J Comp Physiol B (2005) 175: 375–394
DOI 10.1007/s00360-005-0013-3
R EV IE W
John R. Speakman Æ El_zbieta Król
Limits to sustained energy intake IX: a review of hypotheses
Received: 25 October 2004 / Revised: 8 March 2005 / Accepted: 3 May 2005
Springer-Verlag 2005
Abstract Several lines of evidence indicate that animals
in the wild may be limited in their maximal rates of
energy intake by their intrinsic physiology rather than
food availability. Understanding the limits to sustained
energy intake is important because this defines an
envelope within which animals must trade-off competing
activities. In the first part of this review, we consider the
initial ideas that propelled this area and experimental
evidence connected with them. An early conceptual advance in this field was the idea that energy intake could
be centrally limited by aspects of the digestive process,
or peripherally limited at the sites of energy utilisation.
A model system that has been widely employed to explore these ideas is lactation in small rodents. Initial
studies in the late 1980s indicated that energy intake
might be centrally limited, but work by Hammond and
colleagues in the 1990s suggested that it was more likely
that the limits were imposed by capacity of the mammary glands, and other works tended to support this
view. This consensus, however, was undermined by
studies that showed milk production was higher in mice
at low temperatures, suggesting that the capacity of the
mammary gland is not a limiting factor. In the second
part of the review we consider some additional
hypotheses that might explain these conflicting data.
These include the heat dissipation limits hypothesis, the
seasonal investment hypothesis and the saturated neural
control hypothesis. Current evidence with respect to
these hypotheses is also reviewed. The limited evidence
presently available does not unambiguously support any
one of them.
Keywords Sustained energy intake Æ Food
intake Æ Energy expenditure Æ Heat dissipation Æ
Mammary gland Æ Lactation Æ Neuropeptides Æ
Hypothalamus Æ Brown adipose tissue Æ Leptin Æ
Prolactin
Abbreviations a-MSH: Alpha-melanocyte stimulating
hormone Æ AgRP: Agouti-related peptide Æ ARC:
Arcuate nucleus of the hypothalamus Æ BAT: Brown
adipose tissue Æ CART: Cocaine- and amphetamineregulated transcript Æ db/db: Obese diabetic
mouse Æ MC3R, MC4R: melanocortin-3 and -4
receptors Æ MTII: A receptor agonist for MC3R and
MC4R Æ NPY: Neuropeptide Y Æ ob/ob: Obese mutant
mouse Æ Ob-Ra, Ob-Rb.....Ob-Rf: Leptin receptor subtypes a to f Æ POMC: Pro-opiomelanocortin Æ PRL:
Prolactin Æ PrRP: Prolactin-releasing peptide Æ PVN:
Paraventricular nucleus of the hypothalamus Æ SusEI:
Sustained energy intake Æ SusMR: Sustained metabolic
rate Æ TRH: Thyrotropin-releasing hormone Æ UCP1.....UCP-5: Uncoupling proteins 1, 2, 3, 4 and 5 Æ
Y1: Receptor for neuropeptide Y
Limits to sustained energy intake VIII: Król et al. (2003) J Exp Biol
206: 4283-4291.
Communicated by I.D. Hume
J. R. Speakman (&) Æ El_zbieta Król
Aberdeen Centre for Energy Regulation and Obesity (ACERO),
School of Biological Sciences, University of Aberdeen,
Aberdeen, AB24 2TZ UK
E-mail: [email protected]
Tel.: +44(0)-1224272879
Fax: +44(0)-1224272396
J. R. Speakman
ACERO, Division of Energy Balance and Obesity,
Rowett Research Institute,
Bucksburn, Aberdeen, AB21 9SB UK
Extrinsic and intrinsic constraints on energy intake
Everything that animals do requires energy. This includes all the physiological processes that are needed to
maintain cellular homeostasis and functionality. Any
behaviours that animals perform also utilise energy to
power the muscular contractions that underlie movement. Endothermic animals often have to expend energy
to fuel thermogenesis and, finally, energy is also needed
for growth and reproduction. Although the uses to
which energy is diverted are legion, there are only two
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sources of energy input. Some heat energy can be
gathered directly by absorption of solar radiation, or
exceptionally by contact with hot objects such as heated
rocks, to offset the energy demands of thermogenesis,
but this heat energy cannot be used for any other
function. Consequently, all the major biological functions have to be fuelled from a single source food intake.
Sustained energy intake (SusEI) is the maximal rate of
energy intake that animals can sustain over sufficiently
long periods (days to weeks) so that energy demands are
fuelled by food intake rather than by transient depletion
of energy reserves. The limitations on SusEI are of
importance because they define an envelope within
which all the competing biological functions are constrained.
In many situations, the SusEI may be constrained by
food availability, that is, extrinsically determined.
Hibernation is a metabolic shutdown of physiological
systems and a cessation of physical activity that results in
massive energy savings that allow animals to survive even
when the food supply is extremely low. Experimentally
this has been demonstrated by providing hibernal animals with extra food so that they are not extrinsically
limited and, in these situations, the exhibition of a
hibernal phenotype is considerably reduced, although
not entirely eliminated (e.g., Humphries et al. 2003).
However, in many situations increasing the food
supply does not change the level of animal performance
in the manner that might be anticipated if food supply
was limited. Many studies in birds, for example, have
involved artificially increasing food supply (generally
called food supplementation experiments) during the
period when the animals are reproducing (reviewed by
Meijer and Drent 1999). The most significant effects of
such supplementation are to advance the date at which
they commence breeding. This strongly suggests that the
onset of breeding can be extrinsically constrained by
food supply. However, measures of peak performance
are seldom adjusted upwards. Hence in 17 studies
involving increases in food supply during either the
laying, incubation or nestling phases, only three reported increases in brood size or nestling size at fledging.
Studies of food supplementation in mammals are less
common, but a similar pattern emerges. A particularly
graphic example of the responses of breeding mammals
to increased food is illustrated by wood mice (Apodemus
sylvaticus) in sand dune habitats. Wood mice usually live
in woodlands, where they occupy home ranges of
around 300 m2. In sand dune habitats, however, their
home ranges are around 10,000 m2 because the food
supply in dunes is more sparse (Gorman and Ahmad
1993). Litter sizes of the animals in the two habitats do
not differ but the onset times for breeding do (Akbar
and Gorman 1993a). Consequently, despite the apparent
discrepancies in the availability of food, individual animals do not appear to be extrinsically limited in their
peak lactational performance. When the food supply of
the mice in the sand dune habitat was increased, the
animals bred earlier but did not respond by increasing
their peak productivity. Rather they reduced the area
over which they foraged (Akbar and Gorman 1993b)
and the time spent feeding (Akbar and Gorman 1996).
The animals therefore adjusted the area and the time
they spent feeding to match their demands instead of
using the elevated supply to fuel greater demands. These
observations suggest that the animals were not extrinsically constrained but were operating under an intrinsic
constraint on their performance.
Intrinsic constraints on SusEI have probably evolved
to match extrinsic food supplies. However, the manner
in which this matching occurs is unknown. Have animals
evolved such that the intrinsic level allows capacity for
the animals to exploit stochastic variations in external
food supply? The inability of most animals to elevate
their intakes when food supply is augmented suggests
that this is not the case. However, experimental increases
in food supply may go well beyond natural variations,
and we could not reasonably expect evolution to equip
animals for events they never encounter. Before we can
address these issues, we need to understand the nature of
the intrinsic limitation. This review will cover the main
hypotheses and experimental evidence that has been
collected to address this issue.
Central versus peripheral constraints on energy intake
The concept of limits on energy budgets can be traced to
the 1930s (Karasov 1986), but the first explicit hypotheses concerning limitation on SusEI were generated
during the 1980s following the seminal work of Drent
and Daan (1980). A conceptual basis that developed
around the late 1980s (Kirkwood 1983; Peterson et al.
