0021-972X/01/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2001 by The Endocrine Society
Vol. 86, No. 6
Printed in U.S.A.
Adipose Tissue Metabolism in Benign
Symmetric Lipomatosis*
SØREN NIELSEN, JAMES LEVINE, RICKY CLAY,
AND
MICHAEL D. JENSEN
Endocrine Research Unit and Department of Plastic Surgery (R.C.), Mayo Clinic, Rochester, Minnesota
55905
ABSTRACT
Type 2 benign symmetric lipomatosis (BSL) is characterized by
abnormal growth of adipose tissue in the upper back, deltoid region,
upper arms, hips, and upper thigh region. Studies of lipomatous tissue
in vitro have suggested that defective lipolysis may account for excess
fat accumulation; however, in vivo adipose tissue metabolism has not
been evaluated. We measured systemic adipose tissue lipolysis and
regional adipose tissue fatty acid uptake in a patient with type 2 BSL
scheduled for elective brachioplasty. We found increased, rather than
decreased, rates of systemic free fatty acid release coupled with nor-
B
ENIGN SYMMETRIC lipomatosis (BSL) is a group of
syndromes characterized by abnormal adipose tissue
growth. Initially described a century ago (1, 2) under the
eponyms Launois-Bensaude syndrome and Madelungs disease, the syndromes are today termed BSL and at least two
clinical phenotypes are recognized (3). Type 1 BSL affects
primarily men and is characterized by fat accumulation
around the neck, nape of the neck, upper back, shoulders,
and upper arms. Type 2 affects both men and women, producing an exaggerated female fat distribution in the upper
back, deltoid region, upper arms, hips, and upper thigh
region. Unlike lipomas, lipomatous tissue in these syndromes is nonencapsulated, with the ability to infiltrate
spaces between adjacent sc and muscular structures. The
etiology of BSL is not known, although the lipomatous tissue
is characterized by normal-sized or smaller than expected fat
cells (4, 5), consistent with an ongoing recruitment and maturation of preadipocytes to explain adipose tissue growth.
The expansion of adipose tissue mass via fat cell proliferation was termed hyperplastic obesity by Björntorp and
Sjöström (6) to contrast with hypertrophic obesity, in which
increased fat cell size is thought to be the major initial means
by which adipose tissue mass increases. The significance of
this distinction is the association between increasing fat cell
size, but not fat cell number, and the metabolic complications
of obesity (6 – 8). Smaller abdominal sc adipocytes are present
in lower body obesity, the more metabolically normal obesity
phenotype (7). Thus, expansion of adipose tissue stores by fat
Received August 18, 2000. Revision received February 26, 2001. Accepted March 2, 2001.
Address all correspondence and requests for reprints to: Michael D.
Jensen, M.D., Endocrine Research Unit, 5-194 Joseph, Mayo Clinic, Rochester, Minnesota 55905. E-mail: [email protected].
* This work was supported by Grants DK-45343 and DK-50456 (Minnesota Obesity Center) and RR-0585 from the USPHS, the Mayo Foundation, and the Danish Medical Research Council (to S.N.).
mal fatty acid oxidation. The uptake of fatty acids was 19% greater
in deltoid region lipomatous tissue than in abdominal sc fat, whereas
in control studies the relative uptake of fatty acids in deltoid fat
averaged 29% less than that in abdominal fat. Adipocyte size was
smaller than expected in lipomatous tissue. These results suggest
that type 2 BSL is a hyperplastic adipose tissue abnormality that does
not impair systemic lipolysis. The pathophysiology appears similar to
what has been termed hyperplastic obesity. A better understanding
of this condition could lead to insights into the mechanisms of hyperplastic obesity. (J Clin Endocrinol Metab 86: 2717–2720, 2001)
cell proliferation, as opposed to fat cell hypertrophy, may be
a more metabolically benign means of increasing body energy stores. Whether BSL patients develop abnormalities of
lipid fuel metabolism similar to lower body obesity does not
appear to have been examined in vivo in these patients.
