lipid has been exceeded. This condition
is perhaps most dramatically illustrated
by patients with lipodystrophy, who are
severely insulin-resistant and develop dia-
betes at an early age. These individuals lack
certain adipose tissue depots and there-
fore have reduced capacity to buffer excess
lipid (presented in more detail below).
Viewed from this perspective, obesity leads
to diabetes when abnormal amounts of
triglyceride accumulate in nonadipose tis-
sues such as skeletal muscle and pancre-
atic islets. Excess triglyceride deposition
in nonadipocytes might generate a lipid
environment that interferes with cellular
physiology and gene expression in ways
that contribute to insulin resistance and
cell failure associated with type 2 diabetes.
Lipodystrophy – Too Little Fat
The model described above proposes that
obesity promotes the development of type 2
diabetes because adipocytes from obese in-
dividuals have reduced capacity for further
lipid storage, which leads to inappropriate
fat accumulation in nonadipose tissue. As
mentioned above, the effects of aberrant
amounts of adipose tissue on physiology
are best illustrated in the rare, but infor-
mative, lipodystrophy syndromes. These
inherited and acquired syndromes are
characterized by the partial or complete
loss of adipose tissue, insulin resistance,
and diabetes. Several mutations that cause
inherited forms of lipodystrophy, such as
partial familial lipodystrophy (PFLD), have
been identi±ed. One of the most common
genetic defects in PFLD are mutations
in the gene encoding the nuclear lamin
a/c protein. Although the mechanism by
which mutant lamin a/c protein causes
lipodystrophy is not known at this time, it
seems likely that the protein, which plays
a fundamental role in the function of the
nucleus, is required for normal adipocyte
differentiation of maintenance. Patients
carrying PFLD mutations exhibit an ab-
sence of adipose tissue in their extremi-
ties, elevated circulating lipids, abnormally
high levels of intracellular triglyceride in
muscle and liver, and diabetes. Inter-
estingly, mutations causing PFLD have
recently been identi±ed in the PPAR
gene, underscoring the key role of this
transcription factor in the development
and maintenance of adipose tissue.
The conclusions derived from observa-
tions of human lipodystrophy syndromes
are strongly supported by animal models
of lipodystrophy. Several different genetic
methodologies have been used to generate
mice that have reduced amounts of adipose
tissue. Like their human counterparts,
these animals invariably exhibit elevated
circulating lipids, abnormally high levels
of intracellular triglyceride levels in mul-
tiple tissues including muscle and liver,
severe insulin resistance, and diabetes. In-
terestingly, these metabolic defects can be
improved by transplanting adipose tissue
back into the fatless mice. These ±ndings
clearly illustrate the vital role that adipose
tissue plays in protecting the organism
from abnormal lipid accumulation and its
deleterious effects on metabolism.
The Adipocyte as a Therapeutic Target for
Metabolic Disease
As our understanding of the impor-
tance of adipose tissue in controlling
metabolism has grown, so too has the re-
alization that therapeutic agents designed
to modify adipocyte physiology could pro-
vide new avenues for the treatment of
diabetes, obesity, and other metabolic
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