1990; Weiner 1992) was the notion that intakes might be
limited either centrally or peripherally. To understand
these concepts, it is worth thinking about the flow of
energy in the animal (Fig. 1). Energy enters the system
via a single entry point food intake. There may be a
regulation on this intake imposed either by aspects of
feeding behaviour or the extrinsic food supply. Most
animals feed in discreet bouts (meals) that they intersperse with other behaviour, and they have morphological structures such as the crop and stomach where
energy is stored prior to its digestion. The existence of
these adaptations in the alimentary tract is a further
indication that animals are intrinsically limited, because
it would appear that animals can collect energy from
their environments faster than their guts are able to
process the food. The constraint on energy uptake into
the body is therefore unlikely to be imposed at the level
of the mouth and ingestive behaviours, but rather in the
capacity of the alimentary tract to process ingested food
and make its nutrients available for use. Some of the
food is not digested and passes through the alimentary
tract. The remaining energy enters the body. Some energy may be stored (generally as adipose tissue or glycogen), or withdrawn from such stores. The
combination of immediate food supply and energy
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withdrawn from storage may be expended on different
activities which are each subject to independent levels of
regulation. Thus, some energy may be used for cellular
homeostasis (resting metabolism) while other energy is
employed for activity (activity metabolism) or thermoregulation. Relatively little energy generates external
work, such as the mechanical output during locomotion,
or is retained in the system as growth and most energy
leaves the system as heat. Some heat generated by
activity can offset the demands for thermoregulation,
but otherwise the utilisation of energy for different end
uses is generally considered to be additive. Because these
uses are additive, if energy is not used for one function
e.g. growth, it can be diverted to another function, for
example, foraging behaviour or mating. Some energy is
also lost as the excreted end products of metabolism e.g.
urea, uric acid and ammonia. The rate at which animals
can eliminate these end products may actually constrain
the total energy flow. If there is a limit on the rate at
which waste can be eliminated, there is not a simple
diversion of any excess into the flow that becomes
available for other processes.
There are several different points at which flow of
energy in the animal might be constrained (Fig. 1), but
two in particular have attracted attention. The first
constraint may apply either when energy is absorbed
(Fig. 1A) or when waste is eliminated to constrain the
total flow into functional uses (Fig. 1D). Because this
limit applies independently of the ultimate use of the
energy, it is referred to as a ‘central’ limit. Alternatively,
the total flow may be constrained by the summated
ability of the animal to actually utilise the ingested energy (Fig. 1B). As this energy utilisation occurs in
peripheral tissues (e.g. muscles, brown adipose tissue,
mammary glands), it is referred to as a ‘peripheral’ limit.
Since the summated utilisation of energy at the end of
the system is equal to the metabolic expenditure of energy (minus any energy diverted into production), the
concepts of limitations on SusEI have developed in
parallel with the ideas of limitations on sustained energy
expenditure or sustained metabolic rate (SusMR). Indeed, in many publications (e.g. Weiner 1992; Hammond and Diamond 1997) these two have been treated
as virtually synonymous and in many circumstances they
are almost the same. There are, nevertheless, some situations where this is not the case, and this has led to
some confusion in the literature. There are two particular circumstances where there will be a disjunction
between SusEI and SusMR. The first is when there has
been a period in which intake exceeds expenditure and
excess energy is stored. Since in this situation intake has
exceeded expenditure, it is clear that this could also not
be a situation where the flow of energy was extrinsically
constrained. Equally, one might imagine a situation
where energy is withdrawn from storage to supplement
expenditure. The existence of storage potential (either as
short-term glycogen storage or long-term fat storage)
compromises the equivalence of intake and expenditure
in any consideration of energy balance. However, stud-
c
Fig. 1 Schematic diagram to show energy flows in an animal and
the potential points at which such energy flows may be constrained
and thus control the level of the sustained energy intake (SusEI).
The energy flows are denoted by blue arrows and the constraining
points are denoted by red bow-ties. Energy is ingested at the mouth
and enters the alimentary tract where there is a storage capacity to
accommodate excess intake. Some of the ingested energy cannot be
absorbed by the gut and is eliminated as faecal waste. The
remaining energy is absorbed into the body. This energy may be
diverted into two types of storage: short-term storage which is
generally a reserve of glycogen in the liver and long-term storage
which is generally fat deposited into adipose tissue. Energy can be
withdrawn from storage. Energy may also be diverted into growth
and, exceptionally, such energy may also be withdrawn. The boxes
represent the steady state sizes of the reserves and the arrows
movement of energy into and out of these reserves. During these
conversions some energy is lost as heat which contributes to
metabolism. Some energy is lost in materials that are eliminated as
by-products of metabolism (such as the nitrogenous end-products
of protein metabolism—urea, uric acid and ammonia). The
remaining energy has one of two fates. It can be exported from
the animal as specific compounds, which includes the energy lost in
bodily secretions for example. The most significant loss along this
route is the energy exported as milk during lactation. The
remainder is used for metabolism. This includes the energy used
to fuel cellular processes (resting metabolism), thermoregulation
and muscle contraction. Some energy appears outside the animal as
mechanical work as a consequence of metabolic activities—for
example the work done in locomotion. However, the end product
of the metabolic processes is ultimately heat. It has been suggested
that SusEI may be constrained ‘centrally‘ by the capacity of the
alimentary tract to absorb energy (A). Alternatively, the constraint
may be on the capacity to expend energy at the sites of utilisation
called the peripheral limit hypothesis (B). A recent suggestion was
that there might be a constraint on the capacity for total heat
production, due to limits on heat dissipation (C). Animals may also
be constrained by their capacity to excrete end products of
metabolism (D). All these constraints (A–D) are intrinsic to the
animal, but additionally the animal may be limited by the
availability of energy in the environment, which may constrain
the ingestion rate (E). This may work directly, or alternatively may
influence strategic decisions concerning investment and thus
impinges on intake via the brain. The brain may also directly
impact on the level of intake because of neuroendocrinological
constraints independent of immediate food supply
ies of SusMR generally explicitly state that they are
considering time-expenditure over a period of sufficient
duration wherein all the energy expended is supplied by
food intake. In other words, the utilisation of storage is
explicitly ruled out. However, even this explicit statement does not mean that SusEI must equal SusMR. This
is because energy may be utilised, but not metabolised.
One example of this is during growth, and another is
during lactation, when considerable amounts of energy
are exported as milk. Energy intakes and expenditures
during lactation are extremely high, and accordingly
lactation has been widely utilised as a model system to
explore limits. It is possible, however, that during this
period peripheral limits operate on levels of expenditure
at the same time as central limits on intake, but the two
do not match because of the export of energy in milk.
This makes lactation a complex model for investigation
of limits on energy intake and expenditure.
One final problem with identification of limiting steps
in biological processes such as central compared with
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peripheral limits is the concept of symmorphosis (e.g.,
Weibel et al. 1991). Since surplus capacity in any system
is redundant, the expectation is that adaptation might
either reduce capacities at all stages in a sequence to
match the limiting step or increase capacity of the limiting step to match surpluses elsewhere. In either case, all
potential constraining points become co-adapted and
the system is equally constrained at all locations. This
concept is potentially important but is incompatible with
the idea that animals may evolve safety margins in their
capacities to cope with unusual periods of stress (e.g.,
Toloza et al. 1991), which is an equally tenable idea.
Neither concept however has featured significantly in
studies of limitations on SusEI and they are not addressed further here.
A model system lactation in small mammals
Lactation is the most energetically demanding period
encountered by small mammals (e.g., Thompson 1992;
Thompson and Nicol 2002). A typical time-course of
food intake during lactation in a strain of laboratory
mouse (MF1) that we have been studying is shown in
Fig. 2a (Johnson et al. 2001a). Food intake increased
during pregnancy to about 60% above the level of a
non-breeding female. However, the most dramatic increase occurred during lactation. During the initial
10 days this increase was linear, but then it declined to a
plateau. At 21C, the plateau was at about 23 g of food
per day, averaged over 71 litters of mice. Food intake
was related to litter size. Small litters reach plateau intakes of less than 23 g (Fig. 2b), but as litter size increased food intake also increased to a plateau at around
23 g of food per day. It appears that the mice reached a
limit to their food intake at this level.
This limit may simply be an artefact of the situation
in which we house breeding mice in captivity, delivering
pelleted food to them in an overhead hopper. Perhaps
23 g is just the maximum amount of food that a mouse
can pull through the bars in 24 h, or the maximum
amount it can manage to grind up from the hard pellets.
We may have imposed an artificial extrinsic constraint
on the system. Two lines of evidence, however, suggest
that this is not the case. Close observations of mice
showed that although the time spent feeding increased
during lactation, they still only fed for about 30% of the
day and they spent a substantial amount of time resting
(Speakman et al. 2001). It would not immediately appear, therefore, that they were limited in their feeding
time. We confirmed that the hopper configuration was
not generating the effect by giving mice their food either
in the hopper, in a Petri dish inside the cage so that the
animals did not have to pull it through the bars, or in a
Petri dish inside the cage with the food pre-crushed so
that they did not have to grind it up or pull it through
the bars. The plateau food intake at the end of lactation
was independent of the food delivery method (J.R.
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Fig. 2 a Relationship between mean food intake and day of
reproduction for the MF1 mouse. Intake increases over days 1–10,
but then reaches a plateau at days 10–18. b Asymptotic food intake
(average over days 10–18) plotted against litter size. Bigger litters
require greater energy demands, but for litters of more than ten the
total intake is capped at 23 g per day. c Pup body mass at weaning
in relation to litter size. In all cases n=71 unmanipulated litters
Speakman and C. Ogg, unpublished data). We can be
confident, therefore, that the limit to food intake during
lactation was not an artefact of the caging situation.
