1 23
Journal of Comparative
Physiology B
Biochemical, Systems, and
Environmental Physiology
 
ISSN 0174-1578
Volume 181
Number 1
 
J Comp Physiol B (2010)
181:1-17
DOI 10.1007/
s00360-010-0528-0
Hypercarnivory and the brain: protein
requirements of cats reconsidered
1 23
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REVIEW
Hypercarnivory and the brain: protein requirements
of cats reconsidered
Regina Eisert
Received: 26 August 2010 / Revised: 19 October 2010 / Accepted: 25 October 2010 / Published online: 19 November 2010
 Springer-Verlag 2010
Abstract The domestic hypercarnivores cat and mink
have a higher protein requirement than other domestic
mammals. This has been attributed to adaptation to a
hypercarnivorous diet and subsequent loss of the ability to
downregulate amino acid catabolism. A quantitative
analysis of brain glucose requirements reveals that in cats
on their natural diet, a significant proportion of protein
must be diverted into gluconeogenesis to supply the brain.
According to the model presented here, the high protein
requirement of the domestic cat is the result of routing of
amino acids into gluconeogenesis to supply the needs of
the brain and other glucose-requiring tissues, resulting in
oxidation of amino acid in excess of the rate predicted for a
non-hypercarnivorous mammal of the same size. Thus, cats
and other small hypercarnivores do not have a high protein
requirement per se, but a high endogenous glucose demand
that is met by obligatory amino acid-based gluconeogene-
sis. It is predicted that for hypercarnivorous mammals with
the same degree of encephalisation, endogenous nitrogen
losses increase with decreasing metabolic mass as a result
of the allometric relationships of brain mass and brain
metabolic rate with body mass, possibly imposing a lower
limit for body mass in hypercarnivorous mammals.
Keywords Hypercarnivores  Allometry 
Brain metabolism
Introduction
The domestic cat (Felis silvestris) is an example of a
?hypercarnivore?, i.e. an animal that has evolved to con-
sume vertebrate prey almost exclusively (Holliday and
Steppan 2004; Wang and Tedford 2008). Hypercarnivores
such as cats and mink (Mustela vison) have a higher dietary
protein requirement than omnivorous mammals (Greaves
and Scott 1960; Rogers and Morris 1979; NRC 1982;
MacDonald et al. 1984; Damgaard et al. 1998; NRC 2006),
high endogenous nitrogen losses (Table 1), high in vitro
activities of enzymes involved in protein catabolism
(Rogers et al. 1977; S?rensen et al. 1995), and appear to
have a limited ability to adjust protein oxidation to low
dietary intakes of protein (Tarttelin 1991; Damgaard et al.
1998; Rogers and Morris 2002). The specific metabolic
pattern of the cat appears to be preserved even though cats
used for scientific research are generally maintained on
diets that are much higher in carbohydrate, and frequently
lower in protein, than their ancestral prey-based diet. The
current paradigm, based on the work of Rogers, Morris and
others on cats, states that the high protein requirement of
cats is due to an inability to downregulate enzymes that
catabolise amino acids, resulting in a failure to conserve
amino nitrogen at low protein intakes (Rogers et al. 1977;
Rogers and Morris 2002). Thus, the inability of cats to
downregulate protein catabolism is conceptualised as
equivalent to other functional losses associated with
hypercarnivory in cats, such as the inability to synthesise
sufficient taurine, or to convert b-carotene to vitamin A.
However, animals in general have a limited capacity to
store nitrogenous compounds, necessitating tight synchro-
nisation between the intake and catabolism of protein
(Millward 1995; Russell et al. 2000), and this also applies
to cats. Cats can adjust protein oxidation to match a range
Communicated by I.D. Hume.
R. Eisert (&)
Smithsonian Environmental Research Center,
Edgewater, USA
e-mail: eisertr@si.edu
R. Eisert
Gateway Antarctica, University of Canterbury,
Christchurch, New Zealand
123
J Comp Physiol B (2011) 181:1?17
DOI 10.1007/s00360-010-0528-0
Author's personal copy
of dietary protein concentrations provided their diet con-
tains at least 14?20% of metabolisable energy (ME) intake
as protein (Russell et al. 2002, 2003; Green et al. 2008;
Wester et al. 2008). This is considerably higher than the
minimum of 6?8% of ME required by humans, rats and
dogs for maintenance (Rogers and Morris 2002; Rand et al.
2003; NRC 2006; Green et al. 2008). But exactly why cats
cannot adjust the catabolism of amino acids to lower
intakes of protein sufficient for other species is not clear.
According to the general model of nitrogen catabolism in
mammals, the lower limit of amino acid catabolism an
animal can adapt to is dictated by the rate of whole-body
protein turnover and the concomitant obligatory nitrogen
loss (Waterlow 1999). Yet, protein turnover in cats is only
one-half to one-third of rates measured in other mammals
(Russell et al. 2003), and thus cannot explain why cats need
to catabolise amino acids at the high rates observed. In the
words of Russell et al. (2003), ??the apparently high feline
protein requirement remains unexplained and is probably
not a simple reflection of an inability to adapt hepatic
catabolic capacity to variation in protein intake??.
Previous work on the protein requirements of cats has
established the capacity of cats for handling large protein
loads and their failure to sufficiently reduce catabolism
when faced with low-protein diets (Rogers et al. 1977;
Russell et al. 2000, 2002, 2003; Rogers and Morris 2002;
Russell 2002; Green et al. 2008). In this paper, I propose a
mechanistic explanation for why cats are unable to down-
regulate catabolic enzymes, and thus amino acid oxidation,
to the same degree as non-hypercarnivorous mammals.
Cats have a relatively large brain and a high metabolic
demand for glucose that must be met by amino acid-based
gluconeogenesis when the cat is consuming a prey-based
diet. I propose that gluconeogenesis from amino acids in
cats is constitutive and represents a significant metabolic
sink for amino acids that increases the minimum protein
requirements of cats above that of non-hypercarnivorous
mammals. The proposed explanation rests on three
hypotheses:
Hypothesis 1: The cat is a small, hypercarnivorous
mammal with a relatively large brain and hence a large
endogenous glucose demand. The cat has evolved specific
metabolic strategies to meet its endogenous glucose
demand while consuming a very low-carbohydrate diet
without resorting to hyperketonaemia.
Hypothesis 2: In cats, amino acids are channelled into
gluconeogenesis at a rate sufficient to meet the endogenous
glucose demand of brain and other glucose-dependent tis-
sues, independent of dietary carbohydrate intake (obliga-
tory gluconeogenesis).
Hypothesis 3: Because cats have a relatively high
endogenous glucose demand, obligatory gluconeogenesis
results in high rates of amino acid oxidation and endogenous
nitrogen losses that exceed the rate of endogenous nitrogen
loss predicted for a cat-sized, non-hypercarnivorous mam-
mal. Since the endogenous nitrogen loss determines the
Table 1 Comparison of endogenous urinary nitrogen loss (EUNL), obligatory nitrogen loss (ONL), and fasting urinary nitrogen loss (FUNL) in
a range of mammals
Species EUNL ONL FUNL
Rat (Rattus norvegicus) 116a?128b 170c?273d 380e?436d
Rabbit (Oryctolagus cuniculus) ? ? 380f
Mink (Mustela vison) 280g ? 586h,*
Cat (Felis silvestris) 360b,i ? 283j
Dog (Canis lupus) 199k 263k, 360c?431l
Human (Homo sapiens) 99m?108n 140m,o?150p 240q?416r
Pig (Sus scrofa) 163b, ? 194l?240 s
Sheep (Ovis aries) ? ? 350t
Grey seal pup (Halichoerus grypus) ? ? 180u,
Marmoset (Callithrix jacchus) 62.1v ? ?
