Transcript Defective Diet-induced Thermogenesis in the MC4-R

Energy Expenditure
Roger D. Cone, Ph.D.
MPB 333
I. Energy Expenditure in the Context of Energy Homeostasis
II. Forms of Energy Expenditure
A. Resting Metabolic Rate
1. Homeotherms and adaptive thermogenesis
a. non-shivering thermogenesis
b. shivering
B. Voluntary and Involuntary Physical Activity
1. Exercise
2. NEAT
C. Diet-Induced Thermogenesis
III. Techniques for Measuring Energy Expenditure
IV. Regulation of Energy Expenditure
V. Pathophysiology
A. Cachexia
B. Fever/Hypothermia
C. Anorexia – Running Anorexia Model
D. Obesity Epidemic
1. Epidemiology
2. Therapeutic Approaches
II. Forms of Energy Expenditure
Basal Metabolism 60%
Thermic Effect of Food 8-10%
Physical Activity 30-32%
RMR is primarily regulated by the thyroid axis and autonomic
tone
Leptin regulates the thyroid axis
to maintain energy homeostasis
Anatomy of the Thyroid Axis
Leptin regulates the thyroid axis
to maintain energy homeostasis
Symptoms of Hyperthyroidism
Weight Loss
Tachycardia
Sweating
Hypertension
Nervousness
Regulation of Adaptive Thermogenesis
UCP-1 generates heat in
brown adipocytes by
facilitating a proton leak
Thyroid Hormone and
Sympathetic Tone Regulate
UCP-1 Activity
Adaptive Thermogenesis – Acute Response to Cold
Does Inherent Variability in NEAT Determine Obesity?
Creating a NEAT Intensive Environment
B. Voluntary and Involuntary Physical Activity
1. Exercise
2. NEAT
Few people exercise regularly, NEAT varies by up to
2000kcal/day, therefore NEAT is very important!
Percentage of All Trips Made From Home
by Walking, 1977 - 1995
Percent
10
9
8
7
6
5
4
3
2
1
0
9.3%
8.5%
7.2%
5.5%
1977
1983
Source: National Personal Transportation Survey, 1995
1990
1995
Percentage of U.S. High School Students Who
Attended Physical Education Classes Daily, 1991 - 1999
60
Percent
50
42%
40
34%
30
25%
27%
29%
1995
1997
1999
20
10
0
1991
1993
Source: CDC, National Youth Risk Behavior Survey
School Health Policies and Programs Study 2000:
Physical Education Requirements by Grade
Percent of schools
60
51
51
51
52
50
50
40
40
32
26
30
20
25
13
10
10
6
5
0
K
1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th
Average Daily Time Children Spent Using
Media, by Medium and Age, 1999
Medium
Ages 2-18
Ages 2-7
Ages 8-18
Television
2:46
1:59
3:16
Videotapes
0:39
0:29
0:45
Video games
0:20
0:08
0:27
Computer
0:21
0:07
0:31
N = 3,155 children, ages 2-18 (nationally representative); margin of error = +3-5%
Source: Kaiser Family Foundation. Kids and Media at the New Millenium, 1999
Televisions in the Home
1970
1999
% of children who live in
homes with 3 or more TVs
6%
60%
% of 6th graders with a TV
in their bedroom
6%
77%
 Nearly a third (32%) of children live in homes with
4 or more TVs
 53% of all children, ages 2-18, have a TV in
their bedroom
N = 3,155 children, ages 2-18 (nationally representative); margin of error = +3-5%
Source: Kaiser Family Foundation. Kids and Media at the New Millenium, 1999
C. Diet-Induced Thermogenesis (DIT)
or Thermic Effect of Food
The energy expended as a function of differential food consumed, controlling for RMR and
activity
Probably composed of actual energy required for digestion plus a regulatory response to
caloric intake
Defective Diet-induced Thermogenesis
in the MC4-R -/ ob/ob mice have
significantly lower VO2
than wildtype and mc4r-/mice.
 male wt (n=17) and
ob/ob (n=13) increase
basal and total VO2 on
high-fat diet.
 male mc4r-/- mice (n=18)
do not show significant
response to change in
diet.
