The cardiostimulant effects and receptor
affinity of CGP12177 that are observed in
wild-type mice were also observed in the
3 knock-out mice, suggesting that a
cardiac -adrenergic receptor that is dis-
tinct from 1-, 2- and 3-adrenergic
receptors was present.Manipulation of -adrenergic receptor genes
Several techniques currently are used to
alter expression of specific genes in vivo
(see Roher and Kobilka, 1998). Mouse
models have been developed to study the
effects of increased 1-adrenergic receptor
expression in adipose tissue (Soloveva et
al., 1997), inhibition of 3-adrenergic
receptor expression (Susulic et al., 1995;
Revelli et al., 1997) and replacement of the
murine 3-adrenergic receptor gene with
the human gene and regulatory elements
(Ito et al., 1998). Several interesting insights
regarding the effects and interactions of -
adrenergic receptor agonists can be gained
from these experiments. However, these
studies must be interpreted with care
because of differences between the mouse
model and livestock species, and because of
the unusual physiological environment
created by genetic manipulation.
It has been proposed that the 3-
receptor is a primary regulator of lipolysis
because of its abundance relative to 1- and
2-receptors in rodent adipose tissue.
However, significant reductions in the
percentage of white adipose tissue and
adipocyte cell size were reported in mice
with increased expression of 1-adrenergic
receptors in white adipose tissue, indicat-
ing that 1 also has the ability to stimulate
lipolysis (Soloveva et al., 1997).
Furthermore, although two 3 knock-out
models demonstrated increased adiposity,
the increase was not as great as would be
expected if a primary stimulator of lipolysis
were removed (Susulic et al., 1995; Revelli
et al., 1997). One possible explanation for
the lack of obesity in these mice is the
stimulation of lipolysis by adrenergic
receptors other than 3. The mice described
by Susulic et al. (1995) had increased
mRNA expression of the 1-receptor,
particularly in BAT. Therefore, the resultsfrom the 1 transgenic and 3 knock-out
models indicate that the control of lipolysis
may depend more on the total population
of -adrenergic receptors than on the
presence of specific receptor subtypes.
The same mouse models also demon-
strate a potential difference in responsive-
ness of 3-adrenergic receptors between
males and females. Susulic et al. (1995)
reported a greater increase in adiposity in
female compared with male 3 knock-out
mice, indicating that females were more
sensitive than males to changes in 3-
adrenergic receptor activation. Soloveva et
al.(1997) observed a greater decrease in
adiposity of male compared with female
mice that overexpressed 1-adrenergic
receptors. This may be attributed to a more
potent regulation of fat accretion by 3-
adrenergic receptors in females compared
with males, which would make additional
lipolytic effects mediated by over-
expression of the 1-adrenergic receptor
more apparent in males than in females.
The mice described by Ito et al.(1998)
are a very intriguing model that were
generated by transgenic introduction of the
human 3-adrenergic receptor gene and
promoter region into 3 knock-out mice,
resulting in mice that express human but
not murine 3-receptors. Human 3-
receptors were expressed in BAT of trans-
genic mice, but little or no expression was
observed in white adipose tissue. This is
different from the normal expression
pattern of the rodent 3-receptor, which is
abundant in both brown and white adipose
tissues. These mice demonstrate the
importance of species-related differences
in the regulation of expression and func-
tion of -adrenergic receptors and will be
valuable for further investigations of the
human 3-receptor.SummaryThe repartitioning effects of phene-
thanolamines in livestock occur through a
combination of increased protein synthesis
and lipolysis, and decreased protein
degradation and lipogenesis to varying84 D.E. Moody et al.04 Farm Animal Metabolism 04 20/4/00 12:02 pm Page 84