1. 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

2. 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

3. 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

4. Obesity Trends* Among U.S. Adults BRFSS, 1990, 2000, 2010
(*BMI 30)
1990
2000
2010
No Data <10% %–14% %–19% %–24% %–29% ≥30%

5. Why Are Americans Gaining Weight? Change in Environment
Then &
Now
In recent decades we have made much progress in understanding the reasons for these trends. The most important is a shift in environment, from one in which famine was a primary threat to survival and extremes of physical activity were part of everyday life to the opposite, in which calories are plentiful and one need not move to get them

6. What Else Influences Weight Gain?
Of course, for individual patients, there are many other things that may lead to weight gain, including medical conditions such as hypothyroidism or Cushings, genetic susceptibility to weight gain, medications, smoking cessation, excessive gestational weight gain, fetal programming, sleep deprivation, and perhaps even increased ambient temperatures and global warming.

7. Lifestyle Modification: How Much Weight Loss is Typical?
Placebo
Metformin
Lifestyle
What we don’t entirely understand is why maintenance of weight loss is so difficult.
The DPP Research Group, NEJM 346: , 2002

8. Metabolic Adaptation at a Reduced Body Weight: Studies of Rudy Leibel, Michael Rosenbaum, et al.
Studies by Leibel and colleagues have helped characterized the metabolic responses to weight loss
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:
Rosenbaum M et al. J Clin Invest 2008; 118:
Goldsmith R. Am J Physiol Regul Integr Comp Physiol 2009;298: R79–88
Kissileff HR. Am J Clin Nutr 2012; 95:309–17

9. Ancel Keys, PhD Biology of Human Starvation, 1950
I’ll briefly discuss one of the most important studies in the history of nutrition. Keys was asked by the US govt to study the problem of famine in Europe. He recruited 36 conscientious objectors. 1st 3 months (3200 cal) – extensive testing – then 6 months semi-starvation (1800 cal) – lost ¼ of body weight – then 3 month nutritional rehabilitation study (RCT of protein/cal/micronutrient levels). Helped us understand physiology of starvation and optimal rehabilitation of starving patients.
“The Great Starvation Experiment” by Todd Tucker. Keys made innumerable contributions to the field of nutrition, including his landmark study of starvation in conscientious objectors and the 7 countries study of diet and CVD. During WWII he was commissioned by the US government to study human nutrition and performance, and he developed K rations, given to soldiers. Nicknamed Mr. Cholesterol. Promoted the Mediterranean Diet in the 1970s! In the Minnesota Starvation Experiment ( ), 36 young men were studied for one year – 3 months on a normal diet (~3200 kcal), 6 months of semistarvation (~1800 kcal) and 3 months of nutritional rehabilitation (the men were randomly assigned to 1 of 4 energy intake groups; each energy level was subdivided into 2 protein levels, and each protein level into 2 vitamin levels.). Extensive tests were given to the participants throughout the experiment. Body weight, size, and strength were recorded, and basic functions were tracked using X-rays,electrocardiograms, blood samples, and metabolic studies. Psychomotor and endurance tests were given as the men walked or ran on the laboratory treadmills, and participants received intelligence and personality tests from psychologists.

10. 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

11. Metabolic & Hormonal Changes with Weight Loss Attenuated by Leptin Replacement
During starvation, various changes occur. … Unfortunately, our bodies can’t tell the difference between starvation and therapeutic weight loss.
Rosenbaum M et al. J Clin Invest 2005;115:

12. 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.
normal weight young men were subjected to 24 weeks of semi-starvation. The mean decrease in oral temperature from baseline was 1.33°F after 12 weeks of weight loss (mean loss of 17.4% of initial weight) and 0.23°F after 24 weeks of weight loss (mean loss of 24% of initial weight). At 12 weeks, subjects were rapidly losing weight, whereas by 24 weeks, weight changes were extremely subtle, suggesting that short-term energy balance may play a role in modulation of body temperature.

13. Core Body Temperature is Not Reduced in Obesity
Hoffmann ME et al, Obesity 2012;20:
There are no published studies examining the effect of weight loss in obesity on core body temperature.

