6
Adipocytes
closely governed by the phosphorylation
state of perilipin and HSL. Recent work
indicates that phosphorylation of perilipin
on multiple residues allows recruitment of
phosphorylated HSL to the surface of the
lipid droplet where triglyceride hydrolysis
can take place. Phosphorylation of HSL
has only a modest effect on the activity of
the enzyme; rather, the dramatic increase
in lipolysis produced by PKA-activation
reflects the translocation and accessibility
of the enzyme to its substrate within
the cell. HSL appears to be physically
associated with the cytosolic FABP4 (aP2).
The signi±cance of this association is not
known, but could involve regulation of
HSL activity or efflux of mobilized fatty
acids. In this regard, mice lacking FABP4
show reduced rates of lipolysis.
Efflux of fatty acids from the fat cell
and their transport across the capillary
endothelium are thought to occur through
passive diffusion across a concentration
gradient, although this process has not
been studied in detail. Long-chain fatty
acids are essentially insoluble in aqueous
solution and thus rely on carrier proteins
for transport. In plasma, fatty acids are
immediately bound with high af±nity to
serum albumin, which serves as a carrier
of these substrates to the sites of oxidation.
During fasting, mobilized fatty acids are
quickly removed from the circulation, with
a half-life of about two minutes, and
provide an important source of energy for
heart and skeletal muscle.
2.3
Regulatory Mechanisms that Balance Lipid
Storage and Utilization
The pathways that promote FFA up-
take and esteri±cation to triglyceride are
strongly regulated by hormones, particu-
larly insulin. Insulin strongly promotes the
synthesis of LPL whose expression coin-
cides with the peak of triglyceride absorp-
tion. Insulin and chylomicrons also stim-
ulate the secretion of acylation stimulation
protein – a protein made by adipocytes that
strongly promotes triglyceride synthesis.
Insulin also promotes
de novo
fatty acid
synthesis from glucose by stimulating glu-
cose uptake and the expression of lipogenic
enzymes.
Fatty acids, derived from adipose tissues,
are an important energy source during
fasting, exercise, and stress. As men-
tioned above, the overall rate of lipolysis is
largely governed by the relative activation
of PKA. The activity of PKA is governed
by cAMP levels, which in turn are con-
trolled by receptors coupled positively (beta
adrenergic, glucagon, ACTH) or negatively
(adenosine, niacin, alpha2, adrenergic) to
adenylyl cyclase. In addition, insulin reg-
ulates adipocyte cAMP levels by activating
phosphodiesterase PDE3b that degrades
cAMP. The nature of the pathways con-
trolling lipolysis depends on physiological
circumstances. Lipolysis, in response to
stress and exercise, is highly dependent on
the activity of the sympathetic innervation
of adipose tissue as well as the release of
epinephrine from the adrenal gland. Dur-
ing fasting, lipolysis does not depend on
neural activity, but rather appears to result
from decline in insulin that provides tonic
activation of PDE3b.
2.4
Adipose Tissue as an Endocrine Organ
As described above, the primary metabolic
role of the adipocyte is to absorb and
store excess lipid in the form of triglyc-
eride, and to make it available to other
tissues in the body as energy needs dic-
tate, by measured release of fatty acids
into the circulation. Proper functioning of
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