Accepted Article Preview: Published ahead of advance online publication

Lower core body temperature and greater body fat are

components of a human thrifty phenotype

M Reinhardt, M Schlogl, S Bonglio, S B Votruba, J Krakoff,

M S Thearle

Cite this article as: M Reinhardt, M Schlogl, S Bonglio, S B Votruba, J Krakoff,

M S Thearle, Lower core body temperature and greater body fat are components
of a human thrifty phenotype, International Journal of Obesity accepted article
preview 26 October 2015; doi: 10.1038/ijo.2015.229.

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Received 1 August 2015; revised 12 October 2015; accepted 16 October 2015;

Accepted article preview online 26 October 2015

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 1

Lower core body temperature and greater body fat are components of a human thrifty phenotype

Martin Reinhardt1,2; Mathias Schlgl1,3; Susan Bonfiglio1; Susanne B. Votruba1; Jonathan Krakoff1; Marie

S. Thearle1

1
Obesity and Diabetes Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Department of Health and Human Services, 4212 N. 16th Street, Phoenix, Arizona 85016

2
Department of Diagnostic and Interventional Radiology, University Hospital Leipzig, Liebigstrasse 20,
04103 Leipzig, Germany

3
Department of Geriatrics and Aging Research, University Hospital Zurich, Raemistrasse 101, 8091,
Zurich, Switzerland

Corresponding author and person to whom reprint requests should be addressed:

Martin Reinhardt, MD; National Institutes of Health, National Institute of Diabetes and Digestive and
Kidney Disease 4212 N. 16th Street, Phoenix, Arizona 85016; Phone: 602-200-5329, Fax: 602-200-5335
Email: martin.reinhardt@nih.gov

Funding. This research was supported by the Intramural Research Program of the National Institutes of
Health, National Institute of Diabetes and Digestive and Kidney Diseases.

Running title: Body temperature and body fat in thrifty humans

Conflict of Interest: The authors have nothing to disclose.

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Abstract

Background/Objectives: In small studies, a thrifty human phenotype, defined by a greater 24-hour

energy expenditure (EE) decrease with fasting, is associated with less weight loss during caloric

restriction. In rodents, models of diet-induced obesity often have a phenotype including a reduced EE and

decreased core body temperature. We assessed whether a thrifty human phenotype associates with

differences in core body temperature or body composition.

Subjects/Methods: Data for this cross-sectional analysis were from 77 individuals participating in one of

two normal physiology studies while housed on our clinical research unit. 24-hour EE using a whole-

room indirect calorimeter and 24-hour core body temperature were measured during 24 hours each of

fasting and 200% overfeeding with a diet consisting of 50% carbohydrates, 20% protein and 30% fat.

Body composition was measured by dual X-ray absorptiometry. To account for the effects of body size on

EE, changes in EE were expressed as a percentage change from 24-hour EE (%EE) during energy

balance.

Results: A greater %EE decrease with fasting correlated with a smaller %EE increase with overfeeding

(r=0.27, p=0.02). The %EE decrease with fasting was associated with both fat mass and abdominal fat

mass, even after accounting for covariates (=0.16 [95% CI: -0.26, -0.06] %EE per kg fat mass,

p=0.003; =0.0004 [-0.0007, -0.00004] %EE per kg abdominal fat mass, p=0.03). In males, a greater

%EE decrease in response to fasting was associated with a lower 24-hour core body temperature, even

after adjusting for covariates (=1.43 [0.72, 2.15] %EE per 0.1C, p=0.0003).

Conclusion: Thrifty individuals, as defined by a larger EE decrease with fasting, were more likely to

have greater overall and abdominal adiposity as well as lower core body temperature consistent with a

more efficient metabolism.

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Introduction

The energy expenditure response to both caloric restriction (CR) and overfeeding can vary

substantially between individuals (15); however, the meaningfulness of these differences have only

recently begun to be elucidated. In a group of 14 men, 24-hour energy expenditure (EE) changes during

fasting and overfeeding were associated such that those individuals with a greater EE decrease during

fasting had a smaller EE increase with overfeeding defining a potential thrifty phenotype. Conversely,

those individuals with a larger EE increase during overfeeding were more likely to maintain EE during

fasting consistent with a more spendthrift phenotype (1). We recently found that more thrifty obese

individuals defined by a greater EE decrease with fasting lost less weight in a carefully controlled

inpatient weight loss study (6). There are a number of rodent models of diet induced obesity with a

common, coalescing phenotype including decreased core body temperature (CBT) and/or cold

intolerance, and reduced EE (710). A human thrifty phenotype may have similar attributes.

