Metabolic consequences of pregnancy-associated plasma protein-A deficiency in mice: exploring possible relationship to the longevity phenotype ...
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Metabolic consequences of pregnancy-associated plasma protein-A
deficiency in mice: exploring possible relationship to the longevity
phenotype
Cheryl A Conover, Megan A Mason, James A Levine and Colleen M Novak
Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905, USA
(Correspondence should be addressed to C A Conover; Email: conover@mayo.edu)
Abstract
Mice born with the deletion of the gene for pregnancy- However, there was an increase in spontaneous physical
associated plasma protein-A (PAPP-A), a model of reduced activity in PAPP-A KO mice. Both WT and PAPP-A KO
local IGF activity, live w30% longer than their wild-type mice exhibited mild insulin resistance with age, as assessed by
(WT) littermates. In this study, we investigated metabolic fasting glucose/insulin ratios. Oral glucose tolerance and
consequences of PAPP-A gene deletion and possible insulin sensitivity were not significantly different between the
relationship to lifespan extension. Specifically, we determined two groups of mice, although there appeared to be a decrease
whether 18-month-old PAPP-A knockout (KO) mice when in the average size of the pancreatic islets in PAPP-A KO
compared with their WT littermates have reduced energy mice. Thus, neither reduced ‘rate of living’ nor altered
expenditure and/or altered glucose–insulin sensitivity. Food glucose–insulin homeostasis can be considered key
intake, and total energy expenditure and resting energy determinants of the enhanced longevity of PAPP-A KO
expenditure as measured by calorimetry were not different mice. These findings are discussed in the context of those
between PAPP-A KO and WT mice when subjected to the from other long-lived mouse models.
analysis of covariance with body weight as the covariate. Journal of Endocrinology (2008) 198, 599–605
Introduction lifespan in PAPP-A knockout (KO) mice. Decreased body
temperature and lowered metabolism in the Ames and Snell
Pregnancy-associated plasma protein-A (PAPP-A) is a dwarf mice, long-lived growth hormone (GH)- deficient
recently discovered metalloproteinase whose major physio- mouse models, would support this theory (Bartke et al. 2001).
logical function, as so far identified, is to increase local It is of note that these mice have low circulating IGF-I due to
insulin-like growth factor (IGF) bioavailability through the the loss of GH-dependent hepatic IGF-I expression. Studies
cleavage of inhibitory IGF binding proteins (reviewed in of caloric restriction in rats provide evidence for an
Boldt & Conover 2007). Reduced IGF signaling is associated association between lifespan, circulating IGFs, and metabolic
with a prolonged lifespan in a variety of species (Kenyon rate (Krystal & Yu 1994). Caloric restriction in rhesus
2001, Barbieri et al. 2003, Holzenberger et al. 2004, monkeys also results in decreased core temperature and 24 h
Richardson et al. 2004). Indeed, mice born with the deletion energy expenditure (Lane et al. 1996). On the other hand,
of the PAPP-A gene live w30% longer than their wild-type there are several examples of reduced insulin and/or IGF-I
(WT) littermates (Conover & Bale 2007). However, the signaling where the organism does not have to be
mechanism(s) underlying this enhanced longevity have yet to metabolically compromised to age slowly (Barbieri et al.
be determined. With this study, we initiated investigation into 2003, Holzenberger et al. 2003, Hulbert et al. 2004).
key factors involved in lifespan extension in a mammalian Furthermore, a progressive rise in insulin resistance is
model of reduced local IGF action. associated with aging (Ferrannini et al. 1996, Facchini et al.
