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Growth and distribution of human fetal brown fat.

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Growth and Distribution of Human Fetal Brown F a t '
ROBERT J. MERKLIN
Department of Anatomy, J e f f e r s o nMedical College of
Thomas Jefferson University
ABSTRACT
Macroscopic and microscopic examination of adipose tissue was
carried out in a series of 20 human fetuses, ranging in weight from 380-3032
gm, in an attempt to identify all areas of brown (multilocular) fat development
and growth. Brown fat distribution in the human fetus takes the form of a highcollared vest affording coverage to the cervical, thoracic and abdominal viscera.
Much of .this fat lies deep within the body immediately outside the pleural and
peritoneal membranes. The remainder overlies or borders muscles of the shoulder
girdle and neck as distinct brown fat deposits deep to the subcutaneous layer of
white (unilocular) fat. All brown fat bodies contain unilocular cells but they
occur in very small numbers in the brown fat bodies of the posterior cervical
triangle, anterior mediastinum and perirenal and suprailiac regions. Brown fat
bodies usually develop along the course of large blood vessels and several of them
develop direct vascular connections with the liver and kidneys. The total weight
of fetal brown fat increases at a rate directly proportional to that of the liver and
kidneys up to 2134 gm body weight and to that of the liver beyond this weight.
Studies of brown fat in man have been
directed, for the most part, toward an
understanding of the function and ultrastructure of this type of tissue. Information about its development, distribution
throughout the body and relation to other
structures is incomplete and largely based
on studies of the perinate. Hull and Hardman ('70) summed up knowledge of fetal
brown fat distribution by stating there
were major deposits between the shoulder
blades and around the neck with smaller
quantities behind the sternum and along
the anterior surface of the spine. Afzelius
('70) added to this description by mentioning axillary brown fat, masses in the abdomen enveloping the kidneys and deposits
in the region of the pancreas. The anterior
abdominal fat pad was identified as brown
fat by Merklin ('71) who described its
blood supply including vascular connections to the fetal liver. An indication that
there may be racial differences is seen in
the report of Itoh and Kuroshima ('67)
who found little or no cervical or perirenal
brown fat in a series of Japanese neonates.
Evidence that brown fat persists in an
active form into the late years of life is
provided by Heaton ('72) who studied 18
areas of fat deposition in the body, through
ANAT. REC.,178: 637-646.
eight decades of life, and found a high
incident of brown fat in the neck, mediastinum and renal and aortic areas. Although
stillborn or dying shortly after birth, the
fetuses examined in this study appeared to
be normal upon preliminary examination
and at the conclusion of the dissection.
Summaries of the mother's histories were
studied for evidence of pathology or abnormalities (such as diabetes) that may
have affected the fetus and were judged
to be negative in this respect. The fetuses
are arranged by body weight, but not necessarily gestational age, and the presumption
is made that they are normal although failing to survive the incident of birth. The
smallest fetus in the series (380 gm) has
an estimated age of 23 weeks, the largest
nine months. The first three fetuses have
weights that are below a viable birth level;
the other fetuses were potentially viable
since babies as small as 670 gm have been
known to survive. However, a weight of
2500 gm is considered minimal for the
favorable outcome of a premature birth.
The study attempts to provide a more comprehensive description of brown fat in the
Received June 18, '73. Accepted Aug. 20, '73.
1 This research was supported in part by PHS General Research Support grant RR-5414.
637
638
ROBERT J. MERKLIN
human fetus from the standpoint of total
distribution in the body, growth, composition of fat cells and relation to other structures.
MATERIAL AND METHODS
The fetuses examined in this study were
obtained from the Humanity Gifts Registry of the state of Pennsylvania. They were
not embalmed prior to dissection and their
preservation was judged by the condition
of the skin, and internal organs to be excellent.
Exploratory dissections were made in
four fetuses ranging in weight from 5002400 gm. Samples of fat underlying the
subcutaneous tissues of the limbs and
torso and from the thoracic and abdominal
cavities were examined histologically to
distinguish brown fat from white fat deposits. Guided by these results a series of
20 fetuses ranging in weight from 3803032 gm were examined. Only deposits of
brown fat that could be removed as discrete measurable bodies were included in
this study. Small scattered brown fat
bodies behind the sternum and along the
aorta were omitted. The position of brown
fat bodies and their relation to other structures and vascular connections were recorded, They were then removed and
weighed. Samples of each fat body were
examined microscopically after fixation in
10% neutral formalin, sectioning on a
cryostat and staining with hemotoxylin
and eosin.
