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Relationships between oxygen consumption and body composition of obese patients
Relationships Between Oxygen Consumption and Body Composition of Obese Patients By G. BRAY, M. SCHWARTZ, R. ROZIN AND J. LISTER Oxygen consumption was measured in a group of 18 grossly obese females; creatinine excretion in 16; and total body water and exchangeable potassium in 14 members of this group. Body fat, surface area and body weight showed high coefficients of correlation with oxygen consumption whereas, measures of
lean body mass such as total body water, exchangeable potassium, and creatinine had much less satisfactory correlation coefficients. With increasing age, oxygen area surface consumption per unit showed a small decline. (Metabolism 19: NO. 6, June, 418-429, 1970)
0
XYGEN CONSUMPTION is widely used as an indirect measure of energy expenditure. Experimental verification of this technique lies in the work of many investigators and has been summarized elsewhere.‘--’ Utilizing the technique of indirect calorimetry, Rubner and his collaborators5-7 as well as other investigatorsB,7 have shown that oxygen consumption is proportional to surface area. This classic relationship of oxygen consumption to body surface area has frequently been questioned, however, since it appears to have little physiologic basis. Moore et al.8 have suggested that exchangeable potassium (I&), a measure of body cell mass, represents a more rational index to which oxygen consumption might be related. In a large series of patients and normal volunteers representing a heterogeneous population of adult males and females, Kinney, Lister and Moore” observed a relationship between exchangeable potassium and oxygen consumption, which, unlike the relation to surface area, was nonlinear (e.g., parabolic). Their data suggested that K, measured at least two populations of cells, one of which is characterized by a relatively low resting energy expenditure (skeletal muscle) and the other by higher energy expenditure (visceral cells). The group of patients upon which their studies were based did not include obese patients in whom some abnormalities in the usual relationships between energy consumption and body cell mass might be expected. For this reason we have explored some of the relationships between body composition and the expenditure of energy in a group of grossly obese individuals and report the results below. From the New Englund Medical Center Hospitals und Depurtmenf of Medicine, Tufts University School of Medicine, Boston, Mass. Received for publication December 3, 1969. Supported by USPHS Grants FR-54, AM 612 and AM 09897. GEORGE A. BRAY, M.D.: Associate Professor of Medicine, Tztfts University School of Medicine: Assistant Physician, New England Medical Center Hospitals, Boston, Mass. MELVIN SCHWARTZ, M.D.: Associate Professor of Biomathematics, Department of Surgery and Preventive Medicine, Tufts University School of Medicine, Boston, Mass. RONALD ROZIN, M.D.: Research Fellow in Surgery, New England Medical Center Hospitals, Boston, Mass. JULIUS LISTER, M.D.: Associate Professor of Surgery, Tufts University School of Medicine; Pediatric Surgeon, New England Medical Center Hospitals, Boston, Mass.
418
METABOLISM,
VOL.
19, No.
6 (JUNE). 1970
10 11 12 13 14 15 16 17 18
2 3 4 5 6 7 8 9
1
Subject
15 15 22 29 29 33 33 37 37 38 39 40 41 42 44 51 51 62
Age (Yrs.)
119.4 161.4 106.0 123.4 136.2 145.6 164.4 135.1 166.4 107.6 155.9 170.1 175.6 152.5 145.8 135.5 209.7 165.1
%%t 137 74 92 84 114 155 127 179 72 188 180 164 143 120 144 216 142
146
Over Weight
%
160 165 178 160 165 157 157 162 147 165 168 162 167 175 168 160
170
112
y&y
Table 1 .-Measured
2.57 2.08 2.25 2.47 2.36 2.55 2.25 2.46 2.10 2.29 2.65 2.64 2.44 2.44 2.47 2.88 2.47
1.90
Surface Area Mz 67.2 47.1 54.2 62.6 58.7 66.3 55.1 64.0 48.5 57.1 71.1 70.5 61.8 61.6 61.4 80.5 64.6
42.6
LBM
631.4 450.7 457.9 557.1 553.6 618.7 490.2 647.2 496.2 545.0 643.6 674.1 490.9 564.2 486.6 535.5 546.8
387.8
Oxygen Consumption CL./24 hrs.)
1.162 1.029 1.055 0.987
1.538 1.342
1.386 1.280 1.025 1.300 1.414 I .474 1.543 1.099 1.416
0.777
Creatinine Excretion (mg./24 hrs.)
and Derived Data on 18 Obese Patients
39.7 49.6 47.0 54.8 41.3 56.2 52.0 48.3 48.2 56.0 49.7 73.0 55.0
2634 2878 4394 2666 2486 3571 3061 2792 3268 3623 4153 2477
Body Water CL.)
2750
Exchangeable Potassium (KE) (mEa)
420
BRAY ET AL. MATERIALS AND METHODS
Patients The 18 female patients whose data comprise this study were hospitalized on the Clinical Study Unit of the New England Medical Center Hospitals. The clinical information and data on their body composition are summarized in Table 1. Their ages ranged from 1.5 to 62 years but most of them were between 20 and 50. One patient (# 1) grew rapidly and developed obesity at six months of age, following evacuation of a dermoid cyst located in the third ventricle of her brain. Her adult height, however, was below normal. A second patient (#13) had an associated enlargement of the pituitary but she had no evidence of suprasellar extension and no endocrine deficiencies. Caloric intake during these studies varied between 1500 and 3500 calories per day. Patients were weighed each day and urine was collected in 24-hour aliquots for determination of creatinine.
Analytical Procedures The measurement of oxygen consumption was performed by collecting 5-minute samples of expired air in a Douglas bag at six to 11 spaced intervals between 8:00 a.m. and 8:00 p.m. with the patient at rest for 15 to 20 minutes before each collection. The total volume in the bag was recorded by drawing the gas through a precision wet test meter (Precision Scientific Co., Chicago). The concentration of oxygen was measured on a Beckman Oxygen Analyzer (Model E2) and carbon dioxide was determined on a Godart Capnograph (Type 146). Exchangeable potassium (Ku) was determined by the dilution of an injected dose of 150 PC of 4sK after an equilibration period of 22 hours. The specific activity of the urine collected between the 22nd and 24th was used to calculate the isotope dilution and exchangeable potassium. The beta emission from the ‘iaK was counted between anthracene crystals and the concentration of potassium determined by flame photometry on the Autoanalyzer. Total body water (TBW) was calculated from the specific activity of plasma water in a sample of blood taken two hours after injecting 150 pC of :{H.,O. The plasma was frozen and the tritiated water was trapped by vacuum distillation. Creatinme was determined on seven to 10 separate 24-hour collections of urine from each patient, using picric acid and sodium hydroxide as adapted to the Autoanalyzer.
