Am J Physiol Endocrinol Metab 295: E531–E535, 2008.
First published May 20, 2008; doi:10.1152/ajpendo.90357.2008.
Review
Why are we shaped differently, and why does it matter?
Sylvia Santosa and Michael D. Jensen
Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota
Submitted 11 April 2008; accepted in final form 14 May 2008
adipose tissue; lipoprotein lipase; free fatty acids; dietary fat
the metabolic complications are
much more common in those with an upper body/visceral fat
distribution compared with those having lower body fat distribution. Although there is considerable interest in the contribution of adipokines to these comorbidities, we will focus on the
role of fatty acids as they relate to obesity-associated complications and regional adiposity. The objective of this review is
to describe recent findings that contribute to our knowledge of
regional fat distribution and why it matters.
IN THE CONTEXT OF OBESITY,
Consequences of High-Circulating Free Fatty Acids
The effect of free fatty acids (FFAs) on glucose metabolism
in humans has been studied extensively; it is well established
that obesity and increased plasma FFA concentrations are risk
factors for the development of type 2 diabetes mellitus (T2DM)
(20, 26). The ability to manipulate FFA concentrations has
allowed scientists to show that the FFA/metabolic function
associations are not merely related abnormalities but cause and
effect. Studies using acipimox, an inhibitor of lipolysis, to
lower FFA or lipid emulsion infusions to raise FFA have
helped define the contribution of FFA to insulin action with
respect to glucose, lipoprotein, and vascular regulation (32).
Elevated plasma FFAs upregulate glucose production and
impair muscle glucose uptake, oxidation, and storage (15, 32).
FFAs also affect insulin secretion (25) as intracellular metabolites of fatty acids such as long-chain acyl-CoA and diacylglycerol trigger insulin release (29, 30) as well as ␤-cell
dysfunction (31). The perturbations in glucose metabolism and
insulin secretion that reflect increased systemic FFAs are
implicated in the etiology of T2DM.
In addition to its effects on glucose metabolism and diabetes
risk, elevated FFA concentrations have been shown to be risk
Address for reprint requests and other correspondence: M. D. Jensen,
Endocrine Research Unit, Mayo Clinic, 200 1st St. SW, Rm. 5-194 Joseph,
Rochester, MN 55905 (e-mail: [email protected]).
http://www.ajpendo.org
markers for ischemic heart disease (28), perhaps indirectly
through playing a part in the development of hypertension (36,
38) or directly via induction of vascular endothelial injury (27).
Elevation of FFAs induced by lipid emulsion/heparin infusions
has been shown to increase oxidative stress markers (37).
Contribution of Regional Body Fat Distribution
to Circulating FFAs
Circulating FFAs appear to play a significant role in the
development of T2DM and cardiovascular disease. Thus, understanding the origin of FFAs may help in developing therapies that might prevent disease. In the context of obesity, a
predominantly upper body fat distribution, defined as a waistto-hip circumference ratio of ⬎0.85 in women and ⬎0.95 in
men, is associated with greater postabsorptive and postprandial
plasma FFA concentrations. Often times an upper body fat
distribution is associated with large omental and/or mesenteric
fat stores, i.e., visceral fat. The importance of these two depots
as visceral fat relates to the fact that the FFAs and adipokines
they release enter into the portal vein rather than the systemic
circulation. As such, visceral fat may have a disproportionate
effect on hepatic metabolism.
Variations in systemic plasma FFA concentrations are in
large part due to variations in lipolysis (23), although FFA
clearance may play a role regulating FFA concentrations under
some conditions. Visceral fat is a good predictor of insulin
suppression of systemic FFA release in humans (2), but this
does not mean that visceral fat is the source of excess FFAs (2,
24). Although there are some differences in the regional
contribution to plasma FFAs according to fat distribution (19,
24), the majority of FFAs are released from upper body
subcutaneous fat in both the postprandial (19, 24) and postabsorptive (2, 12) states.
The varying contribution of different regional depots to
plasma FFAs emphasizes the importance of understanding
interindividual differences in body fat accumulation. In order
0193-1849/08 $8.00 Copyright © 2008 the American Physiological Society
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Santosa S, Jensen MD. Why are we shaped differently, and why does it matter?
