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Postnatal Diet-Induced Obesity in Rats Upregulates
Systemic and Adipose Tissue Glucocorticoid Metabolism
During Development and in Adulthood
Its Relationship With the Metabolic Syndrome
1,2 1,2 2 1 2
Sandrine Boullu-Ciocca, Anne Dutour, Viviane Guillaume, Vincent Achard, Charles Oliver,
1
and Michel Grino
Downloaded from http://diabetesjournals.org/diabetes/article-pdf/54/1/197/650781/zdb00105000197.pdf by guest on 04 January 2023
Inhumans,ahyperactivityofglucocorticoidmetabolism
was postulated to be involved in the intrauterine pro- umerous clinical and biological findings indi-
gramming of the metabolic syndrome in adulthood. We
studied in rats the effects of overfeeding, obtained by cate that glucocorticoids are involved in the
reducing the size of the litter in the immediate postna- Npathophysiology of abdominal obesity and its
tal period,atimecrucialforneuroendocrinematuration accompanying complications. Indeed, an ex-
such as late gestation in humans. Overfeeding induced cess of glucocorticoids, when associated with hyperinsu-
early-onset obesity and accelerated the maturation of linism, favors an increase of lipogenesis and a decrease of
the hypothalamo-pituitary-adrenal (HPA) axis together lipolysis, together with a stimulation of hepatic neoglu-
with an upregulation of adipose tissue glucocorticoid cogenesis and an inhibition of peripheral glucose utiliza-
receptor (GR) mRNA. In adulthood, neonatally overfed tion (1). Alterations in the hypothalamo-pituitary-adrenal
rats presented with moderate increases in basal and (HPA) axis have been described in human obesity and in
stress-induced corticosterone secretion and striking rodent models of obesity. They could involve a hyperac-
changesinvisceral adipose tissue glucocorticoid signal- tivity of the central command of ACTH secretion, second-
ing, that is, enhanced GR and 11-hydroxysteroid dehy- ary to an increased exposure or sensitization to stress (2)
drogenase type 1 mRNA levels. The above-mentioned or decreased negative glucocorticoid feedback (3). In
alterations in the endocrine status of overfed rats were addition, changes in peripheral glucocorticoid signaling
accompanied by a moderate overweight status and sig- with increased visceral adipose tissue glucocorticoid re-
nificant metabolic disturbances comparable to those ceptor (GR) concentrations and local reactivation of cir-
described in the metabolic syndrome. Our data demon- culating inert cortisone (11-dehydrocorticosterone in
strate for the first time that postnatal overfeeding rodents) to cortisol (corticosterone) driven by 11-hy-
accelerates the maturation of the HPA axis and leads to droxysteroid dehydrogenase type 1 (11-HSD-1) could
permanent upregulation of the HPA axis and increased play a pivotal role (4). However, the origins of the above-
adipose tissue glucocorticoid sensitivity. Thus, the
experimental paradigm of postnatal overfeeding is a mentioned dysregulations have not been established.
powerful tool to understand the pathophysiology of Clinical and experimental evidence shows that the en-
glucocorticoid-induced programming of metabolic axes. vironment during the perinatal period plays an important
Diabetes 54:197–203, 2005 role in the regulation of both metabolic and hormonal axes
in adulthood. In humans, hyperglycemia and hyperinsulin-
emia in macrosomic fetuses of diabetic mothers were
shown to favor later development of overweight (5).
Conversely, it has been demonstrated that intrauterine
growth retardation, with its subsequent catch-up growth
From the 1Laboratory of Hematology, Institut National de la Sante´etdela that is associated with enhanced adiposity (6), is followed
Recherche Me´dicale (INSERM) Unite´ Mixte de Recherche 626, Faculty of by increased prevalence of the metabolic syndrome in
Medicine, University de la Me´diterrane´e, Marseille, France; and the 2Endocri-
nology and Nutrition Unit, North Hospital, Marseille, France. adults (7). The mechanisms underlying these abnormali-
Address correspondence and reprint requests to Michel Grino, MD, PhD, ties are not yet understood. In rodents, nutritional or
Laboratoire d’He´matologie, INSERM UMR 626, Faculte´deMe´decine, 27 Bd pharmacological manipulations during the perinatal pe-
JeanMoulin,13385MarseilleCedex5,France.E-mail:michel.grino@medecine.