Central and peripheral limits in lactation
Given the existence of a probable limit to SusEI in late
lactation, is this limit mediated peripherally or centrally?
To answer this question, studies have been performed by
giving female mice additional pups during lactation. If
the dam could elevate her food intake above the late
lactation limit when given the additional pups, this
would strongly indicate that the limit on energy intake
was not imposed centrally.
Hammond and Diamond (1992) manipulated litters
of Swiss Webster mice and found that females could not
elevate food intake when given up to 23 pups. Similarly,
we have also shown that MF1 mice given up to 19 pups
also could not breach the 23 g limit that they reached
during unmanipulated lactations with litters of greater
than 10 offspring (Johnson et al. 2001a). Although an
increase in food intake with extra pups would show that
the limit was not centrally mediated, the converse result
does not prove that the limit on lactation was centrally
mediated, only that it could be. The alternative hypothesis that the food intake limit was peripherally mediated
is also supported by these data. The most likely peripheral limitation on lactation in this situation was the
capacity of the mammary glands to synthesise milk.
These data do indicate that the capacity of the system
is not controlled by demands of the pups. As pup
number increased, food intake did not increase in parallel, but reached a plateau, and the pups were consequently weaned at progressively smaller body masses
(Fig. 2c; Johnson et al. 2001a). When given more pups,
the masses of the weaned pups also declined. The
downturn in the relation between pup size and litter size
occurred at a litter size of 10, the number of teats the
female mouse has. When litter sizes exceed 10, there
must be considerable pup–pup competition for sucking
opportunities, and total demand may be similar at increased litter sizes, but the consequence is a decline in
milk delivery to each pup. Females attempt to minimise
pup–pup competition early in lactation with large litters
by keeping them in separate groups and suckling them in
rotation (Hammond and Diamond 1992; S. Patterson
and J.R. Speakman, personal observations), but this is
not possible at peak lactation, when pups are more
mobile. These experiments do not therefore unequivocally eliminate central limits on intake, peripheral limits
on milk production capacity, or extrinsic limits in terms
of sucking demands from the litter as being responsible
for the observed plateau in food intake.
Separation of the alternative hypotheses can be better
made by giving female mice additional energy demanding tasks during late lactation. The argument here is that
if the system is centrally constrained, total energy flow
into the system will be fixed. Elevating the flow of energy
into an alternative outflow will restrict that available to
fuel milk production and the consequence will be some
diminution of reproductive output. Three types of
manipulation have been performed: firstly, lactating
mice have been forced to exercise; secondly, they have
been made simultaneously pregnant; thirdly, they have
been simultaneously exposed to the cold.
Perrigo (1987) compared the reproductive strategies
of house mice Mus domesticus and deer mice Peromyscus
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manilculatus by forcing females to run a pre-set number
of revolutions (75, 125, 175, 225 or 275) to obtain a
pellet of food. Despite the combined demands of lactation and locomotor activity, neither house nor deer mice
exceeded the upper limit of food intake of unmanipulated mothers, given free access to food. As a result of
the decreased amount of energy available for reproduction, the wheel-running house mice routinely cannibalised some of the offspring throughout the first
12 days of lactation, whereas deer mice extended lactation well beyond normal weaning age.
Johnson et al. (2001b) followed the intakes of mice
that had been mated immediately post-partum and
found that the mice concurrently lactating and pregnant
did not respond to the increased energy burden by elevating their food intake. Instead, they delayed implantation at the start of the second pregnancy and the
length of this delay was directly related to the numbers
of pups. The animals therefore ‘‘avoided’’ overlapping
their energy demands, perhaps because they could not
elevate their total intake at peak lactation to accommodate both. Similar observations were made in
Rockland-Swiss mice (Biggerstaff and Mann 1992) and
in rats (Rattus norvegicus: Koiter et al. 1999), when food
intake in late lactation was actually reduced in those rats
that carried a simultaneous pregnancy, relative to rats
just lactating. Together, these studies indicate that the
limits are centrally rather than peripherally mediated
although, in case of concurrent pregnancy, the evidence
is less strong as the animals ‘‘avoided’’ the problem.
In the light of the above demonstrations, it would be
expected that animals exposed to the cold during lactation would also suffer problems with their lactation
performance because of the energy needed to fuel thermogenesis. It was surprising, therefore, when Hammond
et al. (1994) after exposing lactating Swiss Webster mice
to 8C (approximately 22C below the lower critical
temperature) found that food intake increased dramatically beyond a previously supposed centrally imposed
limit. Hammond and Kristan (2000) reported similar
observations in deer mice, and Johnson and Speakman
(2001) found the same effect in MF1 mice that had been
constrained at 23 g food per day when lactating at
21C—when transferred to the cold on day 8 of lactation, their food intake increased to around 30 g per day.
Similarly, in cotton rats (Sigmodon hispidus), food intake
was elevated when exposed to the cold during late lactation (Rogowitz 1998).
What had been previously consistent with a centrally
mediated limit to reproductive capacity appeared now to
be a peripherally mediated limit, probably in the
capacity of the mammary glands. This result was
seemingly confirmed by subsequent studies. Hammond
et al. (1996) experimentally manipulated female mice by
surgically removing their mammary glands during late
lactation. The rationale behind this experiment was that
if the capacity of the mammary glands was limited, then,
when the mammary tissue was halved in size, the
remaining tissue would be unable to compensate.
However, if the capacity of the tissue was flexible and
limited only by the centrally controlled supply of energy,
then it would respond to the absence of half the tissue by
expanding its capacity. This could be confounded if the
problem of the number of pups relative to the number of
teats changed, as removing half the mammary tissue also
removed half the outlets for milk to pups. Hammond et
al. (1996) were aware of this problem and also manipulated pup number so that either pup numbers were
reduced by half as well, or maintained at the same level.
They found that productivity in the halved glands did
not increase, suggesting that the mammary gland was
indeed the point at which the system was peripherally
limited.
Under this scenario, the interpretation of the pup
manipulation experiments was as follows. When animals
were manipulated at room temperature by giving them
more pups to raise, food intake did not increase because
milk production was limited by the capacity of the
mammary glands. When exposed to cold conditions,
food intake increased (demonstrating a lack of central
limitation) because of the combined demands for milk
production (at maximal capacity) and increased thermogenesis. There is, however, an alternative interpretation that the increased energy intake at low temperatures
was driven by elevated energy requirements of the pups
under the cold conditions. Given that pup–pup competition for suckling depends on the pup/teat ratio; when
litter sizes were enlarged, the lack of an increase in food
intake may have simply reflected the elevated pup–pup
competition due to the higher pup/teat ratio. The same
happened when half the mammary gland was removed
because the pup/teat ratio was also increased. During
cold exposure, however, the demands on the female did
not include a change in the pup/teat ratio and in this
situation the elevated demands on the mother may have
translated into greater milk production.
Three studies, however, indicated that this is not the
case and that pup demands do not drive the capacity of
the mother to deliver milk energy. Rogowitz (1998)
demonstrated in cotton rats that levels of milk production in rats at 21C and 8C were similar and consistent
with the mammary glands working at maximal capacity.
Drummond et al. (2000) studied milk production in
rabbits (Oryctolagus cunniculus) and observed that following natural deaths of offspring, the flow of milk was
unaltered and that the remaining offspring benefited
from their siblings’ demise. Fink et al. (2001) studied
lactation in captive mink (Mustela vision) and showed
that in mothers raising litters of three, six and nine offspring, milk production did not increase when litters
increased from six to nine offspring.
Other data also indicates that the limits to intake are
not centrally mediated. These include studies that involve manipulation of the energy density of the food. If
the energy density of food is decreased, as animals have
a central processing capacity limit, they should be unable to up-regulate their intake to compensate. Speakman et al. (2001) fed MF1 mice a diet that provided 25%
381
less digestible energy than their normal food and then
mated them. Food intake in the mice fed on the low
energy density food increased at peak lactation by on
average 3.8 g (from 23.1 to 26.9 g per day). This increase
fell short of complete compensation for the lower food
energy density, and when mice were switched to the poor
diet during lactation rather than prior to breeding, the
increase was even lower (asymptote at 25.8 g per day).
This suggests that while alimentary tract can adjust
capacity to imposed demands, indicating the limits are
not centrally mediated, there may be a time factor in the
capacity to respond. Similar data were collected by
Hacklander et al. (2002) for brown hares (Lepus europeaus). When fed on a diet with lower energy content,
asymptotic food intake in late lactation increased from
230–250 to 280–300 g per day. In consequence milk
production was stable across the dietary treatments at
around 35 g per day for females raising single offspring
and 70 g per day for females raising twins. Denis et al.