Together, with insulin, IGFs are important regulators of 2001), and a direct cause and effect relationship has been
cell metabolism and growth. The ‘rate of living’ theory of suggested. The ‘altered glucose–insulin system’ hypothesis
aging posits that a decrease in overall metabolic rate decreases suggests that the lifetime maintenance of low levels of glucose
the production of reactive oxygen species (ROS) during and insulin can explain life extension (Masoro 2005).
respiration, thereby slowing the aging process (reviewed in Invertebrate models have been particularly informative
Masoro 2005). If so, then reduced IGF signaling might result (Broughton et al. 2005). However, animal models of extended
in decreases in metabolism that could explain the increase in lifespan are somewhat controversial in this regard. In support
Journal of Endocrinology (2008) 198, 599–605 DOI: 10.1677/JOE-08-0179
0022–0795/08/0198–599 q 2008 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org
Downloaded from Bioscientifica.com at 03/08/2022 10:21:20PM
via free access600 C A CONOVER and others . Metabolic profile of PAPP-A knockout mice
of this hypothesis, GH-deficient and GH-resistant dwarf mice 60 s for 25 h, except for the reference samples collected for
with reduced circulating IGF-I show decreased fasting levels 5 min after every 30 samples throughout the 24-h measure-
of glucose and insulin and increased insulin sensitivity ment period. Data for each calorimeter were monitored and
(Dominici et al. 2002, Coschigano et al. 2003, Bonkowski compared with ensure that the data collected and reference
et al. 2006). There is a similarly reduced glucose–insulin values were comparable between sets of equipment. Data
profile with caloric restriction (Richardson et al. 2004). collected included VO2 and VCO2 (both in ml/kg per h),
Seemingly against a direct relationship between aging and respiratory exchange ratio (RER, VCO2/VO2), and energy
insulin resistance are the long-lived Klotho transgenic mice. expenditure ((3.815C1.232!RER)!VO2) in kcal/h).
These mice have an increase in lifespan and are insulin and Food and water were supplied ad libitum. The calorimetry
IGF-I resistant (Kurosu et al. 2005). and physical activity data were calculated every minute, and
In this study, we focused on the basic metabolic and activity the energy expenditure data were 60 s behind the activity data,
profile of PAPP-A KO mice, a model of reduced local IGF-I due to the time needed to move and process the air from
action in the context of normal circulating IGF-I levels the calorimetry chamber. To calculate resting energy expendi-
(Conover et al. 2003, Conover & Bale 2007). Specifically, we ture (REE), we calculated the total daily energy expenditure
tested the hypothesis that aged PAPP-A KO mice have (TDEE) for the minutes where there were no activity counts
reduced energy expenditure and/or altered glucose–insulin for the current and previous 5 min (see physical activity, below)
sensitivity when compared with WT littermates. and averaged them. When the REE is subtracted from the
TDEE, this yields energy expenditure of activity (EEA).
Attached to the calorimeters were Opto-M Varimex
Minor activity monitors. These devices contain 45 collimated
Materials and Methods
infrared activity sensors that gather data regarding physical
activity in three axes (horizontal x and y axes, plus vertical
PAPP-A KO mice
activity) as well as ambulatory activity (which excluded
Mice with the targeted deletion of the PAPP-A gene were repetitive signals from a single beam). Data for physical
generated through homologous recombination in embryonic activity and energy expenditure were collected simul-
stem cells (Conover et al. 2003). These mice were on a mixed taneously every minute, allowing correlation of the two
C57BL/6 and 129 background. WT and PAPP-A KO variables in each animal tested.
littermates from heterozygous breeding were used in studies.
Genotyping was performed by PCR as described previously
Oral glucose tolerance and insulin sensitivity testing
(Bale & Conover 2005). For all experimental animals,
genotypes were reconfirmed on tail DNA at time of sacrifice. For oral glucose tolerance testing, food was removed from
Data from mice with obvious tumors (one 18-month-old cages at w2100 h, and glucose (0.01 ml of a 10% glucose
WT mouse) were eliminated from analyses. All mice were solution per g body weight) administered by gavage at
kept on a 12 h light:12 h darkness cycle with the light phase w0900 h the next morning. Blood was collected from the tail
beginning at 0600 h. vein at 0, 5, 10, 15, 30, 45, 60, 90, and 120 min. Glucose was
measured using a One Touch Ultra glucose meter (LifeScan,
Milpitas, CA, USA). Insulin was measured at 0, 5, 10, 15, and
Food intake, energy expenditure, and spontaneous activity
30 min using an Ultra Sensitive Rat Insulin ELISA Kit from
For food intake, mice were housed for 7 days in a controlled Crystal Chem Inc. (Downers Grove, IL, USA). Area under
environment within individual plexiglas cages that matched the curve was measured using the trapezoid method. For
the chamber used for energy expenditure and activity insulin sensitivity testing, overnight-fasted mice were given
measurements. These cages have ceramic bowls designed not food at 0830 h for 30 min. At 1200 h, mice then received an
to tip allowing daily measurement of ad libitum food intake, i.p. injection of regular insulin (75 mU/kg body weight) with
which was performed for 5 consecutive days. Energy blood collections at 0, 20, 40, and 60 min for glucose
expenditure and physical activity were measured as previously measurements. Insulin sensitivity was assessed by comparing
reported (Novak et al. 2006, Barbosa et al. 2007). At least rate-of-decay curves.
