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Department of Dairy and Animal Science, The Pennsylvania State University, University Park, PA 16802
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSomatotropin and Growth.Effects of Somatotropin on...REFERENCES |
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10–15%. These responses occur because
pST has a wide array of biological effects that modulate nutrient
partitioning between adipose tissue and skeletal muscle. The decrease
in adipose tissue growth is due to a reduction in lipogenesis that is
the consequence of pST blunting the effects of many
insulin-dependent events. With respect to fatty acid synthase
(FAS), a pace-setting enzyme in the lipogenic pathway, enzyme
activity is markedly reduced by pST. This is the result of a
pST-mediated decrease in FAS mRNA levels that occurs because FAS
gene transcription is decreased. The consequence of the decrease in
lipid synthesis is that adipocyte hypertrophy is impaired and, hence,
tissue growth. This review will provide an overview of some of the
biological effects of pST in adipose tissue and will discuss what is
known about the underlying mechanisms that account for these
effects.
KEY WORDS: •
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSomatotropin and Growth.Effects of Somatotropin on...REFERENCES |
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70%). The remarkable
effects of pST are due to an impressive array of biological effects of
the hormone on nutrient utilization, nutrient partitioning and the
underlying biological processes that regulate and coordinate these
metabolic events in a variety of tissues. One of the hallmark metabolic
effects of pST in adipose tissue is that it decreases lipid synthesis
and compromises many of the effects of insulin (1
2
3)
.
Several excellent in-depth reviews have been written about the
biological effects of pST on growth and nutrient partitioning and how
insulin action is compromised in the pig. Consequently, this review
provides an overview of the major findings relative to growth and
adipose tissue metabolism; the reader is referred to more extensive
reviews for in-depth information about the efficacy of pST and
what is known about the biological mechanisms that mediate the
effects of the hormone (1
2
3)
. |
Somatotropin and Growth. |
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TOPABSTRACTINTRODUCTIONSomatotropin and Growth.Effects of Somatotropin on...REFERENCES |
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100 µg/(kg body·d)] have
been administered to growing pigs (for 30–77 d). These studies
demonstrated that the average daily gain is increased 10–20%,
feed efficiency (feed consumed/body weight gain) is improved 13-33%
and protein deposition (muscle growth) is increased by as much as 62%
(reviewed in 2
,4
). The anabolic effects of pST in muscle
contrast with the precipitous decrease that occurs in adipose tissue
growth. As shown in Table 1
, lipid accretion rates are decreased by as much as 70%. Similar
effects of human ST administration were observed in growing
children (prepubertal boys) after treatment for 6 mo, albeit the
effects were smaller (10% reduction in body fat), likely because of
the dose administered (5)
.
|
. Thus, any metabolic
modifier such as pST, which decreases glucose uptake by adipose tissue,
creates a physiologic state in which the tissue is deprived of the
primary substrate necessary for lipid accretion. This metabolic
adaptation is important for the following reasons: 1) it
results in a decrease in the rate of adipocyte hypertrophy and, hence,
the rate of adipose tissue accretion; and 2) it accounts for
the effects that pST has on productive efficiency and contributes to
the increase in muscle growth. In concert with the dramatic shifts in
adipose tissue glucose metabolism, glucose that is normally used for
lipogenesis is redirected to other tissues, primarily muscle. |
Effects of Somatotropin on Adipose Tissue Growth. |
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TOPABSTRACTINTRODUCTIONSomatotropin and Growth.Effects of Somatotropin on...REFERENCES |
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.