(2003a) found that when rats were fed a cafeteria style
diet during lactation, energy intake did not increase, but
food intake decreased. Finally, Koteja (1996) compared
the maximal SusEI of deer mice and found that the
maximal SusEI during cold exposure exceeded that at
peak lactation.
The consensus that limits to lactation are imposed
peripherally at the mammary gland was, however,
thrown into confusion by a series of measures of milk
production in mice at peak lactation at 30, 21 and 8C
(Johnson and Speakman 2001; Król and Speakman
2003a, b; Król et al. 2003). As anticipated by the
peripheral limitation model, food intake during peak
lactation at 30C was substantially lower than that at
either 21 or 8C, and averaged around 13 g per day.
However, unexpectedly, milk production and consequently pup growth were not constant across the different temperatures, but mirrored the pattern of food
intake. Mice at 30C exported 88 kJ energy in milk per
day, 167 kJ at 21C and 288 kJ at 8C. These latter
measurements are consistent with the pup demand
model wherein pup thermal requirements dictated milk
flow. Yet, this also seemed to be incorrect since not only
was milk production different across temperatures, but
also was pup growth. The weaning masses of pups at 30,
21 and 8C averaged 6.1, 7.0 and 7.3 g, respectively, and
litter sizes were 9.8, 11.3 and 9.6, respectively. Hence the
colder it got, the more food the mice ate, the more milk
they produced and the heavier their pups were when
they weaned.
Consequently, the totality of data was inconsistent
with either a limitation imposed extrinsically by pup
demands, centrally by the capacity of the digestive system or peripherally by the capacity of the mammary
glands. In the remainder of this review we present three
further hypotheses that have been previously proposed,
or are newly proposed here, to explain these conflicting
data. These hypotheses address different levels at which
control may be exerted from aspects of molecular neuroendocrinology (a proximate mechanism) to evolu-
tionary ecology (an ultimate mechanism) and are
therefore not alternative hypotheses, but potentially
complementary explanations for the phenomenon.
Additional hypotheses
The heat dissipation limit hypothesis
Król and Speakman (2003a, b) suggested that the
capacity to expend energy during lactation at 21C
might be limited by the capacity of the female mouse to
dissipate heat. Hence, all manipulations at 21C that aim
to stimulate both food intake and milk production—
notably increasing litter size (Hammond and Diamond
1992), making them simultaneously pregnant (Johnson
et al. 2001b; Koiter et al. 1999; Biggerstaf and Mann
1992) and making them exercise (Perrigo 1987)—failed
to increase either food intake or milk production, because the animals could not increase their heat production without risking fatal hyperthermia. In effect, this
hypothesis implies an additional central mechanism that
total heat production cannot exceed a critical value that
is defined by the total heat dissipation capacity
(Fig. 1C). Under the heat dissipation limit hypothesis,
when mice are exposed to the cold, it is not an additional
demand, but a relaxation of the heat dissipation limit,
allowing the animals to elevate not only their food intake but also their milk production and thus the size of
their offspring. Similarly, when mice were placed in the
heat, it reduced their capacity to dissipate heat, restricted their food intake and milk production and led to
smaller pups being weaned.
There are two putative mechanisms for how the
capacity to dissipate heat may influence lactational
performance. First (mechanism A), at high ambient
temperatures lactating mice may continuously face difficulties in dissipating heat. This would lead to a perpetually elevated body temperature. There are three
potential routes by which such elevated body temperature might influence the regulation of milk production.
Firstly, it is well established that endogenous opioids in
the pre-optic anterior hypothalamus are of key importance in the regulation of body temperature. Projections
from this area terminate in the paraventricular nucleus
(PVN), where the magnocellular cells synthesise oxytocin. Rayner et al. (1988) showed that intracerebroventricular (ICV) administration of the exogenous opioid
morphine inhibits oxytocin production in the PVN,
mediated via the k-subtype of the opioid receptor. Thus,
elevated endogenous opioids under hyperthermia might
directly reduce oxytocin secretion. It is well established
that morphine administration disrupts maternal suckling behaviour (Cox et al. 1976; Bridges and Grimm
1982). Secondly, thyroid hormone, which may be regulated by differences in body temperature, is an important
modulator of prolactin production. Continual maternal
hyperthermia in relation to external ambient temperatures (or differential capacity to dissipate body heat)
382
may therefore directly inhibit oxytocin and prolactin
secretion, thereby reducing milk production. Links to
food intake via other connections in the hypothalamus
are highly likely and may be directly associated with
prolactin release (see below). Thirdly, another effect of
hyperthermia might be to direct blood to flow away
from the mammary glands to other peripheral areas to
dissipate heat by vasodilatation (Black et al. 1993).
Blood flow in the mammary glands has been shown to
have a direct effect on milk production (Vernon and
Flint 1983). However, in pigs total blood flow to the
mammary gland increases during elevated heat production, evidently to compensate for some of the blood
flowing to the mammary gland surface to enhance heat
dissipation (Renaudeau et al. 2003).
A second mechanism (B) is that suckling schedules of
the mice may be influenced by the development of
maternal hyperthermia in the nest. Although pups act as
heat sinks early in their development (Scribner and
Wynne-Edwards 1994), in late lactation offspring are
capable of considerable independent heat production.
The suckling unit of mother and pups, therefore, may
generate heat that leads to maternal hyperthermia,
ultimately forcing the female to discontinue suckling
(Croskerry et al. 1978). The progress to hyperthermia
would be more rapid as the capacity to dissipate heat
declines. The sucking stimulus is one of the primary
factors stimulating oxytocin release and milk let down,
and also feeds back onto prolactin release, thereby regulating milk production. Continual disruption of suckling, due to intermittent hyperthermia, would be a
second mechanism linking heat dissipation capacity to
lactation performance.
Heat dissipation and brown adipose tissue
During lactation, mice, golden hamsters (Mesocricetus
auratus), rats and 13-lined ground squirrels (Spermophilus tridecemlineatus) experience several morphological and biochemical changes in their interscapular
brown adipose tissue (BAT). These changes include
reductions in the total amount of BAT in rats, ground
squirrels and hamsters (Agius and Williamson 1980;
Wade et al. 1986). Trayhurn et al. (1982) suggested that
BAT mass increases in lactating mice (Aston strain)
relative to non-breeding animals, but we have found that
the mass of BAT in MF1 mice is reduced in lactation
relative to non-reproductive mice (Johnson et al. 2001b).
In addition to reductions in overall tissue mass, there are
also reductions in BAT mitochondrial mass (Trayhurn
et al. 1982; Villaroya et al. 1986; Trayhurn and Jennings
1987). In late lactation, mitochondria-specific content of
uncoupling protein 1 (UCP-1) is reduced to only 8% of
the level found in non-breeding mice (Trayhurn and
Jennings 1987, 1988) and to 26% in ground squirrels
(Nizielski et al. 1993). GDP-binding, which is a measure
of mitochondrial thermogenic capacity, is also reduced
in mice and rats (Trayhurn et al. 1982) and ground
squirrels (Nizielski et al. 2000), but not in hamsters
(Wade et al. 1986). Brown adipose tissue is the key
thermogenic organ in small rodents (Cannon and Nedergaard 2004) and the changes observed in lactating
rodents mediate a reduction in the noradrenaline-induced non-shivering thermogenesis (Trayhurn 1983;
Trayhurn et al. 1982), which is rapidly reversed upon
weaning (Trayhurn and Jennings 1987, 1988). In rats,
the extent of decrease in thermogenic capacity is related
to litter size (Isler et al. 1984), but this does not appear to
be the case in mice (Trayhurn and Wusterman 1987).
These morphological, physiological and biochemical
changes in BAT appear to be controlled by reduced
sympathetic activity in lactation (Trayhurn and Wusterman 1987), which may be responsive to elevated
corticosteroid levels (Vernon and Flint 1983). Treatment
of lactating rats with exogenous leptin completely reversed the down-regulation of UCP-1 gene expression in
BAT (Xiao et al. 2004). Changes in other aspects of
BAT physiology are also apparent during lactation,
including reductions in activity of iodothyronine 5¢-deiodinase, which catalyses conversions of thyroxine (T4)
to triiodothyronine (Giralt et al. 1986). All these changes
are consistent with small lactating animals attempting to
reduce obligatory heat production from BAT. Trayhurn
(1989) interpreted this reduction as an energy saving
mechanism that increased the efficiency of milk production; but an alternative interpretation is that such
heat production would exacerbate heat dissipation
problems during late lactation, and the reduction ameliorates the risk of maternal hyperthermia. The fact that
BAT tissue remains functionally suppressed even at
ambient temperatures as low as 13C (Trayhurn and
Jennings 1987) indicates the heat production from lactation itself is sufficient to supply the thermogenic
requirements to sustain body temperature at these
ambient temperatures. However, at 8C we found that
lactating MF1 mice do have larger interscapular BAT
pads than lactating mice at 21C, suggesting that all the
heat of lactation may not be recovered to supply the
thermogenic requirement at this temperature (Król et al.