The homeostatic mechanisms regulating human CBT, including vasodilation, vasoconstriction,

sweating, non-shivering and shivering thermogenesis, and insulation, help maintain CBT within tightly

regulated limits. On average, variance of more than 0.2C from the 37C set point activates the

thermoregulatory system (11). It is unclear how much these thermoregulatory mechanisms may contribute

to an increased propensity for obesity (12). Since adipose tissue has an insulating effect in many large

mammals (13), it is possible that accumulation of adipose tissue is part of the compensatory strategy of

the human body to prevent heat loss in some individuals. Some authors have reported a relationship

between increased body insulation due to increased adipose tissue and a decreased EE response to both

cold exposure (14) or a mixed meal (14,15), and propose that decreased heat loss due to increased

insulation contributes to a lower energy cost of maintaining CBT (14). A small number of studies have

investigated the relationship of human obesity to 24-hour CBT and found no difference in CBT between

lean and obese individuals at thermoneutrality (16,17), during and after exercise, after a meal, or during

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sleep (17). While individual variation in temperature during low-energy diets has been proposed as a

potential contributor to a thrifty metabolism (12), the relationship of CBT to body composition,

including fat and lean mass and abdominal adipose tissue, has not fully been explored. Nor is it known

how CBT and these body composition measures relate to the EE responses to fasting or overfeeding.

The current study was designed to identify whether differences in 24-hour CBT and body

composition are associated with the EE responses to overfeeding or fasting. We hypothesized that a

human thrifty phenotype defined by a greater EE decrease with fasting and lower EE response to

overfeeding would also have lower 24-hour CBT and greater adiposity.

Subjects and Methods

Subjects

We screened 213 individuals, and 130 individuals met the initial eligibility criteria for admission

into one of two ongoing studies investigating the EE responses to caloric restriction and overfeeding

(NCT00687115), NCT00523627). These initial criteria included evidence of good health and no medical

conditions as assessed by history, physical, EKG and basic laboratory measures. Both studies included

admission to the clinical research unit (CRU) of the Obesity and Diabetes Clinical Research Section of

the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in Phoenix, AZ and

measurement of EE during energy balance, overfeeding with identical diets and fasting while the subjects

were weight stable. A further 53 subjects were excluded during the inpatient phase because they either

left the study for personal reasons (n=13), were diagnosed with impaired glucose tolerance during the 75g

oral glucose tolerance test (OGTT) that occurred on day 4 of admission after an overnight fast (an

exclusion criterion for study NCT00523627, n=20), were diagnosed with diabetes mellitus during the

OGTT (an exclusion criterion for both studies, n=4), developed an acute illness (n=2), or did not have

available data for all three assessments, i.e. energy balance, fasting and overfeeding, included in this

analysis (n=14). Glucose tolerance status was assessed according to the American Diabetes Association

criteria (18). The majority (n=74) of subjects had normal glucose regulation. Data from 77 subjects

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(NCT00687115 (n=17), NCT00523627 (n=60)) were included in the final analyses. Thyroid stimulating

hormone (TSH) was determined by the laboratory of the Phoenix Indian Medical Center on the day of

admission to the CRU (Dimension TSH Flex ELISA Immunoassay Module, Siemens Healthcare

Diagnostics, Inc, East Walpole, MA). Subjects represented a wide BMI range (17.8 50.0 kg/m2). All

subjects reported weight stability for the 6 months prior to admission. Subjects were weighed daily upon

first awakening and were asked not to engage in vigorous exercise for the duration of their stay. Upon

admission, volunteers were provided a standard, weight maintaining diet (WMD) with 50% carbohydrate,

30% fat, and 20% protein content. Initial weight maintaining energy needs were determined using unit

specific equations based on weight, height and sex (19). The caloric content of the WMD was adjusted as

needed to maintain a stable weight (1%). Volunteers were fully informed of the nature and purpose of

the study they participated in, and written informed consent was obtained before admission. Both

protocols were approved by the Institutional Review Board of the NIDDK.

Energy expenditure measurements

The assessment of EE was performed in a whole room indirect calorimeter, as previously

described (2). Breakfast was provided at 07:00, and the subjects entered the calorimeter about 30 minutes

after completion of breakfast. Three other meals were provided within the calorimeter at 11:00, 16:00 and

19:00. To more closely achieve energy balance during the baseline EE assessment, EE was measured

twice during eucaloric conditions. Energy intake during the first eucaloric respiratory chamber was based

on unit specific calculations (20), which is approximately 80% of the WMD to account for the reduction

in physical activity within the whole-room calorimeter. The 24h caloric content of the meals fed during

the second eucaloric measurement was equivalent to the EE calculated from the first assessment.