Calculations Subgroups. For purposes of analysis three groups have been used. All 18 patients were used when data were available. Data for creatinine excretion were not available on two patients and these individuals were excluded in the subgroup of 16. The subgroup of 11 patients excluded those subjects for whom data on creatinine excretion and isotopic body composition were not available and the subgroup of 13 patients included all individuals except those without isotopic data.
Surface area in square meters (M”) was calculated DuBois.10 Area = WO.415 l Ha.zS l 0.007184. Body fat (Kg.) was calculated weight - TBW/0.73.
from the formula
using the equation
of Pace and Rathbun:il
of DuBois
and
fat = body
Lean body mass (Kg.) was calculated from a formula of Humei” for women: LBM = 0.296 W + 0.4181 H - 43.3. Overweight was calculated from the Table of Desirable Weights (Metropolitan Life Insurance, 1959) using the excess above the highest weight for large framed women. Statistical correlation was accomplished in two stages. The single and multiple correlation coefficients were computed by a FORTRAN program or with the aid of a desk calculator using the maximal number of patients (Table 1). The second stage of statistical evaluation was performed on a subgroup of 11 female patients for whom partial correlation coefficients were calculated. The formula for partial correlation coefficient between variable 1 and variable 2 with variable 3 held constant:
OXYGEN
CONSUMPTION
421
AND BODY COMPOSITION
r12.3
=
r12
(1
-
-
r13
r13 2,
r2.1
l
(1
r.‘32)
-
4
I.12 = correlation r 23 = correlation = correlation r13
coefficient coefficient coefficient
between between between
variables variables variables
1 and 2 2 and 3 1 and 3
RESULTS
Reliability of Methods
Figure 1 shows the mean k SEM for the oxygen consumption on one patient at each of 11 time intervals during the day over a six-day period. Oxygen consumption rose after each meal and was lowest in the morning and again at night. The mean value for all measurements is presented to the right of the last timed period and it is this value that has been used in calculating subsequent data. The value for each patient had a standard error at any given time of day which was less than 5 per cent of the mean. Data on the reliability of measuring body water and exchangeable potassium (KE) are presented in Tables 2 and 3. In one patient, TBW and K, were measured on four occasions during which body weight remained within a range of 8 Kg. Total body water showed a range of only 14 L. (2.4% of the mean) but K, ranged more widely (Table 2). In two patients (Table 3) three samples of blood were drawn in succession and the total body water were in close agreement. Correlation Coefficients for Subgroups
of 11 and 13 Patients
Table 4 lists the correlation coefficients for the subgroup of 11 patients for whom all data were available. Among these variables oxygen consumption was significantly correlated with fat and with body weight but showed only a borderline correlation with surface area and LBM. TBW, K,, and creatinine were not MEAL
Fig. l.-Oxygen consumption during the day in one patient. Expired gas was collected and analyzed as described in text. Patient was studied at all times indicated for 12 days. Each point is mean f SE for these 12 collections. Mean f SE of all collections is shown by open circle at right.
E .E
Z
MEAL
MEAL
T
i
520
i
600
$ F a.
480
2 B
460
5
440
F $
420
P t t
.L 1
600
I
I
I
I200
I600 TIME
of DAY
2000
422
BRAY
Table 2.-Total
Body Water and Exchangeable
Date
Bod{$Fight
Potassium
Exchangeable Potassium CmEq.)
Body Water CL.)
13
151.9
59.48
3994
Nov. Dec. June
26 10 3
152.1 145.6 144.1
58.54 58.77 59.89
3620 4460 3862
of Replicate Sampling on Measurement Total Body Water
Sample
Patient
1
2 3 Mean + SEM
A
38.28 38.19 38.54 38.34+
1.03
AL.
in One Patient
Nov.
Table 3.-Effect
ET
of Body Water __ (L.) Patient
B
64.74 66.23 64.74 65.90?
6.0
significantly correlated with Go,. Total body water (TBW) was highly correlated with weight, surface area, lean body mass (LBM) and KE but creatinine had no significant correlation with any parameters. Relationships Between Oxygen Consumption and Measures of Body Composition
In the group of 18 patients (Table 5) \i,s was correlated with surface area (Fig. 2) body weight, height and a function representing the difference between actual and ideal weight. There was no significant correlation with ideal weight or percentage of overweight. A number of multiple correlation coefficients with qo., was also evaluated for the subgroup of 11 patients. These showed little improvement
over the relationship
between \iO, and surface area (Table
5)
or qo, and fat (Table 4). In the studies of Kinney, Lister and Moore,!’ qio, had a parabolic relationship with exchangeable potassium (KE). Attempts were made to improve the correlation between qo,, and K, in our data by using log transformations (Table 6) but these were without effect. The partial correlation coefficients between oxygen consumption and surface area are listed in Table 7. Surface area accounted for just over 29 per cent (r) X 100) of the variability in co,
(first line, Table 5). When fat or weight
were held constant the correlation between \i,? and surface area was eliminated. Holding TBW constant had little effect, but holding KB constant reduced the correlation so that only 17 per cent of the variability in co? was attributable to area. Because surface area and creatinine were negatively correlated (Table 4) holding creatinine constant improved the correlation and increased the variability accounted for by area to 38 per cent. The partial correlation coefficients with \i,,, when surface area was held constant are shown in Table 8. Holding area constant reduced all of the correlation coefficients except that with creatinine. Of interest was the fact that the
* p .l > p > .05 (borderline) t p < 0.01 t p < .05
Oxygen Consumption (L./24 hrs.) Weight (Kg.) Height (cm.) Surface Area (SA) M2 Lean Body Mass (LBM) (Kg.) Creatinine (mgJ24 hrs.) Exchangeable Potassium (Ka) (mEq.) Total Body Water (TBW) (L.)
.7288 .9427 .0884 .8869 .9136 - ..0039 .4614 .6026 $
.233.5 .6128 $ .6036 $ - .2546
.1611 .8136 t .8264 t - .3354
$ I
(mKEEq.)
.3918 S782 *
(L.)
- .3368 - .2222 - .2047
.2264 -.1436
Creatinine (m/24 hrs.)
