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APPETITE, OBESITY AND METABOLISM
1Research Diets, Inc., New Brunswick 08901; 2Neurology Service (127C) Veterans Affairs Medical Center, East Orange 07018; and 3Department of Neurosciences, New Jersey Medical School, Newark, New Jersey 07103
Submitted 30 April 2003 ; accepted in final form 23 May 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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5 wk of age. Here we assessed
the development of metabolic and neural functions for insights into the
origins of their greater weight gain. From week 5 to week 10,
chow-fed DIO rats gained 15% more body weight and ate 14% more calories
but had only slightly greater adiposity and plasma leptin than DR rats. From
day 3 through week 10, DIO and DR rats had similar mRNA
expression of arcuate nucleus neuropeptide Y, proopiomelanocortin,
agouti-related peptide, and all splice variants of the leptin receptor (OB-R).
When fed a high-energy (HE; 31% fat) diet, 7-wk-old DIO rats had a 240%
increase in plasma leptin levels after only 3 days. Despite this early leptin
rise, they maintained a persistent hyperphagia and became more obese than
chow-fed DIO rats and DR rats fed chow or HE diet. Their failure to reduce
caloric intake, despite high levels of leptin, suggests that selectively bred
DIO rats might have reduced leptin sensitivity similar to that seen in the
outbred DIO parent strain. leptin receptor; neuropeptide Y; proopiomelanocortin; agouti-related peptide; arcuate nucleus
In outbred Sprague-Dawley rats fed a 31% fat [high energy (HE)] diet, about one-half develop DIO, while the rest are resistant to obesity and gain no more weight than chow-fed controls (diet resistant, DR) (27). Adult outbred DIO-prone rats overexpress neuropeptide Y (NPY) in the arcuate nucleus (ARC) of the hypothalamus relative to DR-prone rats (22). Once the DIO genotype is achieved after exposure to HE diet, ARC NPY becomes "normalized" or even lower in DIO compared with DR rats (23, 27). This suggests that elevated NPY predisposes DIO rats to gain weight when the energy density of the diet is increased.
While this outbred model is useful for studying adult-onset obesity, it is less useful for examining the early developmental aspects of DIO (30). To address this issue, we selectively bred rats to express either the DIO or DR traits with 100% penetrance (28, 29). Unlike outbred rats, 10-wk-old selectively bred DIO rats weigh more and consume more calories than DR rats even on chow diet (26). Exposure to HE diet for 2 wk exacerbates the weight gain and energy intake differences, and selectively bred DIO rats become more energy efficient and have higher adiposity and plasma insulin levels than selectively bred DR rats (26). Relative to selectively bred DR rats, adult selectively bred DIO rats also underexpress ARC NPY when they become obese (23). This reduced ARC NPY expression is also seen when outbred DIO rats become fully obese after 3 mo on HE diet (22).
Because the data on the early development of these selectively bred DIO and DR substrains are sparse, the present studies were performed to characterize the early development of these rats with regard to weight gain, body composition, and hypothalamic neuropeptide expression. One goal was to determine the developmental period at which body weight and energy intake first differed between the genotypes and to determine if any alterations in NPY, proopiomelanocortin (POMC), agouti-related peptide (AgRP), and leptin receptor (OB-R) mRNA expression might predate these changes. A second aim of this study was to examine the early body weight, energy intake, and plasma leptin response to HE diet in these selectively bred substrains.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Animal usage was in compliance with the animal care committee of the E. Orange Veterans Affairs Medical Center and the "Guiding Principles for Research Involving Animals and Human Beings" of the American Physiological Society (2). Male selectively bred DIO and DR rats raised in our own vivarium were used (26). To reduce potential effects of litter size on body weight gain, litters were culled to n = 10 on postnatal day 2 (P2). Pups were weaned onto Purina 5001 rodent chow and water ad libitum on P21. All rats were housed at 23-24°C on a 12:12-h light-dark cycle (lights off at 1800).
Ontogeny Study
Animals from both selectively bred genotypes were killed from P2 to P70. Pups were removed from litters at P2, P7, P10, P14, and P21 for various terminal measurements. At each period, pups from three unrelated litters were used. The pups remaining in the litters were not used for experimental purposes. During the postweaning period, animals were singly housed for food intake measurements (powdered Purina 5001), and animals were killed at P28, P35, P42, P49, P56, P63, and P70.