Predicted mammalian average 140w 272p 418p
Values are in mg N kg-0.75 day-1
* Short-term fast,  urinary plus faecal nitrogen loss,  immature animals
a Uezu et al. (1983); b Hendriks et al. (1997); c Howe et al. (1912); d Henry et al. (1987); e Goodman et al. (1984), day 3 of starvation;
f Hannaford et al. (1982); g Tauson et al. (2001); h Tauson et al. (1997); i Miller and Allison (1958); j Biourge et al. (1994), average of weeks
2?6; k Kendall et al. (1982), recalculated mean for animals that maintained body mass only; l Lusk (1928); m Calloway and Margen (1971);
n Scrimshaw et al. (1972); o Rand et al. (2003); p Henry and Collingwood (1998); q Owen et al. 1998, obese, average of day 2?18 of fast;
r Go?schke et al. (1975), lean men and women, day 6 of starvation; s Mu?ller et al. (1984), 21-kg minipigs, day 4 of starvation; t Blaxter (1962);
u Nord?y et al. (1990); v Flurer et al. (1988); w Smith (1926)
2 J Comp Physiol B (2011) 181:1?17
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lower limit for protein requirements, obligatory gluconeo-
genesis thus increases minimum protein requirements of
cats relative to non-hypercarnivorous mammals.
The main premises underlying these hypotheses will be
discussed in detail and placed in a comparative mammalian
context. The proposed alternative explanation for the high
protein requirement of the domestic cat also addresses
several as-yet unresolved questions, such as why the fast-
ing urinary nitrogen loss (FUNL) of cats should be lower
than their endogenous urinary nitrogen loss (EUNL), or
why domestic cats may be particularly prone to developing
obesity, insulin resistance and type-II diabetes mellitus.
What is the natural diet of the cat?
Adult, non-reproductive cats have no demonstrable dietary
requirement for carbohydrate (MacDonald et al. 1984), but
like all mammals, cats have certain tissues and organs that
absolutely require glucose. Examples include brain, spinal
cord and peripheral nerves, red blood cells, renal medulla,
testes, mammary gland during lactation, and the pregnant
uterus (Waites and Setchell 1964; Sokoloff et al. 1977;
Oftedal et al. 1993; Berg et al. 2002; Sunehag et al. 2002).
Metabolic dependence on glucose in cats is illustrated
by the fact that feeding behaviour can be triggered if
plasma glucose is lowered by administration of insulin or
2-deoxyglucose (Rowland 1981). Mammalian body stores
of carbohydrate?glycogen in liver and muscle?are quite
limited, and account for only 200?500 g total in humans
(Flatt 1995) and ca. 0.65% of fat-free mass in rats (Even
et al. 2001; Morifuji et al. 2005). Since glucose is an
essential substrate for the cat, the question is how this
demand can be met on a hypercarnivorous diet. As shown
in Table 2, a cat consuming small vertebrate prey would
receive only 1?2% of its ME intake as carbohydrate, unless
ingesting selectively only body parts that are high in
glycogen such as liver (Table 2). Even a mouse fully
Table 2 Composition of potential prey items, human-provided foods, and dietary recommendations for cats
Food item BM
(g)
Fat Protein Water
(% BM)
Ash CHO ME
(kJ g-1)
Fat Protein
(% ME)
CHO
Vertebrate prey
Old-field mousea (Peromyscus polionotus) 11.4 12.0 17.0 64.7 3.67 0.57 7.46 61 38 1.3
Common voleb (Microtus arvalis) 16.1 14.3 16.2 63.5 3.30 0.56 8.18 66 33 1.1
Bank volec (Clethrionomys glareolus) 21.3 4.00 20.5 71.2 3.70 0.62 5.04 30 68 2.1
Lab moused (Mus musculus) 20.5 14.5 18.1 62.7 3.65 0.56 8.57 64 35 1.1
Lab mouse, after a meal of wheat* 22.0 14.3 17.9 61.8 3.60 1.61 8.63 62 35 3.1
Rabbit, newborne (Oryctolagus cuniculus) 53.0 5.75 11.6 79.9 2.20 0.61 4.21 52 46 2.4
1-Day chickf (Gallus domesticus) 4.5 5.73 16.6 74.4 1.16 0.46 5.02 43 55 1.6
Small passerine birdf,g,h,i,j 10?100 5?15 19?21 63?71 *3.2 0.4?0.5 5.5?8.9 35?64 35?64 1?2
Human-provided foods
Whole milkk ? ? ? ? ? ? 2.51 49 21 30
Beef liver, freshk ? ? ? ? ? ? 5.64 25 63 12
Dry kibble 1l ? ? ? ? ? ? 13.5 23 40 37
Dry kibble 2m ? ? ? ? ? ? 20.5 50 33 18
Canned wet 1n ? ? ? ? ? ? 5.49 53 29 18
Canned wet 2o ? ? ? ? ? ? 4.46 46 38 16
Experimental ?high-protein? dietp ? ? ? ? ? ? ? 39 50 11
NRC recommendation for maintenanceq ? ? ? ? ? ? ? 20 20 ?
Carbohydrate (CHO) content of prey was estimated assuming that fat-free mass of rodents contains 0.65% and of birds, 0.50% carbohydrate
(Swain 1992; Edwards et al. 1999; Even et al. 2001; Morifuji et al. 2005). Metabolisable energy (ME) was calculated from Atwater factors for
protein, carbohydrate, and fat of 16.74, 16.74, and 37.66 MJ kg-1 (NRC 2006). Note that foods may vary in digestibility and true ME values may
differ from calculated values
BM body mass
* See Appendix for calculations
a Kaufman and Kaufman (1977); b Sawicka-Kapusta (1970); c Sawicka-Kapusta (1974); d Bailey et al. (1960); e Xiccato et al. (1999);
f Dierenfeld et al. (2001); g Blem (1976); h Swain (1992); i Taruscio and Murphy (1995); j Edwards et al. (1999); k USDA National Nutrient
Database (2009); l ?Hills Science diet for cats, adult indoor?, information provided on manufacturer?s website, Hill?s Pet Nutrition, Inc. (2010);
m ?Eukanuba feline recovery dry?, Martin and Rand (1999); n ?Whiskas selected protein?, Martin and Rand (1999); o ?Iams premium pate with
tender chicken and liver?, information provided on manufacturer?s website, Iams products for cats (2010); p Green et al. (2008); q NRC (2006)
J Comp Physiol B (2011) 181:1?17 3
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?gut-loaded? with digestible carbohydrate (e.g. wheat
grain) contains less than 4% of ME as carbohydrate
(Table 2; Appendix), but secondary consumption of car-
bohydrate is unlikely to be of practical significance as cats
generally do not consume the digestive tracts of their prey
(Leyhausen 1979). To put macronutrient intake by cats into
perspective, a prey-based diet contains 1?2:30?68:30?68%
of ME as carbohydrate:fat:protein (Table 2), compared
with typical macronutrient ratios of ca. 15?35:20?50:30?40
in commercial cat food (Martin and Rand 1999; Table 2),
55:30:15 in human reference diets (Gannon and Nuttall
2004), 20:50:30 in human low-carbohydrate, high-protein
diets (Gannon and Nuttall 2004), and 8:50:42 for the tra-
ditional diet of the Greenland Inuit (??Eskimo??; Heinbecker
1928). Assuming a daily ME consumption of 1,000 kJ or
6?12 small rodents (NRC 2006; Table 2), a cat would
receive between 0.6 and 1.1 g of carbohydrate from its diet.