Because short-term adaptations to fasting or overfeeding are associated with both the amount of

voluntary weight loss during dieting (6) and involuntary weight change during free living conditions in

adults (21) we phenotypically typed individuals EE and CBT changes during 24h of overfeeding and 24h

of fasting. The second eucaloric measurement was considered to be the baseline assessment and was

doubled to determine the caloric intake of the overfeeding diet. The overfeeding diet contained an

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identical macronutrient composition as the eucaloric assessments (50% carbohydrate, 30% fat, 20

protein), and was given for only 24h, during which EE was measured. All subjects also had an EE

assessment while fasting with no caloric intake from 19:00 the night before entering the calorimeter.

Subjects only consumed non-caloric, non-caffeinated beverages during this assessment. The overfeeding

diet and the fasting assessments were done a minimum of 3 days apart from one another. All energy

expenditure responses to overfeeding and fasting are expressed as the percent change from the EE during

energy balance (EEDiet of Interest EEenergy balance / EEenergy balance x 100) to control for EE differences due to

variations in body size.

Dual-energy X-ray absorptiometry

Whole body composition, including percent body fat, fat mass (FM) and fat free mass (FFM) was

estimated by total body dual-energy X-ray absorptiometry (DPX-L;Lunar Radiation,Madison,WI) as

previously described (16). Total abdominal fat mass (AF) and %AF (percent AF from whole body

weight) was determined from a region of interest (ROI), which was defined from the top of the liver down

to the intervertebral disc level of L5/S1, and segmented manually using the enCore 2003 software (GE

Medical Systems, Lunar Radiation, Madison, WI).

Core body temperature

Ingestible sensors (CorTemp, HQ Inc., Palmetto, FL) that transmit temperature values every

minute to a data recorder worn around the volunteers waist were used to measure CBT. Data was

available from a subset of 59 subjects with valid CBT measures during the EE assessments. In female

subjects, the CBT assessments were not consistently synchronized with the follicular phase of the

menstrual cycle. Missing CBT data was due to capsules passing through the gastro-intestinal tract in less

than 16 hours or technical failure of either the sensors or the data recorder. Diurnal CBT included the

CBT between 08:00 to 23:00, which represents the time period when the thermic effect of food can be

observed. Twenty-four hour CBT and diurnal CBT values are expressed as the mean temperature during

the respective time periods. As CBT demonstrated a high intra-individual consistency, and to maximize

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the use of all CBT measures acquired, we also created the combined mean CBT during all three diets for

each individual.

Statistical Analysis

Normally distributed data was described with means and standard deviations. Skewed data (AF,

BMI) was described with medians and interquartile ranges. Pearson correlation coefficients were used to

assess initial associations between continuous, normally distributed variables, and Spearman rank

correlation coefficients were used for skewed variables. Two sample t-tests were used to assess

differences between groups, and paired t-tests were used to assess for differences between diets within

individuals. The contributions of FM and AF to the percent EE changes during the dietary interventions

were assessed in separate linear regression models including age, sex, race, ambient temperature, and

whole body fat free mass as covariates. Effect sizes of multivariate linear regression models are given as

mean standard deviation and [95% confidence limits]. Because of differences in CBT between men and

women and because of menstrual cycle temperature variation in women, all CBT analyses after the initial

comparison by sex were limited to men only. The associations between plasma TSH concentrations and

CBT with the percent EE changes during overfeeding and fasting were assessed with linear regression

models as above but also including FM or AF as a covariate. In order to better understand the differences

between individuals, we categorized them into thrifty or spendthrift phenotypes defined by a median split

of the EE response to fasting (Table 2), as has been done previously (6). The assessments of differences

between FM and AF in thrifty and spendthrift individuals were adjusted for sex.

Results

Associations between EE responses to fasting and overfeeding, and body composition

Characteristics of the study population are shown in table 1. No differences were noted between

ethnicities (Native American, Hispanic, White, Black) in any of the measured variables.