Based upon in vitro evidence of defective adipose tissue
lipolysis in BSL (4, 9), it has been suggested that the excess
adipose triglyceride accumulation is due to reduced fatty
acid release. If systemic lipolysis is also impaired in BSL
patients, one would expect subnormal free fatty acid (FFA)
release into the circulation relative to lean tissue needs and,
therefore, reduced systemic fatty acid oxidation. Conversely,
increased fatty acid uptake by lipomatous tissue could result
in abnormal fat accumulation even in the face of normal or
increased lipolysis and fatty acid oxidation. These adipose
tissue functions can now be assessed using isotope dilution
techniques, thus allowing definitive in vivo assessment of this
issue. In addition, measurement of adipocyte size could help
assess whether adipocyte hypertrophy, as opposed to adipocyte hyperplasia, is occurring in lipomatous and nonlipomatous adipose tissue. The present experiments were undertaken to study the pathophysiology of type 2 BSL, which
could contribute to understanding the physiology of hyperplastic obesity.
Case Report
A 50-yr-old woman (Fig. 1) was evaluated for lipohypertrophy 6 yr after
first noticing increased fat accumulation in both upper shins. The excess fat
gradually expanded to her thighs and appeared separately in her upper
arms; mild tenderness had been noted in her arms and shins. During this
6-yr interval her weight increased from 68 to 103 kg. Her past history was
remarkable for moderate alcoholic liver disease with hypersplenism that
had gradually improved with abstinence. Her medications included ranitidine (150 mg, daily), conjugated equine estrogen (0.625 mg/day), furosemide (40 mg/day), potassium chloride (20 mg/day), and spironolactone
(50 mg/day). The physical examination was normal, except for the abnormal fat distribution and a grade 2/6 systolic ejection murmur at the left
upper sternal border. Laboratory evaluation disclosed evidence of chronic
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Vol. 86 • No. 6
NIELSEN ET AL.
where adipose could be obtained directly. The diameter of at least 200
fat cells/site was measured to determine the average fat cell size. Resting
energy expenditure (REE) and respiratory exchange ratios were assessed
by indirect calorimetry (Deltatrack Metabolic Monitor, Datex, Helsinki,
Finland). The FFA (palmitate) rate of appearance (Ra), an index of whole
body adipose tissue lipolysis in vivo, was determined using [3H]palmitate (American Radiochemicals, Inc., St. Louis, MO) with corrections for
isotopic purity (13). Meal fatty acid oxidation [using breath 14CO2 specific activity (SA)] and adipose tissue meal fatty acid uptake were measured with [1-14C]- triolein (14). We also measured the [3H] triglyceride
SA in adipose tissue to obtain an estimate of adipose tissue very low
density lipoprotein triglyceride uptake.
Eight healthy obese women [body mass index (BMI) range, 31.7–35.9
kg/m2] served as control subjects.
Protocol
FIG. 1. Photographs of the patient with type 2 BSL. Note the marked,
symmetrical accumulation of well demarcated adipose tissue depots
in the upper arms and gluteal/thigh region.
liver disease (2-fold increases in aspartate aminotransferase and alkaline
phosphatase, total and direct bilirubin concentrations of 1.6 and 0.7 mg/dL,
respectively). Her platelet count was 86 ⫻ 109/L (normal, 150 – 450 ⫻
109/L), and her erythrocyte mean corpuscular volume was 102 fL (normal,
81.6 –98.3 fL). Relevant normal laboratory values included cobalamin and
folate concentrations, hemoglobin and white blood cell count, bleeding
time, electrolytes, urea, and creatinine. Her high density lipoprotein cholesterol was 100 mg/dL, with total cholesterol of 167 mg/dL, triglycerides
of 64 mg/dL, and calculated low density lipoprotein cholesterol of 54
mg/dL. The patient was offered bilateral surgical brachioplasty in combination with liposuction to be followed by graded liposuction of the lower
extremities. Metabolic studies were performed during the week preceding
the surgery.