At a fat content of 12% for wild prey, the cat would ingest
an additional 1.8 g of glycerol supplying a maximum of
1.8 g glucose contingent on complete oxidation of ingested
fatty acids (Cahill et al. 1966; Streja et al. 1977; Mac-
Donald et al. 1984). Thus, the amount of carbohydrate
typically available from a prey-based diet (range
2.4?2.9 g day-1) is insufficient to meet the net glucose
demand of the brain (3.1 g day-1; Table 4), even without
considering glucose use by other obligate glucose-con-
suming tissues. No data are available for cats, but glucose
demand by obligate glucose-consuming tissues other than
brain accounts for ca. 40% of brain glucose consumption in
humans (Cahill et al. 1966; Sokoloff et al. 1977), and it is
possible that the proportion of glucose use by extracerebral
tissues is greater in cats as a result of their relatively
smaller brain (Table 4).
It appears that a prey-based diet routinely supplies
insufficient carbohydrate to meet metabolic demands in the
hypercarnivorous cat. In contrast, omnivores and herbi-
vores are likely to encounter carbohydrate deficiency only
sporadically and most likely as a result of starvation or in
the context of physiological states that cause an increase in
endogenous glucose demand. As discussed in the following
sections, omnivores and hypercarnivores differ in their
response to dietary carbohydrate insufficiency: in omni-
vores, glucose is partially replaced by ketone bodies,
whereas high rates of gluconeogenesis remove any
dependence on dietary carbohydrate in hypercarnivores.
Ketone bodies: glucose substitutes
Ketone bodies (acetoacetate, b-hydroxybutyrate, and ace-
tone) are lipid-derived metabolites that provide a substitute
fuel that can be taken up and utilised by most tissues
including heart and brain (Owen et al. 1967; Robinson and
Williamson 1980). Conditions that stimulate ketogenesis
are a low insulin:glucagon ratio, high rates of lipolysis and
fatty acid oxidation, and reduced intracellular availability
of glucose, as is the case in starvation, on carbohydrate-
deficient diets, or in insulin-dependent diabetes mellitus
(Klein and Wolfe 1992; Mitchell et al. 1995). In general,
omnivorous mammals respond to both carbohydrate defi-
ciency and total starvation with an increase in ketone body
production, although the degree of hyperketonaemia may
differ considerably between species (Robinson and
Williamson 1980). Both humans and rats respond to low-
carbohydrate diets with rapidly developing hyperketonaemia
(Likhodii et al. 2002; Astrup et al. 2004). The ketogenic
response is exacerbated if endogenous glucose demands are
increased, e.g. during pregnancy and lactation (Felig 1973;
Doreau et al. 1981; Jeanblain and Durix 1985; Mitchell
et al. 1995; Dalrymple 2004; Ayala et al. 2006). Domestic
ruminants, which rely on gluconeogenesis rather than
dietary carbohydrate to meet their glucose needs, appear
particularly susceptible to pathological hyperketonemia
under conditions of elevated glucose demand (Heitmann
et al. 1987). Simply put, the elevation of ketone bodies
above basal levels signals the carbohydrate-deficient state;
conversely, low circulating concentrations of ketone bodies
indicate that the rate of glucose appearance (dietary plus
endogenous) is sufficient to meet metabolic glucose
demands. Ketone bodies are utilised by brain proportional
to their arterial concentrations (Hawkins et al. 1971;
Robinson and Williamson 1980; Blomqvist et al. 2002) and
in humans, can provide as much as 60% of brain substrate
requirements during prolonged starvation (Cahill 1983).
This partial substitution of glucose by ketones not only helps
to maintain fuel supply to the brain, but also reduces the
need for protein catabolism to provide gluconeogenic pre-
cursors (Cahill 1983; VanItallie and Nufert 2003) and thus
greatly prolongs survival time, as mammals tend to have a
greater capacity for catabolism of body fat than body pro-
tein. However, brain tissue cannot run on ketone bodies as
an exclusive substrate and continues to use glucose at all
times (Sokoloff et al. 1977; Hertz and Dienel 2002).
Adult cats fed very low-carbohydrate diets (B10% of
ME) do not develop hyperketonaemia (Chugani et al. 1991;
Dobenecker et al. 1998; Pazak et al. 1998; Blanchard et al.
2002; Thiess et al. 2004). Nevertheless, cats develop sig-
nificant hyperketonaemia during starvation (Blanchard
et al. 2002) and in insulin-deficient diabetes (Stadie et al.
1940), indicating that lack of ketone body accumulation in
cats on very low-carbohydrate diets is not due to a defect in
ketogenesis. This metabolic pattern in cats is consistent
with high rates of gluconeogenesis sufficient to suppress
ketogenesis in the fed state, and reduction of gluconeo-
genesis and gradual substitution of glucose by ketone
bodies to spare protein during prolonged starvation, as
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indicated by a reduction in daily nitrogen loss (FUNL \
EUNL; Table 1). Cats likely evolved under conditions of
intermittent deprivation, e.g. due to seasonal changes in
abundance and composition of prey, and retain the ability
to utilise hyperketonaemia as an adaptive response during
total starvation.
Gluconeogenesis
A number of authors have proposed that cats have consti-
tutively high rates of gluconeogenesis and in this regard
resemble ruminant mammals (Rogers et al. 1977; Kettelhut
et al. 1980; MacDonald et al. 1984; Lobley 1992). This is
particularly remarkable since most cats used in scientific
studies are maintained on diets (Miller and Allison 1958;
Greaves and Scott 1960; Biourge et al. 1994; Hendriks
et al. 1997; Russell et al. 2000, 2002, 2003; Green et al.
2008) that contribute 5?20 times the amount of carbohy-
drate on a ME basis than what might be considered the
?natural? diet of the species (Table 2). In other words, high
rates of gluconeogenesis in the cat appear to be essentially
preserved despite a significant intake of carbohydrate.
Because postprandial gluconeogenesis has not been mea-
sured in cats, it is currently not possible to assess to what
extent, if any, gluconeogenesis is reduced following the
consumption of carbohydrate. In humans and rats, inges-
tion of a mixed meal suppresses hepatic glucose output by
insulin-mediated mechanisms as well as by the direct
effects of postprandial hyperglycaemia (Tonelli et al.
2005). Insulin suppresses hepatic glucose output directly
by inhibiting glycogenolysis and gluconeogenesis, and
indirectly by inhibiting lipolysis and stimulating lipogen-
esis, thus reducing the availability of non-esterified fatty
acids (Sugden 2007). Insulin resistance and incomplete
suppression of gluconeogenesis in response to insulin result
in reduced glucose tolerance, i.e. an increase in the time
required to restore baseline plasma glucose after carbohy-
drate administration as part of a glucose tolerance test.
