severe obesity in mice when mutated. Lep-
tin is secreted from adipose tissue and
regulates body weight by acting directly
in the CNS to inhibit feeding behav-
ior. 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 en-
ergy deFcit (e.g. fasting, catabolic hormone
stimulation). As such, plasma leptin lev-
els correlate strongly with total adipose
tissue mass, and thereby provide an in-
tegrated, long-term signal indicating the
status of lipid reserves. The actions of
leptin are mediated through speciFc cell
surface receptors, which are located in key
central and peripheral target cells. Activa-
tion of leptin receptors in diverse brain
regions signal a state of positive energy
balance. Leptin-sensitive neural systems
regulate the activity of the autonomic ner-
vous system involved in energy storage
and mobilization, feeding behavior, repro-
ductive physiology, and sexual behavior.
Leptin may also have direct effects on
energy metabolism in peripheral tissues
such as muscle, where it has been re-
ported to cause an increase in fatty acid
oxidation rates. Although leptin behaves
as an antiobesity hormone in certain ani-
mal models, common human obesity does
not appear to be due to abnormally low
leptin levels.
Another recently identiFed adipocyte-
secreted hormone that may play a role
in both obesity and diabetes is adiponectin
(also called ACRP30 or adipoQ). Origi-
nally identiFed as a secreted fat-speciFc
protein whose expression was induced
following adipogenesis, adiponectin lev-
els were found to be reduced in obesity
and increased by weight loss. In addi-
tion, the
gene maps to a region
on chromosome 3 that is associated with
diabetes and metabolic syndrome. Treat-
ment of rodents with adiponectin was
found to increase muscle fatty acid ox-
idation, reverse insulin resistance and
improve hepatic insulin action. Together,
these observations suggest that the phys-
iological role of adiponectin may be to
promote lipid oxidation in nonadipose tis-
sues; 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 identiFed called
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, ADS± or
±IZZ3) was found to be over-expressed
in rodent models of diet-induced obesity
and to induce insulin resistance and glu-
cose 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 ob-
served in all models of the disease and
additional work will need to be carried out
to fully clarify the role of resistin as an-
other potential link between obesity and
diabetes. Another potentially prodiabetic
adipokine is the inflammatory cytokine tu-
mor necrosis factor alpha (TN±
), which is
secreted by adipocytes under some circum-
stances. TN±
production by adipocytes
is elevated in obese rodents and humans
and positively correlates with insulin resis-
tance and in some studies inactivation of
using antibody treatment improved
insulin action. As with resistin, the com-
bination of elevated expression in obesity
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