Mathematical Models of Adipose Tissue Dynamics - The Mechanobiology of Obesity and Related Diseases - page 10

cells from lipotoxicity [ 1 ]. Functional failures of adipose cells result in surplus of
circulating lipids, cytotoxic lipid accumulation in liver, muscle, pancreas, kidney,
and heart. Finally, the spillover of lipid to non-adipose tissues leads to metabolic
disorders such as nonalcoholic fatty liver disease, diabetes, kidney and heart failures.
Obesity and lipodystrophy represent two opposite extremes of the pathologies that
result from an inability to modulate lipid storage. In addition, aging is a physiological
degenerative process that limits efficient lipid storage in adipose tissues [ 2 ].
Adipose tissues increase their volume by enlarging cell size (hypertrophy) and/
or increasing cell number (hyperplasia). Considering that most eukaryotic animal
cells have fixed diameters of a few microns, adipose cells have unique volume
flexibility. The largest adipose cells ( 200 lm diameter) are ten times larger than
the smallest ones. Note that this diameter difference corresponds to a thousand-
fold volume difference. The biochemical processes of lipogenesis and lipolysis
underlie the enlargement and shrinkage of adipose cells. Lipogenesis provides free
fatty acids, required for triglyceride synthesis, from metabolized products of
sugars (e.g., glucose), while lipolysis breaks down triglycerides into free fatty
acids. The hormone insulin, a critical hormone for glucose metabolism, is a key
regulator of the two processes. Secreted when glucose increases, it suppresses
lipolysis and stimulates lipogenesis. Therefore, when glucose availability is high in
blood, lipid is not produced, but stored in adipose tissues. On the other hand, under
fasting conditions when glucose availability is low, lipid is released and contrib-
utes to the generation of glucose via gluconeogenesis. Therefore, insulin plays a
crucial role for switching lipogenesis and lipolysis, and thereby insulin resistance
affects lipid metabolism.
The plasticity of adipose cell number in adults is not clear, partly because it is
technically difficult to accurately measure total adipose cell number. Many reports,
including a recent one [ 3 ], concluded that the total adipose cell number does not
change after early developmental periods. However, adipose cell number can still
increase in adults under stimulating conditions such as lipectomy (partial excision
of adipose tissues) and high-fat diet [ 4 , 5 ]. In the diet-induced volume expansion of
adipose tissues [ 5 ], Faust et al. demonstrated that when adipose cells exceed a
certain critical size, they stimulate the recruitment of new cells, suggesting that
hypertrophy is a default option for small demands on increasing the lipid storage
capacity, while hyperplasia is a backup one for extreme demands as adipose cells
cannot grow indefinitely. Here hyperplasia is irreversible, while hypertrophy is
reversible. Once hyperplasia occurs, due to obesity, the new adipose cells remain
even after losing weight. The irreversibility of hyperplasia may explain the
''yoyo'' effect of easily regaining lost weight.
Adipose tissue growth via hypertrophy has the advantage of reversibility, but
the disadvantage of limited expansion capacity. Considering that lipid uptake/
release occurs through the cell surface, larger cells are less efficient at transferring
lipids through the cell surface due to their decreased surface-to-volume ratio. In
addition, it has been reported that large adipose cells are involved with hypoxia
[ 6 ], inflammation [ 7 ], cell death (necrosis/apoptosis)[ 8 ], and physical fragility [ 9 ].