Transcript View Presentation - Friedman Fellows

The Effect of Weight Loss in Obesity
on Core Body Temperature and
Brown Adipose Tissue Activity
LISA M. NEFF, M.D., M.S.
ASSISTANT PROFESSOR OF ENDOCRINOLOGY
NORTHWESTERN COMPREHENSIVE CENTER ON OBESITY
CENTER FOR LIFESTYLE MEDICINE
Current Research Activity
Northwestern:
 Body temperature/BAT
study
 EndoBarrier Study
 ASPIRE Trial
 MOMFIT: Gestational
weight gain study
 Weight loss study in
infertility population
Rockefeller:
 Dietary Interventions for
Insulin Resistance and
Metabolic Syndrome
The Effect of Weight Loss in Obesity
on Core Body Temperature and
Brown Adipose Tissue (BAT) Activity
 PI: Lisa M. Neff, MD, MS
 Co-Investigators: Lewis Landsberg, MD, Robert
Kushner, MD, MS, Stewart Spies, MD
 Study Staff: Dinah Zeiss, MA, Kirsten Webb, NP
 Research Assistants: Monica Edwards, MD,
MPH, Mindy Hoffmann, Katie Lowry
 Sponsors: David Kabiller and the Joseph and
Bessie Feinberg Foundation
Obesity Trends* Among U.S. Adults
BRFSS, 1990, 2000, 2010
(*BMI 30)
2000
1990
2010
No Data
<10%
10%–14%
15%–19%
20%–24%
25%–29%
≥30%
Why Are Americans Gaining Weight?
Change in Environment
Then & Now
What Else Influences Weight Gain?
Lifestyle Modification:
How Much Weight Loss is Typical?
Placebo
Metformin
Lifestyle
The DPP Research Group, NEJM 346:393-403, 2002
Metabolic Adaptation at a Reduced Body Weight:
Studies of Rudy Leibel, Michael Rosenbaum, et al.
Leibel RL et al. New Engl J Med 1995;332:621-8
Rosenbaum M et al. J Clin Endocrinol Metab 2002; 87:2391-4
Rosenbaum M et al. J Clin Invest 2005;115: 3579-86
Rosenbaum M et al. J Clin Invest 2008; 118:2583-2591
Goldsmith R. Am J Physiol Regul Integr Comp Physiol 2009;298: R79–88
Kissileff HR. Am J Clin Nutr 2012; 95:309–17
Ancel Keys, PhD
Biology of Human Starvation, 1950
Metabolic and Hormonal Changes
Due to Weight Loss in Obesity
 The adaptive response to modest weight loss in
obesity mimics what is seen in starvation and
includes:






Decreased sympathetic nervous system tone
Reduced blood leptin levels
Decreased thyroid hormone levels
Increased skeletal muscle efficiency
Changes in neural activity in areas of the brain involved in the
control of food intake
Total energy expenditure that is 10-15% lower than
would be expected based on changes in body
composition
Why Study Body Temperature?
 Maintenance of body temperature accounts for almost half




of total energy expenditure in a typical human 1
An increase in body temperature of just 1◦C raises energy
expenditure by 10-13% 1
Body temperature falls during starvation 2
Body temperature falls during hypoglycemia 3
Body temperature is very low in rodents with leptin
deficiency, and leptin replacement normalizes this 4,5
1 Landsberg
L, Obes Rev, 2012.
2 Keys A et al, Biology of Human Starvation, 1950.
3 Buchanan TA et al, Metabolism, 1991.
4 Pelleymounter MC et al, Science, 1995.
5 Laposky AD et al, Am J Physiol Reg Integ Comp Physiol, 2006.
Core Body Temperature is
Not Reduced in Obesity
Hoffmann ME et al, Obesity 2012;20:1585-90.
There are no published studies examining the effect of
weight loss in obesity on core body temperature.
Why Study Brown Adipose Tissue?
12 pairs of twins
overfed by 1000
kcal/day for 84 days:
Expect ~ 11 kg gain
On average, 35% of the
excess calories was
dissipated and not
stored as fat, but this
varied from 0 to 60%
Bouchard et al, New Engl J Med 1990.
The Role of Adaptive Thermogenesis
Brown adipose tissue
(staining for UCP1)
Virtanen et al. N Engl
J Med 2009;360:151825
Why Study Brown Adipose Tissue?
 Young, lean subjects with measurable BAT activity
have ~25% higher energy expenditure after mild cold
exposure than young, lean subjects without BAT
activity.1
 Subjects with measurable BAT activity have greater
postprandial energy expenditure than those without
BAT activity. 2
1Yoneshiro
T et al. Obesity 2011;19:13-16
2Saito M. Data presented at 11th Stock Conference,
Montreal, Nov 2012.
Brown Adipose Tissue Activity as Assessed by PET–CT with 18F-FDG.
Lean
Obese
van Marken Lichtenbelt WD et al. N Engl J Med 2009;360:1500-1508.
BAT activity before and after WL. A, PET images of five morbidly obese subjects before
bariatric surgery (A) and after weight loss (B).
Vijgen G H E J et al. JCEM 2012;97:E1229-E1233
©2012 by Endocrine Society
Study Design
 Objective: to determine whether core body temperature
and BAT activity are altered in response to weight loss in
obesity
 N = 20 overweight or obese men and postmenopausal
women studied at three (or more) timepoints:
At baseline (highest body weight)
 After a 10% weight loss while still in a negative energy balance
 After 2 weeks of weight stabilization at a 10% reduced weight
And for select volunteers:
 After a 20% weight loss while in negative energy balance
 After 2 weeks of weight stabilization at a 20% reduced weight