Compared to EE during energy balance, the mean percent EE (%EE) decrease during fasting EE was

84.3% (p<0.0001), and the %EE increase with overfeeding was 9.75.2% (p<0.0001). Individuals with

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a smaller %EE decrease in response to fasting had a greater %EE increase in response to overfeeding

(r=0.27, p=0.02) (Figure 1). When individuals were categorized as thrifty v spendthrift (Table 2), thrifty

individuals had greater FM (30.6 v 22.6 kg, p=0.01) and AF (7.72 v 5.52 kg; p=0.02) compared to

spendthrift individuals; these results were similar after limiting the dataset to men only (26.6 v 19.6 kg,

p=0.02; (6.61 v 4.78 kg; p=0.04). There was a negative correlation between FM, %body fat, AF, %AF

and the %EE response to fasting (r=0.36, p=0.001; r=0.35, p=0.002; =0.34, p=0.003, r=0.30,

p=0.009, respectively), and the %EE response to overfeeding (r=0.27, p=0.02; r=0.36, p=0.002;

=0.25, p=0.03, r=0.32, p=0.005, respectively), i.e. individuals with more total and abdominal fat mass

showed a greater decrease in EE during fasting and a smaller EE increase during overfeeding. After

accounting for covariates (age, sex, race, ambient temperature, and whole body fat free mass), FM and

AF were both independent determinants of the %EE decrease with fasting (=0.16%EE per kg, p=0.003,

[-0.26, -0.06]; =0.0004%EE per kg, p=0.03, [-0.0007, -0.00004], respectively) (Table 3, Figure 2).

Neither FM nor AF were independent predictors of the increase in %EE with overfeeding after

accounting for covariates.

Associations between average CBT, the %EE responses to fasting and overfeeding, and body composition

Men (n=34) had a lower mean CBT than women (n=12) during energy balance (36.82 vs 37.17 oC,

p=0.0002). Similar differences were seen during fasting and overfeeding. Because of these differences

and because of differences in temperature in women due to the menstrual cycle, all further CBT analyses

were limited to men. In men, the mean CBT was greater during overfeeding compared to energy balance

(36.960.18 v 36.820.27C, p=0.02), and fasting (36.960.18 v 36.860.24C, p=0.003). There was no

difference between CBT during fasting and energy balance. The %EE decrease with fasting was

correlated with all measures of CBT including during fasting (r=0.36, p=0.03), energy balance (r=0.42,

p=0.01), overfeeding (r=0.56, p=0.0008), and the combined average CBT (r=0.59, p<0.0001) (Figure 3).

When individuals were categorized as thrifty or spendthrift, thrifty men had a lower combined average

CBT (36.80 v 36.96C; p=0.004) compared to spendthrift men. Even after adjusting for covariates, the

combined average CBT (=1.43%EE per 0.1C, p=0.0003, [0.72, 2.15]) (Table 3) was an independent

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predictor of the %EE response to fasting. Results were similar if the individual CBT values during the

dietary interventions were used. The %EE increase with overfeeding was not associated with any measure

of CBT including during fasting (r=0.22, p=0.2), energy balance (r=0.24, p=0.16), overfeeding

(r=0.13, p=0.5), or combined average CBT (r=0.03, p=0.86), and CBT was not an independent predictor

of the %EE response to overfeeding after adjusting for covariates (all p>0.1). We found no independent

associations between FM, AF and CBT during any of the diets, nor between FM, AF and diurnal CBT.

There were no correlations between the %EE changes during overfeeding and fasting and the

corresponding changes in CBT. Plasma TSH levels did not correlate with the %EE response to fasting,

the response to overfeeding, nor with any CBT measures, in either men or the whole group.

Discussion

In a larger and more diverse population, this study confirmed the previous observation that

humans with a greater EE decrease in response to fasting have a smaller EE increase in response to

overfeeding and vice versa, i.e. thrifty and spendthrift phenotypes (1). Those individuals who were

classified as thrifty, based on a larger decrease in 24h EE with fasting, have increased adiposity (FM

adjusted for body size, i.e. FFM) as well as decreased CBT during all dietary interventions, consistent

with a more efficient metabolism.

There are a number of rodent models with a similar thrifty phenotype including relatively lower

energy expenditure, low CBT (or cold intolerance) and an increased propensity for obesity (8,9,2225).