Glucose tolerance in cats is low compared with dogs,
humans, rats and horses (Kaiyala et al. 1999; Appleton
et al. 2001; Hoffman et al. 2003; Morens et al. 2006),
consistent with the failure to suppress gluconeogenesis in
the presence of excess carbohydrate. A similar pattern of
glucose intolerance, also known as ?starvation diabetes?
(Lundb?k 1948), can be induced in omnivorous species by
adaptation to a high-protein, carbohydrate-free diet
(McClellan and Du Bois 1930; Belo et al. 1976) or by
fasting (Fe?ry et al. 1990; Horton and Hill 2001). When a
glucose load is given to normal rats, hepatic glucose pro-
duction is completely suppressed 1 h after dosing, whereas
there is no detectable suppression of hepatic glucose pro-
duction in starved rats under the same conditions (Smadja
et al. 1990). The crucial difference between cats on the one
hand and humans and rats on the other is while the latter
can be habituated to a high-protein, very low carbohydrate
diet and develop similar metabolic patterns to cats (high
rates of protein-based gluconeogenesis, glucose intoler-
ance), they revert back to their normal omnivorous pattern
(low and variable gluconeogenesis, high glucose tolerance)
when returned to a mixed diet.
Assuming that glucose tolerance in cats is reduced as a
result of constitutively high rates of gluconeogenesis, it
might be predicted that cats are susceptible to developing
obesity and insulin resistance on diets containing high
levels of carbohydrate. Clinical observations confirm that
in cats, consumption of a diet containing a significant
proportion of ME as available carbohydrate may be asso-
ciated with hyperglycaemia, hyperinsulinaemia, insulin
resistance and obesity, whereas isocaloric diets higher in
protein and lower in carbohydrate are beneficial in restor-
ing insulin sensitivity and promoting fat loss in cats (Rand
et al. 2004; Hoenig et al. 2007). Insulin resistance and
obesity are linked to development of non-insulin-depen-
dent (type-II) diabetes mellitus, and cats are considerably
more prone than dogs to development of type-II diabetes
(Hoenig 2002; Rand et al. 2004).
High rates of gluconeogenesis in cats require a steady
supply of precursors. Gluconeogenesis includes extensive
recycling of glucose via lactate and alanine, as well as de
novo production of glucose from non-carbohydrate pre-
cursors (Katz and Tayek 1998, 1999). In cats, the only
quantitatively significant precursors available for de novo
glucose synthesis are amino acids, followed by glycerol.
Glycerol is both readily converted to glucose and relatively
abundant as a constituent of dietary and endogenous tri-
glyceride (Streja et al. 1977), but its utilisation as a glu-
coneogenic substrate is limited by the need to oxidise the
associated free fatty acids. Therefore, the principal sub-
strates for glucose synthesis available to cats and other
hypercarnivores are amino acids.
Amino acid metabolism
The principal metabolic fates of amino acids include pro-
tein synthesis, synthesis of other essential compounds (e.g.
creatine, purine bases), and oxidative catabolism to glu-
cose, ketone bodies, and carbon dioxide (Jungas et al.
1992; Waterlow 2006). Nitrogen generated during amino
acid catabolism is converted to urea and excreted; other
minor nitrogenous end products of mammals include
ammonia and uric acid (Wright 1995). In omnivores,
amino acid oxidation accounts for a small proportion
of total energy expenditure, and assuming that intake of
energy is adequate, use of amino acids for maintenance of
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the body protein mass takes priority over the use of amino
acids as fuel (Moundras et al. 1993; Millward 1995).
Degradation of amino acids involves two metabolic
cycles, the urea cycle and the tricarboxylic acid (TCA)
cycle. While the TCA cycle is common to all cells with
mitochondria, the urea cycle occurs almost exclusively in
the liver (Morris 2002), which is also the principal site of
gluconeogenesis. The urea cycle is functionally linked to
gluconeogenesis via TCA cycle intermediates, resulting in
the coordination of urea formation and gluconeogenesis
(Jungas et al. 1992). After deamination, the nitrogen moi-
ety of amino acids enters the urea cycle, while residual
carbon skeletons are converted into acetyl-CoA or aceto-
acetyl-CoA, pyruvate, and TCA cycle intermediates
(Table 3). Acetyl-CoA and acetoacetyl-CoA cannot be
converted to glucose, but may be oxidised directly in the
TCA cycle, used for ketogenesis, or for the synthesis of
fatty acids or cholesterol. Net lipogenesis from amino acids
is considered a minor pathway in general (Jungas et al.
1992; Welle 1999). The branched-chain amino acids (leu-
cine, isoleucine, valine) are absorbed primarily by muscle,
where they are catabolised by transamination (usually to
glutamate) followed by oxidation. Since oxaloacetate is a
key intermediate in gluconeogenesis, all amino acids that
are catabolised via pyruvate or TCA cycle intermediates
are potentially gluconeogenic; only leucine and lysine are
exclusively ketogenic (Table 3).
The majority of amino acids are catabolised via pyru-
vate or TCA intermediates (Table 3), resulting in entry of
4- and 5-carbon intermediates into the TCA cycle (ana-
plerosis). For every turn of the cycle, one 2-carbon unit
enters as acetyl-CoA and two 1-carbon units leave as CO2.
While pyruvate can enter the cycle as acetyl-CoA after
decarboxylation by pyruvate dehydrogenase, compounds
containing four or five carbons cannot be fully oxidised in
the TCA cycle, and the anaplerotic influx of carbon to the
cycle has to be balanced by an equivalent removal of
carbon (cataplerosis) to maintain cycle function (Owen
et al. 2002). This is achieved by routing oxaloacetate and
other TCA intermediates into metabolic pathways such as
gluconeogenesis via phosphoenolpyruvate carboxykinase
(Owen et al. 2002; Hakimi et al. 2005). Channelling of
amino acid skeletons into gluconeogenesis and ketogenesis
not only maintains TCA cycle function (Owen et al. 2002;
Hakimi et al. 2005), but also converts a large range of
amino acids into universal metabolic currency (glucose,
ketone bodies) that can be taken up and utilised by other
tissues (Jungas et al. 1992), many of which do not possess
the enzymatic machinery for metabolising amino acids
(Jungas et al. 1992) or which, like the brain, cannot take up
amino acids at sufficient rates (Sokoloff et al. 1977). In
humans, conversion of amino acids to substrates that can be
exported and oxidised by extrahepatic tissues is considered
necessary to reduce the functional strain on liver metabo-
lism, as complete postprandial oxidation of dietary amino
acids by the liver would produce surplus ATP and exceed
hepatic capacity for oxidative metabolism (Jungas et al.
1992). This constraint must apply to an even greater extent
to hypercarnivores, given that their protein intakes are
much higher than that of most human populations. Based
on in vitro studies of cat hepatocytes, Beliveau and
Freedland (1982) concluded that amino acids are protected
from complete oxidation and preferentially directed into
synthetic pathways (gluconeogenesis, protein synthesis) in
cats. Glucose is not a precursor for fatty acid synthesis in
cat liver cells (Richard et al. 1989), which would increase
the availability of glucose as a substrate for extrahepatic
tissues. Thus, gluconeogenesis is maximal in carnivores in
the postprandial phase (shortly after a meal), whereas in
omnivores, gluconeogenesis is maximal once the animal is
postabsorptive or fasting (MacDonald et al. 1984). This
may also explain why the preferred meal pattern of the cat
is frequent, small meals distributed throughout its activity
cycle (Bradshaw 2006).