During the preweaning period, a test of independent ingestion was performed
to determine if DIO-prone rats display hyperphagia before chow or HE diet.
This test has been used to identify adultlike ingestive behavior in preweaning
Zucker fa/fa rat pups
(15). Pups (3-4 from the same
litter) were removed from the dam at 0800 and placed in an incubator at
37°C for 4 h. Just before the test, pups were voided by gently brushing
the anogenital region with a soft cotton-tipped applicator and weighed to the
nearest 0.01 g. Pups were then placed in a beaker containing a Kimwipe soaked
with warm, commercially available half-and-half milk-cream. After 20 min, pups
were removed, dried, and weighed again. The difference in body weight was used
to calculate food intake.
Terminally, all animals were weighed and killed between 0800 and 1100 by decapitation. Trunk blood was collected for measurement of plasma leptin and insulin. Brains were rapidly dissected and immediately frozen on powdered dry ice and stored at -80°C for later sectioning. During the postweaning period, the perirenal, retroperitoneal, mesenteric, and epididymal fat pads were dissected and weighed to the nearest 0.01 g. The gastrointestinal tract contents were removed, and all fat pads were returned to the carcass. All carcasses were frozen at -80°C for later compositional analysis.
HE Diet/Chow Study
On P42, a separate group of selectively bred DIO (n = 11) and DR (n = 19) rats was singly housed for 1 wk and given powdered chow. On P49, DIO and DR rats were randomly selected to remain on powdered chow or were switched to powdered HE diet for 14 days. The HE diet is composed of 8% corn oil, 44% sweetened condensed milk, and 48% Purina 5001 (Research Diets, C11024 [GenBank] ) and has an energy density of 4.47 kcal/g with 21% of the metabolizable energy as protein, 31% as fat, and 48% as carbohydrate, 50% of which is sucrose. Food intake and body weight were measured after 1, 2, 3, 7, 10, and 14 days on diet. Tail blood samples (0.5 ml) were taken after 0, 3, 7, 10, and 14 days on diet. Because no direct measure of adiposity was made in this original study, a second set of selectively bred P42 DIO and DR rats was fed either chow or HE diet for 14 days (n = 8/group). Terminally, their epididymal, retroperitoneal, perirenal, and mesenteric fat pad and body weights were obtained.
Plasma Leptin and Insulin Levels
Blood was collected in heparin-coated tubes, and the plasma was assayed by RIA for leptin and insulin (Linco).
Carcass Composition
Analyses were performed as previously described (5). Samples of the ground carcass were sequentially analyzed for water, fat, and ash content. Independent samples were taken for nitrogen analysis. Water content was determined by desiccation. The desiccated sample was analyzed for fat content by extraction in a Soxhlet apparatus, with ethyl ether as the solvent. The defatted samples were combusted in a muffle furnace at 810°C to assess residual ash content. Nitrogen was determined by Kjeldahl analysis on a separate sample. Body protein was calculated from nitrogen wherein protein = nitrogen x 6.25.
In Situ Hybridization
Serial 15-µm sections were taken through the rostrocaudal extent of the
arcuate (ARC) hypothalamic nuclei. Sections were processed for in situ
hybridization by minor modifications of previously described methods
(23). Frozen sections of brain
were freeze thawed onto gel-coated slides and fixed in 4% paraformaldehyde.
The slides were treated with acetic anhydride for 10 min and dehydrated
through six steps of graded ethanol solutions and frozen at -80°C until
use. In situ hybridization was carried out as previously described
(24). Briefly, cRNA was
synthesized and radiolabeled from probes for NPY (511 bp), POMC (923 bp), AgRP
(348 bp), and a probe that recognizes all splice variants of the leptin
receptor (OB-R; 3,559 bp). The probes were hydrolyzed in 0.5 M
NaHCO3 for 15-30 min. The probes were then subjected to our
standard method for in situ hybridization
(23). On completion of
hybridization, slides were opposed to SB-5 X-ray film (Kodak, Rochester, NY)
for 24-48 h (NPY, POMC, AgRP) or for 3 wk (OB-R). The resulting
autoradiograms were read by an experimentally "blinded" observer
using computer-assisted densitometry (Drexel University, Philadelphia, PA).