Somatotropin orchestrates many diverse physiologic processes so that
more nutrients can be used for lean tissue accretion, and fewer,
primarily glucose, are used by adipose tissue. Because the majority
(80%) of lipid in the body is derived from de novo fatty acid
synthesis (7)
and adipose tissue is the major site of
fatty acid synthesis in pigs (7
,8)
, early studies focused
on establishing whether the effects of pST were the result of changes
in lipogenesis. On the basis of in vitro (9
10
11)
and in
vivo kinetic studies (6)
, pST administration dramatically
reduces fatty acid synthesis in adipose tissue. In growing pigs, rates
of de novo synthesis can be decreased by >90%, whereas effects on
rates of lipolysis are minimal (2
,12)
. The effects of pST
on lipogenesis appear to be a direct action of pST because essentially
all effects that occur with in vivo pST treatment can be mimicked when
adipose tissue explants are cultured chronically with pST
(13)
. In addition, administration of insulin-like
growth factor I daily for 28 d to pigs does not mimic the effects
of pST administration on carcass composition (14)
.
One mechanism by which pST alters nutrient partitioning is to
modulate tissue responsiveness to insulin. In adipose tissue, this
involves a decrease in sensitivity with no change in the maximum
response (13
,15)
. The reduction in insulin sensitivity
decreases insulin-regulated events such as glucose transport,
lipogenic enzyme activities, expression of lipogenic enzyme genes and
lipogenesis (reviewed in 2
). Moreover, pST treatment
reduces whole-body glucose response when insulin tolerance tests
are conducted (16)
. This effect of pST is frequently
referred to as insulin resistance; this is somewhat misleading,
however, because the effect is clearly tissue specific and relates only
to certain insulin-responsive processes. Kinetic studies have
demonstrated that the alteration in glucose response to insulin is
almost exclusively related to effects on lipogenesis in adipose tissue
(11)
; insulin sensitivity of skeletal muscle is relatively
unaffected (2
,17)
. The consequence of tissue-specific
control of insulin action is a remarkable shift in nutrient
partitioning such that much of the glucose destined for lipid synthesis
in adipose tissue is redirected to muscle. This adaptation is important
because the additional glucose diverted to muscle appears to play a
critical role in providing additional energy to support the increase in
muscle protein synthesis observed in pigs treated with pST.
The decrease in insulin sensitivity caused by pST in pig adipose tissue
is not associated with any change in insulin receptor number or
tyrosine kinase activity of the insulin receptor (18)
.
This is consistent with the fact that some effects of insulin in the
adipocyte are not diminished by ST treatment (e.g., insulin inhibition
of lipolysis; see 2
). Little is known, however, about the
postreceptor events that mediate the effects of pST on the insulin
signal pathway(s) to antagonize the stimulatory effect of insulin on
expression of lipogenic enzyme genes. For this reason, studies have
been undertaken to use FAS as a model to learn more about how ST
regulates FAS enzyme activity and gene transcription. An important
rationale for selecting FAS as a model to study was based on the
observations that pST markedly reduces FAS enzyme activity (see
Table 2
) and that enzyme activity and FAS gene expression are exquisitely
sensitive to insulin (i.e., insulin increases enzyme activity and gene
expression). In addition, the FAS gene is useful to study because
changes in enzyme activity are the result of changes in enzyme protein
mass that reflect changes in FAS mRNA abundance (reviewed in
19
).
|
,20)
and the fact that changes in enzyme protein levels
reflect changes in FAS protein abundance, it is not surprising that
treatment of growing pigs with pST dramatically decreases adipose
tissue FAS mRNA levels (21)
. In addition, in both rat
liver and cultured 3T3-F442A adipocytes, ST reduces FAS mRNA abundance
and the ability of insulin to increase mRNA, effects that are the
result of a decrease in gene transcription (22
,23)
.
Somatotropin also shortens the half-life of FAS mRNA from 35 to
11 h (23)
. Thus, ST reduces FAS mRNA abundance both
at the transcriptional level as well as by destabilizing FAS mRNA. Little is known about how ST affects the insulin signal pathways that blunt the stimulatory effects of insulin on FAS gene expression. Clearly, the effect has to be postreceptor because insulin binding is unaffected. With respect to how ST might interfere with insulin signaling at the distal end of the signal pathway (i.e., at the level of FAS gene transcription), it is probable that this reflects the presence of a somatotropin response element that acts as a negative control element or that ST affects the abundance or binding of a trans-acting factor(s) that interacts with the insulin response element (IRE) in the FAS gene in a way that blunts insulin regulation.
