AMER. ZOOL., 23:729-738 (1983)
Evolution of Endocrine Regulation of Gastrointestinal
Function in Lower Vertebrates'
STEVEN R. VIGNA
Department of Biology, University of Oregon, Eugene, Oregon 97403
SYNOPSIS. The information available concerning the evolution of endocrine regulation
of three gastrointestinal functions in lower vertebrates—gastric acid secretion, gallbladder
contraction, and pancreatic enzyme secretion—is reviewed. The actions of hormones of
the cholecystokinin/gastrin family of peptides have been the most widely studied and are
emphasized. It is concluded that regulation of pancreatic enzyme secretion is a primitive
action of cholecystokinin and that the sensitivity of gallbladder muscle and gastric acidsecreting cells to these peptides evolved later, possibly in the ancestral lineage that led to
the gnathostomes. The need for increased digestive efficiency to support the higher levels
of activity made possible by the evolution ofjaws is suggested as a strong selection pressure
leading to this pattern of evolution of endocrine regulation of gastrointestinal function.
As is true with most other areas of comparative
vertebrate endocrinology, the
In all vertebrates, as in most other metazoa, digestion is practically completed in perspective needed to pose meaningful
the lumen of the gut prior to absorption comparative questions comes from examof food across the gut wall and into the ining what is known about the endocrine
body. Extracellular digestion, then, appar- regulation of digestion in the more intenently was an early and highly successful sively studied higher vertebrates, the comadaptation in evolution. This success is mon laboratory mammals. The distinctive
probably accounted for by the high degree feature of the regulatory system of the verof specialization of the digestive tract that tebrate gut is that the stimuli for hormone
extracellular digestion has made possible. release arise within the lumen from the
The development of extracellular diges- mechanical and chemical properties of food
tion has resulted in a regional differentia- and digestive secretions. Neural signals are
tion of the gut for food storage, secretion activated simultaneously and the summed
of digestive enzymes, mechanical disrup- neural and endocrine mechanisms control
tion, digestion proper, absorption, and the transverse flow of materials in both
waste evacuation. This specialization directions across the gut wall and the axial
greatly increases the efficiency with which flow of the gut contents within the lumen
ingested food can be converted into met- (Makhlouf, 1974). This complexity, comabolic energy substrates (Yonge, 1937). It bined with the high degree of differentiaseems obvious that the evolution of the tion of the gut into regions specialized for
advanced behavior patterns seen in the one or another digestive function, may
higher vertebrates required the prior evo- explain the large number of regulatory
lution of metabolic systems capable of sup- peptides known or suspected to be involved
porting that activity. Therefore, studies of in gut physiology. Grossman (1979)
the evolution of regulation of the highly recently described 20 peptides isolated
specialized digestive tract of lower verte- from the mammalian gut and pancreas that
brates should contribute to an understand- can affect digestive processes, and this is
ing of how adapting physiological systems undoubtedly an underestimate. Only a few
of these principles have been studied in
influenced the phylogeny of vertebrates.
lower vertebrates. Because of this dearth
of comparative information, our understanding of the evolution of these regula1
From the Symposium on Evolution of Endocrine
tory peptides lags behind that for most
Systems in Lower Vertebrates, A Symposium Honoring Professor Aubrey Corbman presented at the Annual Meet- other hormonal systems. Furthermore, few
ing of the American Society of Zoologists, 27-30 investigators have made systematic studies
INTRODUCTION
December 1982, at Louisville, Kentucky.
729
730
STEVEN R. VIGNA
of the kind that may be expected to yield
real insight into these questions. Therefore, the present review will focus on just
three of the many possible gastrointestinal
functions widely considered to be regulated in mammals by digestive hormones:
gastric acid secretion, gallbladder contraction, and pancreatic enzyme secretion.
Recent advances in comparative studies of
these functions will be summarized and an
attempt made at an overall synthesis of the
pattern of evolution of their endocrine
control. Because of the scarcity of the data
on which they are based, the conclusions
drawn are recognized as clearly provisional. It is hoped that this approach, which
focuses on the target organ systems rather
than on the myriad hormones involved, will
avoid some of the complexity and confusion that often plagues reviews in this field.