univ-mrs.fr. riod have beenshowntoaffectmetabolicand/orendocrine
Received for publication 2 August 2004 and accepted in revised form 6 regulations in adulthood. Nyirenda et al. (8) have demon-
October 2004. strated that chronic dexamethasone injection during the
11-HSD-1, 11-hydroxysteroid dehydrogenase type 1; AT, adipose tissue;
EAT, epididymal adipose tissue; FFA, free fatty acid; GR, glucocorticoid third week of gestation in rats induces glucose intolerance
receptor; HPA, hypothalamo-pituitary-adrenal; MAT, mesenteric adipose tis- together with upregulation of hepatic PEPCK and GR
sue; NF, normo-feeding; OF, overfeeding; PVN, paraventricular nucleus. mRNAinadult offspring. We have demonstrated that late
©2005 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page gestation maternal undernutrition leads to a decrease of
charges. This article must therefore be hereby marked “advertisement” in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact. HPA axis activity at birth (9). However, it should be
DIABETES, VOL. 54, JANUARY 2005 197
POSTNATAL OBESITY AND GLUCOCORTICOID METABOLISM
emphasized that, in rodents, neuroendocrine maturation
occurs mainly during the postnatal period, as opposed to
primates, in which it takes place during the third trimester
of gestation (10). As a consequence, hormonal studies in
rodents are more appropriate in the postnatal rather than
in the prenatal period. It is established that, in rats, during
the immediate postnatal period, environmental or pharma-
cological manipulations permanently program the HPA
axis. Indeed, adult basal and/or stress-induced corticoste-
rone secretion is increased after postnatal maternal sepa-
ration (11), modified maternal behavior (11), or endotoxin
injection (12) and is decreased after handling (11) and
parenteral (13) or maternal (14) glucocorticoid treatment.
Interestingly, it is known that postnatal overfeeding leads FIG. 1. Evolution of body weight (mean SE) during the suckling
to overweight, metabolic disturbances, and hypertension period (A) and after weaning (B)inNF(n 10) or OF (n 9) rats. Downloaded from http://diabetesjournals.org/diabetes/article-pdf/54/1/197/650781/zdb00105000197.pdf by guest on 04 January 2023
in adulthood (15). We hypothesized that postnatal over- ***P < 0.001, ****P < 0.0001 vs. NF animals.
feeding may impair the development of central and/or
peripheral glucocorticoid regulation that could affect the corresponding to bases 261-1020, 1617-2150, 174-531, and 18-271 of their
metabolic regulations. respectivemRNA.SlideswereexposedtoX-rayfilms(BIOMAXMR;Kodak,Le
Pontet, France) together with 14C standards. Hybridization with the sense
RESEARCH DESIGN AND METHODS probes showed no signal, demonstrating the specificity of the probes (not
All experimental procedureswereapprovedbytheLocalAnimalCareandUse shown). Hybridization signals were quantified on the film autoradiograms
using the Image software and converted to nanocuries per gram using the 14C
Committee. Animals were housed under standard conditions of light (12-h standards. Because GR mRNA expression was very high in blood vessels,
light/dark cycle; lights on at 0600) and temperature (22–24°C), with free adult AT GR hybridizations were quantified on nuclear emulsion–dipped (K5,
accesstotapwaterandstandardpelletdiet.VirginfemaleWistarrats(Janvier, Ilford, Saint-Priest, France; diluted 1:1 in water) slides exposed for 1 month
LeGenestStIsle,France)weretime-mated.Atpostnatalday3(P3),malepups and counterstained with eosin. Brightfield images were captured with a
wererandomlydistributed among the mothers. The litter size was adjusted to charge-couple device camera and digitized. Semiquantitative analysis of GR
10 newborns to induce normo-feeding (NF) or to three pups to induce mRNAwasperformedbymeasuringthesurfaceofthehybridizedareasusing
overfeeding (OF). Animals were subsequently left undisturbed, except for the Image software. Ten randomly chosen fields (0.5 mm2) per section were
weighingandcagecleaningatP8andP14.RatswereweanedatP21,andbody analyzed, and the resulting average values were used for statistical analysis.
weight was recorded throughout life. At the adult age, six randomly selected Adipocyte surface was measured on counterstained paraffin AT sections.