Am J Physiol Endocrinol Metab 295: E531–E535, 2008. First published May 20, 2008;
doi:10.1152/ajpendo.90357.2008.—Body fat distribution is an important predictor of
metabolic abnormalities in obese humans. Dysregulation of free fatty acid (FFA)
release, especially from upper body subcutaneous adipose tissue, appears to
contribute substantially to these metabolic disturbances. Why different individuals
preferentially store fat in upper vs. lower body subcutaneous fat or subcutaneous vs.
visceral fat is not completely understood. Current evidence suggests that defects in
regional lipolysis are not the cause of net fat retention in larger fat depots. Regional
variations in the storage of fatty acids, both meal derived and direct reuptake, and
storage of circulating FFAs that may help to explain why some depots expand at the
expense of others have been reported. We review the quantitative data on regional
lipolysis, meal, and FFA storage in adults to provide an overview of fat balance
differences in adults with different fat distribution patterns.
Review
E532
REGIONAL FATTY ACID METABOLISM IN HUMANS
for one fat depot to expand at the expense of another, an
imbalance must exist between in storage and release of fatty
acids in that depot relative to other depots. The reason why
people differ in body fat distribution has not been fully elucidated, but we will review what has been learned.
Differences in Lipolysis Do Not Explain Variations in Body
Fat Distribution
Fatty Acid Uptake Appears to Contribute to Differences
in Regional Body Fat Accumulation
Meal fatty acid metabolism. Adipocytes take up circulating
fat via two pathways. The major and most well-understood
pathway of fatty acid uptake is dependent upon lipoprotein
lipase (LPL), and the other, less well-appreciated mechanism is
direct uptake and storage of circulating FFA. LPL is responsible for the hydrolysis of meal-derived triglycerides in chylomicrons and VLDL-triglyceride (TG) at the capillary endothelium. The fatty acids thus released can be taken up by local
cells or “spillover” into the systemic circulation (21, 34). Given
that dietary fat intake, and thus chylomicron TG delivery to the
circulation, is commonly ⱖ100 g/day and VLDL-TG secretion
is ⬃15–25 g/day, it is easy to understand why variations in
LPL activity would be seen as an important issue for fatty acid
storage.
Regional meal fat storage has been measured by providing
volunteers with a meal containing a (3H or 14C) fatty acid tracer
and then performing adipose tissue biopsies ⬃24 h later. The
storage of dietary fatty acids is traced by measuring the adipose
tissue lipid-specific activity and relating that to the meal fatty
acid-specific activity. The pioneering studies of Mårin and
colleagues (17, 18) stimulated further studies that have shown
that more meal fatty acids (per g adipose lipid) are stored in
abdominal fat than in leg fat in both normal-weight men and
women. However, following the consumption of high-fat,
high-calorie meals, women store an increased proportion of
dietary fat in leg fat compared with men (43), and this is
associated with greater activity of LPL in femoral adipose
tissue. For both normal-weight men and women, the storage of
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If defects in lipolysis were a main cause of differences in
regional fat deposition, lipolysis would vary in a manner that
would be expected to result in retention of fat in certain depots.
Specifically, decreases in regional lipolysis would be expected
to lead to increases in regional fat accumulation. Evidence
against this hypothesis comes from studies showing similar
regional lipolysis patterns in normal-weight women and men
with markedly different fat distributions. Upper body adipose
tissue is more lipolytically active than lower body adipose
tissue, regardless of sex (10). In addition, women with upper
body obesity have greater FFA release from upper body subcutaneous fat per kilogram of fat than do lower body obese
women under fasted (19) and fed (8) conditions. These data
argue that selective regional defects in lipolysis are unlikely to
explain differences in regional subcutaneous fat accumulation
among men and women. The inability to measure FFA release
directly into the portal vein in humans has left us with only
indirect estimates of visceral adipose tissue lipolysis (24), and
thus we cannot know whether defective visceral adipose tissue
lipolysis contributes to visceral fat gain in predisposed individuals.
dietary fatty acids in upper and lower body subcutaneous fat
was strongly correlated with postprandial, but not postabsorptive, adipose tissue LPL activity (42). Of note, we could not
detect a similar relationship between adipose tissue LPL activity and meal fatty acid storage in a mixed group of normalweight, overweight, and obese women despite measuring LPL
in the fed state (43).
