LISA M. NEFF, M.D., M.S.ASSISTANT PROFESSOR OF ENDOCRINOLOGY

NORTHWESTERN COMPREHENSIVE CENTER ON OBESITYCENTER FOR LIFESTYLE MEDICINE

The Effect of Weight Loss in Obesity

on Core Body Temperature and Brown Adipose Tissue Activity

Current Research Activity

Northwestern:Body

temperature/BAT study

EndoBarrier Study ASPIRE Trial MOMFIT: Gestational

weight gain studyWeight 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, MSCo-Investigators: Lewis Landsberg, MD,

Robert Kushner, MD, MS, Stewart Spies, MDStudy Staff: Dinah Zeiss, MA, Kirsten Webb,

NPResearch Assistants: Monica Edwards, MD,

MPH, Mindy Hoffmann, Katie LowrySponsors: David Kabiller and the Joseph and

Bessie Feinberg Foundation

2000

Obesity Trends* Among U.S. AdultsBRFSS, 1990, 2000, 2010

(*BMI 30)

2010

1990

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Then &Then &NowNow

Why Are Americans Gaining Weight?

Change in Environment

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;332:621-8Rosenbaum M et al. J Clin Endocrinol Metab 2002; 87:2391-4Rosenbaum M et al. J Clin Invest 2005;115: 3579-86Rosenbaum M et al. J Clin Invest 2008; 118:2583-2591 Goldsmith R. Am J Physiol Regul Integr Comp Physiol 2009;298: R79–88Kissileff HR. Am J Clin Nutr 2012; 95:309–17

Ancel Keys, PhDBiology 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?

Bouchard et al, New Engl J Med 1990.

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%

The Role of Adaptive Thermogenesis

Brown adipose tissue (staining for UCP1)

Virtanen et al. N Engl J Med 2009;360:1518-25

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;19:13-162Saito M. Data presented at 11th Stock

Conference, Montreal, Nov 2012.

Brown Adipose Tissue Activity as Assessed by PET–CT with 18F-FDG.

van Marken Lichtenbelt WD et al. N Engl J Med 2009;360:1500-1508.

Lean

Obese

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 weightAnd 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 markersAnd at baseline:Habitual food intake (Block FFQ)Habitual physical activity (accelerometer)

Example of Core Temperature Data: Subject 03 Visit 1

Example of Core Temperature Data: Subject 03 Three Visits

24 Hour Average Core Temperature

Mean decrease of 0.15 ◦C from Visit 1 to Visit 2

◦ C

Example PET/CT Images: Subject 03

Visit 2

Visit 1

Future Work

Next steps…Complete enrollment and data collectionData 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

Thank You!

Mentor: Lewis LandsbergStudy Coordinator: Dinah ZeissStudents/Residents: Katie Lowry, Mindy

Hoffmann, Monica EdwardsSponsors: David Kabiller and the Joseph and

Bessie Feinberg Foundation

Special Thanks toThe Gerald J. and Dorothy R. Friedman Foundation

Dr. Lechanand to Jane Friedman and Dr. Poretsky for

organizing the symposium