Materials and Methods
Methods
Total body fat and fat-free mass (FFM) was measured by dual energy
x-ray absorptiometry (10) (Lunar Corp., Madison, WI). Intraabdominal
and abdominal sc fat was assessed using a single slice computed tomography scan of the abdomen at the L2–L3 interspace (11). Fat cell size
was measured as described by DiGirolamo (12). Adipose tissue for fat
cell size was obtained by needle liposuction for all specimens, with the
exception of the surgical brachioplasty material from the BSL patient,
Informed written consent was obtained. The patient was admitted to
the Mayo Clinic General Clinical Research Center and placed on a
weight-maintaining diet providing 30%, 20%, and 50% of energy from
fat, protein, and carbohydrate, respectively. The following day after an
overnight fast an antecubital vein catheter was placed for isotope and
epinephrine infusions, and a contralateral dorsal hand vein catheter was
placed for sampling of arterialized venous blood (15). An infusion of
[3H]palmitate (0.3 ␮Ci/min) was started and continued for 2 h. After 30
min for isotopic equilibration, blood samples were obtained at 10-min
intervals for the next 90 min. During the last 60 min of the 90-min time
interval, epinephrine (10 ng/kg FFM䡠min) was infused to assess the
lipolytic response to catecholamines. Oxygen consumption and CO2
production were measured for 30 min at baseline and during the last 30
min of the epinephrine infusion. After completion of the study the
patient commenced a 3-day fast, during which she drank only water and
nonnutrient-containing beverages without caffeine. On the third day of
the fast, repeat measurements of resting and epinephrine-stimulated
palmitate Ra and indirect calorimetry were performed. After this study
the patient resumed her previous diet. The following morning she consumed a meal providing one third of her usual daily energy intake,
which included Ensure Plus (Ross Laboratories, Columbus, OH) containing 50 ␮Ci [14C]triolein. Breath for measurement of CO2 production
rates and 14CO2 SA was collected every 2 h for 24 h, similar to studies
recently conducted in our laboratory (14). Three days after consuming
the labeled meal, the patient underwent surgery. Adipose tissue samples
were obtained from the surgically removed tissue of the upper arms.
Syringe liposuction was used to obtain fat from the paraumbilical abdominal sc area and the gluteal/thigh region for immediate determination of triglyceride SA and adipocyte size. For comparison, we used
data collected from ongoing studies in our laboratory to relate body
composition to fat cell size.
Results
Body composition
The patient’s BMI was 36.9 kg/m2. She had 60% body fat,
with visceral and abdominal sc fat area of 163 and 410 cm2,
respectively. The average diameter of adipocytes from abdominal sc, arm, and gluteal/thigh regions from this patient
were 104, 90, and 86 ␮m, respectively. In Fig. 2 the abdominal
and gluteal/thigh diameters for this patient are plotted vs.
percent body fat in comparison with values from 36 women
studied in our laboratory; her values were in the lower range
for each site. Because it is difficult to routinely collect upper
arm adipose tissue, we do not have similar data with respect
to arm adipocyte size.
Plasma insulin and catecholamine concentrations
Our patient’s overnight postabsorptive plasma insulin and
catecholamine concentrations together with those of eight
women with similar BMIs (34.3 ⫾ 1.3 kg/m2) studied in our
laboratory are provided in Table 1. After 3 days of fasting,
ADIPOSE TISSUE METABOLISM IN BENIGN SYMMETRIC LIPOMATOSIS
2719
in arm fat in our patient was 19% greater than that in abdominal sc fat. We collected adipose tissue from the triceps
area from six other volunteers 24 – 48 h after undergoing meal
fatty acid tracer studies for comparison; the relative uptake
of meal fatty acids in arm fat was 29 ⫾ 14% (range, 14 –50%)
less than that in abdominal fat.
Discussion
FIG. 2. Abdominal (left panel) and gluteal/thigh (right panel) adipocyte diameter is plotted vs. percent body fat for women without (E) and
the patient with (F) type 2 BSL.
