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Ne W Engl and Journal Medicine
Ne W Engl and Journal Medicine
The
journal of medicine
established in 1812 june 17 , 2004 vol. 350 no. 25
abstract
background
Liposuction has been proposed as a potential treatment for the metabolic complica- From the Center for Human Nutrition,
tions of obesity. We evaluated the effect of large-volume abdominal liposuction on Washington University School of Medicine,
St. Louis (S.K., L.F., V.L.Y., A.R.C., C.K.,
metabolic risk factors for coronary heart disease in women with abdominal obesity. B.W.P., B.S.M.); and the Division of Food
Science, Human Nutrition and Health, Isti-
methods tuto Superiore di Sanità Rome, Rome (L.F.).
Address reprint requests to Dr. Klein at
We evaluated the insulin sensitivity of liver, skeletal muscle, and adipose tissue (with Washington University School of Medi-
a euglycemic–hyperinsulinemic clamp procedure and isotope-tracer infusions) as well cine, 660 South Euclid Ave., Campus Box
as levels of inflammatory mediators and other risk factors for coronary heart disease in 8031, St. Louis, MO 63110.
15 obese women before and 10 to 12 weeks after abdominal liposuction. Eight of the N Engl J Med 2004;350:2549-57.
women had normal glucose tolerance (mean [±SD] body-mass index, 35.1±2.4), and Copyright © 2004 Massachusetts Medical Society.
results
Liposuction decreased the volume of subcutaneous abdominal adipose tissue by 44 per-
cent in the subjects with normal glucose tolerance and 28 percent in those with diabetes;
those with normal oral glucose tolerance lost 9.1±3.7 kg of fat (18±3 percent decrease
in total fat, P=0.002), and those with type 2 diabetes lost 10.5±3.3 kg of fat (19±2 per-
cent decrease in total fat, P<0.001). Liposuction did not significantly alter the insulin
sensitivity of muscle, liver, or adipose tissue (assessed by the stimulation of glucose
disposal, the suppression of glucose production, and the suppression of lipolysis,
respectively); did not significantly alter plasma concentrations of C-reactive protein,
interleukin-6, tumor necrosis factor a, and adiponectin; and did not significantly affect
other risk factors for coronary heart disease (blood pressure and plasma glucose, insulin,
and lipid concentrations) in either group.
conclusions
Abdominal liposuction does not significantly improve obesity-associated metabolic ab-
normalities. Decreasing adipose tissue mass alone will not achieve the metabolic ben-
efits of weight loss.
for subcutaneous and intracompartmental (abdo- for evaluating the effect of insulin on glucose pro-
men or muscle) fat content. duction and lipolysis (stage 1) and on glucose dis-
posal (stage 2). The rates of tracer infusions were
Euglycemic–Hyperinsulinemic Clamp Protocol decreased during each stage of the clamp protocol
The subjects were admitted to the General Clinical to account for the expected changes in endogenous
Research Center (Washington University School of substrate metabolism. Blood samples were obtained
Medicine) and consumed a standard meal (55 per- before the beginning of the tracer infusion to deter-
cent carbohydrate, 30 percent fat, and 15 percent mine baseline plasma concentrations of C-reactive
protein) containing 16 kcal per kilogram of fat-free protein, cytokines, lipids, substrates, and hormones
mass at 7 p.m. At 8 p.m., they consumed a 240-kcal and to determine background substrate tracer-to-
liquid snack (Ensure, Ross Laboratories). The last tracee ratios. Blood was collected every 10 minutes
dose of hypoglycemic medication was taken on the during the last 30 minutes of the basal period and
day of admission. At 5 a.m. the next morning, after during the last 30 minutes of each stage of the eu-
the subjects had fasted overnight, catheters were in- glycemic–hyperinsulinemic clamp procedure to
serted into a radial artery for blood sampling and determine plasma substrate and insulin concentra-
into an antecubital vein for the infusion of insulin, tions and substrate tracer-to-tracee ratios (i.e., the
dextrose, and tracers. At 7 a.m., a primed (priming ratios of labeled to unlabeled substrate in plasma).
dose, 4.1 mg per kilogram [22.5 µmol per kilo- Plasma was separated by centrifugation within 30
gram]), constant infusion of [6,6-2H2]glucose minutes after collection and stored at ¡70°C until
(0.46 mg per minute per kilogram [0.25 µmol per final analyses were performed.