GASTRIC ACID SECRETION
This section will focus on the regulation
of hydrochloric acid secretion from the
stomach in fishes and amphibia. In mammals, the stomach hormone gastrin exerts
a dominant stimulatory influence on acid
secretion which can be modified by neurotransmitters, local paracrine agents, and
other hormones (Debas, 1977). The usual
mammalian bias has resulted in the accumulation of comparative information limited almost exclusively to the effects of gastrin and related molecules on gastric acid
secretion.
In amphibia, there is abundant evidence
that mammalian gastrin and related peptides can stimulate gastric acid secretion
both in vitro (see, for example, Davidson et
al., 1966) and in vivo (see, for example,
Morrissey and So, 1970). The mammalian
intestinal hormone cholecystokinin (CCK)
and its amphibian skin analogue, caerulein,
both of which have the same molecular
center of biological activity as gastrin, also
stimulate mammalian and amphibian gastric acid secretion. As summarized elsewhere (Crim and Vigna, 1983), it appears
that amphibians, unlike mammals, possess
a peptide more closely resembling mammalian CCK than gastrin in their stomachs
and thus represent a stage in \ertebrate
phylogeny before the first appearance of
gastrin as a stomach hormone. Nevertheless, it seems likely that amphibians exhibit
the same basic pattern of control of gastric
acid secretion by CCK/gastrin-like hormones as mammals. However, the effects
of homologous amphibian peptides on acid
secretion and the circulating levels of these
molecules in amphibian blood are not yet
known, so this conclusion must remain tentative.
The potential danger in relying too
strongly on results obtained in lower vertebrates using heterologous hormones
(usually mammalian) to study the evolution
of hormonal actions can be illustrated by
the following example. There has been a
tendency to assume that the amphibian
stomach hormone is identical to caerulein,
a CCK-like decapeptide found in the skin
glands of some but by no means all frogs.
This is an unwarranted assumption because
detailed characterizations of amphibian gut
peptides have not yet been reported. Furthermore, preliminary studies indicate that
bullfrogs have a biologically active CCKlike peptide (tested in mammalian bioassay
systems) in the stomach which is clearly
distinguishable immunologically from
mammalian CCK and gastrin as well as
caerulein (Vigna, unpublished observations). Clearly, the possible role of this peptide in controlling bullfrog gastric acid
secretion must be examined before reliable
conclusions can be drawn about the evolution of hormonal control of this digestive
function in amphibia.
In contrast to the relatively well-studied
amphibia, there is scant information available about the effects of CCK/gastrin peptides on osteichthian gastric acid secretion.
What little information does exist suggests
a major deviation from the tetrapod pattern of regulation. Only one species of
teleost, the Atlantic cod (Gadus morhua),
has been examined in any detail. Holstein
(1982) has shown recently that gastric acid
secretion in cod is inhibited by gastrin,
CCK, and caerulein. Interestingly, very
high doses of gastrin/CCK-5, the
C-terminal pentapeptide fragment shared
bv mammalian gastrin and CCK which is
also the molecular center of biological
acthit) of each hormone, initial!) stimu-
EVOLUTION OF GUT HORMONE FUNCTION
lated cod gastric acid secretion, although
later the response reversed into a poststimulation inhibition.
The inhibition of gastric acid secretion
in cod by a family of peptides that are stimulatory in most vertebrates points to a possible major difference in the evolution of
control of stomach function in two very
successful vertebrate lineages—the bony
fish and the tetrapods. Here, however, caution must be exercised because of the lack
of much information. More work is
required, even in the cod, before final conclusions can be drawn. For example, acid
secretion from the m vitro gastric mucosa
of the urodele amphibian, .\eclurus maculosus, has been reported also to be inhibited
by CCK (Nakajima et al., 1971). As in the
cod, CCK-elicited inhibition was preceded
by a transient stimulation. However,
another group later found that CCK only
stimulated Xecturus gastric acid secretion
in a similar preparation (Berkowitz et al.,
1976). The reasons for this apparent discrepancy are unclear but suggest a cautious
interpretation of the cod results.