.3383 .99.51 i-
S628 * .9766 i
LBM (Kg.)
for Subgroup of 11 Patients
.2674 .8343 t
TBW
of Coefficients
? i
Fat (Kg.) *
Table 4.-Correlation
.4200
s400 * .9528 t
$6,
- .0934 .1286
pk”:
.6147 $
ygi$j
8 z
$ 2
u
5
52
424
BRAY
Table 5.-Correlation Between Oxygen Consumption and Other Variables in 18 Patients -__ Variable
r
Height (cm.) Weight (Kg.) Ideal weight (Kg.) Overweight (% ) Weight = ideal weight Surface Area (ML’) _ _ _._.~
.4791 .6815 .3843 .4285 .6114 .7255
ET
AL.
Table 6.Porrelation Coefficients Between Oxygen Consumption and Exchangeable Potassium for Subgroup of 13 Patients Parameters
4 i-
vs.
VJ0.’
vs. K, v,,
log vo;
.4063
K,
V”.
log
t ;
r
.401X
log K,
.4034
vs. log K,
.3972
vs.
3;p < .(js i p < 0.01
. : :
700 650 1
z : 5 0
450 400 I
0
L I
I .60
I
2.20
2.00
SURFACE
Fig. 2 .-Relationship -30). Table 7.-Partial Variable
between
2.60
2.60
and surface
area
Held Constant
TBW Fat
3.00
( M*)
consumption
Correlation Coefficients for Oxygen Consumption Area for Subgroup of 11 Patients
None Fat Weight TBW KE LBM Creatinine Creatinine, Creatinine, Fat, TBW
oxygen
AREA
a
I
2.40
(y = 238 X
and Surface r
s403 - .3376 - .1864 5748 .4128 - .2665 .6219 * .6415 * - .2764 -.1612 ~~____
* p < .05
OXYGEN
CONSUMPTION
Table &-Partial
AND BODY
425
COMPOSITION
Correlation Coefficients for VOz with Surface Area Held Constant in Subgroup of 11 Patients Variable
vo,
vs.
held
N0ne
Fat
Constant Surface
.4417 .1373 .4224 - .3488 .3229
.7288 * .3918 .2264 .2674 S628
KE Creatinine TBW LBM
Area
*p < .Ol
Table 9.-Correlations
with Excretion of Creatinine Correlation
Coefficient r
N=
Variable
11
.4795 - .2546 - -33.54 .2264 -
Age
KE TBW V Alga Fat LBM K,, TBW Voz, K,, TBW Weight Height Height, Weight
N=
16
-.1387 .4876
- .2222 - .0039 - .2047 .3410 .4970
.2147 .1867 -
-.1346 - .3368 -3517
.0779 .4443 .4477
correlation with fat still accounted for 20 per cent of the variability in Q,,, even when SA was held constant. Partial correlation coefficients were also evaluated when TBW was held constant. The correlations between ‘iO, and fat, or GO2 and area were improved only slightly. However, the correlation between c,? and creatinine increased from .2264 to ~5752 and the correlation between area and creatinine became slightly positive. Creatinine excretion was measured in 16 patients and its correlations with other variables are presented in Table 9 for all 16 patients and for the subgroup of 11 patients. In the smaller subgroup there were no significant correlations with creatinine excretion. In the larger group of 16 patients the correlation between Gjo2 and creatinine improved but was still not statistically significant. Age had a small positive correlation with oxygen consumption (Table 10). Correcting e,, for surface area or holding area constant (partial correlation) produced a small negative correlation between oxygen consumption and age. Age also had a significant positive correlation with weight and surface area (Table 10). DISCUSSION
A relationship
between oxygen consumption
and a function of height and
426
BRAY
Table lO.-Correlations
with Age in Group of 18 Patients
Variable
Oxygen
r
consumption
(Voz)
.1847
V,,, Area !&face Weight
ET AL.
-.2812
Area
.4894 c: .4(j 12 :i:
+ p < .0.5
weight called surface area was first suggested by the classic work of Rubner.; This proportionality between oxygen consumption and surface area was shown to apply to homeothermic animals,0-7 normal man’s” and to obese patients.lS-lZ Our data significant
are in harmony with this concept since VO, and surface positive correlation (Equations 1 and 2) : ir,,
The correlation
area had a
= 29.4 (B WT)“,“““’
(1)
\j,>.’ = 238 (B Wt) - 30 coefficient in equation 1 is t.66 (p <
.Ol).
(2) The exponent
was slightly below the value of .66, which would be expected if V,,, were precisely related to surface area. Surface area accounts for only about 45 per cent of the variability in 9,:: in this group of obese patients. Equation 2 presents the regression line derived from Fig. 2. If one assumes that each liter of oxygen yields 4.8 kCall the slope of this line is equivalent to 1140 kCal/M”/d, a figure only slightly higher than the basal oxygen consumption of normal people, (approximately 1000 kCal/d; see Reference 1, p. 40). Thus, it would appear that the same quantitative relationship applies to the basal energy expenditure of obese individuals as applies to persons of normal weight.’ A principal finding and fat. Investigations tion between
in the present study was the high correlation from other laboratories have demonstrated
oxygen utilization
and surface area,l between
between VO,, the correla:
Vol and exchangeable
potassium,!’ and between V,,, and lean body mass, 1c,-JHbut a relation with fat has not been commented upon. This is particularly surprising since adipose tissue is known to be a metabolically active tissue.l!’ The studies of Miller and Blythl” provide a basis for estimating the contribution . of fat to total energy expenditure. In their studies V,., and lean body mass were related by the following formula: body
LBM = -7.36 + 0.2929 (VOJ mass of our patients as estimated
Using
the lean
water,
we have calculated
the \jO, which can be attributed
difference between this value residual oxygen consumption. residual
their
total
to LBM. Taking
(3) body the
for V,., and the observed VJo, we arrived at the The regression line for the relation between
Q,,,, and fat is presented
in which r = f.66
from
in Equation
4:
Fat = 48.319 $- 0.2615 (VOX) ~1 < .05. The slope of this regression
line (Fig.
(4) 3) and the
OXYGEN
CONSUMPTION
Fig. 3.-Relationship between residual oxygen consumption and body fat.
