting
Exercise
Stress

FFA
FFA

FFA

Triglycerid
es

HSL

Diglyceri
des
Fatty acid

HSL

Monoglyceri
des
Fatty acid

Glycerol

HSL+MG
Glycerol
L

Fatty acid

FFA

Oxidative Stress: the dark cloud

over mitochondria
Superoxi
de
(O2-)

Hydrogen
peroxide
(H2O2)
Hydroxyl radical
(OH)

The Vicious Cycle

Nutritional
excess

Dysfunction
al
mitochondri
a

Impaired
muscle function

Oxidative
stress

Cell death
Physical
inactivity

Decrease
protein
quality

Exercise
intolerance
Protein &
DNA
damage

Energy Balance

Body fat set point

ob/ob
mice
Lepti
n

Decrease
d
appetite
Increased
REE

db/db
mice

Heinonen et al.,

Molecular Transducers of
Physical Activity
Consortium (MoTrPAC)