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LISA M. NEFF, M.D., M.S. ASSISTANT PROFESSOR OF ENDOCRINOLOGY NORTHWESTERN COMPREHENSIVE CENTER ON OBESITY CENTER FOR LIFESTYLE MEDICINE The Effect of.

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Presentation on theme: "LISA M. NEFF, M.D., M.S. ASSISTANT PROFESSOR OF ENDOCRINOLOGY NORTHWESTERN COMPREHENSIVE CENTER ON OBESITY CENTER FOR LIFESTYLE MEDICINE The Effect of."— Presentation transcript:

1 LISA M. NEFF, M.D., M.S. ASSISTANT PROFESSOR OF ENDOCRINOLOGY NORTHWESTERN COMPREHENSIVE CENTER ON OBESITY CENTER FOR LIFESTYLE MEDICINE The Effect of Weight Loss in Obesity on Core Body Temperature and Brown Adipose Tissue Activity

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 2000 Obesity Trends* Among U.S. Adults BRFSS, 1990, 2000, 2010 (*BMI 30) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% 30%

5 Then & Now Why Are Americans Gaining Weight? Change in Environment

6 What Else Influences Weight Gain?

7 Lifestyle Modification: How Much Weight Loss is Typical? Placebo Metformin Lifestyle The DPP Research Group, NEJM 346: , 2002

8 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: 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

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 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, Keys A et al, Biology of Human Starvation, Buchanan TA et al, Metabolism, Pelleymounter MC et al, Science, Laposky AD et al, Am J Physiol Reg Integ Comp Physiol, 2006.

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? Bouchard et al, New Engl J Med 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%

15 The Role of Adaptive Thermogenesis 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 1 Yoneshiro T et al. Obesity 2011;19: Saito M. Data presented at 11 th Stock Conference, Montreal, Nov 2012.

17 Brown Adipose Tissue Activity as Assessed by PET–CT with 18 F-FDG. van Marken Lichtenbelt WD et al. N Engl J Med 2009;360: Lean Obese

18 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

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

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.

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 0.15 C from Visit 1 to Visit 2 C

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

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


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