minute per kilogram]) was started, followed at
9 a.m. by a primed (priming dose, 116 µg per kilo- Liposuction
gram [1.2 µmol per kilogram]), constant infusion Approximately one week after completing the eu-
of [1,1,2,3,3-2H5]glycerol (7.8 µg per minute per glycemic–hyperinsulinemic clamp procedure, each
kilogram [0.08 µmol per minute per kilogram]) and subject underwent large-volume tumescent liposuc-
a constant infusion of [2,2-2H2]palmitate (9.0 µg tion, defined as the removal of more than 4 liters of
per minute per kilogram [0.035 µmol per minute aspirate.12 This procedure involves subcutaneous
per kilogram]). injection of a large volume of Ringer’s lactate con-
After infusion of the tracer for 3.5 hours (the taining dilute epinephrine (1:1,000,000) to induce
basal period), a two-stage euglycemic–hyperinsu- vasoconstriction and thus to minimize bleeding. All
linemic clamp protocol was initiated and continued liposuction procedures were performed by one of
for 6 hours. Euglycemia (a glucose level of approxi- the authors, who primarily removed superficial
mately 100 mg per deciliter [5.6 mmol per liter]) and deep subcutaneous abdominal fat. In addition,
was maintained by variable-rate infusion of 20 per- smaller amounts of fat were removed from the arms,
cent dextrose containing approximately 2.5 percent flanks, hips, or thighs in five subjects without dia-
[6,6-2H2]glucose. During stage 1 of the clamp betes and in four subjects with diabetes. A total of
protocol (from hour 3.5 to hour 6.5 of the tracer- 16±1 liters (12±1 liters from the upper body and
infusion study), insulin was infused at a rate of 4±2 liters from the lower body) of Ringer’s lactate
20 mU per square meter of body-surface area per plus epinephrine-infiltrated adipose tissue was as-
minute after initiation by a two-step priming dose pirated from the subjects with normal oral glucose
of insulin for 10 minutes (80 mU per square meter tolerance and a total of 17±2 liters (16±2 liters from
per minute for 5 minutes, followed by 40 mU per the upper body and 1±1 liters from the lower body)
square meter per minute for 5 minutes). During was aspirated from the subjects with type 2 diabetes.
stage 2 of the clamp protocol (hour 6.5 to hour 9.5
of the tracer-infusion study), insulin was infused at Evaluation after Liposuction
a rate of 50 mU per square meter per minute after Subjects were instructed to resume their normal
initiation by a two-step priming dose of insulin for lifestyle after the initial recovery period and to weigh
10 minutes (200 mU per square meter per minute themselves weekly at home. Each subject was con-
for 5 minutes, followed by 100 mU per square meter tacted by one of the investigators at least once every
per minute for 5 minutes). week by phone to review her medical condition and
These insulin infusion rates result in plasma in- to reinforce the importance of maintaining her
sulin concentrations that provide an optimal range usual food intake and physical activity and to main-
tain a stable body weight. No serious complications without diabetes were analyzed separately. A two-
occurred in any subject, and all were able to return way analysis of variance (time by clamp stage) with
to their usual lifestyle within 10 days after liposuc- repeated measures was used to compare the effects
tion. For each of the seven subjects with type 2 dia- of liposuction on basal and insulin-mediated sub-
betes, hypoglycemic medications were regulated strate metabolism. Changes in body composition
by the subject’s physician. In six of them, the medi- and risk factors for coronary heart disease were
cations were not changed after the clamp procedure; assessed by means of Student’s t-test for paired
in one, rosiglitazone (4 mg per day) was stopped, samples. All reported P values are two-sided, and a
and glipizide and metformin were continued. P value of 0.05 or less was considered to indicate
All the studies performed before liposuction statistical significance.