Areal and optical density measures were made through the entire rostrocaudal
extent of the hypothalamus. Because the product of optical density and area
did not alter the results, the data are presented as area alone.
Statistics
Parameters were compared between DIO and DR groups over time by one-way ANOVA. Where significant intergroup differences were found at a given time point, data were compared with post hoc Bonferroni comparisons. Data for the study assessing responses to chow vs. HE diet were assessed using two-way ANOVA with repeated measures. In addition to direct carcass composition, we calculated fat pad index by dividing the sum of four fat pads (retroperitoneal, perirenal, mesenteric, and epididymal) by body weight. There is very good agreement between the sum of these four fat pads and the total grams of fat as determined by carcass analysis (correlation coefficient r = 0.98). Feed efficiency was estimated by dividing the presumed gain in metabolic mass (body wt in kg0.75) by the number of calories ingested over the same period of observation.
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RESULTS |
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Body weight, adiposity, plasma leptin, and insulin. Although body
weights of DIO and DR rats were similar before weaning, DIO rats became
significantly heavier than DR rats beginning at P35, or 2 wk post-weaning
(Table 1). They remained
15% heavier for the remainder of the study period. Generally speaking,
the increase in body weight of DIO compared with DR rats was due to a
proportional increase in both carcass protein and fat content. Over the entire
period of assessment, DIO rats had greater carcass protein content than DR
rats (Table 1;
F1,74 = 98.13; P = 0.001). While DIO rats did not
have heavier body weights than DR rats until P35, they already had 8% more
total carcass protein mass by 14 days and 43% more by P28. The magnitude of
this difference decreased with age such that DIO rats generally had 14-16%
more carcass protein than DR rats from day 42 to day 70. At
no time did the relative amount (%) of carcass protein differ between DIO and
DR rats. DIO rats were fatter than DR rats when carcass fat was considered as
a percentage of total carcass weight (6.3 vs. 6.0%; F1,174
= 8.8; P = 0.003). Even so, post hoc analysis revealed significance
only on P7, and they never had more total carcass fat mass than DR rats. In
addition, four fat pad weights (retroperitoneal, perirenal, mesenteric, and
epididymal) were recorded in the postweaning period, and the sum of these
weights was used to calculate a fat pad index
(Table 2). During the
postweaning period, DIO rats had greater overall adiposity as a function of
pad to carcass weights (F1,114 = 23.9; P <
0.001), although there were no significant differences at any selected time
point by post hoc analysis for this measure of adiposity.
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Plasma leptin levels were consistently detectable from P10 and on. In general agreement with the measures of adiposity, DIO rats had slightly increased plasma leptin levels overall (1.69 ± 0.12 vs. 1.22 ± 0.07 ng/ml; F1,164 = 19.6; P < 0.001). However, post hoc testing showed higher levels in DIO rats only at P56 (+277%) and P63 (+207%) (Table 1). Plasma insulin levels were similar between the genotypes throughout the study period (Table 2).
Energy intake and feed efficiency. On average, DIO rats consumed
14% more calories per week than DR rats during the postweaning period
(F1,114 = 72.1; P < 0.001;
Table 2). However, post hoc
testing showed that DIO rats consumed 18 and 13% more calories than DR rats
only during weeks 7-8 (P49-P55) and weeks 8-9 (P56-P62),
respectively (P < 0.005). While DIO rats were slightly more feed
efficient (+7%) than DR rats during the postweaning period
(F1,114 = 3.96; P = 0.05), there were no
significant differences between the genotypes at any given week
(Table 2).
To determine whether the hyperphagia that selectively bred DIO rats display in response to a high-energy diet as adults (26) was present during the preweaning period, we employed a model of ingestion independent of the dam (13). The intake of half-and-half was measured over 20 min in thermoneutral pups who were deprived of the dam (but not siblings) for 4 h. Because independent ingestion behavior has more in common with adult ingestive behavior than with suckling (13), this method can be used to identify early hyperphagia of adultlike eating behaviors (15). Selectively bred DIO pups did not ingest more than selectively bred DR pups at any age studied (Fig. 1). Interestingly, selectively bred DR pups were hyperphagic relative to selectively bred DIO pups on P14 (genotype x age interaction; F4,159 = 2.9; P = 0.02; post hoc at P14; P = 0.03).