In summary, glucose synthesis is one of the principal
means of oxidative amino acid disposal, and consumption
of protein is necessarily accompanied by gluconeogenesis
from amino acids. However, the question remains whether
Table 3 Principal intermediates in the oxidative disposal of protein
amino acids according to Berg et al. (2002)
Amino acid Metabolic intermediate
Alanine Pyruvate
Arginine a-Ketoglutarate*
Asparagine Oxaloacetate*
Aspartic acid Oxaloacetate*, fumarate*
Cysteine Pyruvate
Glutamine a-Ketoglutarate*
Glutamic acid a-Ketoglutarate*
Glycine Pyruvate
Histidine a-Ketoglutarate*
Isoleucine Acetyl-CoA, succinyl-CoA*
Leucine Acetyl-CoA, acetoacetyl-CoA
Lysine Acetoacetyl-CoA
Methionine Succinyl-CoA*
Phenylalanine Acetoacetyl-CoA, fumarate*
Proline a-Ketoglutarate*
Serine Pyruvate
Threonine Pyruvate, succinyl-CoA*
Tryptophan Pyruvate, acetyl-CoA, acetoacetyl-CoA
Tyrosine Acetoacetyl-CoA, fumarate*
Valine Succinyl-CoA*
* Tricarboxylic acid cycle intermediate
6 J Comp Physiol B (2011) 181:1?17
123
Author's personal copy
gluconeogenesis in the cat is simply a means of disposing
of excess amino acids (i.e. amino acids not required for the
maintenance of body protein mass or other specific syn-
thetic processes), or whether gluconeogenesis from amino
acids continues despite relative protein deficiency and the
threat of a negative nitrogen balance. In rats on a high-
protein diet (60% casein by mass), the utilisation of dietary
amino acids for gluconeogenesis may limit their avail-
ability for protein synthesis (Moundras et al. 1993). In
humans, pigs, dogs, and rats, fasting amino acid oxidation
(FUNL) is substantially higher than the obligatory amino
acid oxidation (EUNL) in the fed state (Table 1). The
catabolism of additional amino acids provides substrates
for gluconeogenesis during total starvation. These exam-
ples show that under certain conditions, glucose production
takes metabolic priority over conservation of body protein,
and lend support to the possibility that the protein
requirement of cats is increased above that of omnivorous
mammals as a result of homeorhetic partitioning of amino
acids into obligatory gluconeogenesis. In keeping with this,
Silva and Mercer (1985) suggested that cats are ??wasteful??
of amino acids at low protein intakes due to the high pri-
ority of gluconeogenesis. Furthermore, cats do not have a
high requirement for indispensable amino acids, but for
total amino nitrogen (Rogers and Morris 1979), consistent
with utilisation of amino acids for gluconeogenesis, not net
protein synthesis.
Protein turnover and nitrogen loss
Body proteins are constantly ?turned over? that is syn-
thesised and broken down (Welle 1999; Waterlow 2006). A
proportion of the amino acids released by the breakdown of
body protein is oxidised rather than recycled back into
protein synthesis, and nitrogen is continually lost from the
body in urine and faeces, as shed skin and hair, and in skin
gland secretions. Nitrogen loss scales with protein intake
and on a protein-free but otherwise adequate diet, daily
nitrogen loss decreases to a minimum value after a period
of adaptation (Hoffer 1999). This minimum nitrogen loss is
called the obligatory nitrogen loss or ONL (Hoffer 1999).
Because nitrogen loss from the body has to be replaced by
dietary intake, the ONL sets the lower limit for the amount
of protein required to maintain nitrogen balance (Waterlow
1999). In humans, the appropriate nitrogen intake to bal-
ance losses is estimated as 130?140% of the ONL (Young
et al. 1989).
Due to the practical challenge of collecting every last bit
of nitrogen lost from the body, EUNL or total endogenous
nitrogen loss (EUNL plus metabolic faecal nitrogen) is
commonly measured instead of ONL (Kendall et al. 1982;
Flurer et al. 1988; Hendriks et al. 1997; Owen et al. 1998;
Green et al. 2008). In the basal state, EUNL accounts for the
majority of ONL from the body (Table 1), and represents
oxidative catabolism of amino acids as opposed to loss of
nitrogen by other means (e.g. as shed hair, skin, or other
cellular debris). During the transition to total starvation,
amino acids are directed towards gluconeogenesis to meet
endogenous glucose demands to compensate for the absence
of dietary carbohydrate, nitrogen loss increases accordingly,
and thus FUNL generally exceeds ONL and EUNL in
mammals (Lusk 1928; Nielsen et al. 1994; Henry and
Collingwood 1998; Table 1). In long-term starved humans, the
FUNL (240?416 mg N kg-0.75 day-1) is two to four times
greater than estimated EUNL (*100 mg N kg-0.75 day-1)
due to use of amino acids for gluconeogenesis during fasting
(Go?schke et al. 1975; Henry and Collingwood 1998; Owen
et al. 1998; Hoffer 1999; Table 1); feeding small quantities
of carbohydrate significantly reduces urinary nitrogen loss
by decreasing gluconeogenesis from amino acids (Owen
et al. 1998). In contrast, the measured EUNL of cats
of 360 mg N kg-0.75 day-1 (Miller and Allison 1958;
Hendriks et al. 1997) is considerably higher than the mean
FUNL of cats fasted for 1?6 weeks of 283 mg N kg-0.75
day-1 (Biourge et al. 1994; Table 1). Because EUNL
provides an approximation of amino acid oxidation, this
observation provides further support for the proposition that
in cats, minimal rates of gluconeogenesis from amino acids
in the fed state are as high as, or even higher than, during
total starvation (Rogers et al. 1977; Kettelhut et al. 1980).
Constitutively high rates of gluconeogenesis make sense if
ensuring an uninterrupted supply of glucose is a metabolic
priority, e.g. to support an organ system (brain, mammary
gland, conceptus) that absolutely requires glucose to
function.
The brain: glucose demands in relation to brain size
Brain tissue does not tolerate any interruption of its fuel
supply and its default fuel is glucose (Sokoloff et al. 1977;
Hertz and Dienel 2002), although partial substitution by
ketone bodies may occur during prolonged starvation
(Cahill et al. 1966; Owen et al. 1967). Brain glucose
demand depends primarily on brain mass, and there are
large differences among mammals in the proportion of
whole-body glucose demand used by the brain as a result of
the allometry of brain size and taxonomic differences in
encephalisation. For example, uptake of glucose by the
brain accounts for 40?50% of whole-body glucose turnover
in humans, whose brain represents 2% of body mass, but
for only ca. 10% of whole-body glucose turnover in the
sheep with a brain that accounts for only 0.2% of body
mass (Pell and Bergman 1983; Ekberg et al. 1999). In
humans, changes in brain glucose demand from birth to
J Comp Physiol B (2011) 181:1?17 7
123
Author's personal copy
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8 J Comp Physiol B (2011) 181:1?17
123
Author's personal copy
adulthood are thought to be the principal determinant of
hepatic glucose production (Bier et al. 1977).
