Molecular medicine-Lipodystrophy – Too Little Fat

The model described above proposes that
obesity promotes the development of type 2
diabetes because adipocytes from obese individuals
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 informative,
lipodystrophy syndromes. These
inherited and acquired syndromes are
characterized by the partial or complete
loss of adipose tissue, insulin resistance,
and diabetes. Severalmutations that cause
inherited forms of lipodystrophy, such as
partial familial lipodystrophy (PFLD), have
been identified. 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 absence
of adipose tissue in their extremities,
elevated circulating lipids, abnormally
high levels of intracellular triglyceride in
muscle and liver, and diabetes. Interestingly,
mutations causing PFLD have
recently been identified in the PPARγ
gene, underscoring the key role of this
transcription factor in the development
and maintenance of adipose tissue.
The conclusions derived from observations
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 multiple
tissues including muscle and liver,
severe insulin resistance, and diabetes. Interestingly,
these metabolic defects can be
improved by transplanting adipose tissue
back into the fatless mice. These findings
clearly illustrate the vital role that adipose
tissue plays in protecting the organism
from abnormal lipid accumulation and its
deleterious effects on metabolism.