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Hypothalamic expression of NPY, POMC, AgRP, and OB-R mRNA. Given the early postweaning increases in body weight and energy intake in DIO rats, we examined whether alterations in gene expression of key hypothalamic neuropeptides or receptors might predate, and therefore possibly play a causal role in, these phenotypic differences. By hybridization, ARC NPY, POMC, or AgRP mRNA expression was no different between DIO and DR rats at any age (Fig. 2). Similarly, expression of ARC OB-R mRNA expression did not differ between DIO and DR rats at any age (Fig. 2D).
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HE Diet Study
After being weaned onto chow, a subset of DIO and DR rats was given either chow or HE diet at 7 wk of age and fed ad libitum for 14 days. After just 1 wk on diet, DIO rats fed HE diet increased their body weight by 23%, while DR rats fed HE diet and chow-fed DIO and DR rats gained 17, 19, and 19%, respectively (F3,27 = 10.8; P < 0.001; Fig. 3A). The response to HE diet was genotype specific as DR rats fed either chow or HE diet showed no difference in percent body weight gain. The relatively large increase in body weight in DIO rats fed HE diet was due, in part, to increased caloric intake (Fig. 3B). On HE diet, DIO rats rapidly increased their energy intake compared with all other groups. By the end of the first week, average daily energy intake in DIO rats fed HE diet was 111 ± 3 kcal compared with 82 ± 3, 83 ± 4, and 76 ± 2 kcal for chow-fed DIO rats and DR rats fed either HE diet or chow, respectively (F3,27 = 22.0; P < 0.001). The increased caloric intake of DIO rats on HE diet was entirely due to the increased caloric density of the HE diet because they ate the same weight of HE diet (24.8 ± 0.7 g) as did DIO rats fed chow for that period (24.8 ± 0.9 g). Importantly, while DR rats did increase their caloric intake when first exposed to HE diet, they reduced their caloric intake to the level of chow-fed DR rats by the end of the first week. Unlike DIO rats on HE diet, DR rats fed HE diet compensated for the increased caloric density of the HE diet and ate significantly less HE diet by weight (18.6 ± 0.9 g) than chow-fed DR rats (23.0 ± 0.6 g) over the first week. Thus DIO rats on HE diet had a higher average daily energy intake than all other groups from day 2 onward (P < 0.005 for all) and never compensated for the increased caloric density of the HE diet. This increase in caloric intake appeared to be primarily responsible for the increased weight gain in DIO rats on HE diet as their feed efficiency did not differ from any of the other groups at any time (Fig. 3C). By the end of 14 days on HE diet or chow (Table 3), DIO rats, regardless of diet, weighed more than DR rats (F3,28 = 6.34; P = 0.002). However, this greater overall weight was due to the fact that DIO rats on HE diet weighed more than all other groups. Similarly, only the DIO rats on HE diet had elevated adipose mass compared with the other groups when assessed by either total weight of all four depots (F3,28 = 7.16; P = 0.001) or as the weight of these depots expressed as a percentage of body weight (F3,28 = 5.22; P = 0.050).
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After just 3 days on HE diet (before the emergence of any differences in body weight), plasma leptin increased by 230% (P = 0.046) in DIO rats vs. chow-fed DIO rats, as well as both groups of DR rats (F3,24 = 5.9; P = 0.004; Fig. 4A). Thereafter, plasma leptin levels continued to rise and were 270% of those in chow-fed DIO rats after 14 days on HE diet. By comparison, intake of HE diet had no significant effect on plasma leptin levels in DR rats at any time during the 14 days. Plasma insulin levels tended to increase by 3 days in both DIO (70%) and DR (61%) rats on HE diet, but these levels did not differ statistically from their chowfed controls. On average, plasma insulin levels were higher in DIO rats fed HE diet over the course of the 14-day period. However, due to large variability in the data, there were no significant differences between groups at any time (Fig. 4B).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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5%
fatter and generally had only slightly elevated plasma leptin levels compared
with DR rats. Thus chow-fed DIO rats in the current study were larger but only
slightly fatter than DR rats over the first 10 wk of life. This differs from
the original description of these substrains in which chow-fed selectively
bred DIO rats had 44% more carcass fat than selectively bred DR rats at 10 wk
of age (26). However, those
rats were the fifth generation of these substrains, and the current rats
represent over 20 generations of selective breeding. Obviously, continued
breeding has changed the way in which these animals regulate their carcass
composition. The increase in body weight and lean body mass in the current DIO
rats is somewhat puzzling because the outbred DIO rats, from which the
selectively bred DIO rats were derived, actually have reduced growth hormone
secretion before (18) and
after (19) the expression of
DIO on HE diet. Regardless of the underlying mechanism, hyperphagia is
probably the primary reason for the increased weight gain of these animals.