427
AND BODY COMPOSITION
c
z
RESIDUAL
OXYSEN
CONSUMPTION ml/mln.
one derived by Miller and BlythlG are similar suggesting that fat makes a contribution to oxygen consumption comparable to lean body mass. Techniques of isotope dilution have been used to measure the body compobut these data have been correlated sition of grossly obese patients, 8~16-18,zo,‘11 with energy expenditure in only three instances. Two of these studies have shown a good correlation between c,,, and surface area,17 lean body mass,l* cell mass and body weight, findings with which our data concur. Moore and his collaborators8gz’ have observed that \i,., in two obese patients is high in relation to K,. Their suggestion that fat, which has a low KE per unit weight, makes a major contribution to total energy exchange is supported by our data presented above. Careful examination of the relationship between \i,,, and K, (Table 6) have shown that exchangeable potassium is a less satisfactory basis for relating ?,,, than is surface area, BW or fat in obese patients. The constancy in creatinine excretion from day to day has often been noted and has given rise to the concept of a creatinine coefficient (creatinine excretion/Kg. of body weight) which ranges from 20 to 26 for men and 14 to 22 for women of normal weight. In the obese patients (Table 1) the creatinine coefficient was 9.5 & .5 mg. of creatinine/Kg. of body weight and supports other studies which have shown a low creatinine coefficient in obesity.‘” When the coefficients for each patient were corrected for their lean body mass (Table 1) the average value for the creatinine coefficient rose to 20.7 which is within the normal range. This would support the widely held concept that creatinine excretion reflects lean body mass. Surprisingly, creatinine excretion showed only a small positive correlation with oxygen consumption and a small negative correlation with all of the other parameters in the subgroup of 11 patients (Table 7). In the larger group of 16 patients, creatinine excretion showed a higher but still not statistically significant positive correlation with oxygen consumption which was much less satisfactory than the one described by Miller and Blyth.lB Thus, in obese patients creatinine excretion, like exchangeable potassium, provide less satisfactory bases for relating QO, than either fat or surface area.
BRAY
428
ET
AL.
Age influenced both body weight and oxygen consumption. In the 18 patients, age was positively correIated with surface area. With each additional year of age weight increased an average of 10 pounds. However, if the influence of surface area was held constant, oxygen consumption showed a negative correlation with age. This decline in oxygen consumption with increasing age has been repeatedly demonstrated in normal individuals and appears to hold in grossly obese people as well (Table 10). statistical and analytical methods Some attention must be given to the employed in this study. The techniques of isotope dilution for measuring total body spaces, particularly body water and exchangeable body potassium have been standardized with a smaller inherent error in the measurement of TBW than of KE8 (Tables 2 and 3). Creatinine excretion was measured using seven to 10 separate 24-hour urines for each patient and the day to day variability in these measurements was no more than +-5 per cent (-1-2 SE). A small error was also obtained when using the present methods for measuring oxygen consumption, since numerous measurements were made each day and the mean daily value for a six-IO-day period was taken as the average value for each patient. As seen in Fig. 1, this variability was less than i5 per cent around the mean for the individual. Thus, the measurement of exchangeable potassium, because of the inherently larger error of methodology and the fact that it was measured only once, make it less reliable in this group of patients than measurements of weight, creatinine or oxygen consumption. However, none of the analytical errors would seem to negate the interpretations of our data. ACKNOWLEDGMENTS We gratefully acknowledge the technical assistance of A. MacAulay. We wish to express our appreciation to Dr. E. B. Astwood for his continued interest and support and acknowledge the technical assistance of Andrew MacAulay and the staff of the Clinical Study Unit of the New England Medical Center Hospitals.
ABBREVIATIONS TBW: Total body water KE: Exchangeable potassium LBM: Lean body mass SA: Surface Area 30Z : Oxygen Consumption BW: Body Weight REFERENCES 1. Lusk, G.: The Elements of the Science of Nutrition. Philadelphia, Saunders, 1928. 2. DuBois, E. F.: Basal Metabolism in Health and Disease. Philadelphia, Lea and Febiger, 1936. 3. Dabney, .I. M.: Energy balance and obesity. Ann. Int. Med. 60:689, 1964. 4. Grande, F.: Energy balance and body compositional changes. Ann. Int. Med. 68: 467, 1968. 5. Rubner, M., cited by Krogh, A.: The
Respiratory Exchange of Animals and Man. 8614 subjects with especial reference to the normal standards for the estimation of the London, Longmans Green, 1916. 6. Kleiber, M.: Body size and metabolism. Physiol. Rev. 27~511, 1947. 7. Adolph, E. F.: Quantitative relations in the physiological constituents of mammals. Science 109:579. 1949. 8. Moore, F. D., Olesen. K. H., McMurray. J. D., Parker, H. V., Ball, M. R.,
OXYGEN CONSUMPTION
AND BODY COMPOSITION
and Boyden, C. M.: The Body Cell Mass and Its Supporting Environment. Philadelphia, Saunders, 1963. 9. Kinney, J. M., Lister, J., and Moore, F. D.: Relationship of energy expenditure to total exchangeable potassium. Ann. N.Y. Acad. Sci. 110:711, 1963. 10. DuBois, D., and DuBois, E. F.: A formula to estimate the approximate surface area if height and weight be known. Arch. Int. Med. 17:863, 1916. 11. Pace, N., and Rathbun, E.: Studies on body composition. III. The body water and chemically combined nitrogen content in relation to fat content. J. Biol. Chem. 158:685, 1945. 12. Hume, R.: Prediction of lean body mass from height and weight. J. Clin. Path. 19:389, 1966. 13. Means, J. H.: The basal metabolism in obesity. Arch. Int. Med. 17:704, 1916. 14. Boothby, W. M., and Sandiford, I.: Summary of the basal metabolism data on basal metabolic rate. J. Biol. Chem. 54:783, 1922. 15. Newburgh, L. H.: Obesity. I. Energy metabolism. Physiol. Rev. 2:18, 1944. 16. Miller, A. T., and Blyth, C. S.: Estimation of lean body mass and body fat from basal oxygen consumption. J. Appl. Physiol. 5:73, 1952. 17. Johnston, L. C., and Bernstein, L. M.:
429
Body composition and oxygen consumption of overweight, normal and underweight women. J. Lab. Clin. Med. 45:109, 1955. 18. White, R. I., Jr., and Alexander, J. K.: Body oxygen consumption and pulmonary ventilation in obese subjects. J. Appl. Physiol. 20: 197, 1965. 19. Wertheimer, E., and Shafrir, E.: Influence of hormones on adipose tissue as a center of fat metabolism. Recent Progr. Hormone Res. 16:467, 1960. 20. Berlin, N. I., Watkin, D. M., and Gevirtz, N. R.: Measurement of changes in gross body composition during controlled weight reduction in obesity by metabolic balance and body density. Body water techniques. Metabolism 11: 302, 1962. 21. Gilder, H., Cornell, G. N., Grafe, W. R., MacFarlane, J. R., Asaph, J. W., Stubenbord, W. T., Watkins, G. M., Rees, J. R., and Thorbjarnarson, B.: Components of weight loss in obese patients subjected to prolonged starvation. J. Appl. Physiol. 23: 304, 1967. 22. Morgan, A. P., and Moore, F. D.: Jejunoiliostomy for extreme obesity: Rationale, metabolic observations and results in a single case. Arm. Surg. 166:75, 1967. 23. McCluggage, H. B., Booth, G., and Evans, F. A.: Creatinine excretion in abnormal states of nutrition. Amer. J. Med. Sci. 181:349, 1931.