Certainly, the effects of the homologous
cod peptides on acid secretion should be
examined and may help clarify the situation. In this regard, it is noteworthy that
in another teleost, the rainbow trout (Salmo
gairdneri), very low levels of immunoreactive gastrin/CCK have been detected in
the stomach by extraction and RIA and by
immunocytochemistry, whereas higher
levels are found in the intestine (Holmgren
et al., 1982). This contrasts with the situation in tetrapods in which the distal (antral)
region of the stomach contains the highest
concentration of gastrin/CCK in the gut.
In the cod, Larsson and Rehfeld (1977)
found a large population of cells containing a CCK-like peptide and relatively high
levels of extractable hormone in the antrum
whereas Holstein (1982), using a different
antiserum, reported only trace amounts of
gastrin/CCK in gastric relative to intestinal extracts. It is possible that the endogenous teleost stomach peptide, unlike the
intestinal molecule, cross-reacts only weakly
with some of the available antisera raised
against the mammalian hormones. If this
reflects a structural difference between the
731
mammalian and cod hormones in or near
the active site, then injecting mammalian
or even amphibian hormones may lead to
erroneous conclusions regarding the role
of the endogenous cod hormones and
therefore distort our understanding of the
evolution of gastrointestinal regulation of
gastric acid secretion in this group of vertebrates.
It does seem likely that teleosts have
arrived at a different physiological solution
to the problem of regulation of gastric acid
secretion than have tetrapods. It seems
prudent at this early stage of study to propose that teleosts do not use a gastrin/CCKlike molecule synthesized and secf eted from
the gastric mucosa to regulate acid secretion. Intestinal CCK in these fish may act
to inhibit acid secretion after partially
digested food has passed downstream from
the stomach and in this way turn off the
gastric phase of digestion in a graded fashion that has clear adaptive value. Reducing
the proteolytic digestive power of gastric
juice when food is not present may help
prevent self-digestion (ulcer formation).
The mammals have apparently arrived at
a different adaptive solution to the same
physiological problem (Debas, 1977). A
possible candidate for the stimulant of cod
gastric acid secretion is bombesin, a frog
skin tetradecapeptide that has been shown
capable of stimulating cod gastric acid
secretion in low doses (Holstein and Humphrey, 1980). A puzzle here is that bombesin is thought to stimulate mammalian
gastric acid secretion indirectly via release
of antral gastrin. In the cod study, plasma
"gastrin" levels did not change during
bombesin-stimulated acid secretion. A
highly specialized pattern of hormonal
control of gastric acid secretion in teleosts
relative to other vertebrates would be consistent with similar findings in other teleost
endocrine systems, such as the pituitary and
the endocrine pancreas (Epple and Brinn,
1975).
The situation in chondrichthians is
unclear, due to the scarce information
available. Hogben (1967) found that porcine gastrin was a weak stimulant, at the
two doses tested, of in vitro gastric acid
secretion in dogfish (Sc/ualus acanthias). This
732
STEVEN R. VIGNA
CASTRIC ACID SECRETION
LIVING
ACNATHANS
(STOMACHLESS)
LIVING
CHONDRICHTHYEANS
LIVING
OSTEICHTHYEANS
LIVING
TETRAPODS
PRIMITIVE ANCESTORS OF
LIVING OSTEICH. I TETRAPODS
PRIMITIVE CNATHOSTOMES
PRIMITIVE AGNATHANS
(STOMACHLESS)
PRIMITIVE INVERTEBRATE CHORDATES
(STOMACHLESS)
FIG. 1. Proposed evolution of the regulation of gastric acid secretion by cholecystokinin/gastrin-like
(CCK/G) hormones in lower vertebrates. +, CCK/G is stimulatory; —, CCK/G is inhibitory; [ ], hypothetical
CCK/G effect. Because mammalian CCK/G can stimulate gastric acid secretion in living tetrapods and
chondrichthyeans, parsimony dictates that we regard this as retention of a primitive characteristic in these
groups. Therefore, the inhibition of acid secretion by CCK/G in living osteichthians may be regarded as a
derived, advanced specialization.
study is sometimes cited as providing evidence that porcine gastrin is ineffective in
stimulating dogfish acid secretion (Dockray, 1977; Holstein, 1982), but a careful
examination of Hogben's data reveals clear
evidence of increased acid secretion in
response to gastrin. Furthermore, porcine
gastrin stimulates gastric acid secretion in
vivo in dogfish (Vigna, 1978). These few
data thus support the concept that the pattern of regulation of stomach secretion in
dogfish, and perhaps the other chondrichthian species possessing a stomach, resembles the tetrapod more closely than the
osteichthian pattern, further emphasizing
the high degree of specialization of osteichthian endocrine systems.