Their failure to become obese on chow in the face of hyperphagia is probably
related to the combination of the low fat content of chow (4.5%) and their
rapid growth during the early postweaning period. Unfortunately, the
assessment of ARC NPY, AgRP, POMC, or OB-R mRNA expression failed to provide
any clue as to why these rats become spontaneously hyperphagic on chow. However, while the current selectively bred DIO rats no longer become obese as a result of their hyperphagia on chow, their propensity to become obese on HE diet has clearly been retained over the successive breeding cycles. An interesting feature of the development of DIO on HE diet was the failure of DIO rats to downregulate their caloric intake when the caloric density of the diet was increased. Unlike the selectively bred DR rats that quickly reduced the weight of food consumed to compensate for the increased caloric density of the HE diet, DIO rats failed to compensate for their increased caloric intake over 14 days. This occurred despite an early and marked increase in plasma leptin levels that should have led to reduced intake (33). Therefore, the current selectively bred DIO rats require increased caloric density and fat content of their diet to become obese. This obesity develops largely because of hyperphagia, which is unabated by an early increase of plasma leptin levels.
This finding suggested that selectively bred DIO rats might have reduced leptin sensitivity similar to that seen in outbred DIO rats (25). Therefore, it was unexpected that chow-fed selectively bred DIO rats did not exhibit the same increase in arcuate NPY expression seen in chow-fed outbred DIO rats (22, 24), nor did the selectively bred DIO rats have altered leptin receptor mRNA expression using a probe that recognizes all splice variants of the leptin receptor (OB-R). Even so, the fact that selectively bred DIO rats on HE diet remained hyperphagic and had an early elevation of plasma leptin levels, before adipose stores become significantly elevated (31), suggests that they have a reduced ability to sense and regulate leptin. A similar early increase in plasma leptin levels has been reported in unselected (by weight gain genotype) outbred Sprague-Dawley rats (40), both obesity-prone Osborne-Mendel and obesity-resistant S5B/Pl rats (31), and obesity-prone mice (37) fed a high-fat diet. Such increased leptin levels might reasonably be expected to inhibit intake of the HE diet (1). Even without a significant increase in leptin levels, DR rats quickly compensated for the increased caloric density of the HE diet and reduced their total energy intake. However, DIO rats never made this compensation and continued to overeat and become obese on HE diet. Thus, despite normal expression of hypothalamic OB-R mRNA, selectively bred DIO rats appear to have a defect in their ability to monitor and regulate leptin levels, i.e., reduced leptin sensitivity comparable to that seen in the outbred DIO parent strain (25). It is quite possible that, despite their comparable OB-R expression to DR rats, selectively bred DIO rats might have reduced leptin sensitivity based on decreased mRNA and/or receptor protein expression of the long (signaling) form (OB-RB) of the leptin receptor.
Leptin acts through the OB-Rb in the ARC
(39) to reduce the expression
of the anabolic peptides NPY and AgRP
(1,
32) and to elevate POMC mRNA
expression (1). Increased POMC
expression should lead to increased synthesis of
-melanocyte-stimulating hormone, the presumptive agonist for the
catabolic melanocortin-3 and -4 receptors
(11). Thus we had predicted
that selectively bred DIO rats would have elevated ARC NPY expression, as well
as possibly elevated AgRP and reduced POMC expression, preceding the onset of
their hyperphagia. In fact, there were no differences in the expression of any
of these neuropeptides between selectively bred DIO and DR rats throughout
their early postnatal or early adult life. Despite a lack of difference in
neuropeptide mRNA expression, there might still be differences in actual
neuropeptide synthesis or release or in postsynaptic receptor function. There
might also be a more generalized imbalance between anabolic NPY/AgRP and
catabolic melanocortin systems that were not detected by in situ
hybridization. Alternatively, there might well be differences in the
expression of other neuropeptides or transmitters that were not assessed
here.
