adrenergic receptors; and complex inter-
actions involving the -adrenergic recep-
tors are being investigated using transgenic
and knock-out mice that over- or underex-
press, respectively, specific -adrenergic
receptors. Although much of this data is
from rodent studies and species differences
in the pharmacology of -receptors are
known to exist, insights may prove valu-
able to a thorough understanding of the
mechanism of action of phenethano-
lamines in livestock.3-Adrenergic receptor
The 3-adrenergic receptor is the pre-
dominant adrenergic receptor in rodent
brown and white adipose tissue
(Giacobino, 1995), and its effects have been
described in greatest detail in these tissues.
Important functions of 3-adrenergic
receptor activation include the stimulation
of energy expenditure and lipolysis, and
administration of selective 3-agonists
leads to weight loss and resistance to diet-
induced obesity in rodents (Himms-Hagen
et al., 1994; Collins et al., 1997). Selective
agonists of the 3-adrenergic receptor
currently are being investigated as potential
anti-obesity agents for humans (for
reviews, see Yen, 1995; Arch and Wilson,
1996; Strosberg, 1997) and dogs (Sasaki et
al., 1998), but there are no reports to date
of studies using selective 3-adrenergic
receptor agonists in livestock species.
In rodents, the weight-reducing effects
of 3-adrenergic receptor agonists may be
due largely to increased energy expendi-
ture occurring through the stimulation of
brown adipose tissue (BAT) activity.
Increased energy expenditure in BAT is
accomplished in part by increased expres-
sion of the BAT-specific uncoupling
protein 1 (UCP1). UCP1 is located in the
mitochondrial membrane and facilitates
the transport of protons across a concentra-
tion gradient without the capture of energy
as ATP, thereby allowing energy to be
dissipated as heat. Additional proteins
with sequence homology to UCP1 have
been identified in tissues other than BAT,
including UCP2 which is expressed in
many tissues (Fleury et al., 1997; Gimenoet al., 1997) and UCP3 expressed primarily
in skeletal muscle and adipose tissue (Boss
et al., 1997). Changes in expression of
UCP2 and UCP3 mRNA in brown and
white adipose tissue, and in skeletal
muscle of rodents have been reported in
response to 3-agonists (Emilsson et al.,
1998; Savontaus et al., 1998; Yoshitomi et
al., 1998). Additionally, ectopic expression
of UCP1 and the appearance of brown
adipocytes in white adipose tissue follow-
ing treatment with 3-agonists has been
described in rodents (Cousin et al., 1992;
Collins et al., 1997), humans (Garruti and
Ricquier, 1992) and dogs (Champigny et
al., 1991; Sasaki et al., 1998). Thus, 3-
agonists may influence energy expenditure
and body composition of mammals with-
out clearly defined BAT depots through the
regulation of uncoupling protein expres-
sion in several tissues and recruitment of
brown adipocytes in white adipose tissue.Atypical receptors
Several authors have suggested that addi-
tional, or ‘atypical’, -adrenergic receptors
exist. However, a ‘4’-adrenergic receptor
has not yet been cloned. Galitzky et al.
(1997) evaluated lipolytic effects of
CGP12177, a non-conventional partial 3-
agonist that acts as an antagonist of 1- and
2-adrenergic receptors, in rat and human
fat cells. These authors suggested that
lipolysis was stimulated through a novel -
adrenergic receptor that is distinct from the
3-receptor. In rat adipose cells, this novel
receptor appeared to coexist with and
regulate lipolysis in combination with the
3-adrenergic receptor, whereas the novel
receptor appeared to mediate all of the
lipolytic effects of the non-conventional
3-agonist in human adipose cells.
Evidence of an ‘atypical’ binding site was
also found in bovine skeletal muscle and
adipose tissues using radioligand binding
and second messenger adenyl cyclase
assays (Sillence and Matthews, 1994). The
clearest evidence for the existence of
additional -adrenergic receptors has come
from experimentation using mice that do
not express the 3-adrenergic receptor ( 3
knock-out mice; Kaumann et al., 1998).Phenethanolamine Repartitioning Agents 8304 Farm Animal Metabolism 04 20/4/00 12:02 pm Page 83