lean body mass such as total body water, exchangeable potassium, and creatinine had much less satisfactory correlation coefficients. With increasing age, oxygen area surface consumption per unit showed a small decline. (Metabolism 19: NO. 6, June, 418-429, 1970)
0
XYGEN CONSUMPTION is widely used as an indirect measure of energy expenditure. Experimental verification of this technique lies in the work of many investigators and has been summarized elsewhere.‘--’ Utilizing the technique of indirect calorimetry, Rubner and his collaborators5-7 as well as other investigatorsB,7 have shown that oxygen consumption is proportional to surface area. This classic relationship of oxygen consumption to body surface area has frequently been questioned, however, since it appears to have little physiologic basis. Moore et al.8 have suggested that exchangeable potassium (I&), a measure of body cell mass, represents a more rational index to which oxygen consumption might be related. In a large series of patients and normal volunteers representing a heterogeneous population of adult males and females, Kinney, Lister and Moore” observed a relationship between exchangeable potassium and oxygen consumption, which, unlike the relation to surface area, was nonlinear (e.g., parabolic). Their data suggested that K, measured at least two populations of cells, one of which is characterized by a relatively low resting energy expenditure (skeletal muscle) and the other by higher energy expenditure (visceral cells). The group of patients upon which their studies were based did not include obese patients in whom some abnormalities in the usual relationships between energy consumption and body cell mass might be expected. For this reason we have explored some of the relationships between body composition and the expenditure of energy in a group of grossly obese individuals and report the results below. From the New Englund Medical Center Hospitals und Depurtmenf of Medicine, Tufts University School of Medicine, Boston, Mass. Received for publication December 3, 1969. Supported by USPHS Grants FR-54, AM 612 and AM 09897. GEORGE A. BRAY, M.D.: Associate Professor of Medicine, Tztfts University School of Medicine: Assistant Physician, New England Medical Center Hospitals, Boston, Mass. MELVIN SCHWARTZ, M.D.: Associate Professor of Biomathematics, Department of Surgery and Preventive Medicine, Tufts University School of Medicine, Boston, Mass. RONALD ROZIN, M.D.: Research Fellow in Surgery, New England Medical Center Hospitals, Boston, Mass. JULIUS LISTER, M.D.: Associate Professor of Surgery, Tufts University School of Medicine; Pediatric Surgeon, New England Medical Center Hospitals, Boston, Mass.
418
METABOLISM,
VOL.
19, No.
6 (JUNE). 1970
10 11 12 13 14 15 16 17 18
2 3 4 5 6 7 8 9
1
Subject
15 15 22 29 29 33 33 37 37 38 39 40 41 42 44 51 51 62
Age (Yrs.)
119.4 161.4 106.0 123.4 136.2 145.6 164.4 135.1 166.4 107.6 155.9 170.1 175.6 152.5 145.8 135.5 209.7 165.1
%%t 137 74 92 84 114 155 127 179 72 188 180 164 143 120 144 216 142
146
Over Weight
%
160 165 178 160 165 157 157 162 147 165 168 162 167 175 168 160
170
112
y&y
Table 1 .-Measured
2.57 2.08 2.25 2.47 2.36 2.55 2.25 2.46 2.10 2.29 2.65 2.64 2.44 2.44 2.47 2.88 2.47
1.90
Surface Area Mz 67.2 47.1 54.2 62.6 58.7 66.3 55.1 64.0 48.5 57.1 71.1 70.5 61.8 61.6 61.4 80.5 64.6
42.6
LBM
631.4 450.7 457.9 557.1 553.6 618.7 490.2 647.2 496.2 545.0 643.6 674.1 490.9 564.2 486.6 535.5 546.8
387.8
Oxygen Consumption CL./24 hrs.)
1.162 1.029 1.055 0.987
1.538 1.342
1.386 1.280 1.025 1.300 1.414 I .474 1.543 1.099 1.416
0.777
Creatinine Excretion (mg./24 hrs.)
and Derived Data on 18 Obese Patients
39.7 49.6 47.0 54.8 41.3 56.2 52.0 48.3 48.2 56.0 49.7 73.0 55.0
2634 2878 4394 2666 2486 3571 3061 2792 3268 3623 4153 2477
Body Water CL.)
2750
Exchangeable Potassium (KE) (mEa)
420
BRAY ET AL. MATERIALS AND METHODS
Patients The 18 female patients whose data comprise this study were hospitalized on the Clinical Study Unit of the New England Medical Center Hospitals. The clinical information and data on their body composition are summarized in Table 1. Their ages ranged from 1.5 to 62 years but most of them were between 20 and 50. One patient (# 1) grew rapidly and developed obesity at six months of age, following evacuation of a dermoid cyst located in the third ventricle of her brain. Her adult height, however, was below normal. A second patient (#13) had an associated enlargement of the pituitary but she had no evidence of suprasellar extension and no endocrine deficiencies. Caloric intake during these studies varied between 1500 and 3500 calories per day. Patients were weighed each day and urine was collected in 24-hour aliquots for determination of creatinine.
Analytical Procedures The measurement of oxygen consumption was performed by collecting 5-minute samples of expired air in a Douglas bag at six to 11 spaced intervals between 8:00 a.m. and 8:00 p.m. with the patient at rest for 15 to 20 minutes before each collection. The total volume in the bag was recorded by drawing the gas through a precision wet test meter (Precision Scientific Co., Chicago). The concentration of oxygen was measured on a Beckman Oxygen Analyzer (Model E2) and carbon dioxide was determined on a Godart Capnograph (Type 146). Exchangeable potassium (Ku) was determined by the dilution of an injected dose of 150 PC of 4sK after an equilibration period of 22 hours. The specific activity of the urine collected between the 22nd and 24th was used to calculate the isotope dilution and exchangeable potassium. The beta emission from the ‘iaK was counted between anthracene crystals and the concentration of potassium determined by flame photometry on the Autoanalyzer. Total body water (TBW) was calculated from the specific activity of plasma water in a sample of blood taken two hours after injecting 150 pC of :{H.,O. The plasma was frozen and the tritiated water was trapped by vacuum distillation. Creatinme was determined on seven to 10 separate 24-hour collections of urine from each patient, using picric acid and sodium hydroxide as adapted to the Autoanalyzer.