The effects of a high-fat vs. normal-fat meal on regional
meal fatty acid storage, including visceral fat, have also been
studied in women with a wide range of adiposity and body fat
distribution (43). Following consumption of an isocaloric normal-fat (27% fat) meal, meal fatty acid storage (mg meal fat/g
adipose lipid) was greater in women with more leg fat compared with those with less leg fat. This was in contrast to the
patterns of meal fatty acid storage in upper body subcutaneous
fat (no relationship) and visceral fat, where those with more
stored less meal-derived fat per gram of adipose lipid than
those with less visceral fat (43). This suggests to us that the
different adipose depots may have different rate-limiting steps
for meal fatty acid storage. If this is the case, then circumstances that alter these rate-limiting steps could alter regional
fat storage. For example, following consumption of a high-fat
meal, the pattern of meal fatty acid storage in leg, abdominal,
and visceral fat storage changed remarkably (43). Specifically,
within each regional depot, those with more fat stored less
meal fat per gram of adipose lipid than those with less fat (43).
This change suggests that consumption of high-fat, highcalorie meals might impact body fat distribution over time.
Direct uptake and storage of FFA. During intravenous
glucose infusions (5) and following meal ingestion (3), disappearance of circulating FFAs across abdominal subcutaneous
adipose has been detected using the stomach vein catheterization techniques. Despite this, we had assumed that adipose
tissue would not simultaneously take up and store circulating
FFAs in the postabsorptive state because under these conditions adipose tissue actively exports FFAs. In the process of
performing experiments to test this assumption, we made the
surprising observation that subcutaneous adipose tissue does
indeed store a detectable fraction of systemic FFAs in humans
(16, 35). These FFAs, released from adipocytes into the systemic circulation, appear to be taken up and reesterified in
distant adipocytes. The pattern of direct FFA storage is different in men and women, and these differences suggest that this
LPL-independent pathway of fatty acid storage may be a
significant process in the regulation or maintenance of body fat
distribution (35).
In vivo detection of direct FFA storage can be measured
through bolus intravenous administration of 3H- or 14C-labeled
FFAs followed by carefully timed adipose tissue biopsies (35).
Direct storage measurement in subcutaneous adipose tissue in
lean and obese men and women showed greater overall direct
FFA storage in women. This is consistent with in vitro data
demonstrating that subcutaneous adipose tissue from women
took up and esterified extracellular radiolabeled FFAs twice as
well as comparable tissue from men (6). This greater subcutaneous storage in women is concordant with the fact that
females have more subcutaneous body fat than males at any
given body mass index (BMI). We also found that the efficiency of FFA storage per gram of fat was 30% greater in
abdominal subcutaneous fat than in femoral subcutaneous fat
in nonobese men, but there was no difference between these
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REGIONAL FATTY ACID METABOLISM IN HUMANS
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Integrating Regional Fatty Acid Storage and Release
Tracer studies have allowed us to follow the pathways
through which fat is metabolized in the body and quantify the
extent to which these pathways may modulate body fat distribution. A summary of the extent to which oxidation, storage,
and lipolysis contribute to regional body fat accumulation in
normal-weight men and women is depicted in Fig. 1. For this
example, we used normal-weight men and women (BMI ⬃22.5
kg/m2) with average body fat content (15% for men, 30% for
women). Both men and women were assumed to consume a
diet that provides 75 g/day of fat over three meals, and
energy/macronutrient balance is maintained. We assume that
2 h of the day are spent doing physical activity at a level that
will affect lipolysis and fat oxidation and that 8 h are spent in
the postprandial state. We used data for meal fat storage, data
for regional FFA release under fed, fasted, and exercise conditions, and direct FFA storage data to display what is known
about the interchange of fatty acids between various sources.
Data from tracer studies measuring meal fatty acid oxidation
using were used to calculate 24-h meal fat oxidation as depicted by CO2 in Fig. 1, assuming 22 h of nonexercise (14, 33,
39, 42, 43) and 2 h of exercise (40). Average nonexercise
oxidation is estimated to be ⬃21 g/day in women and ⬃25 g
in men. Meal fatty acid oxidation with prior exercise was
estimated to be 3.3 g (41). Thus, of the 75 g of fatty acids
oxidized over 24 h, ⬃25–30 g are from dietary fat and the
remainder from endogenous fatty acids, most likely FFAs.
Meal fatty acid storage in visceral, upper body, and lower
body subcutaneous depots was estimated using published data
where normal-fat meals were employed (14, 33, 39, 42, 43).
The storage in visceral and upper and lower body subcutaneous
fat in women and men is provided as green arrows in Fig. 1.