TABLE 1. Plasma insulin and catecholamine concentration data
Fasting insulin (pmol/L)
Epinephrine (pmol/L)
Norepinephrine (nmol/L)
Patient
Control
subjects
25
56
1.24
57 ⫾ 26
73 ⫾ 21
0.65 ⫾ 0.18
Patient values are the mean of three or four samples collected over
30 min. The control subjects were eight females. Values for controls
are the mean ⫾ SD.
baseline plasma insulin, epinephrine, and norepinephrine
concentrations were 12 pmol/L, 124 pmol/L, and 0.73
nmol/L, respectively.
Energy metabolism
Basal postabsorptive REE was 7.155 mJ/24 h, which is
within 5% of the predicted value according to standard equations (16). The respiratory quotients before and after the
3-day fast were 0.73 and 0.68, respectively, indicating that
fatty acids were the major oxidative substrate. On both study
days a 27% increase in REE was observed during epinephrine
infusion, which is consistent with previous studies (17).
Fatty acid kinetics
Overnight postabsorptive plasma FFA concentrations and
FFA Ra were 705 ␮mol/L and 17.7 ␮mol/kg FFM䡠min, respectively. Typical values for upper body obese and lower
body obese women in our laboratory are 726 ⫾ 42 and 617 ⫾
33 ␮mol/L and 15.0 ⫾ 1.2 vs. 14.5 ⫾ 0.5 ␮mol/kg FFM䡠min,
respectively (18). Plasma FFA concentrations during the last
30 min of the epinephrine infusion increased to 955 ␮mol/L,
with an average FFA Ra of 29.1 ␮mol/kg FFM䡠min. After the
3-day fast, basal and epinephrine-stimulated FFA Ra were
29.1 and 44.1 ␮mol/kg FFM䡠min, respectively. The average
fasting FFA concentrations before and during the epinephrine infusion were 986 and 1395 ␮mol/L, respectively.
Twenty-six percent of the 14C administered as [14C]triolein
appeared as breath 14CO2 in the 24 h after consumption of the
labeled meal, which is consistent with previous observations
(14, 19). The adipose tissue [3H]- and [14C]triglyceride SA
were greater in the upper arms than in either sc abdominal
or femoral adipose tissue (0.90, 0.74, and 0.83 dpm/mg fat
and 0.86, 0.72, and 0.56 dpm/mg fat for [3H]- and [1-14C]triglyceride SA, respectively). Thus, the meal fatty acid uptake
This patient with type 2 BSL had different abnormalities
of lipid and adipose tissue metabolism than we anticipated
on the basis of previously published studies. Instead of reduced FFA release relative to lean tissue needs, systemic
adipose tissue lipolysis was grossly elevated, with further
increases in response to fasting and epinephrine. Energy
expenditure was normal and, consistent with the increased
FFA availability, substrate oxidation was shifted toward lipids. Fatty acid uptake in arm lipomatous tissue was greater
than that in abdominal sc fat, suggesting avid fat storage.
Finally, lipomatous arm adipose tissue was characterized by
normal-sized adipocytes, which, given the massive increase
in fat content, implies active proliferation and differentiation
of preadipocytes. Thigh adipose tissue in this patient, which
had a lipomatous appearance, took up meal fatty acids less
well than abdominal adipose tissue. This is the same pattern
we observed in lean, healthy men and women (20). Of note,
the 3H fatty acids were more concentrated in thigh than
abdominal adipose tissue in this BSL patient, perhaps suggesting that FFA that reenter adipose tissue (probably via
VLDL triglyceride) are targeted differently than mealderived fatty acids.
The patient’s lipomatous tissue accumulated primarily as
symmetrical, sc, nonencapsulated masses in the upper arms
and as well defined regions in the hip and thigh areas. The
finding of normal size adipocytes in lipomatous tissue suggests that active, localized recruitment and differentiation of
preadipocytes were occurring in concert with exaggerated
uptake of circulating triglyceride fatty acids. The lipomatous
tissue in type 2 BSL thus appears to behave in a manner
similar to that proposed for hyperplastic obesity, albeit in a
more aggressive manner. The virtual lack of metabolic complications of obesity (dyslipidemia, hypertension, and glucose intolerance) in this patient despite the elevated FFA
concentrations and flux is of interest.