The agnathans (the living representatives are the hagfishes and lampreys) have
no acid-secreting stomach and this is
thought to be a primitive feature of this
group (Barrington, 1942). In contrast, the
lack of a stomach in some other vertebrates
(?-g-, ratfish, lungfish, some teleosts such as
the Cyprinidae, the echidna, the vampire
bat) represents a secondary loss (Barrington, 1942). Figure 1 depicts a hypothetical
scheme for the evolution of regulation of
gastric acid secretion in the vertebrate
stomach based on the present meager evidence.
GALLBLADDER CONTRACTION
This section will review the evidence for
the endocrine control of gallbladder
smooth muscle contraction in lower vertebrates. In mammals, the intestinal hormone cholecystokinin is named for its
potent action in eliciting gallbladder muscle contraction, thereby regulating bile
delivery to the small intestine after a meal.
Also, bombesin stimulates and pancreatic
polypeptide (PP) inhibits gallbladder contraction in some mammalian species, but
733
EVOLUTION OF GUT HORMONE FUNCTION
GALLBLADDER CONTRACTION
0
LIVINC
ACNATHANS
LIVINC
CHONDRICHTH YEANS
LIVINC
OSTEICHTHYEANS
LIVINC
TETRAPODS
PRIMITIVE ANCESTORS OF
LIVINC OSTEICH. £ TETRAPODS
PRIMITIVE CNATHOSTOMES
PRIMITIVE ACNATHANS
PRIMITIVE INVERTEBRATE CHORDATES
(CALLBLADDERLESS)
Fic. 2. Proposed evolution of the regulation of gallbladder contraction by cholecystokinin-like (CCK) hormones in lower vertebrates. +, CCX is stimulatory; 0, CCK has no effect; ?, CCK effect is equivocal or unknown;
[ ], hypothetical CCK effect. Because the experimental data available are still incomplete, we cannot yet
conclude whether gallbladder sensitivity to CCK first arose in a common gnathostome ancestor or in the
common ancestor of osteichthians and tetrapods. CCK stimulation of gallbladder contraction is a shared,
derived character among at least those gnathostomes which have been adequately tested and thus can serve
further to distinguish them phylogenetically from the Agnatha (Atz, 1973).
the physiological significance of these
effects is unclear. The only comparative
information available regarding the endocrine control of gallbladder contraction in
lower vertebrates concerns the effects of
mammalian CCK.
A crude CCK extract tested in vivo
(Seager, 1939) and pure porcine CCK
tested in vitro (Vigna, 1978) stimulate frog
gallbladder muscle contraction. Homologous amphibian CCK-like factors, including caerulein, apparently have not been
tested.
The only study of the action of CCK on
gallbladder contraction in bony fish utilized a teleost, the coho salmon, Oncorhynchus kisutch (Vigna and Gorbman, 1977).
Porcine CCK was found to be a potent
stimulant of contraction of the salmon gallbladder muscle in vitro.
Only very equivocal results have been
obtained concerning the ability of mammalian CCK to stimulate gallbladder contraction in a chondrichthian. In a study of
the effects of CCK on the contraction of
dogfish (Squalus acanthias) gallbladder
muscle in vitro, it was observed that very
few preparations responded to porcine
CCK (Vigna, 1978). However, some gallbladder muscle strips did exhibit a weak
and transient contractile response. The
CCK response found in salmon and tetrapod gallbladder muscle in vitro is sustained
over many minutes. The irregularity of the
responses and the peculiarity of the few
apparent positive effects made it impossible to conclude with any confidence that
dogfish gallbladder muscle can respond to
CCK. The resolution of this question
requires further investigation.
