Molecular medicine-Developmental Origin of Adipocytes 3.1 Adipose Tissue Development and Plasticity

The basic functional unit of adipose tissue
is the adipocyte. Nevertheless, adipose
tissue is complex and contains several
cell types in addition to adipocytes, such
as endothelial cells, interstitial cells, undifferentiated
mesenchymal cells, pericytes,
and ‘‘very small adipocytes’’. Indeed,
adipocytes constitute less than 20% of the
cells residing in typical adult fat tissue.
Moreover, there are very important interactions
among the various cell types that
are critical to the proper functioning of
the tissue. In view of the huge increase
in obesity rates in the United States, and
its negative impact on health, new attention
has been focused on the development,
maintenance, and plasticity of this important
tissue.
Analysis of adipose tissue histogenesis
and remodeling has relied mainly upon
descriptive approaches to define cell phenotypes
and deduce their transition to
mature cells. In humans, adipose tissue appears
as distinct lobules during the second
trimester of fetal development. The specific
timing of adipose tissue histogenesis
and fat cell differentiation varies according
to location in the body. Adipocytes within
fat tissue are thought to derive initially
from mesenchymal progenitors capable
of differentiating into bone, muscle, as
well as fat. Mesenchymal cells that are
highly committed to the adipocyte lineage
first appear closely associated with vessel
formation, and there appears to be a
close reciprocal association of developing
fat cells with angiogenesis. This is not
surprising since early committed cells express
lipoprotein lipase that is targeted
at the capillary lumen, and provides the
mechanism for the transport of dietary
triglyceride to fill the developing fat cells.
As fat cells develop, triglycerides coalesce
into small lipid droplets (nearly all of which
are triglycerides) within the cytoplasm that
eventually fuse to form a large single lipid
droplet. The typical mature adipocyte is relatively
large (30–50 micron diameter) and
can reach a size of greater than 120 μm
under certain conditions (Fig. 2).
Experimental investigations of adipose
tissue havemainly utilized rodent models,
although it is important to note that the
ontogeny of adipose tissue varies widely
among species, and even among fat depots
within a given species. In rodent models,
white adipose tissue generally appears late
in embryonic development and continues
to expand and differentiate during the
neonatal period prior to weaning. Classic
‘‘flash’’ labeling experiments with an
3H thymidine have shown that most
proliferation of cells that are destined
to become adipocytes occurs in the first
postnatal week. Mitoses are mostly found
in poorly differentiated mesenchymal cells
that are closely associated with developing
capillaries. The transition of cells from
mesenchymal progenitors to mature cells
can be deduced by evaluating the cellular
distribution of 3Hlabel over time following
10 Adipocytes
Fig. 2 Histological appearance of normal mouse adipose tissue. Shown is a 6-μm
paraffin section stained with hematoxylin and eosin. Note the single large lipid
droplet with numerous interstitial cells.
flash labeling. Over time, the percentage
of labeled mesenchymal cells declines
as the label appears in cells that have
accumulated lipid. In contrast, labeling
of endothelial cells remains relatively
constant. These data suggest a dynamic
process in which mature adipocytes are
derived from committed mesenchymal
progenitors that divide and develop into
adipocytes. Interestingly, nearly 90% of
the initial label is lost by five months,
strongly indicating that cellular renewal
occurs throughout life. In this regard, it is
well established that cells can be isolated
from human and rodent adipose tissue that
readily differentiate into mature adipocytes
in vitro. Indeed, pluripotent progenitors
derived from adult adipose tissue may
have numerous therapeutic applications.
These observations indicate that adipose
tissue contains a significant population of
committed progenitors that are capable
of contributing to tissue renewal and
remodeling under appropriate conditions.
Under normal laboratory conditions, cellular
proliferation in rat adipose tissue
drops to very low levels after weaning.
Nonetheless, a variety of physiological
and pharmacological conditions reveal dynamic
regulation of adipose tissue. For
example, Hirsch and colleagues demonstrated
in the 1970s that the obesity produced
by high fat diets in rats involves both
fat cell hyperplasia as well as hypertrophy.
Fat cell renewal has also been observed
after partial lipectomy, and elevated fat
cell turnover has been observed in models
of hypothalamic obesity. One of the best
examples of physiological adipose tissue
plasticity occurs in seasonal fat deposition
of hibernators. Although the mechanisms
involved in fat cell proliferation are largely
unknown, adipose tissue itself is a rich
source of growth factors and cytokines
Adipocytes 11
that could trigger tissue expansion. As
discussed below, certain pharmacological
agents that exhibit antidiabetes properties
in rodents and man target receptors that
are enriched in fat tissue, and produce pronounced
tissue remodeling that is likely
related to the therapeutic actions of these
agents.