Calculations Subgroups. For purposes of analysis three groups have been used. All 18 patients were used when data were available. Data for creatinine excretion were not available on two patients and these individuals were excluded in the subgroup of 16. The subgroup of 11 patients excluded those subjects for whom data on creatinine excretion and isotopic body composition were not available and the subgroup of 13 patients included all individuals except those without isotopic data.
Surface area in square meters (M”) was calculated DuBois.10 Area = WO.415 l Ha.zS l 0.007184. Body fat (Kg.) was calculated weight - TBW/0.73.
from the formula
using the equation
of Pace and Rathbun:il
of DuBois
and
fat = body
Lean body mass (Kg.) was calculated from a formula of Humei” for women: LBM = 0.296 W + 0.4181 H - 43.3. Overweight was calculated from the Table of Desirable Weights (Metropolitan Life Insurance, 1959) using the excess above the highest weight for large framed women. Statistical correlation was accomplished in two stages. The single and multiple correlation coefficients were computed by a FORTRAN program or with the aid of a desk calculator using the maximal number of patients (Table 1). The second stage of statistical evaluation was performed on a subgroup of 11 female patients for whom partial correlation coefficients were calculated. The formula for partial correlation coefficient between variable 1 and variable 2 with variable 3 held constant:
OXYGEN
CONSUMPTION
421
AND BODY COMPOSITION
r12.3
=
r12
(1
-
-
r13
r13 2,
r2.1
l
(1
r.‘32)
-
4
I.12 = correlation r 23 = correlation = correlation r13
coefficient coefficient coefficient
between between between
variables variables variables
1 and 2 2 and 3 1 and 3
RESULTS
Reliability of Methods
Figure 1 shows the mean k SEM for the oxygen consumption on one patient at each of 11 time intervals during the day over a six-day period. Oxygen consumption rose after each meal and was lowest in the morning and again at night. The mean value for all measurements is presented to the right of the last timed period and it is this value that has been used in calculating subsequent data. The value for each patient had a standard error at any given time of day which was less than 5 per cent of the mean. Data on the reliability of measuring body water and exchangeable potassium (KE) are presented in Tables 2 and 3. In one patient, TBW and K, were measured on four occasions during which body weight remained within a range of 8 Kg. Total body water showed a range of only 14 L. (2.4% of the mean) but K, ranged more widely (Table 2). In two patients (Table 3) three samples of blood were drawn in succession and the total body water were in close agreement. Correlation Coefficients for Subgroups
of 11 and 13 Patients
Table 4 lists the correlation coefficients for the subgroup of 11 patients for whom all data were available. Among these variables oxygen consumption was significantly correlated with fat and with body weight but showed only a borderline correlation with surface area and LBM. TBW, K,, and creatinine were not MEAL
Fig. l.-Oxygen consumption during the day in one patient. Expired gas was collected and analyzed as described in text. Patient was studied at all times indicated for 12 days. Each point is mean f SE for these 12 collections. Mean f SE of all collections is shown by open circle at right.
E .E
Z
MEAL
MEAL
T
i
520
i
600
$ F a.
480
2 B
460
5
440
F $
420
P t t
.L 1
600
I
I
I
I200
I600 TIME
of DAY
2000
422
BRAY
Table 2.-Total
Body Water and Exchangeable
Date
Bod{$Fight
Potassium
Exchangeable Potassium CmEq.)
Body Water CL.)
13
151.9
59.48
3994
Nov. Dec. June
26 10 3
152.1 145.6 144.1
58.54 58.77 59.89
3620 4460 3862
of Replicate Sampling on Measurement Total Body Water
Sample
Patient
1
2 3 Mean + SEM
A
38.28 38.19 38.54 38.34+
1.03
AL.
in One Patient
Nov.
Table 3.-Effect
ET
of Body Water __ (L.) Patient
B
64.74 66.23 64.74 65.90?
6.0
significantly correlated with Go,. Total body water (TBW) was highly correlated with weight, surface area, lean body mass (LBM) and KE but creatinine had no significant correlation with any parameters. Relationships Between Oxygen Consumption and Measures of Body Composition
In the group of 18 patients (Table 5) \i,s was correlated with surface area (Fig. 2) body weight, height and a function representing the difference between actual and ideal weight. There was no significant correlation with ideal weight or percentage of overweight. A number of multiple correlation coefficients with qo., was also evaluated for the subgroup of 11 patients. These showed little improvement
over the relationship
between \iO, and surface area (Table
5)
or qo, and fat (Table 4). In the studies of Kinney, Lister and Moore,!’ qio, had a parabolic relationship with exchangeable potassium (KE). Attempts were made to improve the correlation between qo,, and K, in our data by using log transformations (Table 6) but these were without effect. The partial correlation coefficients between oxygen consumption and surface area are listed in Table 7. Surface area accounted for just over 29 per cent (r) X 100) of the variability in co,
(first line, Table 5). When fat or weight
were held constant the correlation between \i,? and surface area was eliminated. Holding TBW constant had little effect, but holding KB constant reduced the correlation so that only 17 per cent of the variability in co? was attributable to area. Because surface area and creatinine were negatively correlated (Table 4) holding creatinine constant improved the correlation and increased the variability accounted for by area to 38 per cent. The partial correlation coefficients with \i,,, when surface area was held constant are shown in Table 8. Holding area constant reduced all of the correlation coefficients except that with creatinine. Of interest was the fact that the
* p .l > p > .05 (borderline) t p < 0.01 t p < .05
Oxygen Consumption (L./24 hrs.) Weight (Kg.) Height (cm.) Surface Area (SA) M2 Lean Body Mass (LBM) (Kg.) Creatinine (mgJ24 hrs.) Exchangeable Potassium (Ka) (mEq.) Total Body Water (TBW) (L.)
.7288 .9427 .0884 .8869 .9136 - ..0039 .4614 .6026 $
.233.5 .6128 $ .6036 $ - .2546
.1611 .8136 t .8264 t - .3354
$ I
(mKEEq.)
.3918 S782 *
(L.)
- .3368 - .2222 - .2047
.2264 -.1436
Creatinine (m/24 hrs.)