734
STEVEN R. VIGNA
In the agnathan hagfish, Eptatretus stouti,
porcine CCK and caerulein in wide dose
ranges failed to elicit any contractile
response from the gallbladder tested in vivo
and in vitro (Vigna and Gorbman, 1979).
The hagfish gallbladder muscle, unlike the
dogfish organ, responded vigorously and
reproducibly to acetylcholine, indicating
that it was fully capable of contractile
responses. The effects of the endogenous
hagfish CCK-like factor have not been
tested. It is possible that the hagfish represents a stage in vertebrate phylogeny
before the evolution of gallbladder smooth
muscle possessing CCK receptors linked to
the cellular contractile apparatus.
Figure 2 illustrates a hypothetical scheme
for the evolution of regulation of gallbladder contraction in vertebrates.
does not exist as a discrete, compact organ
in most bony fish species. Instead, the pancreas is usually diffuse; glandular tissue can
often be found along the portal veins, penetrating the liver, suspended in the mesenteries between the intestine and liver,
associated with the principal islet of endocrine tissue, and dispersed among the
pyloric caeca (Kapoor el ah, 1975). It is thus
not possible to study pancreas function in
these fish using the traditional in vivo and
in vitro techniques. However, this is a lame
excuse because several osteichthians have
a tetrapod-like pancreas, and are therefore
amenable to experimental manipulation.
Two examples are the lungfish, Protopterus,
and the eel, Anguilla. Furthermore, even
in those species with a diffuse pancreas it
should be possible to study pancreatic
enzyme secretion in vivo using methods such
as have been successful in the hagfish, an
PANCREATIC ENZYME SECRETION
In this section, evidence concerning the organism without a pancreas at all (see
endocrine control of secretion of digestive below).
enzymes from the fish and amphibian exoAmong the chondrichthians, only the
crine pancreas will be reviewed. Again, the dogfish {Squalus acanthias) has been examfew investigations in this area have taken ined. In a preliminary study, it was reported
their cue from the experimental founda- that one very high dose of porcine CCK
tion provided by the large literature con- stimulated lipase release from pancreatic
cerning the control of the mammalian exo- slices incubated in vitro (Vigna, 1978).
crine pancreas. The pancreatic acinar cell
The living Agnatha do not possess an
in mammals has been shown to secrete exocrine pancreas, and thus seem to repdigestive enzymes in response to four classes resent a stage of vertebrate evolution
of regulatory peptides: the CCK, bom- before the appearance of this gland as a
besin, substance P, and secretin families, separate organ. However, the modern
as well as in response to cholera toxin Agnatha, the cyclostomes, do have zymo(Gardner and Jensen, 1980). As was the gen cells scattered in the intestinal epithecase for comparative studies of control of lium which are considered to be homogastric acid secretion and gallbladder con- logues of the pancreatic acinar cells of
traction, only a few of these secretagogues higher vertebrates (Barrington, 1972). This
appear to have been tested for their ability feature was exploited to show that porcine
to stimulate pancreatic enzyme secretion CCK was capable of stimulating secretion
in lower vertebrates.
in vivo of lipase, a pancreatic enzyme in
Gater and Balls (1977) found that por- higher vertebrates, from the intestine of
cine CCK could stimulate amylase secre- the hagfish, Eptatretus stouti (Vigna and
tion from in vitro cultured pancreatic frag- Gorbman, 1979). It may well be that
ments of the urodele amphibian, Amphiuma CCKergic regulation of "pancreatic"
means. Again, no studies of the effects of enzyme secretion predated the actual evocaerulein or any other amphibian CCK- lution of the pancreas in vertebrates. Barlike peptide on amphibian pancreatic rington (1971) has pointed out that it is
difficult to understand how the pancreas
enzyme secretion have been reported.