animals per group were housed in metabolic cages to measure daily mean Statistical analysis. Data are presented means SE. Statistical analysis was
food intake and to collect urine. performed using the Statview analysis program. For body, hormonal basal
Basal study. Ten NF and nine OF P8, P14, P21, or adult (4 months) rats were measurements, and PVN in situ hybridizations, statistical analysis was per-
killed by stressless decapitation between 1400 and 1600. Trunk blood was formed using the Student’s t test or two-way ANOVA followed by the Fisher’s
collected in tubes with or without a 5% EDTA solution. Blood was centrifuged test, when appropriate. Circulating parameters during stress exposure or
at 4,000 rpm for 20 min at 4°C, and the resulting plasma or serum was stored intraperitoneal glucose loading were analyzed using repeated-measures
at 70°C until assay. Brain, adrenals, and liver were removed and frozen on ANOVAfollowedbytheFisher’stest.ForATinsituhybridization,weusedthe
dry ice. White fat pads were dissected, weighed, and frozen or paraffin- Mann-Whitney U test to compare mRNA expression between NF and OF rats
embedded. Fat pads were not dissected at P8 for methodological reasons. and the paired Wilcoxon’s test to compare mRNA expression between EAT
Tissues were stored at 70°C until further processing. and MAT. Adipocytes surfaces were compared with the Kolmogorov-Smirnov
Intraperitoneal glucose tolerance test. Rats (n 8/group) were fasted test. P 0.05 was considered significant.
overnight and then injected intraperitoneally with 1.5 mg/kg D-glucose (30%
stock solution in saline). Blood samples were taken under light Forene
anesthesia by tail venesection before injection and 30 and 120 min after the RESULTS
glucose load. Postnatal overfeeding induces early-onset obesity
Hormonal response to stress. Five days before the experiment, adult rats and overweight in adulthood. Body weight was not
(n7/group)weresubjectedtointracarotidcanulationunderdeepequitesine statistically different between groups at P3 and P8. Signif-
anesthesia (0.25 ml/100 g body wt). Canulae were flushed every day with a
heparin-saline solution. Rats were placed into cages attached to a shaking icant overweight was found in P14 and P21 and adult OF
platform for 10 min at 0800. Blood samples were taken from the canula before compared with NF rats (Fig. 1). An increase in all fat pad
and 15, 30, 45, 60, 90, and 120 min after the onset of stress. weight was found in P21 and adult OF rats and in
Assays. Corticosterone was assayed in plasma and urine (after ethanol or adipocyte surface in adult animals (Table 1).
dichloromethane extraction, respectively) using a radioimmunoassay previ- Developing OF rats have glucose intolerance and
ously described (16). Adrenals were dissected free of fat, weighed to the
nearest milligram, and homogenized in a solution of 0.9% NaCl. Adrenal increased circulating leptin and FFA levels. In the NF
corticosterone content was measured using the above-mentioned radioimmu- group, plasma glucose did not differ with age, whereas
noassay. Plasma glucose was measured using an enzymatic method (Bio- insulin and insulin-to-glucose ratio were significantly de-
Me´rieux, Marcy l’Etoile, France). Plasma insulin and leptin were assayed creased at P14. In OF animals, none of the above-men-
using radioimmunoassays (Linco Research, St. Charles, MO). Plasma lipids
were assayed using automatized enzymatic assays (Vitros, Ortho-Clinical tioned parameters was affected at P8, whereas glycemia
Diagnostics, Rochester, NY). Free fatty acids (FFAs) were assayed using an was increased at P14 but not at P21, and insulin and
enzymatic method (Roche, Penzberg, Germany). insulin-to-glucose ratio were enhanced at P14 and P21.