2003a).
In recent years, a number of additional uncoupling
proteins have been described (UCP-2, UCP-3, UCP-4
and UCP-5), with varying tissue distributions. The role
of these UCPs in resting and thermogenic heat production has been an issue of some debate (e.g., ErlansonAlbertsson 2002, 2003; Liebig et al. 2004). Studies of the
UCP-1 knockout mouse indicate that the other UCPs
cannot reverse the lack of thermogenic capacity that
comes with the absence of UCP-1 (Enerbäck et al. 1997;
Golozoubova et al. 2001; Nedergaard et al. 2001). Although UCP-3 cannot be facultatively up-regulated to
replace the function of UCP-1, when it is transgenically
over-expressed the resultant mice would have elevated
resting metabolism (Clapham et al. 2000). However, the
extent of over-expression involved in the transgenic is
over 100 times greater than in the wild-type genotype; so
this effect may well be unphysiological (Cadenas et al.
383
2002). Surprisingly, it has recently been shown that
UCP-3 is also down-regulated enormously in BAT
during lactation, and this is reflected in reduced protein
levels as well (Pedraza et al. 2000, 2001; Xiao et al.
2004), but UCP-2 is unchanged (Pedraza et al. 2001).
Muscle levels of UCP-3 gene expression are also decreased in lactation (Xiao et al. 2004). These effects
appear to reflect circulating levels of free-fatty acids
(Pedraza et al. 2000). This may mean one of two things.
Either UCP-3 is thermogenically significant and the
down-regulation of UCP-3 parallels the reduction in
expression of UCP-1 to reduce the heat burden on the
lactating animal. Alternatively, UCP-3 may be thermogenically insignificant and this may call into question
why UCP-1 is down-regulated in lactation. At present
we cannot distinguish between these alternatives.
Heat dissipation: evidence from small and large mammals
The negative effects of high ambient temperatures,
exposure to solar radiation and high humidity on milk
production by dairy cattle (Bos taurus) have been known
for at least 50 years (Cobble and Herman 1951; Brody et
al. 1958) and has led to the development of many
practical aids to elevate heat dissipation capacity in
dairy cows lactating in tropical climates such as providing shade, cooling fans and water sprays. Similar
negative effects of high temperatures are evident in other
large domestic animals such as sheep (Ovis aries: Abdalla et al. 1993) and pigs (Sus scrofa: Black et al. 1993;
Quiniou and Noblet 1999; Renaudeau and Noblet
2001). Since dairy cows and sheep do not huddle with
their calves during suckling, the mechanism mediating
this effect must be independent of suckling schedule effects. Indeed, many larger animals show chronic
hyperthermia during lactation (e.g. sows, Ulmershakibaei and Plonait 1992). However, the average 400 kg
dairy cow has a surface to volume ratio about 22 times
lower than a 40 g mouse. In other words, each metabolising gram of tissue in the mouse has about 22 times
the area over which to dissipate the heat it generates.
Heat dissipation difficulties in dairy cattle and other
large domestic animals during lactation may bear little
relevance to heat dissipation limits in much smaller
mammals. Nevertheless, direct measurements of maternal body temperatures (E. Król and J.R. Speakman,
unpublished data) confirm that lactating mice are hotter
than their non-reproducing equivalents, even when not
suckling. Similar effects have been observed in rats
(Croskerry et al. 1978; Kittrell and Satinoff 1988; Leon
et al. 1978, 1985) and Siberian hamsters Phodopus
sungorus (Scribner and Wynne-Edwards 1994a). Hence,
an effect via mechanism A is possible in small mammals.
Supporting this viewpoint, rabbits which deliver all their
milk to offspring during a very short period and hence
are unlikely to be affected by hyperthermia from the
litter also show negative effects of high temperatures on
food intake and pup growth—effects that can be re-
versed by giving the females cold water to drink (Marai
et al. 2001). Studies of blood flow during lactation
indicate that there is no major redirection of blood away
from the mammary glands to facilitate heat loss (cattle,
Lough et al. 1990; goats Capra hircus, Sano et al. 1985;
rabbits, Lublin and Wolfenson 1996); thus the direct
effects of hyperthermia by mechanism A are probably
mediated centrally.
There is a substantial body of behavioural literature
following the pioneering work of Leon et al. (1978)
which suggests that suckling behaviour of small mammals may be influenced by the risks of maternal hyperthermia and hence milk production may be limited by
mechanism B. These studies included observations that
rats terminated suckling bouts when their body temperatures rose. Similar effects have been reported in
larger lactating animals that have contact with their
offspring such as sows (Renaudeau and Noblet 2001),
where elevated temperature led to reduced durations and
greater frequencies of suckling bouts coupled with lowered milk production and piglet growth. Perhaps the
best evidence comes from direct experimental manipulations of body temperature and examination of the
subsequent effects on suckling behaviour. These experiments have only been performed on rats, but have involved two separate manipulations. Direct heating of the
pre-optic area of the brain, which led to premature termination of suckling bouts (Woodside et al. 1980) and
injection of rats with morphine, that elevated body
temperature and caused disruption of maternal suckling
behaviour (Bridges and Grimm 1982). However, rats are
an order of magnitude larger than mice and so perhaps
of greater relevance are the studies of Siberian hamsters,
which show that during the daytime, the time spent with
the litter in late lactation may be constrained by ambient
temperature (Scribner and Wynne-Edwards 1994b).
Interestingly, the two sub-species of Siberian hamster (P.
sungorus sungorus and P. sungorus campbelli) differ in
the rates at which the offspring develop their own thermoregulatory capacities faster in P. s. campbelli (Newkirk et al. 1998). This difference is reflected in greater
and earlier problems in maintaining body temperature
during suckling bouts by female P. s. campbelli (Scribner
and Wynne-Edwards 1994b) and consequent negative
effects on pup growth in this sub-species (Newkirk et al.
1998).
Despite a large literature indicating that there are
direct effects of the litter on maternal hyperthermia,
there are some contradictory data. For example, the
body temperatures at which rats discontinue suckling
are generally lower than the levels they tolerate while
exercising outside the nest (Kittrell and Satinoff 1988).
Perhaps more telling are experimental inductions of reduced body temperature using sodium salicylate, which
did not extend suckling bouts (Bates et al. 1985). Although treatment of lactating rats with morphine
simultaneously elevates body temperature and disrupts
maternal suckling (above), the negative effect of morphine appears to be independent of its effects on body
384
temperature. This is shown by experiments in which
morphine was administered with naloxone, an opioid
receptor antagonist. Blocking morphine with naloxone
reversed the negative effects on maternal behaviour
(Bridges and Grimm 1982) but not maternal hyperthermia (Cox et al. 1976). Rats with experimentally induced increases in body temperature using morphine
and naloxone combinations (Stern and Azzara 2002) did
not shorten their suckling bouts. However, this latter
manipulation was performed only 7 days into lactation
and it would be instructive to know if a similar absence
of the effects of combined morphine/naloxone treatment
were apparent later in lactation when pup heat stress is
more profound. Finally, rats fed low-quality protein in
their diets did not show reduced performance when
raised at 30C compared to 20C (Jansen and Binard
1991), even though their litters probably generated
similar heat dissipation problems.
Overall, there is a definite negative effect of ambient
temperature on lactation performance of large animals,
but the significance of these effects in smaller animals
like mice remains uncertain. The balance of evidence
indicates that a direct effect via mechanism A (i.e. direct
effects of heat generated during lactation) is more likely
than indirect effects via heat from the litter (mechanism
B), but this also requires verification.
The seasonal investment hypothesis
One of the oldest ideas about limits in reproduction is
that animals do not reproduce maximally because this
reduces the probability of their own survival. Many
observations have been made on this phenomenon following the seminal observations of Lack (1954) that
clutch sizes of birds were on average lower than the
clutch size that maximised the number of fledglings.
Instead, average clutch sizes maximised lifetime productivity of the adults when the effects of large clutches
on adult survival were factored into the calculation.
Many studies involving brood manipulation experiments in diverse species have confirmed the general
nature of these effects (e.g., Jacobsen et al. 1995; Golet et
al. 1998; Koivula et al. 2003 but also see Horak 2003).