Interestingly, these models are produced by a variety of genetic defects (8,9,2325). An association

between low body temperature (although not all have been 24 hour assessments) and human obesity has

been indicated in some (26,27), but not all, (16,17,28) studies. Our results add to this prior literature by

confirming that there are human individuals with a lower CBT and a more energy conserving phenotype

during fasting similar to phenotypes observed in the above mentioned rodent models. Twelve obese

individuals included in this analysis were also participants in a caloric restriction study (caloric restriction

occurred after these initial phenotypic profiling assessments) which demonstrated that more thrifty obese

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individuals were less successful at losing weight during 50% caloric restriction over 6 weeks of carefully

controlled conditions (6). The integration of these subjects (BMI range: 30.050.0 kg/m2) into a

population with a wider BMI range (17.850.0 kg/m2) demonstrates that these individuals with obesity

were in fact positioned more towards the middle and thrifty end of the spectrum of EE responses to

fasting. Nevertheless, even within this small obese population, there was sufficient intra-individual

difference in the EE response to fasting to characterize more spendthrift individuals who lost more weight

with the same degree of caloric restriction (6).

To put our main findings into context, a 0.1C lower CBT was associated with a 1.4% greater

decrease in EE during fasting, the trait we used to define the thrifty phenotype. Fat mass and abdominal

fat were each negatively related to the EE decrease with fasting. On average, thrifty men had a 0.16C

lower CBT, 7.0 kg more FM and 1.7 kg more AF compared those with a spendthrift phenotype. However,

the cross-sectional study design does not allow conclusions about the directionality of our findings.

Whether more efficient EE responses to fasting and overfeeding predisposes a person to increased

adiposity, or whether adiposity modulates the EE responses to dietary extremes through its insulating

properties remains to be established. However, evidence demonstrating that the amount of voluntary

weight loss over longer periods in obese individuals (6) and future weight change during free living

conditions in adults (21) may be reflected in the short term energy expenditure adaptations to fasting or

overfeeding may support the former possibility. Because CBT is tightly controlled (11) through

homeostatic mechanisms, it seems plausible that inter-individual variations in CBT may impact the EE

responses to fasting rather than the other way around. Data from the Baltimore Longitudinal Study of

Aging indicate that men with body temperature below the median live longer (29), which makes it

tempting to speculate that a more energy-conserving (thrifty) phenotype can result in increased longevity.

Such a phenotype would also likely promote increased survival in times of food scarcity; however, with

the current food abundance associated with modern living conditions, a thrifty phenotype is more likely to

contribute to an increased predisposition to weight gain. The speculation that a more energy conserving

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phenotype may increase lifespan is supported by prior reports of an association between increased 24h EE

and mortality (30).

Although they were both significant, the estimate of the relationship between the %EE decrease

with fasting and abdominal fat volume was multifold smaller than the estimate for whole body fat mass.

This is most likely because abdominal fat represents a smaller absolute amount of adipose tissue.

However, a past study has shown evidence of greater postprandial heat leakage across the abdominal wall

in un-insulated lean men compared to obese or lean men with artificial insulation placed around the

abdomen. These results were based on CBT measurements for two hours following the ingestion of a

large meal (15). In our study, neither whole body fat mass nor abdominal fat volume was associated with

CBT nor daytime CBT, with daytime CBT representing the period when diet induced thermogenesis is

apparent. Of note, we measured CBT for >16h versus the 2 postprandial hours evaluated in this previous

study (15). While more abdominal adipose tissue may provide an insulating layer that decreases heat

leakage across the abdominal wall acutely and especially during the immediate postprandial period, given

time, obese individuals likely redistribute the heat to augment heat release from the extremities, thereby

helping to maintain the individual temperature set point over 24 hours (3135). To fully understand the

presumably complex interplay of CBT and obesity in metabolically thrifty and spendthrift individuals,

prospective investigation will be needed.

Whether the combination of energy conserving traits in the thrifty phenotype is the result of

genetics (36), sympathetic nervous system responses (3739), prior weight loss attempts (40), differing

levels of physical fitness or individual hormonal responses is unclear. Plasma TSH levels did not correlate

with the EE responses to fasting and overfeeding or with CBT, however, we did not have measures of

other hormones including thyroxine or triiodothyronine. It is possible that our subjects had variable

amounts of brown adipose tissue (BAT), which may influence both human energy expenditure and

maintenance of CBT (41). The inpatient nature of the study combined with the high demand and limited

availability of the whole room indirect calorimeter made it impractical to synchronize the multiple CBT

measurements with the follicular phase of the menstrual cycle in women. However, the number of men in

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the study provided a large enough sample size to explore the relationships between CBT and other

variables. Although we found lower CBT and increased FM in thrifty individuals, we did not observe a

correlation between FM and CBT. The relationship between CBT and FM is likely complex and probably

includes modifying factors as the accumulation of FM will provide insulation, thus potentially increasing

CBT slightly and therefore, obscuring a clear correlation between CBT and FM, which would have been

expected and could have possibly been shown with a larger sample size. Since our measurements of CBT

were limited to a subset of our subjects, additional studies will be needed to verify our results.