MC4-R is Required for High Fat Diet
Induced Upregulation of UCP-1
III. Techniques for Measuring Energy Expenditure
1. In indirect calorimetry, oxygen consumption and/or
carbon dioxide production is measured and converted
to energy expenditure using formulae
2. In direct calorimetry, the rate of heat loss from the
subject to the calorimeter is measured.
3. A number of non-calorimetric techniques have been
used to predict the energy expenditure by extrapolation
from physiological measurements and observations.
Comparing Energy Expenditure in Different
Animals is Highly Problematic
Comparing Metabolic Rates in Different
Animals is Highly Problematic
How to normalize?
Weight is misleading because lean mass is
more metabolically active than fat mass
Estimates are based on:
Weight 0.66
Weight 0.75
Determination of lean mass
Best Method – relationship of EE to fat free
mass within group, then comparison of
groups
IV. Regulation of Energy Expenditure
Stability of Body Weight
400
350
300
250
200
150
100
50
0
0
1
2
3
4
5
Time (years)
6
7
8
Short and Long Term Weight Regulation
Counter regulation
Weight
gain
Usual
weight
Weight
loss
Counter regulation
Energy Expenditure Response to Weight Gain and
Loss
Leibel RL, et al. N Engl J Med 1995;332:621-628
10% gain
Mean (+/- SD) Observed minus
Predicted Total Energy Expenditure
(Kcal/day)
110
600
100
% of Initial
Weight 90
400
10%
loss
0
Initial
Weight
– 400
10% loss
80
200
– 200
Initial
Weight
10%
gain
70
Time 
Effect of Exercise on Body Weight in Overweight
Men and Women
Irwin, et al. Obes Res. 15(6):1496-1512, 2007.
 Target of ~ 60-minutes moderate-intensity, aerobic exercise 6-days a
week x 1 yr. Verified by increased V02 max.
Men, Ave  370 min / wk
-3 kg FM
+1.2 kg FFM
Women, Ave  295 min / wk
-1.9 kg FM
+0.5 kg FFM
NO difference in food intake between exercisers and
controls after 12 months.
V. Pathophysiology
A. Cachexia
B. Fever/Hypothermia
C. Anorexia – Running Anorexia Model
D. Obesity Epidemic
1. Epidemiology
2. Therapeutic Approaches
Illness-Induced Cachexia
 Appetite Decreases (even
in a starved state)
 Metabolic Rate Elevated
 Increased Wasting of
Lean Body Tissues
 Diminished Protective
Endocrine Response
Cachexia in Disease
 Cancer
 Renal Failure -
26,000 deaths/yr, 87,534
new cases/yr, 245, 910 on dialysis, current cost of
treatment: $16.74b (1998).
 HIV Infection
 Tuberculosis
 Cystic Fibrosis
 Failure to Thrive -
5% of peds. admissions
 Cong. Heart Failure  COPD -
16% incidence
50% incidence
 Anorexia Nervosa -1% of young women
 Anorexia of Aging to 60% of hospitalized elderly
22% of 70yr olds, up
MC4-R Signaling is Involved in Cachexigenic Signaling
MC4-RKO Mice
1000
750
500
Saline
LPS
250
0
MC4-RKO
MC4 WT
Examples of a experimental models of cachexia
Marks et al.,
Endocrinology 144, 2003
D. Obesity Epidemic
1. Epidemiology
2. Therapeutic Approaches
Is BMR Reduced in Obesity?
After tens of thousands of measurements, it is a universal observation
that BMR is raised not suppressed in obese people because of the fact that they
have a greater lean body mass (LBM) than their lean counterparts
Does Reduced BMR Cause Obesity?
Do Differences in TEF Cause Obesity?
Could we even measure them accurately
enough?
20 year old male
170 lb.
50 year old male
200 lb.
1 lb. per year = 3500 kcal / 365 days…or…
about 10 kcal / day
= 2 lifesavers or 1 potato chip
The Adipostat Does Not Seem to Respond to Slow Weight gain
D. Obesity Epidemic
1. Epidemiology
2. Therapeutic Approaches
b3 adrenergic agonists to activate fat
Non-cardiac acting thyroid hormone analogues
but…….
Any compounds that increase energy expenditure may increase heart rate as
the body requires additional oxygen