Although these ideas and experimental tests have generally not been couched in terms of limitations on energy
intake, they are clearly related, since all reproductive
output must be fuelled by energy supply. Do mice also
respond to temperature during lactation in terms of the
trade-off between current reproductive output and future adult survival?
The implication of the seasonal investment hypothesis is that mice perceive the reproductive value of their
offspring to be greater at colder than at warmer temperatures, and that investment becomes progressively
lower as it gets hotter. Thus ambient temperature may
be a proxy used by animals to gauge the time of year.
Seasonally reproducing rodents generally commence
breeding in early spring and stop around the peak of
summer. This cycle occurs because there is a strong
selective pressure to breed early, since offspring born
early have enough time to mature and to have offspring
themselves before the onset of winter (Lambin and
Yoccoz 2001). The reproductive value of offspring born
early in the season is therefore high. In contrast, offspring born late in the year have much lower reproductive value because they do not have sufficient time to
mature before the winter, when food shortage presumably constrains breeding. Since mice born late in summer must survive the winter before they breed, their
value is lower. There is consequently a negative correlation between the ambient temperature at which mice
breed and the reproductive value of their offspring. If
mice utilise the ambient temperature as a cue to gauge
their investment in offspring, then we might predict that
they would invest more when it is colder. This matches
exactly the pattern observed in the laboratory.
However, a post-hoc correlation of expectation and
observation is insufficient to support the seasonal
investment hypothesis. Moreover, how the observations
regarding manipulated litter sizes, exercise and simultaneous pregnancy fit into the framework is unclear. If this
hypothesis does explain why mice seem to invest more in
their offspring at colder temperatures, then other conditions must also be met. In particular, the trade-off
model implies negative consequences of reproduction
that constrain animal performance. One such possibility
is oxidative stress. Animals during lactation have high
rates of metabolism that may result in elevated generation of free radicals. These free radicals may cause oxidative damage to macromolecules if the mice do not
simultaneously up-regulate their oxidative defence and
repair mechanisms. Wiersma et al. (2004) showed that
birds feeding nestlings, which is the most energetically
expensive phase in avian reproduction, do not up-regulate the levels of superoxide dismutase, catalase and
glutathione peroxidase, the main defences against radical oxygen species. However, that study did not include
measures of oxidative damage; so the lack of elevation
of defence mechanisms may have been because there was
no increase in free radical production to defend against.
Indeed, the links between radical oxygen species production and metabolic rate are not straightforward
(Speakman et al. 2002; Speakman 2003) and in some
cases increased metabolism may actually reduce oxidative stress (Speakman et al. 2004). However, the reduction in levels of UCP-1 and UCP-3 in lactation (above)
would suggest that mitochondria in lactating animals are
more closely coupled supporting the suggestion that this
may be a time of elevated oxidative stress (Demin et al.
1998a, b; Brand 2000; Speakman 2003).
Alternatively, immune capability may be sacrificed
during lactation, which would compromise the animal
survival. There is some evidence in birds that individuals
at the peak of reproduction are immuno-compromised
(Cichoń et al. 2001). However, the reasons for this effect
are unclear because the energy demands of raising an
immune response are generally regarded to be trivial. So
385
why such a trade-off should exist is uncertain. One
possibility is that the reduction in body fatness at peak
lactation itself mediates reduced immunity since studies
in voles and hamsters have shown that surgical removal
of body fat decreases immune capability (Demas et al.
2003; Demas 2004). A mechanism for this effect might
involve changes in circulating levels of leptin (see below)
as leptin has direct effects on immune cells stimulating
T-cell immunity, phagocytosis, cytokine production and
hematopoesis, resulting in attenuated susceptibility to
infectious insults (Ingvartsen and Boisclair 2001).
The saturated neural control hypothesis
Over the past half-century considerable advances have
been made in our understanding of the neuroendocrine
processes that underpin feeding behaviour. These advances have been primarily stimulated by discoveries
stemming from work with mutant mice that have disruptions of their feeding behaviour. For example, during
the 1950s, a spontaneous mutant mouse occurred at the
Jackson laboratories in the USA, which became excessively fat; it was called the ob/ob mouse because it was
clear that the original mutation was a single gene
recessive defect causing obesity. When heterozygous ob/
+ mice breed together, one quarter of the offspring are
homozygous ob/ob mutants, and they feed voraciously
relative to their littermates and become very obese. On
average, by 12 weeks of age they weigh almost twice as
much as their heterozygous and wild-type littermates.
Since that time, many other mutant mice with disruptions of their feeding behaviour have been bred and
developed such as the db/db diabetic mouse.
During the 1970s, a series of parabiosis experiments
with ob/ob and db/db mice were performed to try to
clarify the functional aspects of their genetic defects
(Coleman 1973, 1978). Parabiosis involves surgically
joining the blood circulation of pair mice, with the result
that factors in the blood of one animal pass to the other
and vice versa. When the fat ob/ob mouse was joined in
parabiosis with a lean wild-type mouse (+/+), the ob/ob
mouse started to eat less food and lose body mass.
However, when a fat db/db mouse was joined with a
wild-type (+/+) mouse, the db/db mouse was unaffected, but the wild-type mouse started to eat less food
and eventually died of starvation. Joining together ob/ob
and db/db mice had a similar result to joining ob/ob with
+/+. The ob/ob mouse reduced its food intake and
started to lose mass but the db/db mouse continued
eating and remained fat.
From these experiments it was clear that the ob/ob
mouse had a defect in the signal telling it how fat it was.
In the absence of this signal, the mice elevate their food
intake because they ‘think’ they are dangerously thin. In
parabiosis with wild-type mice, they receive a signal
from the fat in the body of the wild-type mouse, which
suppresses food intake. Since this also happens when ob/
ob mice are in parabiosis with db/db mice, the db/db
mutation cannot also be a problem with the signal. The
mutation in db/db mice must actually be a problem with
reading the signal in the brain. Hence, they also ‘think’
they are dangerously thin and effect changes in their
food intake. When placed in parabiosis with wild-type
mice, there is no effect on food intake because they are
already producing lots of the signalling factor; as it is
just not being read receiving more signals from the wildtype mouse has no effect. However, it is more serious for
the wild-type mouse because in parabiosis with db/db it
receives a massive signal from the db/db animal and it
shuts down its food intake to try to lose mass. As the db/
db partner keeps eating, however, there is always a signal
‘‘telling’’ the wild-type mouse not to eat and eventually it
dies of starvation. In spite of these insights, it was another 20 years before the signalling compound was finally identified as leptin. The mutation causing the ob/ob
mouse was a single base mutation in a gene located on
chromosome six (Zhang et al. 1994).
Hypothalamic control of energy homeostasis
Zhang et al. (1994) showed that leptin is produced
exclusively in adipose tissue. Subsequent work has shown
other sites of production, at much lower levels, in
developing fetuses and the placenta (Hoggard et al. 1997;
Senaris et al. 1997; Hassink et al. 1997; Masuzaki et al.
1997a), the stomach (Bado et al. 1998) and mammary
glands (Chilliard et al. 2001). When recombinant leptin
was injected into ob/ob mice, the animals ate less food
and dramatically declined in body mass (Pelleymounter
et al. 1995; Romsos et al. 1996; Mistry et al. 1997; Halaas
et al. 1997; Pelleymounter et al. 1998) and other features
of the genetic pathology were also normalised, for
example, the ability to sexually mature and breed (Chehab et al. 1996). Moreover, in mice with targeted transgenic over-expression of leptin production, there is a
dramatic fall in body fatness (Masuzaki et al. 1997b).
The leptin receptor (Ob-R) is a cytokine receptor with
several splice variant forms including short forms (ObRa, -Rc, -Rd, -Re and -Rf) and a long form (Ob-Rb)
(Tartaglia et al. 1995). Ob-Rb receptor contains an
intracellular signalling domain that is missing from the
short receptor isoforms. Leptin binding (Malik and
Young 1996) and receptor localisation studies revealed
that Ob-Rb is predominantly expressed in several nuclei
of the hypothalamus, particularly the arcuate nucleus
(ARC) (Mercer et al. 1996b, c) and also in the brain stem
(Mercer et al. 1998a). It is now known that at least two
subsets of neuron in the ARC receive the peripheral
leptin signal (Mercer et al. 1996a, b, c, 1998a) (Fig. 3).
One type, known as neuropeptide Y/agouti-related
protein (NPY/AgRP) neurons, co-express NPY and
AgRP (Hahn et al. 1998) and have projections that can
be traced into the brain stem, to the PVN, and to the
second type of cell that receives the leptin signal in the
ARC. Neurons of this second type are called pro-opiomelanocortin/cocaine- and amphetamine-regulated
386
Fig. 3 Hormonal factors in the
periphery and the brain which
are believed to underpin
stimulation of food intake
following a period without
feeding. The diagram should be
read from the bottom upwards.