were repeated 10 to 12 weeks after liposuction. The
10-to-12-week delay was intended to eliminate the results
confounding effects of postsurgical inflammation
on our study end points. body composition
Liposuction decreased body weight and body-mass
analyses of blood samples index (the weight in kilograms divided by the square
Plasma glucose concentrations were determined of the height in meters) because of a marked de-
with use of a glucose analyzer (Yellow Springs In- crease in body fat (Table 1). Ten to 12 weeks after
struments), and plasma fatty acid concentrations surgery, the mass of body fat had decreased by
were quantified by means of gas chromatography.13 9.1±3.7 kg from baseline (18±3 percent of the total
Plasma insulin and leptin concentrations were mea- fat mass, P=0.002) in the subjects with normal oral
sured by radioimmunoassay (Linco Research). glucose tolerance and by 10.5±3.3 kg (19±2 per-
Plasma lipid concentrations were determined enzy- cent of the total fat mass, P<0.001) in the subjects
matically (Roche/Hitachi 747 Analyzer, Roche Di- with type 2 diabetes. The decrease in measured fat
agnostics). Enzyme-linked immunosorbent assay mass was consistent with the amount of fat aspi-
kits were used to measure plasma C-reactive pro- rated during liposuction; approximately 60 percent
tein (American Laboratory Products), adiponectin of the liposuction aspirate was composed of fat.
(B-Bridge International), interleukin-6, and tumor The decrease in body fat was greater than the total
necrosis factor a (Quantakine High Sensitive, R&D decrease in body weight, however, because of ab-
Systems). Plasma glucose, glycerol, and palmitate dominal-tissue edema, which often persists for
tracer-to-tracee ratios were determined with the use months after liposuction.16 The measured truncal
of gas chromatography–mass spectrometry.13,14 fat-free mass, which included tissue fluid, increased
from 24.5±2.7 kg to 27.4±3.0 kg (P<0.001) in the
calculations two groups overall. Liposuction decreased the vol-
A physiologic and isotopic steady state was achieved ume of subcutaneous abdominal adipose tissue by
during the last 30 minutes of the basal period and 44 percent in the subjects with normal glucose toler-
the insulin-infusion period, so the rates of appear- ance and 28 percent in those with diabetes, where-
ance and disappearance of substrate were calculat- as the volumes of visceral adipose tissue and thigh
ed as the tracer infusion rate divided by the tracer- adipose tissue did not change significantly (Fig. 1
to-tracee ratio.15 The rate of appearance of total and Table 1).
free fatty acid was calculated by dividing the rate
of appearance of palmitate by the percent contribu- circulating inflammatory mediators
tion of palmitate to total plasma free fatty acids. and other risk factors for coronary
heart disease
statistical analysis Liposuction caused a decrease in waist circumfer-
The number of subjects to be enrolled was deter- ence in both groups, but it did not significantly alter
mined as the estimated number needed for the study other risk factors for coronary heart disease (Table
to detect a statistically significant effect of liposuc- 2). Liposuction also decreased plasma leptin con-
tion on glucose kinetics with a power of at least 0.8, centrations in both groups, but it did not signifi-
if the subjects had lost a similar amount of body fat cantly alter the concentrations of other circulating
by dieting. Data on subjects with diabetes and those cytokines or of C-reactive protein (Table 3).
Table 1. Effects of Liposuction on Body Composition in Obese Women with Normal Glucose Tolerance or Type 2 Diabetes.*
* Plus–minus values are means ±SD. Body-composition studies were performed within 9 days before liposuction and were repeated 10 to 12
weeks after liposuction. CI denotes confidence interval, minus signs decreases, and plus signs increases.
substrate kinetics and insulin sensitivity risk factors for coronary heart disease in women
In the subjects with normal glucose tolerance, plas- with abdominal obesity who had either moderate
ma insulin concentrations after liposuction were insulin resistance and normal glucose tolerance or
similar to those before liposuction for both stages more severe insulin resistance and type 2 diabetes.
1 and 2 of the clamp procedure (stage 1 and 2 values Weight stability was carefully maintained before
before liposuction, 44±7 and 90±12 µU per millili- and after liposuction to eliminate the confounding
ter [264±42 and 540±72 pmol per liter], respective- effects of changes in energy balance on the study
ly; stage 1 and 2 values after liposuction, 42±5 and end points. Our data show that the aspiration of
89±6 µU per milliliter [252±30 and 534±48 pmol large amounts of subcutaneous abdominal adipose
per liter], respectively); the same was true of the tissue resulted in a considerable decrease in body
subjects with type 2 diabetes (stage 1 and 2 values weight, waist circumference, and plasma leptin con-
before liposuction, 40±2 and 86±7 µU per milliliter centrations but did not have a significant effect on
[240±12 and 516±42 pmol per liter], respectively;
stage 1 and 2 values after liposuction, 41±3 and
86±6 µU per milliliter [246±18 and 516±36 pmol
per liter], respectively). Insulin infusion during
stage 1 caused the expected decreases in the rates of
Before
appearance of glucose, glycerol, and free fatty acids, Liposuction
and insulin infusion during stage 2 caused the ex-
pected increase in the rate of disappearance of glu-
cose both in subjects with normal glucose tolerance
and in those with type 2 diabetes (Fig. 2 and 3).