In conclusion, in this diverse population, we found that individuals with a larger decrease in

energy expenditure during fasting had a lower CBT and also had greater adiposity. Thus, body

temperature may be a further defining feature of the human thrifty phenotype and offer insight into

contributors to the inter-individual variation observed in energy expenditure responses to caloric

restriction or excess. It is possible that in the future CBT may be useful to identify an individuals

phenotype (thrifty or spendthrift), and thus, be harnessed to direct weight loss or weight maintenance

efforts during life style interventions.

Acknowledgments. The authors thank the dietary, nursing, and technical staff of the National Institutes

of Health Clinical Unit in Phoenix, AZ, for their assistance. Most of all, the authors thank the volunteers

for their participation in the study.

Authors Contributions. M.R. wrote the manuscript. M.R. and M.S.T. analyzed the data. M.S.T. and

S.B.V. designed the study. M.S. and S.B. contributed to the study design and collected data. M.R.,

M.S.T., M.S., S.B., J.K., and S.B.V. contributed to the interpretations of findings and commented on and

edited the drafts. M.S.T. is the guarantor of this work and, as such, had full access to all the data in the

study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of Interest: The authors have nothing to disclose.

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 16

Legend - Figure 1

Correlation of 24 hour-energy expenditure responses to fasting and overfeeding (r = 0.27, p = 0.02).

Filled circles represent subjects with a wide BMI range (17.850.0) participating in study NCT00523627;

open triangles represent 12 obese individuals (BMI range: 30.050.0) that with evaluation prior to their

participation in a caloric restriction weight loss study (NCT00687115; details can be found here: (6)).

Legend - Figure 2

A and B. Correlation of fat mass, abdominal fat and percent change in 24 hour energy expenditure in

response to fasting (r=0.36, p=0.001; =0.34, p=0.003, respectively). C and D. Correlation of fat mass,

abdominal fat, and percent change in 24 hour energy expenditure in response to fasting after adjustment

for fat free mass, age, sex, race, and ambient temperature (=0.16%EE per kg, p=0.003, [-0.26, -0.06];

=0.0004%EE per kg, p=0.03, [-0.0007, -0.00004], respectively). Filled circles represent subjects with a

wide BMI range (17.850.0) participating in study NCT00523627; open triangles represent 12 obese

individuals (BMI range: 30.050.0) evaluated prior to participation in a caloric restriction weight loss

study ((NCT00687115; details can be found here: (6)).

Legend Figure 3

Correlation between the EE response to fasting in men and average 24 hour core body temperature during

fasting (A. r=0.36, p=0.03, N=36), energy balance energy balance (B. r=0.42, p=0.01, N=34), overfeeding

(C. r=0.56, p=0.0008, N=32), and the combined average 24 hour core body temperatures during fasting,

energy balance, and overfeeding (D. r=0.59, p<0.0001, N=44).

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Table 1. Demographic and anthropometric characteristics of the study population.

All Men Women

N 77 58 19
26W, 25NA, 13B,
Race 20W, 19NA, 9B, 10H 6W, 5NA, 4B, 3H
13H
Age (years) 35.9 10.2 37.7 10.3** 30.7 8.2
Body weight (kg) 83.8 18.0 84.2 17.7 82.6 19.2
BMI (kg/m2) 26.2 [24.3; 30.8] 26.0 [24.0; 29.5] 30.0 [25.1; 37.3]
Body fat (%) 30.4 11.8 26.0 8.8*** 44.0 8.9
FM (kg) 26.6 14.0 23.0 11.8** 37.8 14.8
FFM (kg) 57.2 10.7 61.2 8.7*** 44.8 5.5
AF (kg) 5.92 [3.68; 8.97] 5.28 [3.30; 7.33] ** 8.87 [5.76; 14.1]
AF (% of body weight) 7.5 3.9 6.4 3.1*** 10.8 4.3
EE (kcal) 2098 328 2163 319** 1900 277
Intake in energy balance (kcal) 2128 351 2190 337** 1937 329
Fasting glucose (mg/dl) 92.7 5.5 92.4 5.7 93.5 4.8
2h glucose (mg/dl) 109.7 28.1 106.7 2.1 119.1 29.6
TSH (IU/mL) 1.55 0.86 1.55 0.84 1.56 0.94
Combined average CBT (oC) 36.94 0.22 N=59 36.89 0.18** N=44 37.12 0.22 N=15
CBT energy balance (oC) 36.91 0.30 N=46 36.82 0.27** N=34 37.18 0.23 N=12
o
CBT fasting ( C) 36.90 0.25 N=46 36.86 0.24* N=36 37.06 0.26 N=10
o
CBT overfeeding ( C) 37.02 0.21 N=45 36.96 0.18**N=32 37.17 0.21 N=13