Arrows adjacent to the boxes
indicate the directions of
change following a period
without food. PYY peptide YY;
CCK cholecystokinin, ARC
hypothalamic arcuate nucleus,
Ob-Rb leptin receptor. Two
populations of cells in the ARC
have leptin and insulin
receptors on them: NPY/AgRP
neurons and POMC/CART
neurons. GhR ghrelin receptor;
GABA gamma aminobutyric
acid; PVN hypothalamic
paraventricular nucleus; MC4R
and MC3R melanocortin-4 and
-3 receptors; a-MSH alphamelanocyte stimulating
hormone. See text for
additional explanation
transcript (POMC/CART) neurons (Cheung et al. 1997;
Schwartz et al. 1997a). POMC/CART neurons also receive projections from neurons in other brain areas
expressing serotonin (5-HT) and have 5-HT receptors on
their surfaces. There are several other cell populations in
the ARC that have various other neuropeptide receptor
profiles including cells that respond to insulin and others
that respond to ghrelin.
Both NPY/AgRP and POMC/CART neurons project to cells in the PVN that express the melanocortin-4
receptor (MC4R) and possibly melanocortin-3 receptor
(MC3R). Both these melanocortin receptors are Gprotein coupled receptors. At these projections in the
PVN, POMC/CART neurons secrete a-melanocyte
stimulating hormone (a-MSH), while NPY/AgRP neurons secrete AgRP. a-MSH is an agonist, and AgRP an
387
antagonist, of the melanocortin receptors (MC3R and
MC4R) (Zemel and Shi 2000) (Fig. 3). When leptin
molecules from the periphery dock with their receptors
on NPY/AgRP neurons in the ARC, there is a suppression of NPY release (Schwartz et al. 1997b; Yokosuka et al. 1998) and a reduction in gamma aminobutyric acid (GABA) release at the synapses that interface the NPY/AgRP neurons with the POMC/CART
neurons. Under GABA mediated dis-inhibition, combined with the direct stimulation by leptin, the POMC/
CART neurons release a-MSH at the MC4R on neurons
in the PVN at the same time so that the antagonist
AgRP derived from the leptin stimulated NPY/AgRP
neurons is reduced. Secretion of a-MSH depends on
successful cleavage of the POMC molecules brought
about by the pro-convertase-1 enzyme. The increased aMSH and reduced AgRP stimulate the MC4R, inhibiting food intake (Fig. 3). The resultant negative energy
balance causes leptin levels to drop. Subsequently this
reduced signal has the opposite effects in the ARC:
NPY/AgRP cells are stimulated to release NPY, POMC/
CART cells are inhibited (directly and indirectly) and at
the MC4R in the PVN, AgRP release is enhanced, while
a-MSH is reduced. This leads to the stimulation of
feeding behaviour (Fig. 3)
There is considerable evidence that the leptin system
interplays with other signals that may also be involved in
long- and short-term regulation of food intake (Fig. 3).
The best characterised of these so far is insulin. Like
leptin, the secretion of insulin is proportional to the
magnitude of the body fat stores. Neurons in the ARC
that express the leptin receptor also often express the
insulin receptor. The insulin receptor signals via the
phosphoinositide 3-kinase pathway and there is a suggestion that there might be some intracellular interaction
between leptin and insulin signalling (Kellerer et al.
1998; Niswender et al. 2004). Insulin is known to inhibit
NPY (Schwartz et al. 1997c) and animals with reduced
numbers of insulin receptors have elevated food intake
consistent with increased NPY levels (Obici et al. 2002).
Insulin may act as both a long- and short-term signal,
given its responsiveness to altered glucose levels following feeding. Similar signals include glucose and free
fatty acids, and peptides secreted from the gut such as
cholecystokinin (Moran 2000), ghrelin (Horvath et al.
2001) and peptide YY, receptors for which also colocalise to the cells in the ARC. Moreover, endogenous
cannabinoids, the serotinergic and the opioid-dopaminergic (Tozzo et al. 1996) systems are also involved (see
also above under temperature effects), but the details of
the interactions presently remain obscure.
Our expanding knowledge of neuroendocrine mechanisms underlying feeding behaviour provides an additional hypothesis concerning the limits to SusEI during
lactation. It is clear that food intake is stimulated by a
number of peripheral signals that act in concert with
several pathways in the brain to promote feeding
behaviour (Fig. 3). Endocrine systems, however, cannot
be infinitely stimulated because receptors become satu-
rated. It is possible, therefore, that food intake during
lactation is stimulated by a combination of different
signals that reaches a point of maximal stimulation
during the latter half of the lactation period. Whatever
manipulations are performed on animals at this stage,
such as making them exercise or giving them more pups
to raise, they do not alter the SusEI because the endocrine pathway regulating food intake is already maximally stimulated. However, ambient temperature may
act via a separate signalling route. Thus, declining
temperatures can promote greater food intake and the
animals can utilise this to invest more energy in their
offspring.
Neuroendocrine control of lactational and cold-induced
hyperphagia
At present our knowledge of the neuroendocrine basis of
elevated food intake in lactation is incomplete. However, some amount of information is already known
(Fig. 4). Leptin levels in lactation are generally suggested to be reduced (Pickavance et al. 1996; Brogan et
al. 1999, 2000; Vernon et al. 2002; Denis et al. 2003a, b;
Kunz et al. 1999; Herrera et al. 2000), but Lopez-Soriano et al. (1999) demonstrated that leptin levels are
unchanged in lactation, and both Mistry and Romsos
(2002) and Mukherjea et al. (1999) indicated that leptin
levels in lactation are increased. Other studies suggested
that the nocturnal rise in circulating leptin observed in
non-breeding rats was attenuated during lactation (Denis et al. 2003a, b; Vernon et al. 2002; Kunz et al. 1999;
Pickavance et al. 1998). This latter effect appeared to be
at least partly mediated via the suckling stimulus (Denis
et al. 2003b). In dairy cows leptin levels in lactation
seemed to reflect whether the individual animals were in
energy balance or not (Liefers et al. 2003), suggesting
that the variation observed in the above investigations in
rodents may reflect individual energy states in the different studies. The changes in circulating leptin levels
during lactation parallel alterations in the balance of
different leptin receptor isoforms: with Ob-Rb decreased
and the normal nocturnal decreases in Ob-Rb, -Rc and Ra absent (Denis et al. 2003b). Brogan et al. (2000)
found that leptin receptor levels were increased in the
supraoptic nucleus (co-localised with oxytocin and
vasopressin expressing neurons), but were decreased in
the ventromedial nucleus.
The orexigenic neuropeptides NPY and AgRP, which
are both key downstream effectors of the leptin signal in
the brain, are greatly elevated in the ARC, PVN and
dorsomedial nucleus (DMH), and in the median eminence of lactating rats (Smith 1993; Malabu et al. 1994;
Pape and Tramu 1996; Chen et al. 1999, 2004; Li et al.
1998, 1999a, b; Pickavance et al. 1999a; Garcia et al.
2003; Crowley et al. 2004). Stimulation of the NPY cells
in the DMH (Fig. 4) seems to be a novel pathway
stimulated by MC4R expressing cells during lactation
(Chen et al. 2004). However, Y1 receptor levels remain
388
Fig. 4 The contribution of
additional pathways to food
intake stimulation during
lactation. PRL prolactin; PrRP
prolactin-releasing protein;
TRH thyrotropin-releasing
hormone; DA dopamine; PYY
peptide YY; CCK
cholecystokinin; ARC
hypothalamic arcuate nucleus;
Ob-Rb leptin receptor. Two
populations of cells in the ARC
have leptin and insulin
receptors on them: NPY/AgRP
neurons and POMC/CART
neurons. GhR ghrelin receptor;
GABA gamma aminobutyric
acid; PVN hypothalamic
paraventricular nucleus, MC4R
and MC3R melanocortin -4 and
-3 receptors; a-MSH alphamelanocyte stimulating
hormone. See text for
additional explanation
unchanged (Pickavance et al. 1999b). Li et al. (1999)
suggested that arcuate NPY levels might be stimulated
directly by the suckling stimulus; but this is not supported by observations that elevated NPY levels are
normalised if leptin or insulin is provided exogenously
via ICV infusion (Crowley et al. 2004). Moreover, leptin
levels increase when insulin is supplied exogenously,
possibly suggesting that insulin is the primary signalling
factor (Crowley et al. 2004). Levels of NPY were negatively correlated with circulating insulin levels across
lactating and non-lactating groups of rats (Pickavance et
al. 1996), but the correlation with leptin levels was not
explored. Moreover, the converse effect of elevated
exogenous leptin levels in lactation, leading to increased
insulin levels, has also been observed (Lopez-Soriano et
al. 1999), and insulin levels did not change during lactation in unmanipulated rats (Brogan et al. 1999). An
effect of reduced insulin on leptin during lactation was
demonstrated in dairy cows (Block et al. 2003; Leury et
al. 2003), but no effect on leptin levels was caused by
elevated growth hormone levels, which are also increased during lactation in dairy cattle. In contrast to
changes in NPY and AgRP, the gene expression of
POMC was not significantly different between lactating
389
and non-lactating rats and was unaffected by leptin or
insulin treatment (Crowley et al. 2004). However, again
there is conflicting information, as Mann et al. (1997),
Brogan et al. (2000) and Smith (1993) all indicated that
POMC is decreased in the ARC during lactation.