24 h before the time of measurement, each mouse was allowed
to acclimate to the testing conditions in a cylindrical chamber
Pancreas immunohistochemistry
(7 l; 30 cm diameter!10 cm high) in the testing area. To
measure energy expenditure, custom made small animal The pancreas was carefully dissected, fixed in formalin,
calorimeters with a 7 l cylindrical chamber (Columbus embedded, and processed as described by Devedjian et al.
Instruments; Columbus, OH, USA) were used. For (2000). Briefly, the entire pancreas was cut in 5 mm sections
calorimetry, the sample flow rate was set at 0.4 l per min every 150 mm and every other section stained for insulin by the
(lpm), and the chamber flow rate at which room air pumped Tissue and Cell Molecular Analysis Core Lab using guinea
through the chamber was set at 0.45–0.7 lpm, depending pig anti-swine insulin antibody from Dako (Carpinteria, CA,
on the size of the mouse. Samples were collected once every USA). The Nikon Microphot-FXA and Nikon ACT-1 Version
Journal of Endocrinology (2008) 198, 599–605 www.endocrinology-journals.org
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via free accessMetabolic profile of PAPP-A knockout mice . C A CONOVER and others 601
2.6.2 (Melville, NY, USA) were used to photo-capture the littermates. However, in this case dividing by body weight
slides. The number of islets and islet cell mass were measured may overcorrect energy expenditure values of the larger
using the polygonal lasso tool in Adobe PhotoShop 6.0.1. animals (Packard & Boardman 1999, Arch et al. 2006).
Therefore, the data were subjected to the analysis of covariance
which uses the group (genotype) comparison of regression
Results lines to determine whether the groups differ when body
weight is a covariate. The results of these analyses are presented
Food intake, energy expenditure, and physical activity in Table 2. Differences in TDEE and REE were accounted for
Food intake, energy expenditure, and spontaneous physical by body weight and not by genotype. EEA was not significantly
activity were measured in 18-month-old WTand PAPP-A KO different in WT and PAPP-A KO mice and could not be
mice. Both male and female mice were studied, and the results accounted for by body weight. However, vertical activity was
are presented in Table 1. Food intake, expressed as g/day, and increased 30–110% in PAPP-A KO mice, reaching signi-
TDEE and REE, expressed as kcal/day, were significantly ficance in males (Table 1). Thus, there was no decrease in
decreased in male and female PAPP-A KO when compared energy expenditure in 18-month-old PAPP-A KO mice
with WT mice. However, these calculations do not take into when compared with WT mice which would suggest that a
account the significantly smaller size of the PAPP-A KO compensatory slowing of metabolism was the direct link to
mouse (Conover et al. 2003, Bale & Conover 2005). The longevity. On the contrary, there may be an increase in physical
normalization of the data for body weight indicated activity in the PAPP-A KO mice.
significantly increased food intake (males only), TDEE, and
REE in PAPP-A KO mice when compared with WT Glucose and insulin sensitivity
Table 1 Food intake, energy expenditure, and physical activity. See
Fasting glucose and insulin levels were not significantly different
Materials and Methods for descriptions and calculations. Results are between WTand PAPP-A KO mice at 4 months or 18 months
meanGS.E.M. of (n) mice of age (Table 3). In general, female mice had lower fasting insulin
levels than male mice, which were independent of genotype.