Within a mammalian order, relative brain mass as a
percentage of body mass generally decreases with
increasing species size (Eisenberg 1981; Kruska 2005).
Mammalian orders differ in their degree of encephalisation
so that the brain mass predicted at a given body mass is
greater in the Carnivora and Artiodactyla than in Insec-
tivora and Rodentia (Kruska 2005). For example, the stoat
(Mustela erminea) weighs approximately the same as a
Norway rat (Rattus norvegicus) but has a brain that has
twice the mass of rat brain (Kruska 2005; Table 4). Lastly,
not only does brain mass vary with body mass and taxo-
nomic order, but the metabolic rate of the brain also
decreases allometrically with brain mass (Mink et al. 1981;
Karbowski 2007), rather than being constant as previously
assumed (Grande 1980; Kuzawa 1998). The relationship
between cerebral glucose utilisation, CMRglu, and total
brain mass is shown in Fig. 1 and Table 4. Similar rela-
tionships have been found for brain metabolic rate versus
brain volume (Karbowski 2007) and for oxygen con-
sumption versus mass of the vertebrate central nervous
system (Mink et al. 1981). Thus, within a taxon of com-
parable degree of encephalisation, smaller species have not
only relatively larger brains, but also brains with a higher
mass-specific metabolic rate; at the same time, whole-body
metabolic rate (and therefore the capacity to supply sub-
strates to the brain) increases with decreasing species size.
To compare the glucose demand of the cat brain with that
in other mammalian species, a predictive allometric model
was derived from published data of brain mass and whole-
brain glucose utilisation (CMRglu) for adult mammals
ranging from mouse to Weddell seal (Table 4; Fig. 1; n = 8
species). In humans, non-lethal techniques such as arterio-
venous difference and positron emission tomography are
used, and these methods tend to overestimate glucose uptake
relative to the terminal 2-deoxyglucose method used in
animal studies (Sokoloff et al. 1977). A value of
29?31 lmol glucose 100 g-1 min-1 is commonly assumed
for human brain, but net uptake of glucose in human brain is
closer to 26 lmol 100 g-1 min-1 (Sokoloff et al. 1977) and
therefore this lower CMRglu value for human brain was used
to allow comparison with animal data (Table 4). The accu-
racy of prediction from the resulting allometric model was
tested by computing the regression for n - 1 values, using
the regression parameters to predict the nth value, and
repeating this process to calculate an independent predicted
value for each species that was then compared to the actual
published value (Dielman 2005). The median difference
between predicted and published glucose utilisation values
was -1% of the actual value (range -7 to ?8%), and actual
and predicted values were not significantly different (paired
t-test, P = 0.9). A Deming linear regression model (Linnet
1998) incorporating all published data (Fig. 1) was then
used to predict brain glucose requirements for (a) cat-sized
species from a range of mammalian orders (Rodentia,
Lagomorpha, Xenarthra, Hyracoidea, Artiodactyla, Prima-
tes), and (b) hypercarnivorous members of the order Car-
nivora with body masses ranging from 0.2 to 365 kg (stoat,
mink, mountain lion, tiger, and polar bear; Table 4). Esti-
mates of brain glucose requirements were expressed as
absolute demand (mass of glucose per day) and as relative
brain glucose demand (RCMR) expressed on the basis of
metabolic body mass (BM0.75). RCMR is an index of brain
glucose demand relative to the organism?s metabolic
capacity to supply this demand.
The results of this analysis are shown in Table 4. Firstly,
RCMR of cat brain is only exceeded by a primate among
mammals in the same size range, consistent with the fact
that members of the order Carnivora are highly encepha-
lised. Estimated relative brain glucose demand expressed
on a metabolic-mass basis (RCMR), as proposed here,
correlates well with known differences in encephalisation
between mammalian orders (Kruska 2005) and may be a
more useful metric than the encephalisation quotient for
comparative purposes; it not only takes into account the
allometric scaling of brain metabolism, but also avoids the
problems associated with scaling of brain mass across
mammalian taxa that affect the concept of the encephali-
sation quotient (Gittleman 1986; Pagel and Harvey 1989;
Kruska 2005).
Secondly, cats have a high brain glucose requirement
compared with larger species of Carnivora (Table 4). In
keeping with this greater need of cats for brain substrates, the
cat develops hyperketonaemia more rapidly and to a greater
degree than the dog during total starvation (Owen et al.
1967; De Bruijne 1979; Blanchard et al. 2002). A special
case is the mink (M. vison) in that predicted RCMR of adult
Fig. 1 Allometric scaling of cerebral metabolic rate (glucose
utilisation, CMRglu) with brain mass in adult conscious mammals.
Data and sources, see Table 4
J Comp Physiol B (2011) 181:1?17 9
123
Author's personal copy
mink is similar to that of a cat, even though the mink is a
considerably smaller species and would be predicted to have
a relatively larger brain. The explanation for this anomaly is
that mink undergo an absolute reduction in brain mass and
volume during the later stages of ontogeny (Kruska 1993),
and thus adults have a smaller brain and lower brain glucose
requirement than may be expected based on body mass
(Table 4). Currently, there is no explanation for this phe-
nomenon, although a reduction in brain mass may convey an
adaptive advantage for small, semi-aquatic hypercarnivores
by reducing brain glucose demands.
As a result of having a relatively large brain, cats indeed
have a large endogenous glucose demand (Table 4) that
needs to be met through gluconeogenesis on a hypercar-
nivorous diet. The net brain glucose demand of cats listed in
Table 4 represents ca. 30% of measured gluconeogenesis of
cats after an overnight fast (Kley et al. 2009). This is a large
proportion considering that gluconeogenesis includes sig-
nificant recycling of glucose and that the equivalent value
for humans, with their much larger brain, is ca. 44%
(Ackermans et al. 2001). The question remaining is whether
the estimated glucose requirement of the cat brain is suffi-
cient to explain the elevated protein requirements of cats.
Contribution of gluconeogenesis to protein
requirements
As a result of the functional interdependency of urea pro-
duction and gluconeogenesis from amino acids, urinary
nitrogen loss provides an estimate of hepatic amino acid
oxidation (Welle 1999), and hence an upper limit for the
rate of gluconeogenesis from amino acids. The EUNL of
rats and humans represents a minimal estimate for oxida-
tion of amino acids released from the breakdown of body
proteins due to turnover. The hypothesis presented in this
paper is that in cats and other hypercarnivores, the lower
threshold value for amino acid oxidation is determined by
the endogenous glucose demand of the brain and other
tissues (obligatory gluconeogenesis). Because cats have
relatively large brains, obligatory gluconeogenesis from
amino acids should result in endogenous nitrogen losses
that are higher than predicted for a cat-sized, non-hyper-
carnivorous mammal. This proposition can be tested by
comparing observed EUNL values (as a proxy for total
amino acid oxidation) with the theoretical nitrogen cost of
meeting the endogenous glucose demand entirely from
amino acid-based gluconeogenesis. According to the pro-
posed model, the estimated minimum nitrogen cost of
gluconeogenesis should match observed EUNL in hyper-
carnivores cats and mink, but not in humans and rats, since
in the latter endogenous nitrogen loss is limited to losses
incurred due to protein turnover, and metabolic glucose
demands in the fed state are primarily met through dietary
carbohydrate.