The factors responsible for the rapid and sustained increase in plasma leptin in selectively bred DIO rats on HE diet or in other rodents on high-fat diet (12, 14, 34, 37) are presently unknown. It is possible that selectively bred DIO rats have reduced renal clearance of leptin. While long-term elevations in leptin are likely due to increased fat mass, hormonally driven shortterm changes in plasma leptin levels can occur in the face of unaltered adipose tissue stores. After 3 days on diet, when leptin levels had increased by 240% in DIO rats on HE diet, there were no differences in body weight [and presumably adipose tissue mass (31)]. While insulin acutely increases leptin release from rat adipose tissue in vitro (3) and plasma leptin levels in vivo in rodents (35), the lack of differences in plasma insulin between the groups in the present study make it unlikely that increased insulin drove the early increase in leptin. Glucocorticoids can increase (7) and sympathetic activity can decrease (38) leptin levels in rodents. However, selectively bred DIO adults have reduced basal corticosterone levels (29) and elevated 24-h urine norepinephrine levels, suggesting a generally elevated level of basal sympathetic activity (26). The most parsimonious explanation is that selectively bred DIO rats have a reduced ability to detect their early increases in plasma leptin and thus are unable to inhibit its release from adipose stores.
The lack of difference between the genotypes in the preweaning independent ingestion test suggests that, at least at an early age, DIO rats do not eat larger meals. However, it should be noted that this test would only detect differences in the ability of the animal to control individual meal size, not meal number. Also, it is possible that performing this test in the morning hours (when pups are less active) precluded us from finding real differences between the groups. However, using a similar protocol, Kowalski et al. (16) found that fa/fa pups had larger single meals compared with wild-type littermates, suggesting that this method is valid for uncovering deficits in the control of single meals during the preweaning period. Clearly, postweaning DIO rats eat more calories when given HE diet. Whether these extra calories are due to increased meal size and/or number and the developmental period during which this first occurs are presently unknown.
In summary, we have identified the early postweaning period as the time when selectively bred DIO rats begin to increase their body weight and caloric intake on chow diet compared with selectively bred DR rats. Unlike early generations of selectively bred DIO rats (26), weight gain in the current generation of DIO rats, produced by more than 20 breeding cycles, was due to a roughly proportional increase in both carcass protein and fat mass. It took exposure to the increased caloric density and fat content of the HE diet to increase plasma leptin and adipose stores in the current selectively bred DIO rats. Their propensity to become obese was not predated by differences in the mRNA expression of ARC NPY, POMC, or AgRP, suggesting that alterations in these neuropeptides might not play a causal role in DIO in this model, nor do differences in the neuropeptide mRNA expression explain the onset of spontaneous hyperphagia of DIO rats on a low-fat diet during the early postweaning period. However, the early rise in leptin levels and failure to respond by decreasing energy intake on an HE diet suggest that reduced leptin sensitivity might underlie their propensity to develop DIO on a diet of increased caloric density and fat content.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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J. N. Gorski, A. A. Dunn-Meynell, T. G. Hartman, and B. E. Levin Postnatal environment overrides genetic and prenatal factors influencing offspring obesity and insulin resistance Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R768 - R778. [Abstract] [Full Text] [PDF]
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B. E. Levin, A. A. Dunn-Meynell, M. R. Ricci, and D. E. Cummings Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats Am J Physiol Endocrinol Metab, November 1, 2003; 285(5): E949 - E957. [Abstract] [Full Text] [PDF]
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B. E. Levin, A. A. Dunn-Meynell, J. E. McMinn, M. Alperovich, A. Cunningham-Bussel, and S. C. Chua Jr. A new obesity-prone, glucose-intolerant rat strain (F.DIO) Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1184 - R1191. [Abstract] [Full Text] [PDF]
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0.05 when postnatal day
14 (P14) DIO rats were compared with P10 DIO rats. bP