RESULTS
The largest brown fat bodies in the
human fetus are the posterior cervical,
axillary, suprailiac and perirenal. Intermediate in size are the interscapular, lateral trapezial and deltoid. The anterior
mediastinal, intercostal, anterior abdominal and retropubic bodies are relatively
small and the urachal and inferior epigastric are the smallest of all the bodies studied. The location of these bodies is illustrated in figures 1 and 2 and their weights
are recorded in table 1 . The posterior cervical brown fat bodies develop in close association with the major cervical blood
vessels and lymphatics. In the full-term
fetus they extend deep into the root of the
neck and under the trapezius and sterno-
cleidomastoid muscles. The axillary brown
fat bodies are closely related to the axillary
blood vessels and lymphatics but have a
more circumscribed growth with only
slight extension under the pectoral muscles. The suprailiac brown fat bodies lie
deep to the abdominal wall muscles, immediately outside the peritoneum. They extend from the inner surface of the ilia,
along the lateral body wall and onto the
lower surface of the diaphragm. They are
in close contact with perirenal fat but distinctly separate from it. The major blood
supply to these bodies is from the subcostal vessels. Perirenal brown fat develops within the perirenal fascia along the
interlobar septa and receives blood supply
from capsular vessels rather than hilar
renal vessels. The interscapular fat pad
overlies the trapezius muscle and assumes
a somewhat irregular outline as i t develops
along the course of segmental vessels
which pierce the muscle and run a course
out to its lateral borders. Well developed
veins pass to the external posterior vertebral plexus and posterior cervical region.
The lateral trapezial and deltoid brown fat
bodies are distinctly separate from the
interscapular fat pad although the former
has a similar blood supply. The deltoid
brown fat body receives bood supply from
vessels of the quadrangular and triangular
spaces. The anterior mediastinal brown fat
bodies lie in the lower part of the thorax
and receive blood from the pericardiophrenic and superior epigastric vessels.
The intercostal brown fat bodies appear
first near the heads of the ribs. They grow
lateralward along the course of the intercostal vessels. At first inspection they appear to have a rather large collective
weight. They are very thin, however, and
consequently add little to the brown fat
stores of the fetus. Left and right anterior
abdominal brown fat bodies develop along
the ensiform branches of the superior epigastric vessels. They lie between the rectus
sheath and peritoneum and with continuing growth coalesce into one body. In 900
gm and larger fetuses, blood vessels appear
in the falciform ligament and provide vascular connections to the liver hilum. The
retropubic brown fat bodies lie deep in the
pelvis on either side of the bladder and
receive blood supply from the vesical ves-
TABLE 1
0.20
0
0.20
0
0.24
0.20
0.30
0.20
0.22
0.24
0.20
0.26
0.50
0.40
0.24
0.28
0.32
0.04
0.04
0.16
0.11
0
0.24
0.11
1.oo
0.26
0.24
0.20
0.28
0.30
0.16
0.44
0.26
0.14
0.16
0.58
0.48
0.24
0.36
0.36
Retropubic
Inferior
epigastric
Tate
Minor
Tracy
Pinckney
Early ( B )
Williams
Early ( A )
H allig an
Hawkins
Reed
Abel
Massey
Quigley
Forvour
Kovach
Williams
Baker
Dubrana
Kelly
Knight
19.0
20.0
20.5
21.5
22.0
24.0
24.0
25.0
25.0
26.0
28.0
26.0
23.0
26.5
28.5
30.5
29.0
34.0
32.0
32.0
380
500
660
690
820
867
896
902
950
1094
1120
1215
1300
1512
1730
1920
2134
2554
2600
3032
Tate
Minor
Tracy
Pinckney
Early ( B )
Williams
Early ( A )
Halligan
Hawkins
Reed
Abel
Massey
Quigley
Forvour
Kovach
Williams
Baker
Dubrana
Kelly
Knight
C-R length
Body weight
Name
0.38
0.62
0.64
0.66
1.80
0.92
1.28
1.70
0.62
1.16
1.26
1.42
2.20