Study Design
 Objective: to determine whether core body temperature and
BAT activity are altered in response to weight loss in obesity
 Hypothesis 1: Core body temperature will decrease
significantly with active weight loss. A partial recovery of body
temperature will occur with weight stability.
 Hypothesis 2: BAT activity will decrease with active weight
loss, due to reduced sympathetic activity. If decreased BAT
activity plays a causative role in the development of obesity,
BAT activity should be similar at baseline and during weight
stability at a 10% reduced body weight. However, if decreased
BAT activity is an effect of obesity, then BAT activity should
increase significantly from baseline to weight stability at a
10% reduced body weight.
Novelty of This Study
 This is the first study to examine the effects of caloric
restriction and weight loss in obesity on core body
temperature
 This is the first study to examine the effect of a
standardized weight loss on brown adipose tissue
activity
Outcomes of Interest
At each timepoint:
24-hour core body temperature (CorTemp monitor)
Brown adipose tissue activity after 2 hr mild cold
exposure (PET/CT)
Body composition (DXA)
24-hour skin temperature (iButtons at 14 sites)
Resting energy expenditure (indirect calorimetry)
Blood levels of leptin, glucose, insulin, thyroid hormones,
inflammatory markers
And at baseline:
Habitual food intake (Block FFQ)
Habitual physical activity (accelerometer)
Example of Core Temperature Data:
Subject 03 Visit 1
38
Bike
Dinner
37.8
Sleep
Wake
Cold Room
37.6
37.4
Temperature C
37.2
37
36.8
Visit 1
36.6
36.4
36.2
36
35.8
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Elapsed Visit Time in Hours
14
15
16
17
18
19
20
21
22
23
Example of Core Temperature Data:
Subject 03 Three Visits
38
37.5
Temperature C
37
Visit 1
36.5
Visit 2
Visit 3
36
35.5
35
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Elapsed Visit Time in Hours
15
16
17
18
19
20
21
22
23
24 Hour Average Core Temperature
37.4
37.2
37
36.8
◦C
V1 24 Hr
36.6
V2 24 Hr
V3 24 Hr
36.4
36.2
36
35.8
LF
KC
WJ
AC
RH
TQ
Mean decrease of 0.15 ◦C from Visit 1 to Visit 2
CK
JN
Example PET/CT Images: Subject 03
Visit 1
Visit 2
Future Work
Next steps…
 Complete enrollment and data collection
 Data analysis, including exploration of:
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
Predictors of change in core body temperature with weight loss
Predictors of BAT activity
Future directions…
 Interventions aimed at attenuating a drop in core temperature
(if present) or increasing BAT recruitment and activity, such
as:
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Leptin or low dose thyroid hormone replacement
Exercise
Capsinoids
Orexin
Cold acclimation
Thank You!
Mentor: Lewis Landsberg
Study Coordinator: Dinah Zeiss
Students/Residents: Katie Lowry, Mindy Hoffmann,
Monica Edwards
Sponsors: David Kabiller and the Joseph and Bessie
Feinberg Foundation
Special Thanks to
The Gerald J. and Dorothy R. Friedman Foundation
Dr. Lechan
and to Jane Friedman and Dr. Poretsky for
organizing the symposium