In situ hybridization. Coronal 12-m sections were cut in a cryostat Plasma FFA levels decreased with age and were not
microtome at 20°C through the hypothalamic paraventricular nucleus different between groups. Circulating leptin decreased
(PVN). Sections (12 or 20 m) were cut in liver or epididymal adipose tissue
(EAT) and mesenteric adipose tissue (MAT). Sections were thaw-mounted after P8 in both groups, whereas it was elevated in OF rats
onto gelatin-coated slides, dried on a slide warmer, and kept at 70°C. In situ compared with NF animals (Table 2). The nutritional
hybridization was performed as previously described (17). Corticotropin- manipulation did not change the concentrations of the
releasing hormone (CRH), GR, PEPCK, and 11-HSD-1 antisense probes were
generated by in vitro transcription in the presence of 35S-uridine triphosphate mRNAscodingforGR,11-HSD-1,andPEPCKintheliver
(Perkin Elmer, Paris, France) from cDNA inserted into pPCR script and of P21 animals (299 10 vs. 301 11, 333 41 vs. 323
198 DIABETES, VOL. 54, JANUARY 2005
S. BOULLU-CIOCCA AND ASSOCIATES
TABLE 1 circulating ACTH and corticosterone at P8, whereas it
Fat pad weight and adipocyte surface in P14, P21, and adult NF induced significant increases at P14 and P21 (Fig. 3). CRH
(n 10) or OF (n 9) rats mRNAconcentrationsinthePVNdecreasedwithage,with
NF OF significant lower values in OF rats compared with NF rats.
OFratPVNGRmRNAlevelswereincreasedatP8andP14
Age P14 (Fig. 4).
Epididymal (mg) 87.1 4.8 128.8 14.0* Adult OF rats presented with a significant adrenal
Retroperitoneal (mg) 100.0 9.0 161.0 11.5* hypertrophy (58.4 3.1 vs. NF 47.9 2.4 mg, P 0.05)
Perirenal (mg) 49.2 6.6 59.0 5.1* and an increased adrenal corticosterone content (56.1
Mesenteric (mg) 177.1 15.7 210.4 17.7* 4.0 vs. NF 37.7 5.1 pmol/mg tissue, P 0.05). Urinary
Age P21
Epididymal (mg) 186.2 10.5 363.7 30.4† free corticosterone concentrations were significantly ele-
Retroperitoneal (mg) 180.4 8.3 434.2 43.2† vated in adult OF rats at the time of peak (Fig. 5). When
Perirenal (mg) 114.3 10.7 165.4 21.1‡ exposed to a mild psychological stress adult NF and OF
Mesenteric (mg) 329.1 28.3 621.9 51.8† rats showed similar kinetic patterns of corticosterone
Age 4 months response (Fig. 5). However, OF rats displayed increased Downloaded from http://diabetesjournals.org/diabetes/article-pdf/54/1/197/650781/zdb00105000197.pdf by guest on 04 January 2023
Epididymal (g) 6.33 0.39 10.65 0.87§ corticosterone secretion during the ascending phase of
Retroperitoneal (g) 7.00 0.58 9.34 0.83‡ corticosterone hypersecretion (repeated-measures ANOVA
Perirenal (g) 1.91 0.17 2.79 0.21‡ t0–t30: P 0.05; peak value: 1,220 75 vs. NF 900 110
Mesenteric (g) 6.16 0.30 8.37 0.64§
Adipocytes surface nmol/l, P 0.01). CRH mRNA concentrations in the PVN
2
Epididymal (m ) 3,578 64 3,986 112† were not different in adult OF rats compared with NF rats
2
Mesenteric (m ) 2,593 111 3,042 70† (114.9 2.3 vs. NF 107.4 4.8 nCi/g, P 0.05), whereas
Data are means SE. The experiment was repeated once with the PVN GR mRNA levels were decreased (60.0 6.5 vs. NF
same consistent results. *NS; †P 0.0001, ‡P 0.05, §P 0.01 vs. 87.5 7.9 nCi/g, P 0.05).