A defect in fat cell lipolytic pathways is a suggested mechanism for accumulation of BSL adipose tissue. Some investigators have reported defective in vivo (4, 21) and in vitro (4,
9) lipolysis, whereas others have reported normal or increased in vivo (22) and in vitro (22, 23) lipolysis. Differences
in the patient populations studied (type 1 vs. type 2) and in
the response of lipomatous vs. normal tissue may explain the
discrepancies. Moreover, previous studies used plasma FFA
concentrations to evaluate in vivo lipolysis, which could be
misleading if clearance is abnormal in this condition. We
therefore employed isotopic tracer techniques to directly
measure in vivo lipolysis and to determine fat uptake in BSL
adipose tissue. A high rate of basal FFA release rate relative
to fat-free mass was observed, which increased further with
fasting and epinephrine. These rates were similar to or
greater than those noted in obese women (18, 24). Thus, our
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NIELSEN ET AL.
findings do not support reduced sensitivity of systemic lipolysis in type 2 BSL, although without direct measures
across the lipomatous tissue we cannot rule out regional
insensitivity. We note that relative to total fat mass, basal FFA
(palmitate) release in this BSL patient (2.6 ␮mol/kg fat䡠min)
was less than we have found in comparably overweight
women (3.9 ␮mol/kg fat䡠min) (18). Although this could be
taken as an indication of impaired lipolysis in BSL, it should
be pointed out finding lesser rates of FFA release relative to
fat mass in women with more body fat is not unexpected (24,
25). This BSL patient had 50% more body fat mass than
comparably overweight non-BSL women. Thus, the lesser
rates of FFA release per unit fat mass could reflect a partial
down-regulation of adipose lipolysis to prevent overwhelming the capacity of lean tissue to deal with FFA.
We found evidence of increased triglyceride fatty acid
uptake in upper arm adipose tissue in our patient. It is
possible that increased clearance of circulating triglycerides
by lipomatous tissue may prevent the hypertriglyceridemia
that is often associated with increased FFA availability in
obesity (26).
In summary, the rapid increase in fat mass of this type 2
BSL patient would appear to resemble hyperplastic obesity
in terms of adipocyte size. The abnormalities of adipose
tissue metabolism include elevated lipolysis and preferential
triglyceride fatty acid uptake in lipomatous tissue. These
findings are consistent with accelerated adipose tissue proliferation, thereby permitting enhanced removal triglycerides from the circulation. This scenario could account for the
unexpectedly normal serum lipoprotein concentrations in
the face of high FFA availability.
Acknowledgments
We thank Joan Aikens, Rita Nelson, Carol Siverling, and the staff of
the Mayo Clinic General Research Center for excellent technical
assistance.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
References
1. Madelung OW. 1988 Uber den Fetthals. Arch Klin Chir. 37:106.
2. Launois PE, Bensaude R. 1989 De l’adeno-lipomatose symetrique. Bull Mem
Soc Med Hosp Paris. 1:298 –318.
3. Stavropoulos PG, Zouboulis CC, Trautmann C, Orfanos CE. 1997 Symmetric
lipomatoses in female patients. Dermatology. 194:26 –31.
4. Enzi G, Inelmen EM, Baritussio A, Dorigo P, Prosdocimi M, Mazzoleni F.
24.
25.
26.
JCE & M • 2001
Vol. 86 • No. 6
1977 Multiple symmetric lipomatosis: a defect in adrenergic-stimulated lipolysis. J Clin Invest. 60:1221–1229.
Enzi G, Favaretto L, Martini S, et al. 1983 Metabolic abnormalities in multiple
symmetric lipomatosis: elevated lipoprotein lipase activity in adipose tissue
with hyperalphalipoproteinemia. J Lipid Res. 24:566 –574.
Bjorntorp P, Sjostrom L. 1971 Number and size of adipose tissue fat cells in
relation to metabolism in human obesity. Metabolism. 20:703–713.
Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. 1983 Relationship of
androgenic activity to body fat topography, fat cell morphology, and metabolic
aberrations in premenopausal women. J Clin Endocrinol Metab. 57:304 –310.
Krotkiewski M, Bjorntorp P, Sjostrom L, Smith U. 1983 Impact of obesity on
metabolism in men and women. J Clin Invest. 72:1150 –1162.
Desai KS, Zinman B, Steiner G. 1979 Multiple symmetric lipomatosis (Launois-Bensaude syndrome): adipose tissue insensitivity to cyclic AMP. J Clin
Endocrinol Metab. 49:E307–E309.
Jensen MD, Kanaley JA, Roust LR, et al. 1993 Assessment of body composition with use of dual-energy x-ray absorptiometry: evaluation and comparison with other methods. Mayo Clin Proc. 68:867– 873.
Jensen MD, Kanaley JA, Reed JE, Sheedy PF. 1995 Measurement of abdominal and visceral fat with computed tomography and dual-energy x-ray absorptiometry. Am J Clin Nutr. 61:274 –278.
Di Girolamo M, Mendlinger S, Fertig JW. 1971 A simple method to determine
fat cell size and number in four mammalian species. Am J Physiol.
221:850 – 858.
Jensen MD, Haymond MW, Gerich JE, Cryer PE, Miles JM. 1987 Lipolysis
during fasting. Decreased suppression by insulin and increased stimulation by
epinephrine. J Clin Invest. 79:207–213.
Romanski SA, Nelson R, Jensen MD. 2000 Meal fatty acid uptake in human
adipose tissue: technical and experimental design issues. Am J Physiol Endocrinol Metab. 279:E447–E454.
Jensen MD, Heiling VJ. 1991 Heated hand vein blood is satisfactory for
measurements during free fatty acid kinetic studies. Metabolism. 40:406 – 409.
Harris JA, Benedict FG. 1919 A biometric study of basal metabolism in man.
Washington DC: Carnegie Institution of Washington; Publ. no. 279.
Jensen MD, Cryer PE, Johnson CM, Murray MJ. 1996 Effects of epinephrine
on regional free fatty acid and energy metabolism in men and women. Am J
Physiol. 270:E259 –E264.
Guo ZK, Hensrud DD, Johnson CM, Jensen MD. 1999 Regional postprandial
fatty acid metabolism in different obesity phenotypes. Diabetes. 48:1586 –1592.
Roust LR, Hammel KD, Jensen MD. 1994 Effects of isoenergetic, low-fat diets
on energy metabolism in lean and obese women. Am J Clin Nutr. 60:470 – 475.
Romanski SA, Nelson R, Jensen MD. 2000 Meal fatty acid uptake in adipose
tissue: Gender effects in non-obese humans. Am J Physiol Endocrinol Metab.
279:E455–E462.
Kodish ME, Alsever RN, Block MB. 1974 Benign symmetric lipomatosis:
functional sympathetic denervation of adipose tissue and possible hypertrophy of brown fat. Metabolism. 23:937–945.
Leung NW, Gaer J, Beggs D, Kark AE, Holloway B, Peters TJ. 1987 Multiple
symmetric lipomatosis (Launois-Bensaude syndrome): effect of oral salbutamol. Clin Endocrinol (Oxf). 27:601– 606.
Kather H, Schroder F. 1982 Adrenergic regulation of fat-cell lipolysis in multiple symmetric lipomatosis. Eur J Clin Invest. 12:471– 474.
Jensen MD, Haymond MW, Rizza RA, Cryer PE, Miles JM. 1989 Influence
of body fat distribution on free fatty acid metabolism in obesity. J Clin Invest.
83:1168 –1173.
Martin ML, Jensen MD. 1991 Effects of body fat distribution on regional
lipolysis in obesity. J Clin Invest. 88:609 – 613.
Kissebah AH, Alfarsi S, Adams PW, Wynn V. 1976 Role of insulin resistance
in adipose tissue and liver in the pathogenesis of endogenous hypertriglyceridaemia in man. Diabetologia. 12:563–571.