Molecular medicine-Obesity – Too Much Fat

Obesity – Too Much Fat
A long-standing observation in the field of
diabetes research is that obese individuals
have an increased risk of developing
insulin resistance and type 2 diabetes.
The current epidemic of diabetes in western
cultures began about thirty years ago
and correlates precisely with the concurrent
explosion of obesity. This has led
to the assumption that there is a functional,
or causative relationship between
these two disorders; that the presence of
obesity increases susceptibility to diabetes.
Although the relation between these two
metabolic disorders is unmistakable, it is
not understood how obesity precipitates
the multiple functional defects that precede
overt diabetes. However, an emerging
candidate is the acquired inability of
adipocyte to protect important tissues and
cells throughout the body from exposure
to excessive lipids.
Normally, excess calories are stored in
the body in the form of triglycerides,
mainly in adipocytes of white fat tissue.
However, nonadipocyte cells also store
low levels of triglycerides to meet internal
metabolic requirements. In these
cells, the amount of stored triglyceride is
maintained within a very narrow range.
A fatty acid homeostatic system functions
in healthy individuals to direct excess fat
to adipocytes while maintaining normal
amounts of triglyceride in nonadipocytes.
Under conditions of chronic positive energy
balance and ensuing obesity, however,
the capacity for adipose tissue to buffer
excess lipid energy may be exceeded, resulting
in the pathological accumulation
of lipid within key metabolic tissues.
The elevation of free fatty acid (FFA) in
the blood is predictive of conversion from
impaired glucose tolerance to diabetes,
suggesting that FFA themselves could contribute
to organ defects that precede type
2 diabetes, such as insulin resistance of
skeletal muscle, and reduced pancreatic
insulin secretion. More recently, it has
been shown that intracellular accumulation
of lipid within myocytes strongly
predicts insulin resistance independent of
the magnitude of obesity. Thus, it is not the
accumulation of lipid in fat cells per se that
is problematic, rather it is the redirection
of lipid to other key cells that occurs once
the capacity of the adipocyte to handle
Adipocytes 15
lipid has been exceeded. This condition
is perhaps most dramatically illustrated
by patients with lipodystrophy, who are
severely insulin-resistant and develop diabetes
at an early age. These individuals lack
certain adipose tissue depots and therefore
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 tissues
such as skeletal muscle and pancreatic
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 β-
cell failure associated with type 2 diabetes.