There are no studies of the endocrine could have evolved without the simultacontrol of pancreatic enzyme secretion of neous elaboration of some mechanism for
osteichthians, probably because the gland regulation of its activity. CCK can thus be
EVOLUTION OF GUT HORMONE FUNCTION
735
PANCREATIC ENZYME SECRETION
LIVING
PROTOCHORDATES
LIVING
AGNATHANS
LIVING
CHONDRICHTHYEANS
NT
LIVING
OSTEICHTHYEANS
LIVING
TETRAPODS
PRIMITIVE ANCESTORS OF
LIVING OSTEICH. t TETRAPODS
PRIMITIVE CNATHOSTOMES
PRIMITIVE INVERTEBRATE CHORDATES
Fic. 3. Proposed evolution of the regulation of pancreatic enzyme secretion by cholec)stokmin-like (CCK)
hormones in lower vertebrates. +, CCK is stimulatory: NT, CCK has not been tested: | ], hypothetical CCK
effect. It seems clear that CCK stimulation of pancreatic enzyme secretion is a shared, primitive characteristic
among vertebrates and probably originated in protochordate or invertebrate lineages ancestral to the vertebrates. Living protochordates and Agnatha do not have a pancreas as such. See text for explanation.
implicated in the adaptive mechanisms
during vertebrate evolution which resulted
in the collection together and migration of
intestinal zymogen cells to form a new
gland, the pancreas, remote from the intestine. Support for the concept of a primitive
role for CCK in regulating digestive enzyme
secretion comes from a recent study showing that porcine CCK stimulates release of
acid phosphatase and other proteins from
the gut of the protochordate, Stxela clava
(Bevis and Thorndyke, 1981).
Figure 3 depicts a hypothetical proposal
for the evolution of regulation of "pancreatic" enzyme secretion in vertebrates.
It seems clear that the involvement of CCK
in this digestive function is an ancient feature.
DISCUSSION
While it is probable that the hypothetical
phylogenetic schemes presented in Figures
1-3 are premature, as they are based on
few studies generally performed on only
one species per class, nevertheless it is
impossible to resist the temptation to speculate about possible selection pressures in
vertebrate evolution thay may have generated such patterns. If it is accepted that
the evolution of regulatory systems which
increased the efficiency of digestion may
have influenced the phylogeny of vertebrates (see Introduction), then it is incumbent upon the student of this area to propose a tentative scenario tracing this
influence. Bern (1972) has pointed out that
it is only in this endeavor that we are practicing true comparative endocrinology.
The hypothetical scenarios for evolution
of control over vertebrate gastrointestinal
functions by members of the CCK/gastrin
family of hormones depicted in Figures 13 indicate that hormonal control of gallbladder contraction and gastric acid secretion may have evolved together and later
in vertebrate phylogeny than hormonal
736
STEVEN R. VIGNA
control of pancreatic enzyme secretion. It
seems likely that hormonal regulation of
gallbladder contraction and gastric acid
secretion may have first appeared in the
common ancestor of gnathostomes that was
not also an ancestor of living agnathans. It
is interesting that the Agnatha are stomachless and that the first appearance of a
stomach in gnathostomes has been correlated with the habit of macrophagous feeding made possible by the prior evolution
of jaws (Barrington, 1942). It is reasonable
to assume that the stomach first arose as a
storage organ for the relatively large fragments of food that jaws made possible to
ingest in ancestral gnathostomes. Subsequently, the secretion of acid and pepsinogen into the stomach might have arisen
as an adaptation for killing prey, preventing bacterial infection, and initiating the
extracellular digestion of protein, which
was probably the most abundant and
important nutrient of early forms (Barrington, 1942).
The phylogenetic record clearly supports the concept that the concurrent
appearance of jaws and the stomach were
key features in the ultimate success of vertebrates. Ancestral agnathans seem to have
been heavily armored, sluggish bottom
dwellers dependent for food on filtering or
ingestion of their substrates (Denison,
1961). Jaws released ancestral gnathostomes from the burden of expending most
of their energy and virtually all of their
time performing a single behavior, feeding, by allowing periodic rather than continuous food consumption. Thus, it became
possible for these animals to become relatively active as evidenced by the first
appearance of paired appendages and a
reduction in dermal armor in this lineage.