Relative to the latter hypothesis, there is an IRE located in the
proximal region (from -71 to -50) of the FAS promoter that appears to
mediate the stimulatory effect of insulin on FAS gene transcription
(24)
. In this IRE, there is an E-box DNA binding motif
(5'-CANNTG-3') for basic-helix-loop-helix transcription factors such as
upstream stimulatory factors (USF); both USF1 and USF2 have been shown
to bind to this site (25)
. A study reported that USF
binding to the E-box at -65 was required for insulin regulation of
the FAS promoter (26)
. However, it is uncertain whether
USF1 mediates the insulin antagonistic effect of ST on FAS gene
expression. Studies we have conducted (Yin, D., and Etherton, T. D., unpublished data) demonstrated that neither insulin nor ST affect
the abundance of USF1 or binding of USF1 to the FAS-IRE in vitro in
3T3-F442A adipocytes. Thus, our findings indicate that USF1 is not
involved in mediating the effects of insulin and ST on the regulation
of FAS gene transcription, suggesting that other mechanisms exist. The
nature of these mechanisms is not clear and much work remains to be
done to clarify how pST decreases FAS gene transcription.
Lipolysis.
In pigs, the predominant effect of pST on adipose tissue growth is the
result of changes in lipogenesis; lipolysis is relatively unaffected
(2
,12)
. The conclusion that lipolysis not affected by pST
was definitively established by Dunshea et al. (12)
. These
investigators quantified glycerol and nonessential fatty acid kinetics
using a primed, continuous infusion of
[2-3H]glycerol and
[9,10(n)-3H]oleic acid in pigs treated with 120
µg pST/(kg body · d) for 8 d. Kinetics were
examined under both basal conditions and during a
hyperinsulinemic/euglycemic clamp. Although indices of fat mobilization
tended to be higher in pigs treated with pST, the magnitude of the
increases was small and would be sufficient to account for only a minor
fraction of the decreased lipid accretion observed in pST-treated
pigs.
The evidence to date clearly indicates that pST has potent effects on a number of key metabolic events that control adipose tissue growth. The mechanisms by which pST affects nutrient utilization in adipose tissue involve tissue-specific changes in key metabolic pathways as well as alterations in tissue responsiveness to insulin. In many cases, the cellular sites of the alterations in metabolic pathways and signal transduction have been identified, and it is clear that the biological effects of pST are dependent upon multiple changes. This metabolic regulation occurs in an orchestrated manner that results in the redirection of glucose away from lipid synthesis to muscle to provide additional ATP to support the increase in muscle protein deposition that occurs. The consequence of a decrease in lipid synthesis is that adipose tissue growth is dramatically reduced. At the gene level, we have much to learn about how pST blunts the effects of insulin on FAS gene transcription. The diverse spectrum of effects of pST in a variety of tissues as well as in a specific tissue reinforces the fact that multiple intracellular signaling events likely mediate the effects of the hormone. The nature of these signal pathways is obscure; with respect to adipose tissue, much remains to be unraveled about the mechanisms that account for the precipitous decrease in tissue growth. Nonetheless, it is evident that pST plays a key role in regulating adipose tissue metabolism. As we learn more about the mechanisms by which pST blunts adipose tissue growth, it is not unreasonable to speculate that we may discover innovative strategies that can be implemented clinically for the prevention and treatment of human obesity. The large body of evidence from studies conducted with growing pigs treated with pST provides compelling support for the idea that with respect to adipose tissue, ST is not a "growth" hormone; rather, it is a potent metabolic hormone that has remarkable antiobesity effects.
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FOOTNOTES |
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2 Abbreviations used: FAS, fatty acid synthase; IRE, insulin response element; pST, porcine somatotropin; ST, somatotropin; USF, upstream stimulatory factor.
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REFERENCES |
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