Males
There was an increase in insulin levels in the older animals to
WT (7) PAPP-A KO (12) maintain the same glucose levels, suggesting mild insulin
resistance. This increase tended to be less in the PAPP-A KO
Food intake 4.0G0.16 3.2G0.16a mice but the data did not reach statistical significance. Oral
TDEE 19.4G0.80 16.2G0.41a
REE 17.7G0.94 14.4G0.29a glucose tolerance testing was performed on 12 h fasted WTand
BW 36G2.3 20G0.8a PAPP-A KO mice, both males and females at 18 months of age.
Food intake/BW 0.11G0.005 0.15G0.004b There was no significant difference in the endogenous glucose
REE/BW 0.49G0.016 0.72G0.031b or insulin response to the glucose challenge between PAPP-A
TDEE/BW 0.54G0.019 0.82G0.037b
EEA 1.7G0.14 1.8G0.17 KO and WT mice, either male (Fig. 1A) or female (Fig. 1B).
Horiz 24.6G3.30 26.0G3.19 Total pancreatic islet area and number were not significantly
Vert 4.6G0.92 10.0G1.31b different in 18-month-old WTand PAPP-A KO mice (Table 4).
Ambul 5.8G0.93 5.3G0.77 However, there was a significantly smaller, by w30%, average
Females size of islets in PAPP-A KO when compared with WT mice.
Sensitivity to exogenously administered insulin was not
WT (13) PAPP-A KO (18)
Food intake 3.3G0.17 2.6G0.24a Table 2 Analysis of covariance (ANCOVA) for energy expenditure
TDEE 12.7G0.53 10.5G0.24a measurements. The data in Table 1 were subjected to ANCOVA
REE 11.4G0.55 9.3G0.29a with body weight (BW) as the covariate. Group P value indicates
BW 30G1.7 21G0.8a whether groups are different in the dependent variable (food intake
Food intake/BW 0.11G0.009 0.12G0.009 or EE) after BW is factored out. BW indicates whether the covariate
TDEE/BW 0.43G0.017 0.50G0.021b had a significant effect on the measure. Group*BW interaction
REE/BW 0.38G0.014 0.44G0.020b indicates whether the effect of BW on the food intake or EE of each
EEA 1.1G0.12 1.2G0.07 group is the same. If this is significant, then the interpretation of a
Horiz 24.7G2.90 26.4G1.92 group effect would be hampered
Vert 7.3G1.25 9.7G1.16
Ambul 6.3G0.94 7.2G0.79 P value
Food intake TDEE REE EEA
Food intake (g/d). TDEE, total daily energy expenditure (kcal/d); REE, resting
energy expenditure (kcal/d); BW, body weight (g); EEA, energy expenditure Group 0.640 0.508 0.547 0.432
activity (kcal/d); Horiz, horizontal activity; Vert, vertical activity; Ambul,
ambulatory activity.
BW 0.069 0.016 0.006 0.781
a
Significantly decreased compared with WT. Group*BW 0.546 0.104 0.104 0.444
b
Significantly increased compared with WT.
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Table 3 Fasting glucose and insulin levels
WT PAPP-A KO
n Glucose Insulin n Glucose Insulin
4 months
Males (9) 81G3 0.69G0.137 (9) 89G2 0.46G0.124
Females (8) 88G8 0.38G0.080 (8) 91G8 0.36G0.088
18 months
Males (11) 82G6 1.23G0.194a (10) 79G6 0.94G0.250a
Females (7) 89G7 0.88G0.294a (9) 78G6 0.59G0.100a
Glucose: mg/dl. Insulin: ng/ml. Results are meanGS.E.M. of n mice.
a
Significant difference between 4 months and 18 months.
significantly different in 18-month-old WT and PAPP-A KO longevity of PAPP-A KO mice. Although the underlying
mice, either male (Fig. 2A) or female (Fig. 2B). mechanism was not identified in this series of experiments
designed to test specific hypotheses, the data are relevant in
the context of current controversies in the biology of aging.