1.74
3.24
3.50
4.82
6.76
6.12
7.48
Suprailiac
F
M
F
M
M
F
M
F
M
F
M
M
F
M
M
F
F
F
F
F
Sex
0.12
0.24
0.14
0.58
1.00
0.58
1.12
1.22
0.72
1.64
1.30
1.68
1.42
2.32
2.38
3.66
5.50
6.42
9.92
5.50
Perirenal
0.26
0.26
0.49
0.43
0.56
0.28
0.49
1.10
0.22
0.60
0.78
1.96
1.19
1.37
2.21
1.60
3.38
2.06
2.62
1.29
Interscapular
0.10
0.10
0.10
0.21
0.32
0.13
0.16
0.15
0.26
0.29
0.24
0.22
0.41
0.68
0.40
1.04
0.92
0
0
0
Anterior
mediastinal
0.24
0.26
1.30
0.30
0.36
0.26
0.62
1.04
0.48
0.30
0.72
0.94
0.38
0.60
1.44
1.04
1.42
1.68
3.82
1.36
Lateral
trapezia1
0
0
0.10
0
0.10
0.10
0.20
0.80
0.24
0.24
0.12
0.80
0.70
0.48
0.40
0.94
0.70
0.28
0.80
0.50
Intercostal
0.26
0.32
0.44
0.40
0.38
0.28
0.60
0.40
0.32
0.68
0.82
0.88
1.32
0.86
0.85
1.24
3.20
0.88
0.82
1.58
Deltoid
2.53
2.91
4.62
3.88
8.35
5.57
8.10
12.24
5.31
8.80
10.23
12.68
14.88
13.52
15.85
23.70
35.35
29.63
39.48
35.07
Total weight
of brown fat
0.56
0.62
0.54
0.72
1.28
1.30
1.14
2.74
1.10
2.18
2.36
2.32
3.50
3.24
2.40
5.32
7.00
5.36
6.30
6.90
Posterior
cervical
10.40
13.20
15.50
37.20
17.46
18.64
19.20
7.64
3.54
3.26
5.20
6.06
4.04
5.06
4.06
6.56
6.28
8.68
6.68
12.54
Kidneys
0.26
0.40
0.38
0.42
1.10
1.00
1.58
2.18
0.70
0.96
1.96
1.28
2.68
1.82
1.88
4.60
6.70
4.88
7.00
8.60
Axillary
22.0
20.0
32.0
50.0
24.1
52.0
25.0
30.0
58.0
38.0
49.0
42.0
44.0
48.0
80.0
66.0
138.0
100.0
104.0
130.0
Liver
0.14
0.19
0.15
0.16
0.32
0.18
0.21
0.22
0.17
0.23
0.29
0.30
0.33
0.16
0.29
0.39
1.04
0.55
0.60
0.38
Anterior
abdominal
The 20 fetuses examined i n this study are arranged according to weight and crown-rump length. The weights o f all the brown f a t bodies
examined i n this study are shown as well as the total brown f a t weight and weight o f the liver and kidneys
0
0
0
0.11
0.11
0.11
0.12
0.11
0.11
0.11
0.14
0.11
0.15
0.14
0.14
0.11
0.08
0.04
0.04
0
Urachal
640
ROBERT J. MERJSLIN
sels. The inferior epigastric brown fat
bodies, although found along the course of
good-size vessels, remain small throughout
fetal period. However, they share a characteristic of the posterior cervical and axillary bodies in being associated with lymph
nodes. The urachal body is the smallest of
the brown fat bodies studied and is rather
poorly supplied with blood vessels that
course along the urachus.
The foregoing description of fetal brown
fat is comprehensive but by no means exhaustive. It is quite likely that brown fat
exists between and among muscle groups
and small amounts are scattered along the
aorta and above and behind the sternum.
Fat overlying the limb muscles and developing the course 5f superficial veins is distinct and separate from subcutaneous fat.
It is unilocular fat and appears to be identical to the fat of the inguinal region,
ischiorectal fossa and lower back. No difference in the quantity of brown fat or
cellular morphology is apparent from the
standpoint of race or sex. There is a difference in composition of fat cells among the
various brown fat bodies. The posterior cervical, suprailiac, anterior mediastinal and
perirenal bodies were composed almost
exclusively of multilocular fat cells with
just an occasional unilocular cell (fig. 3 ) .
The other brown fat bodies were composed
of more of less equal numbers of unilocular and multiloculas cells (fig. 4).
Excluding the smaller bodies, the growth
of brown fat in various parts of the fetus
proceeded at a fairly uniform rate. Weights
of the individual bodies are recorded in
table 1 and the total weight of brown fat
in each fetus is plotted in figure 5. The
weights of brown fat and of the liver and
kidneys, also plotted in figure 5, increase
at directly proportional rates with several
exceptions. In several of the smaller
fetuses (690, 867 and 902 gm) liver weight
was high and brown fat weight was low;
and in the last three fetuses there was a
drop in the rate of kidney growth.
