Molecular medicine-Adipose Tissue as an Endocrine Organ

As described above, the primarymetabolic
role of the adipocyte is to absorb and
store excess lipid in the form of triglyceride,
and to make it available to other
tissues in the body as energy needs dictate,
by measured release of fatty acids
into the circulation. Proper functioning of
Adipocytes 7
Tab. 1 Metabolically active proteins secreted by adipocytes.
Protein/hormone Physiological effects
Leptin Appetite, autonomic nervous activity
Adiponectin Insulin sensitivity, fatty acid oxidation
Resistin Insulin sensitivity
TNF-α Insulin sensitivity, adipocyte differentiation, inflammation
ANG II Lipogenesis, blood pressure
ASP Lipogenesis
IGF Lipogenesis, adipocyte differentiation
Interleukin-6 Lipolysis in adipocytes, inflammation
Kinins Insulin sensitivity, tissue remodeling
PAI-1 Insulin sensitivity, blood clotting, atherosclerosis
TGF-β Lipolysis, angiogenesis
Notes: ANG: angiotensin; ASP: acylation-stimulating protein; IGF: insulin-like
growth factor; PAI-1: plasminogen activator inhibitor; TNF: tumor necrosis factor;
TGF: transforming growth factor. Table adapted from Schling, P., Loffler, G.
(2002) Cross talk between adipose tissue cells: impact on pathophysiology, News
Physiol. Sci. 17, 99–104.
this system requires communication between
adipose tissue and essentially all
the organ systems in the body. In addition
to the hormonal and neural signals
that regulate lipid uptake and storage,
or induce lipolysis and release of fatty
acids into the circulation during a fast
(discussed above), there are signals that
originate in adipose tissue that act to
modify various physiological activities in
tissues and organs throughout the body.
For example, to insure that dietary intake
is sufficient to maintain an adequate
level of adiposity, there must be communication
between adipose tissue and
the centers in the brain that control appetite.
Likewise, there is communication
between adipose tissue and the organs,
and the tissues that utilize fat for energy
to insure that fatty acid delivered to
nonadipose tissues, such as muscle and
liver, are handled properly and do not accumulate
to abnormal levels. One of the
major advances in metabolic research in
the last few years has been the discovery
that adipocytes secrete hormones that act
at specific sites in the body and have important
effects on many aspects of energy
metabolism. This new understanding of
adipose tissue as an endocrine organ has
dramatically changed our understanding
of the significance of adipocytes in the
regulation of metabolism. It is now believed
that the adipose-derived hormones
(referred to as adipokines) are important
components of the integrated system of
hormonal and neural signaling pathways
that function to regulate the storage and
use of metabolic energy. The following is
a brief summary of the biology of four
of the adipokines that have relatively clear
effects on metabolism. Table 1 presents a
more complete list of hormone like proteins
produced by adipocytes.
The seminal contribution to the concept
that adipose tissue produces hormones
with importantmetabolic effectswas made
by Friedman and colleagues in 1994. These
investigators identified the protein product
of the obese (ob) gene that causes
8 Adipocytes
severe obesity inmice whenmutated. Leptin
is secreted from adipose tissue and
regulates body weight by acting directly
in the CNS to inhibit feeding behavior.
The control of leptin synthesis and
secretion is still poorly understood. In
general, leptin production and secretion
are promoted under conditions of positive
energy balance (fed state, high insulin)
and suppressed by conditions of net energy
deficit (e.g. fasting, catabolic hormone
stimulation). As such, plasma leptin levels
correlate strongly with total adipose
tissue mass, and thereby provide an integrated,
long-term signal indicating the
status of lipid reserves. The actions of
leptin are mediated through specific cell
surface receptors, which are located in key
central and peripheral target cells. Activation
of leptin receptors in diverse brain
regions signal a state of positive energy
balance. Leptin-sensitive neural systems
regulate the activity of the autonomic nervous
system involved in energy storage
and mobilization, feeding behavior, reproductive
physiology, and sexual behavior.
Leptin may also have direct effects on
energy metabolism in peripheral tissues
such as muscle, where it has been reported
to cause an increase in fatty acid
oxidation rates. Although leptin behaves
as an antiobesity hormone in certain animalmodels,
common human obesity does
not appear to be due to abnormally low
leptin levels.
Another recently identified adipocytesecreted
hormone that may play a role
in both obesity and diabetes is adiponectin
(also called ACRP30 or adipoQ). Originally
identified as a secreted fat-specific
protein whose expression was induced
following adipogenesis, adiponectin levels
were found to be reduced in obesity
and increased by weight loss. In addition,
the adiponectin gene maps to a region
on chromosome 3 that is associated with
diabetes and metabolic syndrome. Treatment
of rodents with adiponectin was
found to increase muscle fatty acid oxidation,
reverse insulin resistance and
improve hepatic insulin action. Together,
these observations suggest that the physiological
role of adiponectin may be to
promote lipid oxidation in nonadipose tissues;
in essence it may be a signal from
fat indicating to the rest of the body
that lipid energy is available and should
be used.
In contrast to adiponectin, an adipokine
that has recently been identified called resistin
appears to have diabetes-promoting
effects on metabolism. While adiponectin
clearly promotes fatty acid oxidation and
appears to have insulin-sensitizing effects
throughout the body, resistin (also known
as adipocyte secreted factor, ADSF or
FIZZ3) was found to be over-expressed
in rodent models of diet-induced obesity
and to induce insulin resistance and glucose
intolerance in normal mice. These
data suggest that resistin acts in a converse
manner to adiponectin, increasing insulin
resistance and promoting the development
of diabetes. However, this relationship
between resistin and diabetes was not observed
in all models of the disease and
additional work will need to be carried out
to fully clarify the role of resistin as another
potential link between obesity and
diabetes. Another potentially prodiabetic
adipokine is the inflammatory cytokine tumor
necrosis factor alpha (TNFα), which is
secreted by adipocytes under some circumstances.
TNFα production by adipocytes
is elevated in obese rodents and humans
and positively correlates with insulin resistance
and in some studies inactivation of
TNFα using antibody treatment improved
insulin action. As with resistin, the combination
of elevated expression in obesity
Adipocytes 9
and insulin resistance promoting activity
of these adipokines raises the possibility
that it contributes to the functional link
between obesity and diabetes. Although a
great deal more work needs to be done in
this area before we can fully appreciate the
multiple roles that adipokine hormones
play in the regulation of metabolism, it
is clear that they are a crucial component
of the physiological system that regulates
energy balance and fuel partitioning.