4
Adipocytes
that controls lipid storage, distribution,
and utilization throughout the body. Our
current knowledge of the regulation of
adipokine production and their down-
stream metabolic effects is reviewed below.
Our increased understanding of the ac-
tive role that adipocytes play in regulating
metabolism has stimulated a growing in-
terest in adipose tissue as a therapeutic
target for new agents to treat diabetes,
obesity, and other metabolic diseases.
The underlying assumption for this ef-
fort is that drugs acting on adipocyte lipid
metabolism parameters or on hormone
production pathways could have beneF-
cial effects on metabolic abnormalities of
diabetes and obesity. In support of this
possibility are recent Fndings, which are
reviewed below, demonstrating that an im-
portant family of antidiabetic drugs acts,
at least in part, by modulating adipocyte
physiology. A complete understanding of
the medical signiFcance of the adipocyte
will require a comprehensive knowledge
of the development of adipocytes and
adipose tissue, of molecular biology and
physiology of mature adipocyte, as well
as the interaction of adipose tissue with
the broader regulatory systems that con-
trol the whole body energy balance and
fuel partitioning.
2
Physiology of the Adipocyte
Perhaps the most well-established func-
tion of adipose tissue in man is as a
reservoir for the storage and mobilization
of energy. Cells of the body utilize energy
continuously, yet fuel is obtained from
external sources intermittently. Thus, an-
imals have a need to be able to efFciently
store energy when food is available and ac-
cess that energy during periods of fasting.
Adipose tissue is highly specialized for
the storage of lipid energy in the form of
triglycerides and the mobilization of that
energy in the form of free fatty acids. Of
the energy substrates utilized by tissues,
lipid is most efFciently stored and pro-
vides greater than twice the energy per
gram than either carbohydrate (glycogen)
or protein. The signiFcance of this energy
reserve is readily appreciated when consid-
ering that a man of normal body weight
(70 kg, 10% body fat) can survive 40 days
on energy reserves stored in adipose tissue.
2.1
Absorption and Storage of Circulating Lipid
Energy is stored in adipocytes in the form
of triglycerides and is mainly derived from
dietary fat, and
de novo
biogenesis from
liver and within adipose tissue. Although
human adipose tissue is capable of synthe-
sizing lipid
de novo
, most triglycerides that
accumulate in the tissue are derived di-
rectly or indirectly from dietary fat. Dietary
fatisdigestedinthegutandrepackagedas
chylomicrons that are delivered to the sys-
temic circulation via the lymphatics. The
liver also plays a major role in the produc-
tion and packaging of lipids in the form
of various lipoproteins that are targeted
for utilization in various target tissues,
including adipose tissue.
A
major
mechanism
for
clearing
chylomicrons
and
very
low
density
lipoproteins (VLDL) from the circulation
is through the action of lipoprotein lipase
(LPL). As mentioned above, adipocytes
express
LPL,
which
is
released
and
targeted
to
the
capillary
endothelium
(┬▒ig. 1). There, LPL acts on circulating
chylomicrons and VLDL, hydrolyzing the
neutral lipid core and releasing free fatty
acids. The free fatty acids that are released
can cross cell membranes and enter
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