DISCUSSION
The results of this study indicate a
more widespread distribution and an
earlier appearance of fetal brown fat than
is generally believed to occur. A report by
Itoh and Kuroshima ('67) failed to men-
tion brown fat in the anterior mediastinum, anterior abdominal wall, inferior
epigastric region and urachal, retropubic
and suprailiac regions of six Japanese
neonates. They found only small amounts
of cervical and perirenal brown fat and
suggested there may be racial differences
between Japanese and Caucasian infants.
Descriptions by Aherne and Hull ('66),
Hull and Hardman ('70) and Afzelius
('70) are even less complete, perhaps because these workers were primarily interested in the cytology and function of brown
fat rather than its distribution. In the present study several brown fat bodies were
absent or just making an appearance in
the three smallest fetuses in the series but
the majority of them had reached significant size. It would seem that brown fat is
well established early in the fifth month
of fetal life.
The presence of brown fat in an active
state after infancy has been confirmed by
Heaton ('72). In a study covering the
decades from birth to age 80, she examined
fat samples from 18 different areas of the
body. Brown fat was found in dl areas
during the first decade, but samples from
the inguinal and anterior abdominal areas
yielded the fewest positive samples. From
age ten up through the seventies, these
areas and the mesocolon, greater omentum, interscapular, pancreatic and splenic
areas had little or no fat. The greatest
yields of brown fat at all ages were from
the cervical, intercostal and perirenal
areas. Brown fat, then, is an active tissue
from early in development through to late
life with a gradual but selective replacement by white fat.
Viewed in its totality (figs. 1, 2 ) , one is
struck by the vest-like arrangement of
brown fat. Its deeper components line the
thorax and much of the abdomen, with a
concentration over the kidneys in the form
of penrend and suprailiac brown fat. The
posterior cervical, axillary and interscapular bodies make up the superficial component and overlie or border the shoulder
girdle muscles. The posterior cervical, axillary and inferior epigastric bodies are
closely associated with lymph nodes but
this fact seems to be incidental to the development of both kinds of tissue along
the course of blood vessels. On the other
SCANNING MICROSCOPY OF VAGlNAL EPITHELIUM
hand, the direct vascular connections of
the perirenal bodies with the kidneys and
the anterior abdominal body with the liver
suggests a direct association of brown fat
with the metabolism of these two organs.
It is generally agreed that in their active
form brown fat cells have a round nucleus,
a granular cytoplasm and many small vacuoles of fat. The granular cytoplasm is due
to the numerous, large, complex mitochondria that lie adjacent to the fat vacuoles (Napolitano and Fawcett, '58). Hull
('66), working with newborn rabbits, demonstrated that brown fat cells lose their
vacuoles when the animal is exposed to
cold and that these vacuoles fuse to form
a single large vacuole after a rich carbohydrate or fat feeding. Similar changes
occur in the malnourished infant or in the
overnourished infant, such as the obese
newborn of a diabetic mother (Aherne and
Hull, '66). Brown fat cells in their unilocular form may be confused with white fat
cells. The latter, however, are larger and
have a narrower and less granular rim of
cytoplasm surrounding the single large
vacuole. The presence of white fat cells in
brown fat bodies was mentioned by both
Aherne and Hull ('66) and Itoh and Kuroshima ('67) and similar observations were
made in the present study. The significance
of this is unknown, however, in the present
study the posterior cervical, suprailiac,
anterior mediastinal and perirenal contained very few white fat cells. In contrast,
the axillary, intersacpular, anterior abdominal and other brown fat bodies contained
white and brown fat cells in almost equal
proportions (fig. 3, 4). One would expect
the former group to play a greater role in
heat production through non-shivering
thermogenesis and consequently be placed
near organs that require warming or are
themselves heat producers.
Briick ('70), speaking of the perinate,
states that on cold exposure, fatty acids
are liberated from neutral fats deposited in
brown adipose tissue. These fatty acids are
partly oxidized within the cells of the tissue
and the remainder is released and oxidized
in other organs such as skeletal muscle
and the liver. Brown fat, then, is both the
most important site of NST and an important fuel source for NST in other organs.