NFrats. Neonatal overfeeding programs AT glucocorticoid
sensitivity through an upregulation of local GR and
40, and 216 22 vs. 253 21 nCi/g in NF or OF rats, 11-HSD-1 mRNA levels. Overfeeding induced a signif-
respectively; P 0.05). icant increase in GR mRNA concentrations in both EAT
Adult animals neonatally overfed show hyperphagia, and MATofP21rats. The nutritional manipulation did not
glucose intolerance, and plasma lipid and leptin dis-
turbances. OF rats had higher total and nocturnal food TABLE 2
intake (24.1 0.5 vs. NF 20.6 0.4 g/day, P 0.001, and Circulating metabolic parameters in fed P8, P14, P21, and adult
18.2 1.1 vs. NF 13.0 1.3 g/12 h, P 0.05, respectively). NF(n10)orOF(n9)ratskilled between 1400 and 1600
Fed OF rats showed increases in circulating insulin, glu-
cose, and FFAs compared with controls. Circulating total NF OF
cholesterol, HDL cholesterol, and triglycerides did not Age P8
change between groups (Table 2). Compared with normo- Glucose (mmol/l) 7.6 0.1 7.9 0.2*
feeding, overfeeding induced an increase in fasting plasma Insulin (pmol/l) 11023 17028*
insulin, insulin-to-glucose ratio, and FFAs (93 18 vs. NF Insulin-to-glucose ratio 14.5 3.0 21.4 3.7*
27 3 pmol/l, P 0.05; 20.0 4.3 vs. NF 4.9 0.6, P FFAs (g/l) 0.24 0.02 0.23 0.02*
0.05; and 0.23 0.03 vs. NF 0.12 0.02 g/l, P 0.01, Leptin (ng/ml) 5.95 1.11 13.84 2.19†
respectively), whereas fasting glycemia was not changed Age P14
(5.2 0.2 vs. NF 5.4 0.1 mmol/l, P 0.05). After an Glucose (mmol/l) 7.4 0.1 9.1 0.3†
intraperitoneal glucose load (Fig. 2), OF rats had higher Insulin (pmol/l) 2710 11823‡
circulating levels of glucose and insulin compared with Insulin-to-glucose ratio 2.1 0.5 12.7 2.3‡
controls. Adult OF rats presented with increased plasma FFAs (g/l) 0.14 0.01 0.17 0.01*
leptin levels (Table 2), which were clearly disproportion- Leptin (ng/ml) 1.79 0.18 7.25 0.70†
Age P21
ately elevated because circulating leptin concentrations Glucose (mmol/l) 7.7 0.2 8.1 0.1*
werestill significantly increased after adjustment for body Insulin (pmol/l) 7525 21237§
weight (11.82 1.32 ng/ml, P 0.05 vs. NF). The nutri- Insulin-to-glucose ratio 9.1 2.6 25.7 4.4§
tional manipulation did not change the concentrations of FFAs (g/l) 0.09 0.01 0.14 0.01*
the mRNA coding for GR, 11-HSD-1, and PEPCK in the Leptin (ng/ml) 2.43 0.32 7.49 0.95
liver of adult animals (251 10 vs. 264 13, 396 35 vs. Adults
37123,and84440vs.91859nCi/ginNForOFrats, Glucose (mmol/l) 6.6 0.2 7.5 0.3‡
respectively; P 0.05). Insulin (pmol/l) 9011 12813‡
Postnatal overfeeding induces a hyperactivity of the Insulin-to-glucose ratio 13.6 1.5 17.0 1.3*
HPA axis during development and exposes adult FFAs (g/l) 0.09 0.01 0.17 0.01†
Total cholesterol (mmol/l) 1.88 0.09 1.92 0.09*
animalstogreaterbasalandstress-inducedglucocor- HDLcholesterol (mmol/l) 0.97 0.06 0.90 0.04*
ticoid signals throughout their lifespan. In OF com- Triglycerides (mmol/l) 1.43 0.18 1.54 0.16*
pared with NF rats, adrenal weight was not changed at P8 Leptin (ng/ml) 7.7 1.0 13.6 1.5§
and P14 and was significantly increased at P21, whereas Data are means SE. The experiment was repeated once with the
adrenal corticosterone content was not modified at P8 and sameconsistentresults. *NS; †P 0.0001, ‡P 0.05, §P 0.01, P
wasenhancedatP14andP21.Overfeedingdidnotchange 0.001 vs. NF rats.
DIABETES, VOL. 54, JANUARY 2005 199
POSTNATAL OBESITY AND GLUCOCORTICOID METABOLISM
FIG. 2. Changes in plasma glucose and insulin levels
(meansSE)afterintraperitonealglucoseloadinginadult
NF(n10)orOF(n9)rats.Thearrowindicatesthetime
of glucose injection. *P < 0.05, **P < 0.01, ****P < 0.0001
vs. NF animals.
