Mentored Professional Enrichment Experience
Applicant: Katie Lowry
Name of Project/Experience: Changes in Core Body Temperature, Brown Adipose Tissue
Activity and Leptin Due to Weight Loss in Obesity
Location where Project/Experience will take place:
Northwestern University Comprehensive Center on Obesity, Chicago, IL
Mentor Name and Contact Information:
Lisa Neff, MD, MS
645 N Michigan Ave., 5th floor, suite 530-30
Chicago, IL 60611
l-neff@northwestern.edu
312-503-3267
RATIONALE: Significant progress has been made in the understanding of metabolic and
hormonal processes involved in weight control, but critical knowledge gaps remain. In
controlled underfeeding and overfeeding studies, for example, significant inter-individual
variation has been observed with respect to the magnitude of the resulting changes in body
weight, despite similar energy deficits or excesses in all subjects.1 The mechanisms responsible
for this variation are unknown, but processes involved in adaptation to energy imbalance, or
metabolic efficiency, clearly play a role.
During weight loss, there is a decrease in total energy expenditure that is at least 10-15% below
what would be expected on the basis of changes in body composition alone.2 Other important
components of the adaptive response to weight loss include decreased sympathetic tone,
decreased thyroid hormone levels, and increased skeletal muscle efficiency.3, 4 The metabolic
adaptation to a reduced body weight is thought to persist long after weight loss (perhaps
indefinitely) and may be a key factor responsible for the high rates of recidivism seen in obesity
treatment.5 Many of these changes are attenuated by administration of physiologic doses of
leptin, suggesting that maintenance of a reduced body weight in obesity produces a state of
relative leptin deficiency.3, 4
Changes in body temperature and brown adipose tissue (BAT) activity may play an important
role in the process of adaptation to weight loss in obesity. Maintenance of body temperature is a
major component of energy expenditure, accounting for nearly half of total energy expenditure in
a typical human. Body temperature is known to decrease in starvation and in leptin deficient
states, but there are no published studies of the effect of therapeutic weight loss on body
temperature in obesity.6,7 BAT is the tissue primarily responsible for adaptive thermogenesis,
and energy expenditure appears to increase in proportion to BAT activity.8 BAT activity is
significantly higher in lean than obese individuals, although it is not known whether this is a
cause or consequence of obesity. 9
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MPEE
The study in which I will be involved is the first to examine the effects of weight loss in obesity
on core body temperature. The study will also provide critical data regarding the relationship
between BAT activity and body weight. For this study, overweight or obese men and postmenopausal women will be studied at three time points: 1) before weight loss, 2) immediately
after achievement of a 10% weight loss during continued negative energy balance, and 3)
following two weeks of weight stability at a 10% reduced body weight.
We predict that core body temperature will decrease acutely with therapeutic weight loss,
through mechanisms that may be related to decreases in leptin. Once active weight loss stops
and weight maintenance is achieved, there may be partial recovery of body temperature. Given
the suppressive effect of fasting on sympathetic activity, it is expected that BAT activity will
decrease with active weight loss, when one is still in negative energy balance. If the decreased
BAT activity seen in obesity is related to a decreased need for heat generation due to the
insulating effects of adipose tissue, then BAT activity should be higher during weight stability at
a reduced body weight, as compared to at baseline. However, if decreased BAT activity actually
plays a causative role in the development of obesity, BAT activity should not change
significantly from baseline to weight maintenance at a lower weight.
GOALS: My focus in this study will be to explore the correlations between leptin levels, core
body temperature, BAT activity, energy expenditure, and thyroid hormone levels in response to
weight loss in obesity. During the course of the research project, my goals are as follows:
1. Participate in key aspects of clinical research, including subject screening (including
phone screening and assisting with history and physical exams) and recruitment
2. Assist with the collection and analysis of study data
3. Gain experience in behavioral counseling techniques for weight loss
4. Gain experience in endocrinology and nutrition in medicine.
METHODS: Overweight or obese men and postmenopausal women will be studied during
overnight admissions in the Clinical Research Unit at three time points: 1) before weight loss, 2)
immediately after achievement of a 10% weight loss during continued negative energy balance,
and 3) following two weeks of weight stability at a 10% reduced body weight. Weight loss will
be achieved using a standard very low calorie diet (800 kcal/day). Weight stabilization will be
accomplished using packaged nutritional products at a calorie level deemed appropriate for
weight maintenance, with daily caloric adjustment as needed. At each time point, testing will
include measurement of 24-hour core body temperature (using the CorTemp system), 24-hour
skin temperature (using Thermochron iButtons at 14 sites), resting energy expenditure (by
indirect calorimetry), BAT activity and volume (using PET-CT) after two hours of cold exposure
at 16°C, body composition (using DEXA), and fasting serum levels of glucose, insulin, TSH, T3,
T4, leptin, C-reactive protein and other metabolic markers.
ANALYSIS: Data analysis will be conducted using data from all subjects who have completed
the study by summer’s end, including subjects that started before my arrival. Two tailed paired
T tests will be used to assess changes in core body temperature, BAT volume and activity,
anthropometric variables, body composition, energy expenditure, and biochemical variables
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MPEE
(including leptin and thyroid hormone levels) in response to weight loss. Comparisons will be
made separately between data collected at admissions 1 and 2 and admissions 1 and 3.
Correlations between changes in leptin levels and changes in body temperature will be made.
Correlations between changes in other variables (such as energy expenditure and BAT activity)
will be explored as well. In this way, we expect to gain important insights into the metabolic
changes that occur during weight loss. These insights may lead to novel obesity treatment
approaches in the future.
SUPPORT
1. Do you request support funds? Yes
2. Would you be able to participate if a scholarship is not available? No
References:
1.
Bouchard C, Tremblay A. Genetic influences on the response of body fat and fat
distribution to positive and negative energy balances in human identical twins. J Nutr.
1997;127(5):943S-947S.
2.
Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from
altered body weight. New Engl J Med. 1995;332(10):621-628.
3.
Rosenbaum M, Goldsmith R, Bloomfield D, et al. Low-dose leptin reverses skeletal
muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J
Clin Invest. 2005;115(12):3579-3586.
4.
Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL. Low dose leptin
administration reverses effects of sustained weight-reduction on energy expenditure and
circulating concentrations of thyroid hormones. J Clin Endocrinol Metab. May 1, 2002
2002;87(5):2391-.
5.
Rosenbaum M, Hirsch J, Gallagher DA, Leibel RL. Long-term persistence of adaptive
thermogenesis in subjects who have maintained a reduced body weight. Am J Clin Nutr.
October 1, 2008 2008;88(4):906-912.
6.
Keys A, Brozek J, Henschel A, Mickelsen O, Taylor H. The biology of human starvation.
Minneapolis: The University of Minnesota Press; 1950.
7.
Pelleymounter MC, MJ, Baker M, Hecht R, Winters D, Boone TC, F. Effects of the obese
gene product on body weight regulation in ob/ob mice. Science. 1995;269(5223):540543.
8.
Yoneshiro T, Aita S, Matsushita M, et al. Brown adipose tissue, whole-body energy
expenditure, and thermogenesis in healthy adult men. Obesity. 2010;19(1):13-16.
9.
Van Marken Lichtenbelt W, Vanhommerig J, Smulders N, et al. Cold-activated brown
adipose tissue in healthy men. N Engl J Med. 2009;360:1500-1508.
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