Values are presented as mean SD. Differences between men and women were assessed by two sample

Students t-test *= p < 005; **= p <001; ***= p < 0.0001. Abbreviations: W = White; H = Hispanic;

NA = Native American; B = Black; BMI = Body mass index; FM = Fat mass; FFM = Fat free mass; AF

= Abdominal fat mass; EE = 24-hour energy expenditure; TSH = Thyroid stimulating hormone; CBT =

average 24 hour core body temperature. Combined average CBT are values from average CBT

measurements during energy balance, fasting and overfeeding.

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Table 2. Thrifty vs Spendthrift phenotype

Thrifty Spendthrift
N 39 (28 men; 11 women) 38 (30 men; 8 women)
Race 12W, 13NA, 7B, 7H 14W, 12NA, 6B, 6H
Age (years) 37.3 9.5 34.6 10.8
Body weight (kg) 87.3 16.8 80.2 18.7
2
BMI (kg/m2) 28.0 [25.4; 33.4] 25.8 [22.9; 27.9]
Body fat (%) 34.0 9.9** 26.8 12.5
FM (kg) 30.6 13.0* 22.6 14.1
FFM (kg) 56.8 10.3 57.6 11.5
2,
AF (kg) 7.1 [5.16; 10.37] * 4.5 [2.05; 7.33]
AF (% of body weight) 8.6 3.5* 6.4 4.0
EE (kcal) 3 2099 [2036; 2162]** 1992 [1930; 2055]
EE response to fasting (%) 1
11.4*** 4.6 2.4
EE response to overfeeding (%) 8.3 5.3* 11.0 4.7
Fasting glucose (mg/dl) 4 94.9 5.3** 90.4 4.8
2h glucose (mg/dl) 112.0 31.3 107.4 24.4
TSH (IU/mL) 1.56 0.77 1.55 0.95
o
Combined average CBT ( C ) 36.80 0.18 N=25** 36.96 0.15 N=19

In order to better understand the differences between individuals, we categorized them into thrifty or

spendthrift phenotypes 1 defined by a median split of the 24h-energy expenditure (EE) response to fasting.

Values are presented as mean SD, unless otherwise indicated. 2 Presented as medians and interquartile

range. Differences between men and women were assessed by two sample Students t-test *= p < 005;

**= p <001; ***= p < 0.0001. 3 EE = 24-hour energy expenditure during energy balance, results are

shown as least square means and [95% confidence limits], adjusted for differences in age, sex, race, FM,

FFM, and ambient temperature. 4 Adjusting for differences in percentage of body fat did not alter the

results for group differences in fasting glucose values (p<0.01).

Abbreviations: W = White; H = Hispanic; NA = Native American; B = Black; BMI = Body mass index;

FM = Fat mass; FFM = Fat free mass; AF = Abdominal fat mass; TSH = Thyroid stimulating hormone;

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CBT = average 24 hour core body temperature. Combined average CBT are values from average CBT

measurements during energy balance, fasting and overfeeding in men only.

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Table 3. Multivariate models for the determinants of the EE response to fasting.

Model 3 (p) Model 4 (p)

Model 1 (p) Model 2 (p) [95% CI] [95% CI]

[95% CI] [95% CI] (men only) (men only)

AF -0.0004 (0.03)

FM -0.16 (0.003) [-0.0007, - FM -0.12 (0.07) AF -0.0003 (0.17)

FM (kg) or AF (kg) [-0.26, -0.06] 0.00004] [-0.26, 0.01] [-0.0007, 0.0001]

0.01 (0.89) -0.01 (0.89) 0.07 (0.34) -0.05 (0.54)

FFM (kg) [-0.14, 0.16] [-0.15, 0.13] [-0.08, 0.22] [-0.11, 0.20]

-0.03 (0.54) -0.07 (0.24) 0.06 (0.4) 0.06 (0.41)

Age (yrs) [-0.13, 0.07] [-0.17, 0.04] [-0.08, 0.19] [-0.08, 0.19]

-1.98 (0.39) -0.08 (0.97)

Sex [-6.49, 2.54] [-4.2, 4.05]