Discussion There was no decrease in total or REE in 18-month-old
PAPP-A KO mice when compared with WT mice when the
Mice lacking PAPP-A have relatively normal energy significantly smaller size of the PAPP-A KO mice was taken into
metabolism and glucose/insulin sensitivity compared with account (Packard & Boardman 1999, Arch et al. 2006). Methods
WT, age-matched littermates. Therefore, the findings of this of normalization for body weight can lead to different
study do not support reduced ‘rate of living’ or an ‘altered conclusions and may explain some of the studies with caloric
glucose–insulin system’ as key determinants of the enhanced restriction and apparent decreases in metabolic rate. Further-
more, recent studies have suggested that, after an initial
reduction, caloric restriction leads to equal or higher metabolic
rates than ad libitum fed animals (Faulks et al. 2006). It has been
assumed that a decrease in metabolic rate would prolong lifespan
by deceasing exposure to ROS produced during respiration.
Alternatively, under normal metabolic conditions, tissues from
PAPP-A KO mice may be less vulnerable to oxidative damage
by the virtue of increased ability to eliminate ROS or show
increased mitochondrial efficiency thereby reducing ROS
production. These have been suggested as contributors to
longevity in other model systems (Balaban et al. 2005).
Furthermore, the PAPP-A KO mice had increased physical
activity in the vertical axis. This reached statistical significance
in males, although a similar trend for increased activity was seen
in the females as well. What this behavior might mean can only
be speculated upon at this time. Mice were monitored
individually so it is not likely to be aggressive posturing, but
rather spontaneous physical activity. There have been few
studies monitoring physical activity in the various mouse
Table 4 Islet cell immunohistochemistry. Sections of pancreata
were stained for insulin as described in Materials and Methods.
Results are meanGS.E.M. of (n) mice
Figure 1 Oral glucose tolerance curves from (A) male and (B) female WT (7) PAPP-A KO (8) P value
PAPP-A KO and WT mice. Eighteen-month-old PAPP-A KO (closed
symbols, solid lines) and WT (open symbols, dashed lines) mice Islet
underwent an oral glucose tolerance test as described in Materials Area (Pixels) 49 786G25 531 39 492G8696 0.441
and Methods. Thicker lines represent the glucose response curve Number 147G36 136G25 0.802
and thinner lines represent the insulin response curve. Values are Average size 390G50 278G20 0.048
meanGS.E.M., nZ10. There were no significant differences in AUC (Pixels)
for glucose or insulin between WT and PAPP-A KO groups.
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Fasting insulin/glucose ratios increased significantly with age
in both WT and PAPP-A KO mice, suggesting mild insulin
resistance. Notably, for the purpose of this study, it occurred in
both groups and in both sexes. Thus, PAPP-A deficiency does
not necessarily translate into a ‘youthful’ insulin–glucose profile,
and there was no evidence for sexual dimorphism in insulin
resistance as was seen in liver-specific IGF-I deficient mice with
reduced circulating IGF-I levels (Tang et al. 2005). Eighteen-
month-old WTand PAPP-A KO mice challenged with glucose
had similar glucose tolerance curves. Insulin secretory capacity
was assessed by immunohistochemistry of insulin-producing
b-cells in pancreatic islets. Multiple sections of the total pancreas
were stained for insulin to try to account for heterogeneity of
islet distribution and size. Interestingly, the average size but not
the number or total mass of pancreatic islets was significantly
decreased in PAPP-A KO mice. b-Cell-specific IGF-I receptor
KO mice exhibit normal development of b-cells but defective
glucose-stimulated insulin secretion and impaired glucose
tolerance (Kulkarni et al. 2002). Thus, local IGF signaling
does not appear to be essential for normal growth of pancreatic
islets, which may partially explain the normal islet mass and
number in PAPP-A KO mice. However, secretion of insulin
Figure 2 Insulin sensitivity in (A) male and (B) female PAPP-A KO from pancreatic b-cells is dependent on IGF-I, and a diminished
and WT mice. Eighteen-month-old PAPP-A KO (closed symbols, (but not complete) loss of local IGF-I action in PAPP-A KO
solid lines) and WT (open symbols, dashed lines) mice underwent mice may affect optimal secretory response without major
insulin sensitivity testing as described in Materials and Methods.