In the absence of quantitative data on whole-body glu-
cose demand of cats and mink, brain glucose data (Table 4)
were used to derive a minimal estimate of the endogenous
glucose demand and the associated nitrogen cost. As shown
in Table 5, there is close agreement between nitrogen loss
Table 5 Comparison of endogenous urinary nitrogen loss (EUNL) with brain glucose demand in (a) hypercarnivores cat and mink and in (b)
omnivores rat and human
Parameter Cat Mink Rat Human
Theoretical nitrogen costs of brain glucose demand
Body mass (kg) 3.41a 1.10b 0.205 70.0d
Metabolic body mass (kg0.75) 2.51 1.07 0.305 24.2
Brain mass (g) 30.2a 7.70c 1.75 1,400d
Brain glucose demand (g day-1) 3.1e 1.0e 0.29e 94e
Protein equivalent (amino acids to glucose) (g day-1) 5.5f 1.7f 0.51f 165f
Theoretical nitrogen cost of glucose (mg N kg-0.75 day-1) 350 260 270 1,094
Comparison with reported nitrogen loss
EUNL (mg N kg-0.75 day-1) 360g,h 280b 122i,j 105k,l
EUNL (mg N day-1) 902 301 37.2 2,542
Protein equivalent of EUNL (g day-1) 5.6 1.9 0.23 15.9
Glucose equivalent of EUNL (g day-1) 3.2 1.1 0.13 9.1
Theoretical nitrogen cost of brain glucose demand relative
to reported endogenous urinary nitrogen loss (%)
97 93 221 1042
Protein is assumed to contain 16% nitrogen
a Ro?hrs and Ebinger (1999), b Tauson et al. (2001), c Kruska 1993, d Sokoloff et al. 1977, e Table 4, this paper, f Jungas et al. (1992), g Hendriks
et al. (1997), h Miller and Allison (1958), i Uezu et al. (1983), j Hendriks et al. (1997), k Calloway and Margen (1971), l Scrimshaw et al. (1972)
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predicted from brain glucose demand and reported EUNL
for both cats and mink. By contrast, the theoretical protein
cost of brain glucose requirements greatly exceeds
observed EUNL values in rats and humans, because in the
fed state endogenous nitrogen loss is determined by protein
turnover, not by glucose demand.
The relationship between brain glucose demand and
EUNL shown in Table 5 strongly supports the hypothesis
that high endogenous nitrogen losses in cats and mink are
the consequence of augmentation of the ONL sensu stricto
by constitutive protein-based glucose production, or
obligatory gluconeogenesis. The brain is not the only tissue
with an absolute glucose requirement, but cats have large
brains that are likely to account for at least half of the
obligatory glucose demand in the non-reproductive, resting
state. Underestimation of the whole-body glucose demand
of cats by considering only the needs of the brain is offset
to some degree by the fact that cats will derive a proportion
of their endogenous glucose production from glycerol, as
discussed above. Pending further studies, the model of
endogenous nitrogen loss in cats presented here must be
considered hypothetical. But if the protein requirements of
cats and other small hypercarnivores are indeed determined
by two factors, obligatory gluconeogenesis and protein
turnover, then this explains not only the high protein
requirement of cats and the observed discrepancy between
rates of protein synthesis and protein oxidation (Russell
et al. 2003), but also the question of why fasting nitrogen
excretion in cats is lower than the EUNL (Table 1). The
discrepancy resolves if it is assumed that all or most of the
cat?s endogenous glucose demand is synthesised from
amino acids in the fed state. During the transition to pro-
longed starvation, cats develop increasing hyperketona-
emia (Blanchard et al. 2002). Partial replacement of brain
glucose by ketone bodies (Owen et al. 1967) permits
reduction of the rate of gluconeogenesis from protein, and
thus results in a decrease of nitrogen excretion.
Considering possible objections to the model proposed
here, two obvious points are: (1) obligatory gluconeogen-
esis carries a metabolic cost; and (2) why should obligatory
gluconeogenesis be maintained in domestic cats provided
with high-carbohydrate, low-protein foods by humans?
1. While obligatory gluconeogenesis releases hypercar-
nivores from any dependence on dietary carbohydrate,
a potential disadvantage is that it reduces metabolic
flexibility and renders the animal incapable of adapting
to diets low in protein. However, cats evolved to
consume a highly digestible diet containing 30% or
more of ME as protein and less than 5% of ME as
carbohydrate (Table 2). On such a diet, the risks
associated with a transiently negative nitrogen balance
as a result of obligatory gluconeogenesis are small
relative to the acute threat of impaired function of the
brain and other organ systems due to hypoglycaemia.
It follows that for a hypercarnivore, not only there is
no adaptive advantage in developing a tolerance for
low-protein diets, but also there is a need to maintain
the capacity for high rates of protein-based
gluconeogenesis.
2. Even if wild felids rarely consume carbohydrate in
nature, the domestic cat consumes a large proportion
of human-supplied foods containing 15?35% of ME as
carbohydrate (Table 2). Thus, domestication would
seem to favour cats that can adapt to carbohydrate
loads by reducing obligatory gluconeogenesis from
protein; on the other hand, it is not clear that the
selection pressures cats have been subject to have been
sufficient to force this kind of metabolic reassessment.
Systematic feeding of cats, although ritually practiced
by the ancient Egyptians (MacDonald et al. 1984), is a
phenomenon of the twentieth century (Siewert 2003).
For most of their history together, humans have
contributed little to the feeding of cats (Siewert
2003; Driscoll et al. 2009), and to this day cats will
supplement their diet with prey (Liberg 1984; Weber
and Dailly 1998; Baker et al. 2005; Biro? et al. 2005),
unless confined indoors in rodent-free premises (e.g.
research laboratories). Thus, the diet to which the
modern domestic cat is habituated is a mixture of
human-supplied food and high-protein vertebrate prey,
and is likely to contain a least 30% of ME as protein
(Table 2). Farmed mink, another domesticated hyper-
carnivore, are fed diets that contain 30?40% of ME as
protein to promote fur production (Damgaard et al.
1998). It follows that failure to adapt to provision of
dietary carbohydrate by reducing obligatory gluconeo-
genesis from protein is unlikely to carry the risk of
protein deficiency in cats and mink, and continued
exposure to large dietary protein loads provides an
ongoing incentive to maintain the metabolic status
quo. However, as discussed above, there is evidence to
suggest that excess dietary carbohydrate increases the
risk of obesity and diabetes in pet cats.
One consequence of the composite ONL of hypercar-
nivores proposed here is that it alters the relationship
between metabolic mass and endogenous nitrogen loss. It
has been known for a long time that endogenous nitrogen
loss in mammals (ONL and EUNL) is proportional to basal
metabolic rate and metabolic body mass, BM0.75 (Smith
1926; Lusk 1928; Brody 1945; Kleiber 1975; Henry and
Collingwood 1998). But if endogenous nitrogen loss in
hypercarnivores is in fact an incremental combination of
two factors, one (the nitrogen cost of protein turnover)
expected to scale with metabolic body mass and the other
J Comp Physiol B (2011) 181:1?17 11
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(the nitrogen cost of glucose synthesis) expected to scale
with brain mass, then the ONL of hypercarnivores is pre-
dicted to increase with decreasing species size, because
brain mass and brain metabolic rate do not scale with
metabolic mass (Eisenberg 1981; Gittleman 1986; Kruska
2005; Fig. 1; Table 4). Conversely, in very large hyper-
carnivores, the basal rate of oxidation of amino acids due to
protein turnover is likely to be sufficient to meet endoge-
nous glucose demands, making catabolism of additional
amino acids for gluconeogenesis unnecessary.