.3383 .99.51 i-
S628 * .9766 i
LBM (Kg.)
for Subgroup of 11 Patients
.2674 .8343 t
TBW
of Coefficients
? i
Fat (Kg.) *
Table 4.-Correlation
.4200
s400 * .9528 t
$6,
- .0934 .1286
pk”:
.6147 $
ygi$j
8 z
$ 2
u
5
52
424
BRAY
Table 5.-Correlation Between Oxygen Consumption and Other Variables in 18 Patients -__ Variable
r
Height (cm.) Weight (Kg.) Ideal weight (Kg.) Overweight (% ) Weight = ideal weight Surface Area (ML’) _ _ _._.~
.4791 .6815 .3843 .4285 .6114 .7255
ET
AL.
Table 6.Porrelation Coefficients Between Oxygen Consumption and Exchangeable Potassium for Subgroup of 13 Patients Parameters
4 i-
vs.
VJ0.’
vs. K, v,,
log vo;
.4063
K,
V”.
log
t ;
r
.401X
log K,
.4034
vs. log K,
.3972
vs.
3;p < .(js i p < 0.01
. : :
700 650 1
z : 5 0
450 400 I
0
L I
I .60
I
2.20
2.00
SURFACE
Fig. 2 .-Relationship -30). Table 7.-Partial Variable
between
2.60
2.60
and surface
area
Held Constant
TBW Fat
3.00
( M*)
consumption
Correlation Coefficients for Oxygen Consumption Area for Subgroup of 11 Patients
None Fat Weight TBW KE LBM Creatinine Creatinine, Creatinine, Fat, TBW
oxygen
AREA
a
I
2.40
(y = 238 X
and Surface r
s403 - .3376 - .1864 5748 .4128 - .2665 .6219 * .6415 * - .2764 -.1612 ~~____
* p < .05
OXYGEN
CONSUMPTION
Table &-Partial
AND BODY
425
COMPOSITION
Correlation Coefficients for VOz with Surface Area Held Constant in Subgroup of 11 Patients Variable
vo,
vs.
held
N0ne
Fat
Constant Surface
.4417 .1373 .4224 - .3488 .3229
.7288 * .3918 .2264 .2674 S628
KE Creatinine TBW LBM
Area
*p < .Ol
Table 9.-Correlations
with Excretion of Creatinine Correlation
Coefficient r
N=
Variable
11
.4795 - .2546 - -33.54 .2264 -
Age
KE TBW V Alga Fat LBM K,, TBW Voz, K,, TBW Weight Height Height, Weight
N=
16
-.1387 .4876
- .2222 - .0039 - .2047 .3410 .4970
.2147 .1867 -
-.1346 - .3368 -3517
.0779 .4443 .4477
correlation with fat still accounted for 20 per cent of the variability in Q,,, even when SA was held constant. Partial correlation coefficients were also evaluated when TBW was held constant. The correlations between ‘iO, and fat, or GO2 and area were improved only slightly. However, the correlation between c,? and creatinine increased from .2264 to ~5752 and the correlation between area and creatinine became slightly positive. Creatinine excretion was measured in 16 patients and its correlations with other variables are presented in Table 9 for all 16 patients and for the subgroup of 11 patients. In the smaller subgroup there were no significant correlations with creatinine excretion. In the larger group of 16 patients the correlation between Gjo2 and creatinine improved but was still not statistically significant. Age had a small positive correlation with oxygen consumption (Table 10). Correcting e,, for surface area or holding area constant (partial correlation) produced a small negative correlation between oxygen consumption and age. Age also had a significant positive correlation with weight and surface area (Table 10). DISCUSSION
A relationship
between oxygen consumption
and a function of height and
426
BRAY
Table lO.-Correlations
with Age in Group of 18 Patients
Variable
Oxygen
r
consumption
(Voz)
.1847
V,,, Area !&face Weight
ET AL.
-.2812
Area
.4894 c: .4(j 12 :i:
+ p < .0.5
weight called surface area was first suggested by the classic work of Rubner.; This proportionality between oxygen consumption and surface area was shown to apply to homeothermic animals,0-7 normal man’s” and to obese patients.lS-lZ Our data significant
are in harmony with this concept since VO, and surface positive correlation (Equations 1 and 2) : ir,,
The correlation
area had a
= 29.4 (B WT)“,“““’
(1)
\j,>.’ = 238 (B Wt) - 30 coefficient in equation 1 is t.66 (p <
.Ol).
(2) The exponent
was slightly below the value of .66, which would be expected if V,,, were precisely related to surface area. Surface area accounts for only about 45 per cent of the variability in 9,:: in this group of obese patients. Equation 2 presents the regression line derived from Fig. 2. If one assumes that each liter of oxygen yields 4.8 kCall the slope of this line is equivalent to 1140 kCal/M”/d, a figure only slightly higher than the basal oxygen consumption of normal people, (approximately 1000 kCal/d; see Reference 1, p. 40). Thus, it would appear that the same quantitative relationship applies to the basal energy expenditure of obese individuals as applies to persons of normal weight.’ A principal finding and fat. Investigations tion between
in the present study was the high correlation from other laboratories have demonstrated
oxygen utilization
and surface area,l between
between VO,, the correla:
Vol and exchangeable
potassium,!’ and between V,,, and lean body mass, 1c,-JHbut a relation with fat has not been commented upon. This is particularly surprising since adipose tissue is known to be a metabolically active tissue.l!’ The studies of Miller and Blythl” provide a basis for estimating the contribution . of fat to total energy expenditure. In their studies V,., and lean body mass were related by the following formula: body
LBM = -7.36 + 0.2929 (VOJ mass of our patients as estimated
Using
the lean
water,
we have calculated
the \jO, which can be attributed
difference between this value residual oxygen consumption. residual
their
total
to LBM. Taking
(3) body the
for V,., and the observed VJo, we arrived at the The regression line for the relation between
Q,,,, and fat is presented
in which r = f.66
from
in Equation
4:
Fat = 48.319 $- 0.2615 (VOX) ~1 < .05. The slope of this regression
line (Fig.
(4) 3) and the
OXYGEN
CONSUMPTION
Fig. 3.-Relationship between residual oxygen consumption and body fat.