14. 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%
twin studies – Bouchard, pairs of young adult monozygotic twins were overfed by 1000 kcal each day for 84 days (mathematically, enough to gain 11 kg). Actual weight gain varied from 4.3 to 13.3 kg but was similar within pairs. 2, 3 On average, 35% of the excess calories was not stored as fat, but there was great individual variation in metabolic efficiency, from almost no dissipation of excess calories to dissipation of about 60% of the dietary excess. Importantly, the variation between twin pairs was greater than within twin pairs, suggesting that metabolic efficiency is in part determined by heritable factors.
Bouchard et al, New Engl J Med 1990.

15. The Role of Adaptive Thermogenesis
Adaptive thermogenesis = modulation of energy expenditure and heat generation during cold exposure, underfeeding, or overfeeding
During AT, electron transport in the mitochondria is partially uncoupled from ATP production, and heat is formed (instead of ATP)
Brown adipose tissue (staining for UCP1)
Virtanen et al. N Engl J Med 2009;360:

16. 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.

17. Brown Adipose Tissue Activity as Assessed by PET–CT with 18F-FDG.
Lean
Obese
Brown-Adipose-Tissue Activity as Assessed by PET–CT with 18F-FDG. The results of PET–CT scanning in 9 of 24 subjects show variable physiologic uptake and distribution of 18F-fluorodeoxyglucose (18F-FDG) in adipose tissue (Panel A). The images in the top row are from lean subjects with the highest levels of brown-adipose-tissue activity (>500 kBq), images in the middle row are from lean subjects with median levels of activity, and images in the bottom row are from obese or overweight subjects with the lowest levels of activity (<100 kBq). The supraclavicular region has the greatest amount of brown adipose tissue. A PET scan in the transverse plane (Panel B) shows the areas of brown adipose tissue (e.g., arrow), and a CT scan (Panel C) confirms the areas of brown adipose tissue (arrow) according to fat density and location. Fusion of the PET and CT scans (Panel D) shows that 18F-FDG uptake is localized in fatty tissue (arrow). Comparative PET–CT scans (Panel E) reveal the patterns of 18F-FDG uptake in the same subject from the lean group after exposure to cold and under thermoneutral conditions.
van Marken Lichtenbelt WD et al. N Engl J Med 2009;360:

18. BAT activity before and after WL
BAT activity before and after WL. A, PET images of five morbidly obese subjects before bariatric surgery (A) and after weight loss (B).
Gastric Banding: mean percentage of weight loss of ± 6.23%. BAT activity before and after WL. A, PET images of five morbidly obese subjects before bariatric surgery (A) and after WL (B). C, PET image, CT image and PET-CT-fusion image of the subject who showed the largest increase in BAT activity before (C) and after WL (D). BAT activity was recruited in both supraclavicular and paravertebral areas, indicated by solid and dashed arrows, respectively. Solid arrows indicate bilateral supraclavicular regions in which BAT activity was observed after WL. Dashed arrows indicate bilateral paravertebral regions in which BAT activity was observed after WL. E, BAT activity in kilobequerels and total SUV (F) before and after WL for the five subjects depicted in A and B. Baseline characteristics of subjects shown are from a report published elsewhere (10).
Vijgen G H E J et al. JCEM 2012;97:E1229-E1233
©2012 by Endocrine Society

19. 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
A partial recovery of body temperature will occur with weight stability at a 10% reduced body weight.

20. 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.
A partial recovery of body temperature will occur with weight stability at a 10% reduced body weight.

21. 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

22. 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)

23. Example of Core Temperature Data: Subject 03 Visit 1

24. Example of Core Temperature Data: Subject 03 Three Visits

25. 24 Hour Average Core Temperature
Mean decrease of 1.33 °F (.74 C) after 12 weeks and 0.23 °F after 24 weeks
Mean decrease of 0.15 ◦C from Visit 1 to Visit 2

26. Example PET/CT Images: Subject 03
Visit 1
Visit 2

27. Future Work Next steps… Complete enrollment and data collection
Data analysis, including exploration of:
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:
Leptin or low dose thyroid hormone replacement
Exercise
Capsinoids
Orexin
Cold acclimation

28. 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