Rates of appearance of glucose, glycerol, and free
fatty acid and the rate of disappearance of glucose After
during basal conditions and during each stage of Liposuction
the clamp procedure were not significantly differ-
ent before and after liposuction in either group
(Fig. 2 and 3).
Figure 1. Photographs and Abdominal Magnetic Resonance Images Obtained
discussion before and after Liposuction.
The photographs of one study subject and images of another show the large
In the present study, we evaluated the effects of amount of subcutaneous abdominal fat removed by liposuction.
large-volume liposuction on insulin sensitivity and
Table 2. Effects of Liposuction on Risk Factors for Coronary Heart Disease in Obese Women with Normal Glucose Tolerance
or Type 2 Diabetes.*
* Plus–minus values are means ±SD. To convert the values for glucose to millimoles per liter, multiply by 0.0555. To convert the values for insu-
lin to picomoles per liter, multiply by 6. To convert the values for cholesterol to millimoles per liter, multiply by 0.0259. To convert the values
for triglycerides to millimoles per liter, multiply by 0.0113. The measurements were made within 9 days before liposuction and again 10 to 12
weeks after liposuction. CI denotes confidence interval, minus signs decreases, and plus signs increases.
Table 3. Effects of Liposuction on Mediators of Inflammation in Obese Women with Normal Glucose Tolerance or Type 2 Diabetes.*
* Plus–minus values are means ±SD. The measurements were made within 9 days before liposuction and again 10 to 12 weeks after liposuc-
tion. CI denotes confidence interval, minus signs decreases, and plus signs increases.
† Values were obtained from six subjects in each group.
insulin sensitivity in skeletal muscle (assessed as subjects is equivalent to the weight loss achieved by
the stimulation of glucose uptake), in the liver (as- optimal behavioral and pharmacologic treatments.3
sessed as the suppression of glucose production), A total weight loss of approximately 12 percent of
or adipose tissue (assessed as the suppression of body weight would be required to achieve the fat
lipolysis). In addition, liposuction had no signifi- loss resulting from liposuction in our study sub-
cant effects on other risk factors for coronary heart jects, because about 75 percent of the decrease in
disease, including blood pressure; fasting plasma body-mass that occurs by dieting is due to loss of
glucose, insulin, and lipid concentrations; and con- body fat.17 This amount of weight loss usually re-
centrations of plasma markers of inflammation sults in marked improvement in the metabolic ab-
and insulin resistance (C-reactive protein, tumor normalities associated with obesity and improves
necrosis factor a, interleukin-6, and adiponectin). insulin sensitivity,18 blood pressure,19 and concen-
The amount of fat removed by liposuction in our trations of serum lipids20 and circulating markers
Disappearance of Glucose
3000
1000
(µmol/min)
2000
500
1000
0 0
Basal Stage 1 Stage 2 Basal Stage 1 Stage 2
Appearance of Glycerol (µmol/min)
400 600
(µmol/min)
200
200
100
0 0
Basal Stage 1 Stage 2 Basal Stage 1 Stage 2
Figure 2. Mean Rates of Appearance and Disappearance of Glucose and Rates of Appearance of Glycerol and Free Fatty
Acids in the Basal State and during the Euglycemic–Hyperinsulinemic Clamp Procedure in Obese Women with Normal
Glucose Tolerance before and after Liposuction.
Stage 1 of the euglycemic–hyperinsulinemic clamp procedure involved the infusion of insulin at a rate of 20 mU per
square meter of body-surface area per minute, and stage 2 involved the infusion of insulin at a rate of 50 mU per square
meter per minute. The T bars represent the SD.
of inflammation.21 Therefore, it is striking that the cutaneous abdominal fat and reduces the total
amount of fat loss achieved by liposuction in our number of body fat cells, without altering visceral
diabetic and nondiabetic subjects did not improve fat mass,31 the size of the remaining fat cells,10 in-
any of these metabolic variables. tramyocellular fat, or intrahepatic fat.