427
AND BODY COMPOSITION
c
z
RESIDUAL
OXYSEN
CONSUMPTION ml/mln.
one derived by Miller and BlythlG are similar suggesting that fat makes a contribution to oxygen consumption comparable to lean body mass. Techniques of isotope dilution have been used to measure the body compobut these data have been correlated sition of grossly obese patients, 8~16-18,zo,‘11 with energy expenditure in only three instances. Two of these studies have shown a good correlation between c,,, and surface area,17 lean body mass,l* cell mass and body weight, findings with which our data concur. Moore and his collaborators8gz’ have observed that \i,., in two obese patients is high in relation to K,. Their suggestion that fat, which has a low KE per unit weight, makes a major contribution to total energy exchange is supported by our data presented above. Careful examination of the relationship between \i,,, and K, (Table 6) have shown that exchangeable potassium is a less satisfactory basis for relating ?,,, than is surface area, BW or fat in obese patients. The constancy in creatinine excretion from day to day has often been noted and has given rise to the concept of a creatinine coefficient (creatinine excretion/Kg. of body weight) which ranges from 20 to 26 for men and 14 to 22 for women of normal weight. In the obese patients (Table 1) the creatinine coefficient was 9.5 & .5 mg. of creatinine/Kg. of body weight and supports other studies which have shown a low creatinine coefficient in obesity.‘” When the coefficients for each patient were corrected for their lean body mass (Table 1) the average value for the creatinine coefficient rose to 20.7 which is within the normal range. This would support the widely held concept that creatinine excretion reflects lean body mass. Surprisingly, creatinine excretion showed only a small positive correlation with oxygen consumption and a small negative correlation with all of the other parameters in the subgroup of 11 patients (Table 7). In the larger group of 16 patients, creatinine excretion showed a higher but still not statistically significant positive correlation with oxygen consumption which was much less satisfactory than the one described by Miller and Blyth.lB Thus, in obese patients creatinine excretion, like exchangeable potassium, provide less satisfactory bases for relating QO, than either fat or surface area.
BRAY
428
ET
AL.
Age influenced both body weight and oxygen consumption. In the 18 patients, age was positively correIated with surface area. With each additional year of age weight increased an average of 10 pounds. However, if the influence of surface area was held constant, oxygen consumption showed a negative correlation with age. This decline in oxygen consumption with increasing age has been repeatedly demonstrated in normal individuals and appears to hold in grossly obese people as well (Table 10). statistical and analytical methods Some attention must be given to the employed in this study. The techniques of isotope dilution for measuring total body spaces, particularly body water and exchangeable body potassium have been standardized with a smaller inherent error in the measurement of TBW than of KE8 (Tables 2 and 3). Creatinine excretion was measured using seven to 10 separate 24-hour urines for each patient and the day to day variability in these measurements was no more than +-5 per cent (-1-2 SE). A small error was also obtained when using the present methods for measuring oxygen consumption, since numerous measurements were made each day and the mean daily value for a six-IO-day period was taken as the average value for each patient. As seen in Fig. 1, this variability was less than i5 per cent around the mean for the individual. Thus, the measurement of exchangeable potassium, because of the inherently larger error of methodology and the fact that it was measured only once, make it less reliable in this group of patients than measurements of weight, creatinine or oxygen consumption. However, none of the analytical errors would seem to negate the interpretations of our data. ACKNOWLEDGMENTS We gratefully acknowledge the technical assistance of A. MacAulay. We wish to express our appreciation to Dr. E. B. Astwood for his continued interest and support and acknowledge the technical assistance of Andrew MacAulay and the staff of the Clinical Study Unit of the New England Medical Center Hospitals.
ABBREVIATIONS TBW: Total body water KE: Exchangeable potassium LBM: Lean body mass SA: Surface Area 30Z : Oxygen Consumption BW: Body Weight REFERENCES 1. Lusk, G.: The Elements of the Science of Nutrition. Philadelphia, Saunders, 1928. 2. DuBois, E. F.: Basal Metabolism in Health and Disease. Philadelphia, Lea and Febiger, 1936. 3. Dabney, .I. M.: Energy balance and obesity. Ann. Int. Med. 60:689, 1964. 4. Grande, F.: Energy balance and body compositional changes. Ann. Int. Med. 68: 467, 1968. 5. Rubner, M., cited by Krogh, A.: The
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OXYGEN CONSUMPTION
AND BODY COMPOSITION
and Boyden, C. M.: The Body Cell Mass and Its Supporting Environment. Philadelphia, Saunders, 1963. 9. Kinney, J. M., Lister, J., and Moore, F. D.: Relationship of energy expenditure to total exchangeable potassium. Ann. N.Y. Acad. Sci. 110:711, 1963. 10. DuBois, D., and DuBois, E. F.: A formula to estimate the approximate surface area if height and weight be known. Arch. Int. Med. 17:863, 1916. 11. Pace, N., and Rathbun, E.: Studies on body composition. III. The body water and chemically combined nitrogen content in relation to fat content. J. Biol. Chem. 158:685, 1945. 12. Hume, R.: Prediction of lean body mass from height and weight. J. Clin. Path. 19:389, 1966. 13. Means, J. H.: The basal metabolism in obesity. Arch. Int. Med. 17:704, 1916. 14. Boothby, W. M., and Sandiford, I.: Summary of the basal metabolism data on basal metabolic rate. J. Biol. Chem. 54:783, 1922. 15. Newburgh, L. H.: Obesity. I. Energy metabolism. Physiol. Rev. 2:18, 1944. 16. Miller, A. T., and Blyth, C. S.: Estimation of lean body mass and body fat from basal oxygen consumption. J. Appl. Physiol. 5:73, 1952. 17. Johnston, L. C., and Bernstein, L. M.:
429
Body composition and oxygen consumption of overweight, normal and underweight women. J. Lab. Clin. Med. 45:109, 1955. 18. White, R. I., Jr., and Alexander, J. K.: Body oxygen consumption and pulmonary ventilation in obese subjects. J. Appl. Physiol. 20: 197, 1965. 19. Wertheimer, E., and Shafrir, E.: Influence of hormones on adipose tissue as a center of fat metabolism. Recent Progr. Hormone Res. 16:467, 1960. 20. Berlin, N. I., Watkin, D. M., and Gevirtz, N. R.: Measurement of changes in gross body composition during controlled weight reduction in obesity by metabolic balance and body density. Body water techniques. Metabolism 11: 302, 1962. 21. Gilder, H., Cornell, G. N., Grafe, W. R., MacFarlane, J. R., Asaph, J. W., Stubenbord, W. T., Watkins, G. M., Rees, J. R., and Thorbjarnarson, B.: Components of weight loss in obese patients subjected to prolonged starvation. J. Appl. Physiol. 23: 304, 1967. 22. Morgan, A. P., and Moore, F. D.: Jejunoiliostomy for extreme obesity: Rationale, metabolic observations and results in a single case. Arm. Surg. 166:75, 1967. 23. McCluggage, H. B., Booth, G., and Evans, F. A.: Creatinine excretion in abnormal states of nutrition. Amer. J. Med. Sci. 181:349, 1931.