Sorensen et al. (2002) also observed that CART levels
were reduced during lactation in sheep. Decreases in
gene expression in the ARC have been observed in both
melanin-concentrating hormone (MCH) and preproorexin during lactation in rats (Garcia et al. 2003),
although Cai et al. (2001) observed no change in either
pre-proorexin or hypothalamic orexin A levels, but orexin B levels increased when lactating rats were food
deprived. No changes in orexins during lactation were
observed by Brogan et al. (2000).
Maximal stimulation of the leptin system occurs when
leptin is completely absent (in the ob/ob mouse) and,
while ob/ob mice eat much more than their heterozygous
littermates, they still only eat 8–10 g per day. This intake
is much lower than that of wild type mice at peak lactation. Thus other signals must be involved in stimulating
food intake at peak lactation. Vernon et al. (2002) also
concluded that lowered leptin levels were a consequence
of negative energy balance in lactation rather than being
the prime driver of hyperphagia. This is consistent with
the observations that leptin status in dairy cattle during
lactation reflects their energy balance (Liefers et al. 2003),
and observations that the level of hypoleptineamia in
lactation is independent of litter size and food intake
(Denis et al. 2003b). Finally, the NPY knock-out mouse
has normal food intake during lactation (Hill and Levine
2003), and ICV infusion of NPY in lactation actually
reduced litter growth (Woodside et al. 2002).
That reduced leptin levels do not play a sole role in
increasing food intake in lactation is confirmed by
studies in which lactating mice had their leptin levels
artificially increased using mini-osmotic pumps (Mistry
and Romsos 2002; Stocker et al. 2004). Food intake at
peak lactation declined below that of mice with salinefilled pumps, but they still ate substantially more than
non-lactating animals and were able to successfully raise
their litters. Similar incomplete inhibition of food intake
effects were observed when lactating rats were injected
ICV with an MC3/4R receptor antagonist, MTII (Chen
et al. 2004), which is the main downstream effector of
leptin signalling. Something else, in addition to low
leptin levels, must switch on food intake during lactation. A probable additional factor is prolactin (PRL)
(Fig. 4). Prolactin is secreted from the adrenohypophysis of the pituitary and plays a key role in stimulating
milk synthesis in the mammary gland. This stimulation
involves in part an effect of PRL on local leptin production by the mammary alveolar epithelium cells and
mammary gland leptin receptor levels, which stimulates
fat synthesis (Feuermann et al. 2004) (Fig. 4).
Prolactin is implicated in the regulation of food intake from several lines of evidence. In non-lactating female rats injected with PRL for 10 days food intake was
stimulated in a dose-dependent manner (Noel and
Woodside 1993; Gerardo-Gettens et al. 1989; Sauve and
Woodside 1996, 2000). The effects were not repeated in
males (Heil 1999), suggesting a sex dependency of the
effect. How this is mediated, however, is unclear since
gonadectomised females show responses similar to intact
virgins (Heil 1999). Prolactin receptor levels are increased in many hypothalamic nuclei during lactation
(Pi and Grattan 1999). Dopamine has a negative effect
on PRL secretion, while thyrotropin-releasing hormone
(TRH) and prolactin-releasing peptide (PrRP) are both
stimulatory. However, while PrRP stimulates prolactin
release, its effects are much lower than TRH, and PrRP
is not found in the median eminence. This suggests that,
despite its name, PrRP has another primary function
(Ellacott et al. 2002). PrRP is reduced during lactation
(Lawrence et al. 2000) and when injected, has an acute
negative effect on food intake (Ellacott et al. 2002).
Ninety percent of PrRP neurons contain leptin receptors, suggesting that it may be regulated by leptin (Ellacott et al. 2002). The reduction in PrRP during
lactation may therefore contribute to hyperphagia
(Fig. 4).
Some evidence suggests that PRL effects are independent of leptin. For example, while injecting PRL in
non-lactating rats stimulates food intake, it has no effect on the GDP binding in BAT, an effect known to be
stimulated by declining leptin levels (above). Moreover,
increasing levels of PRL by a pituitary graft did not
affect levels of NPY gene expression (also generally
regarded as a downstream effect of leptin reduction),
but did mimic the reductions in both MCH and preproorexin observed in lactation (Garcia et al. 2003). Li
et al. (1999b) observed changes in gene expression following separation of rat mothers from their pups for
48 h, followed by resuckling, and also suggested that
elevation of NPY was not mediated by PRL. However,
studies of FOS-immunoreactivity in the ARC suggests
that PRL may act via an effect on POMC neurons
(Pape et al. 1996; Fig. 4) and knocking down PRL
levels using PRL-antisera resulted in an increase in
POMC, but this role of PRL via POMC is also disputed (Nahi and Arbogast 2003). Finally, PRL secretion is stimulated by elevated leptin levels (Gonzales et
al. 1998) and inhibited by NPY in culture (Wang et al.
1996) and following NPY infusion (Woodside et al.
2002; Toufexis et al. 2002), effects opposite to those one
might anticipate, given the lowered leptin and increased
NPY levels in lactation. These findings suggest that
leptin and PRL have independent and contrasting effects. Other centrally expressed genes known to be involved in food intake regulation, but not necessarily
directly linked with leptin, are also modulated in lactation. For example, gene expression of galanin-like
peptide is increased in the neurohypophysis of the
pituitary (Cunnningham et al. 2004), receptor binding
of angiotensin II and gene expression of angiotensinogen are reduced in the ARC (Speth et al. 2001), and
oestrogen receptors are elevated in the PVN during
lactation (Zhang et al. 2004). Prodynorphin and
390
proenkephalin are both reduced in the ARC during
lactation (Kim et al. 1997).
The stimulation of food intake during short-term
cold exposure in non-lactating mice is mediated by the
leptin signalling system mice with defective leptin signalling (ob/ob and db/db mice) cannot raise their food
intake levels when placed in the cold, although they do
increase their energy expenditure (J.R. Speakman and C.
McIvor, unpublished observations). Whether leptin
alone signals food intake in the cold and which signals
are utilised in lactation when the leptin system may already be fully engaged remain unclear. However, the
fact that food restriction in lactation further increases
NPY levels suggests that the leptin-NPY axis is not fully
engaged in lactation (Wilding et al. 1997; Abizaid et al.
1997; Pickavance et al. 1996). Studies are needed of the
neuroendocrine expression profiles of mice during lactation at different temperatures to test the neural saturation hypothesis.
Overall, despite the often confused nature of our
knowledge of the neuroendocrine control of food intake
during lactation, there is some evidence that multiple
pathways are engaged, and that reduced leptin levels
may be a response to negative energy balance rather
than a primary driving factor for the hyperphagia. In
contrast, leptin seems to be necessary for the cold-induced increase in food intake. Therefore different systems are potentially involved that may be differentially
recruited in lactation and cold exposure leading to
additive effects on food intake.
Conclusions
Substantial progress has been made over the last quarter
century in our understanding of the limits to sustained
rates of energy intake during lactation in small mammals. It is now clear that a central focus of limitation in
the alimentary tract does not explain the totality of the
available data. However, a peripheral limitation mediated by the mammary gland is also inadequate. We have
highlighted here three hypotheses, the heat dissipation
limits hypothesis, the seasonal investment hypothesis,
and the saturated neural control hypothesis, which
provide contrasting approaches to our understanding of
the intrinsic limitations on food intake. In all these cases
the present state of knowledge does not provide us with
unambiguous support for any particular hypothesis. We
hope therefore that this review might provide a stimulus
for future studies.
Acknowledgements Our work on energetics of lactation and SusEI
has been funded by the UK Biotechnology and Biological Sciences
Research Council. We are grateful to the numerous honours students that have worked on these projects and to Peter Thomson
and the staff of the animal house facility at the University of
Aberdeen for their invaluable technical support. Julian Mercer, Ian
Hume and two anonymous referees made valuable comments on
earlier drafts of the manuscript.
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