The absence of an apparent therapeutic effect of The results of the present study also show that
liposuction provides insight into the mechanism by removing a large amount of abdominal subcutane-
which conventional therapy for obesity — namely, ous fat by liposuction does not significantly affect
diet, pharmacotherapy, and bariatric surgery — im- the levels of circulating mediators of inflammation
proves insulin sensitivity. Our results suggest that that are probably involved in the development of
induction of a negative energy balance, not simply insulin resistance and coronary heart disease.32 Ad-
a decrease in the mass of adipose tissue, is critical ipose tissue is now recognized as an important
for achieving the metabolic benefits of weight loss. endocrine organ that produces several bioactive pro-
Even small amounts of weight loss induced by a teins, including interleukin-6, tumor necrosis fac-
negative energy balance affects many variables per- tor a, and adiponectin. Interleukin-6 and tumor
taining to body-fat composition and lipid metab- necrosis factor a can cause insulin resistance and
olism — variables that probably contribute to the atherosclerosis by impairing insulin signaling, stim-
metabolic abnormalities associated with obesi- ulating lipolysis and fatty acid release, increasing
ty.22-25 Weight loss decreases visceral fat mass,26 hepatic synthesis of C-reactive protein, and increas-
intramyocellular fat,27 intrahepatic fat,28 fat-cell ing systemic inflammation,32-34 whereas the pro-
size,29 and the rate of release of fatty acids from adi- duction of adiponectin by adipose tissue can im-
pose tissue.30 In contrast, liposuction removes sub- prove insulin sensitivity and inhibit vascular
Disappearance of Glucose
3000
1000
(µmol/min)
2000
500
1000
0 0
Basal Stage 1 Stage 2 Basal Stage 1 Stage 2
Appearance of Glycerol (µmol/min)
400 600
(µmol/min)
200
200
100
0 0
Basal Stage 1 Stage 2 Basal Stage 1 Stage 2
Figure 3. Mean Rates of Appearance and Disappearance of Glucose and Rates of Appearance of Glycerol and Free Fatty
Acids in the Basal State and during the Euglycemic–Hyperinsulinemic Clamp Procedure in Obese Women with Diabetes
before and after Liposuction.
Stage 1 of the euglycemic–hyperinsulinemic clamp procedure involved the infusion of insulin at a rate of 20 mU per
square meter of body-surface area per minute, and stage 2 involved the infusion of insulin at a rate of 50 mU per square
meter per minute. The T bars represent the SD.
inflammation.35,36 Fat loss achieved by convention- improve insulin sensitivity in the liver, skeletal mus-
al obesity treatments decreases the plasma concen- cle, or adipose tissue; serum concentrations of
trations of C-reactive protein, interleukin-6, and markers of inflammation; or other risk factors for
tumor necrosis factor a37,38 and increases the con- coronary heart disease. These findings offer impor-
centration of adiponectin39; in contrast, liposuction tant insights into the mechanisms responsible for
in our subjects did not significantly change the the metabolic benefits observed with moderate diet-
plasma concentrations of any of these markers. induced weight loss, which decreases hepatic and
However, fat removal by liposuction did decrease muscle fat content, fat-cell size, visceral fat mass,
the plasma leptin concentration, which is a marker and circulating concentrations of proinflammatory
of adipose-tissue mass.40 These results suggest that cytokines. The effects of a negative energy balance
a negative energy balance influences adipocyte and on specific endogenous triglyceride depots and in-
monocyte activation and the gene expression of flammation, which are not altered by liposuction,
selected cytokines, but that long-term leptin pro- may be necessary to achieve many of the clinical
duction is influenced primarily by total fat mass. benefits of therapy for obesity.
The results of the present study suggest that ab- Supported by grants (HD 01459, DK 37948, RR-00954 [to the Bio-
medical Mass Spectrometry Resource], RR-00036 [to the General
dominal liposuction should not, by itself, be con- Clinical Research Center], and DK 56341 [to the Clinical Nutrition
sidered a clinical therapy for obesity. Aspiration of Research Unit]) from the National Institutes of Health.
large amounts of subcutaneous abdominal fat in We are indebted to the nursing staff of the General Clinical Re-
search Center for their help in performing the studies, to Freida
women with abdominal obesity may have cosmetic Custodio and Junyoung Kwon for their technical assistance, and to
benefits, but the procedure does not significantly the subjects for their participation in the study.
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