AJP-Endocrinol Metab • VOL
Fig. 1. Fatty acid kinetics (in g) over 24 h in a normal-weight (body mass
index ⬃22.5 kg/m2) man with 15% body fat and a normal-weight woman with
30% body fat are depicted. To make the calculations, we assumed that 14, 8,
and 2 h of the day were spent in the postprandial state, in the postabsorptive
state, and doing physical activity at a level that would affect lipolysis and fat
oxidation, respectively. Regional fatty acid metabolism is represented from
legs to chest as lower body subcutaneous adipose tissue, visceral adipose
tissue, and upper body subcutaneous adipose tissue. Green arrows represent the
regional meal fat storage via lipoprotein lipase-mediated pathways and oxidation assuming a 75 g/day ingestion of meal fat. Blue arrows represent the direct
storage of free fatty acids into regional depots from the circulating free fatty
acid (FFA) pool. Red arrows indicate the regional flow of FFAs that enter the
circulation via lipolysis. Size of arrow is proportional to the contributory flow
of FFAs to each pool. Reprinted with permission from the Mayo Foundation
for Medical Education and Research.
Entry of FFAs from leg, visceral, and upper body subcutaneous adipose tissue lipolysis into the systemic circulation was
estimated from regional catheterization studies performed under resting, overnight postabsorptive (8, 10, 12, 19, 22, 24),
postprandial (8, 10, 22), and exercise (1, 4, 44). The FFA
release values as shown by red arrows in Fig. 1 represent the
integrated estimates from these studies and are time-weighted
averages for 14 h in the postabsorptive state, 8 h postprandial,
and 2 h of exercise.
As expected, postabsorptive lipolysis was a large contributor
to overall daily lipolysis. Over 14 h, lipolysis in women is
estimated to be 88, 27, and 11 g from subcutaneous upper body
fat, subcutaneous lower body fat, and visceral adipose tissue,
respectively. In men, the 14-h postabsorptive lipolysis is estimated to be 102, 16, and 17 g, respectively. The visceral data
represent FFAs that enter the systemic circulation from the
hepatic vein, which underestimates true visceral adipose tissue
lipolysis.
For 8 h in the postprandial state, upper body lipolysis is ⬃13
g in women and ⬃18 g in men, lower body lipolysis is ⬃5 g
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two depots in nonobese women (35). In obese women, the
direct storage of FFAs was 40% more efficient in the femoral
than in the abdominal region (35), and the efficiency of FFA
storage increases as a function of leg fat mass in premenopausal women (16). In contrast, direct FFA storage into upper
body subcutaneous and visceral fat does not follow this pattern.
In women, upper and lower body subcutaneous fat store 6.7
and 4.9% circulating FFA, respectively, directly, whereas storage of FFAs in visceral adipose tissue was only ⬃1.0%
irrespective of visceral fat mass (16). The differences in regional efficiency of direct FFA uptake support sex-related
variations in body fat distribution, where women tend to store
more fat in the lower body and men in the upper body.
The reason(s) for the regional and sex differences in direct
FFA storage is not known. Sex hormones may play a potential
role, since variations in hormone levels are accompanied by
changes in body fat distribution, such as is the case after
menopause (7, 9). We did not find blood flow differences that
could account for greater storage in women than men or
between abdomen and thigh in men (16). We did find greater
expression of mRNA encoding fatty acid transport proteins in
women than men and in the abdominal vs. femoral subcutaneous adipose tissue in men (16). Thus, regional variation in
membrane uptake of FFAs may affect regional body fat accumulation, but many other possible explanations need to be
explored.
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REGIONAL FATTY ACID METABOLISM IN HUMANS
Conclusion
We are making progress in understanding how differences in
body shapes develop in humans. Preferential accumulation of
body fat in specific regions is more likely due to preferential fat
uptake than defective release. Recent evidence suggests that
both LPL-mediated and LPL-independent fat storage may play
a role in sex-related variations in fat distribution. The mechanisms that determine why some fat cells store more fatty acids
than others, differences in delivery, plasma membrane transport, or intracellular processing remain to be clarified. The
rate-controlling steps by which fatty acids are stored in adipocytes may vary according to depot (16, 43). Future research
will hopefully provide a more complete picture of fatty acid
trafficking into adipocytes in the hopes of understanding why
some people are shaped differently than others. The answer to
this question is important, because how fat is distributed in our
bodies is related to disease risk.
GRANTS
This study was supported by National Institute of Diabetes and Digestive
and Kidney Diseases Grants DK-40484, DK-45343, and DK-50456 and the
Mayo Foundation.
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