Summary and outlook
Cats have evolved a high capacity for de novo production
of glucose from amino acids to solve the problem of how to
thrive on a hypercarnivorous diet while being a small
mammal with a large brain. According to the model pre-
sented here, cats do not have a high protein requirement per
se, but rather a secondarily elevated protein requirement in
response to a high endogenous glucose demand, thus
resolving the paradox identified by Russell et al. (2003).
Constitutively high rates of gluconeogenesis in cats are
adaptive on their natural diet, i.e. when little or no carbohy-
drate is consumed, but may predispose cats to developing
hyperglycaemia and insulin resistance, and their metabolic
sequelae, on diets that contain significant proportion of ME as
carbohydrate. Actual avoidance of excess carbohydrate
intake may help explain poor acceptance of synthetic diets
offered to cats in anthropogenic settings (Green et al. 2008),
and it would be interesting to test whether hypercarnivores
balance carbohydrate intake, as has been found for fat and
protein (Mayntz et al. 2009). Further study is required to
specifically quantify rates of gluconeogenesis, protein syn-
thesis, and protein oxidation in cats fed different levels of
protein and carbohydrate. The available evidence suggests
that cats do not significantly downregulate gluconeogenesis in
response to carbohydrate intake, but this assumption remains
without direct experimental support. For example, if gluco-
neogenesis in cats is suppressed to a small degree by dietary
carbohydrate, then this effect may, at marginal intakes of
protein, make the difference between positive and negative
nitrogen balance. The potential effects of high or variable
dietary carbohydrate content in experimental diets need to be
considered in the design and interpretation of nutritional and
metabolic studies. Given the proposed relationship between
endogenous glucose demand and nitrogen metabolism, it
would also be interesting to investigate changes in rates of
gluconeogenesis and protein requirements in physiological
states characterised by an increased glucose demand, such as
immaturity, pregnancy, lactation, and trauma.
In summary, the allometric relationship between brain
size, metabolic rate, and nitrogen requirements is predicted
to follow a different trajectory in hypercarnivores com-
pared with other mammals as a result of the additional
nitrogen cost of obligatory gluconeogenesis, a hypothesis
that can be tested by comparing hypercarnivores of a
similar degree of encephalisation but different body size
(e.g. stoat, tiger). Thus, it may be predicted that hyper-
carnivory in mammals imposes constraints on minimal
body size and degree of encephalisation that differ from the
effects of metabolic rate alone. It also suggests that care
should be taken when using protein requirements of the
domestic cat as the basis for predicting requirements of
larger hypercarnivores in captivity.
Acknowledgments Much of the work on an earlier draft of this
paper was done while I was a fellow at the Smithsonian National
Zoological Park, and I thank J. Seidensticker for his encouragement
and support of this endeavour. I also wish to thank S. Lumpkin and M.
Power for commenting on an earlier version of the manuscript, and J.
Noordhof and in particular O. Oftedal for critical discussions of the
subject matter. I also thank my anonymous reviewers, D. Millward
and especially G. Lobley for their time and constructive comments.
This work was supported by a grant from the National Science
Foundation-Office of Polar Programs No. 0538592.
Appendix: Total carbohydrate in a mouse
The calculation presented here was intentionally done as a
?best-case scenario? to estimate the maximal amount of
digestible carbohydrate a cat could derive from consuming
gut contents of small, granivorous rodent prey. Data used
in the calculation include body composition of Swiss
albino mice (Bailey et al. 1960) and mouse gut volumes
from Cizek (1954). Mice were chosen because they are
granivorous rather than herbivorous, have a relatively large
gut volume (Cizek 1954), and body composition data are
readily available. It is assumed that gut contents consist
entirely of finely ground whole wheat grain (composition
of dry matter: 11.2% fibre, 73.9% starch and dextrins, 2.6%
sugars: Paul and Southgate 1978), and that digestibility of
starch in gut contents is 97.2% in cats (Morris et al. 1977).
It is further assumed that cats cannot digest non-starch
polysaccharides to a significant extent (NRC 2006) but that
simple sugars are completely digested. BM, body mass.
Glycogen in liver and muscle
(a) Liver mass and glycogen content
Liver mass of adult mice = ca. 5% of body mass
(Von Ehrenstein 1958; Barnett and Widdowson
1965; Chaffee et al. 1966).
Liver glycogen content in mice (Ryder et al. 1999):
100?400 lmol glucose g-1 liver wet mass, equiv-
alent to 1.8?7.2 g glucose 100 g-1 liver.
12 J Comp Physiol B (2011) 181:1?17
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(b) Skeletal muscle mass and glycogen content
Skeletal muscle mass in rats is ca. 64% of lean body
mass and ca. 45% of BM (Even et al. 2001); this is
consistent with ash-free, fat-free carcass mass (an
approximation of total skeletal muscle mass) in mice
of ca. 44% of BM (Corva and Medrano 2000).
Muscle glycogen content (Ryder et al. 1999):
20 lmol glucose g-1 wet muscle, 0.4 g glucose
100 g-1 wet muscle.
Please note that mouse muscle contains consider-
ably less glycogen than human muscle tissue
(0.2?0.4 vs. 2%).
Combining (a) and (b):
Assume mouse 22 g, 14% body fat, 18.92 g lean mass
Approximate liver mass (5% BM) 1.1 g
Glycogen in liver (7%) 77 mg
Muscle mass (45% of BM) 9.9 g
Glycogen in muscle (0.4%) 40 mg
Total glycogen 0.124 g
Digestible carbohydrate in the digestive tract of prey
Body mass mouse 22 g
Gut contents (DM) 0.30 g
73.8% starch ? dextrins 0.219 g
90.972 0.212 g
Sugars, 2.6% 0.008 g
Total available CHO 0.220 g
3.69 kJ
Summary: total carbohydrate (CHO)
Glycogen in liver and muscle
(see also Table 2)
0.124 g
Available carbohydrate
in gut contents (above)
0.220 g
Total available CHO
(916.76 kJ g-1)
0.344 g
5.76 kJ
Total ME of mouse (see Table 2) 8.60 kJ g-1
188.3 kJ
Carbohydrate as %ME (5.76/188.3) 9 100 = 3.1%
In 6 mice (equivalent to daily ME)
Total ME 1,135.2 kJ
ME from carbohydrate 34.6 kJ
Total carbohydrate 2.1 g
Even in the best-case scenario presented here, consump-
tion of gut contents would contribute insufficient glucose
equivalents to meet estimated whole-body carbohydrate
demand (the brain alone consumes ca. 3 g glucose day-1;
Table 4), assuming that cats actually consume gut contents.
Prey larger than mice, such as rabbits, tend to be herbivorous
rather than granivorous and possess fermentative digestion;
it is questionable whether cats would consume partially
digested herbage and if they did, it is unlikely cats could
derive significant carbohydrate from this source. In general,
neither cats (Leyhausen 1979) nor large felids such as tigers
(Panthera tigris) and mountain lions (Puma concolor)
consume the gut contents of their prey (J. Seidensticker, pers.
comm., 01 June 2009).
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