(p=0.60) (p=0.79) (p=0.43) (p=0.50)

Race

0.23 (0.52) 0.5 (0.17) -0.005(0.99) 0.11 (0.78)

Ambient Temp (oC) [-0.47, 0.93] [-0.22, 1.22] [-0.77, 0.76] [-0.66, 0.87]

1.43/ 0.1o (0.0003) 1.42/ 0.1o (0.0004)

CBT (oC) [0.72, 2.15] [0.69, 2.16]

Models 1 and 2 include the whole study population (men and women). Models 3 and 4 include CBT

measurements and were limited to men because of differences in CBT between men and women and

because of menstrual cycle temperature variation in women. Abbreviations: FM = Fat mass; FFM = Fat

free mass; AF = Abdominal fat mass; CBT = Average combined 24 hour core body temperature (values

from average CBT measurements during energy balance, fasting and overfeeding).

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Figure 1. 24 hour-energy expenditure responses to fasting and overfeeding

-1 4 9 14 19 24
0
Percent change EE during

-5
fasting

-10

-15

-20
Percent change EE during overfeeding

Correlation of 24 hour-energy expenditure responses to fasting and overfeeding (r = 0.27, p = 0.02).

Filled circles represent subjects with a wide BMI range (17.850.0) participating in study NCT00523627;

open triangles represent 12 obese individuals (BMI range: 30.050.0) that with evaluation prior to their

participation in a caloric restriction weight loss study (NCT00687115; details can be found here: (6)).

2015 Macmillan Publishers Limited. All rights reserved.

Figure 2. Associations between EE responses to fasting with fat mass and abdominal fat mass.

60
50

Fat mass (kg)

40
30
20
10
0
-20 -18 -16 -14 -12 -10 -8 -6 -4 -2 0
A Percent change EE during fasting (%)

20

Abdominal fat (kg)

15

10

0
-20 -18 -16 -14 -12 -10 -8 -6 -4 -2 0
B Percent change EE during fasting (%)

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 70
60

Fat mass (kg)

50
40
30
20
10
0
-12 -9 -6 -3 0 3 6 9
Percent change EE during fasting (adjusted for
C covariates)

20
18
16

Abdominal fat (kg)

14
12
10
8
6
4
2
0
-12 -9 -6 -3 0 3 6 9
Percent change EE during fasting (adjusted for
D covariates)

A and B. Correlation of fat mass, abdominal fat and percent change in 24 hour energy expenditure in

response to fasting (r=0.36, p=0.001; =0.34, p=0.003, respectively). C and D. Correlation of fat mass,

abdominal fat, and percent change in 24 hour energy expenditure in response to fasting after adjustment

2015 Macmillan Publishers Limited. All rights reserved.

for fat free mass, age, sex, race, and ambient temperature (=0.16%EE per kg, p=0.003, [-0.26, -0.06];

=0.0004%EE per kg, p=0.03, [-0.0007, -0.00004], respectively). Filled circles represent subjects with a

wide BMI range (17.850.0) participating in study NCT00523627; open triangles represent 12 obese

individuals (BMI range: 30.050.0) evaluated prior to participation in a caloric restriction weight loss

study ((NCT00687115; details can be found here: (6)).

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Figure 3. Core body temperature and EE responses to fasting.

0
Percent change EE during

-2
-4
-6
fasting

-8
-10
-12
-14
-16
36.3 36.8 37.3

A Average core body temperature during fasting (oC)

0
Percent change EE during

-2
-4
-6
fasting

-8
-10
-12
-14
-16
35.8 36 36.2 36.4 36.6 36.8 37 37.2 37.4

Average core body temperature during energy

B
balance (oC)

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 Percent change EE during 0
-2
-4
-6
fasting

-8
-10
-12
-14
-16
36.6 36.8 37 37.2 37.4
Average core body temperature during
C
overfeeding (oC)

0
Percent change EE during

-2
-4
-6
fasting

-8
-10
-12
-14
-16
36.3 36.5 36.7 36.9 37.1 37.3 37.5
D Average combined core body temperature during dietary
interventions (oC)

Correlation between the EE response to fasting in men and average 24 hour core body temperature during

fasting (A. r=0.36, p=0.03, N=36), energy balance energy balance (B. r=0.42, p=0.01, N=34), overfeeding

(C. r=0.56, p=0.0008, N=32), and the combined average 24 hour core body temperatures during fasting,

energy balance, and overfeeding (D. r=0.59, p<0.0001, N=44).

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