Increased capacity for activity is a profound selective advantage (Bennett and
Ruben, 1979), but inevitably incurs
increased energetic costs. There appear to
be no differences in the efficiency of muscle
energy utilization between living agnathans and gnathostomes that could account
for the increased activity exhibited by the
first jawed vertebrates with stomachs
(Ruben and Bennett, 1980). Therefore,
development of mechanisms to increase
efficiency of energy assimilation from the
environment may have been required to
support increased activity. I suggest that
one adaptation that occurred to increase
the efficiency of energy metabolism was
increased digestive efficiency which
resulted in part from the first appearance
of a stomach as a specialized region of the
gut. A population of pre-existing CCK cells,
used at least in part to regulate digestive
enzyme secretion from the intestinal "pancreatic" cells in ancestral agnathan forms,
then may have colonized the new gastric
epithelium. The "old" hormone, CCK, now
present in a "new" anatomical site, the
stomach, may have been free to be
recruited by new target cells in the acidsecreting part of the stomach. In the gastric epithelium, the CCK cells would be
advantageously located to serve the regulatory role of signalling the presence of
food in the stomach. Another important
selective advantage would be gained here:
the simultaneous evolution of regulatory
mechanisms and of a proteolytic enzyme-,
acid-secreting organ would be required to
ensure that the potentially self-digesting
secretions would be limited only to periods
when an exogenous substrate, food, was
available. In these ways, possibly, the evolution of macrophagy was accompanied by
the evolution of adaptive regulatory mechanisms which allowed the full benefits of
this new feeding habit to be expressed. That
macrophagy, made possible by the evolution of jaws followed by the stomach and
its regulatory mechanisms, was a pivotal
feature in the evolution of the higher vertebrates is supported by the nearly explosive adaptive radiation of fishes that
occurred in the Devonian.
It must be mentioned that there are some
potential problems with this scenario. In
mammals, the stomach exhibits what
appears to be a direct secretagogue control
of acid secretion (acid-secreting cells
respond directly to contact with food),
although this is thought to be of little significance in normal gastric physiology
(Debas, 1977). Such a mechanism, however, could conceivably be primitive and
antedate hormonal regulation. Studies of
gastric physiology in modern fish species
EVOLUTION OF GUT HORMONE FUNCTION
737
the origin oflife, pp. 176-190. North Holland Pubclose to the main line (Bern, 1972) of
lishing Co., Amsterdam.
gnathostome evolution may shed light on
Barrington, E. J. W. 1972. The pancreas and intesthis question.
tine. In M. W. Hardisty and I. C. Potter (eds.),
The apparent co-evolution of CCK regThe biology of lampreys, Vol. 2, pp. 135-169. Academic Press, New York.
ulation of gallbladder contraction with the
first appearance of the stomach may not Bennett, A. F. andj. A. Ruben. 1979. Endothermy
and activity in vertebrates. Science 206:649-654.
be significant. On the one hand, it seems Berkowitz,
J. M., M. Praissman, and M. E. LeFevre.
plausible that an increase in digestive effi1976. Effects of peptide hormone structure on
ciency would be gained by linking the conH+ secretion of Necturus gastric mucosa. Am. J.
Physiol. 231:573-578.
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presence of food in the intestine via a gas- Bern, H. A. 1972. Comparative endocrinology—State
of the field and the art. Gen. Comp. Endocrinol.
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Suppl. 3:751-761.
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lation of gastric enzyme secretion by porcine cholecystokinin in the Ascidian, Styela clava Gen.
have no gallbladder and thus presumably
Comp. Endocrinol. 45:458-464.
rely on continuous, unregulated biliary
J. W. and S. R. Vigna. 1983. Brain, gut and
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181.
provisional. It is hoped that this review will Dockray, G.J. 1977. Molecular evolution of gut horhelp identify major gaps in our knowledge
mones: Application of comparative studies on the
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358.
field. The CCK/gastrin family of regulaEpple,
A. and J. E. Brinn, Jr 1975. Islet histophystory peptides seem admirably suited to
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comparative investigations that may be of
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real significance in the ongoing struggle to Gardner, J. D. and R. T.Jensen. 1980. Receptor for
secretagogues on pancreatic acinar cells. Am. J.
outline the history of vertebrate life.
ACKNOWLEDGMENTS
I thank Aubrey Gorbman for first suggesting to me that comparative studies of
gastrointestinal hormones might be interesting. Support for some of the studies
reviewed here from NSF grant PCM 8104338 is gratefully acknowledged.
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