A life vest concept of brown fat distribu-
641
tion seems to be compatible with the
known physiological function of this
tissue. It could be postuIated that posterior
cervical brown fat plays a major role in
warming the blood supply of the head and
that suprailiac and perirenal brown fat
have a similar role with respect to the kidney. The relation of brown fat to the liver
appears to be more complex. Its strategic
position with respect to fetal and maternal
blood supply provides abundant energy
sources and makes it unlikely that the anterior abdominal body has a special role in
liver activity.
The sharp rise in liver weight and drop
in brown fat weight in three fetuses (690,
867, 950 gm) suggests that increased liver
size occurred at the expense of brown fat
deposition. It further suggests that this
was a response to some disturbance in the
nourishment or metabolism of the fetus.
Addition dissections as well as a closer
scrutiny of the mothers well-being is indicated. Such studies may also cast some
light on the rather large decrease in kidney
weight of the last three specimens.
LITERATURE CITED
Afzelius, B. A. 1970 Brown adipose tissue: Its
gross anatomy, histology and cytology. Chapter
1, page 10. Brown Adioose Tissue. Olav Lindberg, ed. American Elsevier Publishing Co.,
New York.
Aherne, W., and D. Hull 1966 Brown adipose
tissue and heat production i n the newborn infant. J. Path. Bact., 91: 223-234.
Bruck, K. Heat production temperature regulation. Chapter 16, page 518. Physiology of the
Perinatal Period. Uwe Stave, ed. AppletonCentury, Crofts, New York.
Dawkins, M. J. R., and D. Hull 1964 Brown
f a t and the response of the newborn rabbit to
cold. J. Physiol., 172: 216-238.
Heaton, J. M. 1972 The distribution of brown
adipose tissue i n the human. J. Anat., 112:
35-39.
Hull, D. 1966 The structure and function of
brown adipose tissue. Brit. Med. Bull., 22:
92-96.
Hull, D., and M. J. Hardman 1970 Brown adipose tissue in newborn mammals. Chapter 4,
page 100.Brown Adipose Tissue. Olav Lindberg,
ed. American Elsevier Publishing Co., New
York.
Itoh, S., and A. Kuroshima 1967 Distribution
of brown adipose tissue in Jauanese newborn
infants. Physiol. SOC. Japan, 29: 660-661.
Johannson, B. 1959 Brown fat: A review. Metabolism, 8: 221-240.
Merklin, R. J. 1971 The anterior abdominal fat
body. Am. J. Anat., 232: 33-43.
642
ROBERT J. MERKLIN
Miller, H. C., and K. Hassanein 1971 Diagnosis
of impaired fetal growth in newborn infants.
Pediatrics, 48: 511-522.
Napolitano, L., and D. W. Fawcett 1958 The
fine structure of brown adipose tissue in the
newborn mouse and rat. J. Biophy. Biochem.
Cytol., 4: 685-692.
Smith, R. E. 1961 Thermogenic activity of the
hibernating gland in the cold-acclimated rat.
Physiologist, 4: 113.
PLATE 1
E X P L A N A T I O N O F FIGURES
1 Anterior view of the fetus illustrating the position of brown fat bodies
and fat cell composition.
2
Posterior view of the fetus illustrating the position of brown fat
bodies and f a t cell composition.
1. Posterior cervical
8. Inferior epigastric
9. Retropubic
2. Axillary
3. Intercostal
10. Suprailiac
4. Anterior mediastinal
11. Interscapular
5. Anterior abdominal
12. Deltoid
13. Lateral traFezia1
6. Perirenal
7. Urachal
_.____.
.____
______
_____
____.
.__
____
_-________
_____
___._
Predominantly mu1tilocular fat cells
..............................
....................... Mixed multilocular and unilocular fat cells
~
.
.___
~r------.-.-----=:
,
,
~
3
Suprailiac brown fat body of a seven month fetus. Multilocular cells
predominate. H&E x 250.
4
Axillary brown fat body of a seven month fetus. There is a mixture
of unilocular and multilocular fat cells. H&E x 250.
GROWTH AND DISTRIBUTION OF HUMAN FETAL BROWN FAT
Robert J. Merklin
PLATE 1
5
PLATE 2
The weight of brown fat, liver and kidneys is plotted against body
weight. Liver weights are reduced t o one-quarter to facilitate comparison with brown fat development.
EXPLANATION OF FIGURE
FAT
0 KIDNEYS
I) L I V E R ( 1 / 4 S C A L E
A BROWN
GROWTH AND DISTRIBUTION OF HUMAN FETAL BROWN FAT
Robert J. Merklin
PLATE 2
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