Values are meanGS.E.M., nZ6–12. There were no significant impact on overall glucose homeostasis. Comparable studies in
differences in rate-of-decay curves for WT and PAPP-A KO mice. other mouse models of aging indicated decreased glucose
tolerance in Ames and GH-resistant dwarf mice that was due to a
models associated with aging research. In caloric-restricted decrease in total volume of the islets (Parsons et al. 1995, Liu et al.
mice and IGF-I receptor heterozygous mutant mice, there was 2004), perhaps reflecting reduced GH and/or circulating IGF-I.
no difference in total physical activity when compared to Circulating IGF-I, which is not decreased in PAPP-A KO mice,
controls, although dimensional aspects were not recorded is an important component of overall insulin action in peripheral
(Holzenberger et al. 2003, Faulks et al. 2006). Interestingly, tissues (Yakar et al. 2001). This may account for unaltered insulin
spontaneously wiggling Caenorhabditis elegans were longer- sensitivity in PAPP-A KO mice. Caloric-restricted mice
lived than their counterparts that needed to be prodded to maintain glucose homeostasis with markedly less insulin,
move (Herndon et al. 2002). Apfeld et al. (2004) suggest that in which may be associated with increased insulin sensitivity
this model system there is a direct link between activity levels, (Richardson et al. 2004). The co-existence of insulin resistance
insulin-like signals and lifespan. Thus, this aspect of the and enhanced longevity in Klotho male transgenic mice
longevity profile warrants further study. (Kurosu et al. 2005) makes sense, as discussed below, if insulin
Table 5 Metabolic parameters of long-lived mouse models. Data from the present study and other published studies were use to compile this
table comparing PAPP-A KO, Ames dwarf, Snell dwarf, GH receptor KO, Klotho transgenic, calorically restricted (CR) and heterozygous IGF-I
receptor mutant (IGFRC/K) mice. References can be found in the text
PAPP-A KO Ames Snell GHRKO Klotho CR IGFRC/Ka
Lifespan [ [ [ [ [ [ [
Metabolic rate Z Y Y ? Z ZY[ Z
Activity [ ? ? ? ? Z Z
Fasting insulin/glucose Z Y Y Y [Z Y Z
Glucose tolerance Z Y ? Y ? ? Z
Insulin sensitivity Z [ ? [ Y [Z ?
GH Z Y Y [ ? ? ?
Circulating IGF-I Z Y Y Y Z Y [
Local IGF-I action Y ? ? ? Y ? Y
Gluc, Glucose; [, increased compared with control; Y, decreased compared with control; Z, no difference compared with control; ?, not known.
a
Females only.
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via free access604 C A CONOVER and others . Metabolic profile of PAPP-A knockout mice
and/or insulin sensitivity per se was not a key determinant of Declaration of interest
enhanced lifespan. Indeed, the extended lifespan of fat-specific
insulin receptor KO mice may not be primarily due to reduced There is no conflict of interest that would prejudice impartiality.
insulin signaling in adipose tissue, but rather a result of decreased
fat mass (Bluher et al. 2003). The percentage fat is similar in WT Funding
and PAPP-A KO mice (data not shown). Thus, although we
cannot completely rule out a role for reduced insulin signaling as This work was supported by NIH Grant AG028141 and the Ellison Medical
a contributing factor to the longevity of PAPP-A KO mice, the Foundation (to C A C), NINDS 55859, 0635113N from the American Heart
similar fasting and fed levels of insulin ad libitum in WT and Association, and a grant from the Minnesota Obesity Consortium (to C M N),
and NIH grants DK56650, DK63226, DK66270, and R04-0771 (to J A L).
PAPP-A KO mice and the similar insulin sensitivity curves in
the longer-lived PAPP-A KO mice indicate that this role would
not be a decisive one. References
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