Downloaded from http://diabetesjournals.org/diabetes/article-pdf/54/1/197/650781/zdb00105000197.pdf by guest on 04 January 2023
affect 11-HSD-1 mRNA concentrations in EAT and MAT light on some of the pathophysiological mechanisms un-
(Fig. 6). derlying obesity and its associated complications in hu-
GR mRNA concentrations were significantly enhanced mans. It is known that obese patients have mild increased
in MAT compared with EAT in both NF or OF adult basal and stress-induced glucocorticoid synthesis (2,20)
animals. Compared with NF rats, OF animals had higher and enhanced GR mRNA and 11-HSD-1 mRNA and
GR mRNA concentrations in EAT and MAT. In NF rats, activity in stromal and adipocyte compartments of AT
11-HSD-1 mRNA levels were lower in MAT compared (20–24), which correlate with several features of the
with EAT. OF animals showed an opposite pattern of metabolic syndrome such as central adiposity, fasting
11-HSD-1 mRNA distribution with higher concentrations glucose, insulin, insulin resistance (25), and AT expression
in MATthaninEAT(Fig.6).Changesin11-HSD-1mRNA of plasminogen activator inhibitor type 1 mRNA (26).
expression in AT were mainly located in the stromal Animportantquestionthatarisesfromourobservations
portion of the tissue (not shown). is what is the primary defect responsible for the overfeed-
ing-induced hormonal and metabolic disturbances. Our
DISCUSSION findingshowingthathypothalamicCRHmRNAlevelswere
Our experiments demonstrate for the first time that post- altered in OF P8 rats, at a time at which neither body
natal overfeeding associates an acceleration of the matu- weight nor metabolic parameters were affected, strongly
ration of the HPA axis and, in adulthood, a permanent suggests that changes in the central components of the
upregulation of the HPA axis and an increased AT glu- HPA axis represent the primary target of the nutritional
cocorticoid sensitivity. We show that overfeeding acceler- manipulation, even though plasma ACTH and corticoste-
ates the dynamic changes that characterize the rone levels were not changed. Indeed, we have previously
development of the HPA axis in rats, that is, the progres- reported that the functional maturation of the peripheral
sive decrease in PVN CRH mRNA expression and increase components of the HPA axis in the developing rat is
in circulating ACTH and corticosterone. This phenomenon scheduled by CRH (27). We found that overfeeding was
was accompanied by an upregulation of AT GR mRNA. In accompanied by a decrease in hypothalamic CRH mRNA
adulthood, neonatally overfed rats presented with moder- levels and an increase in GR mRNA levels, suggesting that
ate increases in basal and stress-induced corticosterone the negative glucocorticoid feedback appears earlier in OF
secretion and striking changes in visceral AT glucocorti- rats. Several mechanisms may be involved for the accel-
coid metabolism, that is, enhanced GR and 11-HSD-1 erated maturation of the central components of the HPA
mRNA levels. The above-mentioned alterations in the axis. It has been suggested that shortage of nutrients is
endocrine status of OF rats were accompanied by a directly responsible for the postnatal decreased adrenal
moderate overweight condition and significant metabolic cortex activity associated with intrauterine growth retar-
disturbances comparable to those described in the meta- dation or prematurity with fetal growth inhibition in
bolic syndrome. Our findings confirm and substantially humans (28). It is conceivable that an excess of nutrients
extend previously published data that show that cortico- could have per se a stimulatory effect on the maturation of
sterone secretion in response to a neurogenic stress was the HPA axis. Alternatively, the increased circulating
elevated in perinatally overfed rats (18) and that matura- leptin levels found in overfed developing rats, which are
tion of the adrenocortical rhythm was delayed in underfed presumably related to the increased caloric intake (29)
animals (19). The model of postnatal overfeeding differs and/or to the enhanced adipose mass, could play a role.
from previously published postnatal manipulations in rats Indeed, it has been demonstrated that chronic leptin
(11–14) in that 1) it uses a mild exclusively environmental injection in developing rats accelerates the maturation of
stimulus and does not involve any pharmacological treat- the glucocorticoid feedback (30). The increased basal and
ment, 2) the changes of corticosterone status found in stress-stimulated corticosterone secretion in adult OF rats
adults parallel those of developing animals, 3) it associates may be, at least in part, related to the diminished hypo-
systemic and AT changes in glucocorticoid metabolism, thalamic GR expression leading to a decreased sensitivity
and4)itinducesthemetabolicsyndromeinadulthood.As to the negative glucocorticoid feedback. The increase in
a consequence, the experimental paradigm of neonatal circulating FFAs could represent an additional mechanism
overfeeding in rats is an interesting model that could shed responsible for the hyperactivity of the HPA axis of OF
200 DIABETES, VOL. 54, JANUARY 2005
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