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Liggins Institute for Medical Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand 92019
Address all correspondence and requests for reprints to: Associate Professor Bernhard H. Breier, Liggins Institute for Medical Research, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: bh.breier{at}auckland.ac.nz
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have developed an animal model of fetal programming in which we apply maternal undernutrition throughout gestation, generating a nutrient-deprived intrauterine environment that results in fetal growth retardation and postnatal growth failure and leads to changes in allometric growth patterns and endocrine parameters of the somatotrophic axis (5, 6). We have recently shown that programmed offspring develop profound hyperphagia, obesity, hypertension, hyperinsulinemia, and hyperleptinemia during adult life and that postnatal hypercaloric nutrition amplifies the metabolic and cardiovascular abnormalities induced by fetal programming (4). Thus, our animal model closely resembles the clinical and metabolic abnormalities seen in humans born of low birth weight and, furthermore, displays the phenotype of syndrome X (7, 8). Epidemiological studies have shown that babies born of low birth weight develop increased rates of obesity in adult life (9). This was most clearly shown in a recent report from the Dutch Famine Study in which poor nutrition in the first trimester of pregnancy resulted in increased rates of obesity during adult life (10). Animal studies have also shown that maternal malnutrition during pregnancy results in the development of adult-onset obesity in offspring (9, 11, 12).
IGF-I is one of the most important regulators of growth, and IGF-I deficiency is associated with prenatal and postnatal growth failure (13, 14). Under conditions of adequate nutrition, IGF-I has been shown to promote postnatal catch-up growth in rats with intrauterine growth retardation caused by gestational protein deficiency (15). IGF-I therapy is associated with increased insulin sensitivity in normal subjects as well as in patients with GH deficiency, type 2 diabetes mellitus, and type A insulin resistance (16). IGF-I can reduce hyperglycemia in patients with severe insulin resistance by direct effects mediated via the IGF-I receptor (17). IGF-I infusion lowers insulin and lipid levels in healthy humans and reduces plasma leptin concentrations in rats (18), suggesting that IGF-I may reduce the degree of insulin resistance in type 2 diabetes, obesity, and hyperlipidemia (19). Clinical studies of IGF-I in hypertension are limited, but IGF-I has previously been shown to have vasodilatory effects and to improve cardiac function in healthy volunteers (20). In animal studies, IGF-I treatment has been shown to cause partial reversion of hypertension-induced changes in cardiac function and to increase cardiac output and stroke volume (21). Furthermore, recent evidence suggests that IGF-I can interact with the renin-angiotensin system (RAS) and may alter angiotensin II expression via angiotensin type 1 receptor regulation (22, 23). The reported effects of IGF-I on cardiovascular and metabolic homeostasis may be mediated by the IGF-binding proteins (IGFBPs). IGFBP-1 and -2 levels closely reflect changes related to nutrition, insulin secretion, and disease states such as obesity and type 2 diabetes. IGFBP-3 correlates with IGF-I and is a chronic indicator of GH- dependent growth status (24). Previous work by our group (5) and others (25, 26) has shown differential expression of IGFBPs following fetal growth retardation.
The present study investigates the morphometric, metabolic, and endocrine responses to IGF-I treatment in postnatal life following fetal programming alone or in combination with hypercaloric nutrition. The aim of the present study was to establish whether IGF-I treatment can alleviate hyperinsulinemia, hyperleptinemia, hyperphagia, obesity, and hypertension caused by fetal programming and postnatal hypercaloric nutrition.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood pressure measurements
Systolic blood pressure (SBP) was recorded by tail cuff
plethysmography according to the manufacturer’s instructions (blood
pressure analyser IITC, Life Science, Woodland Hills, CA).
Rats were restrained in a clear plastic tube in a prewarmed room
(25–28 C). After the rats had acclimatized (10–15 min), the cuff was
placed on the tail and inflated to 240 mm Hg. Pulses were recorded
during deflation at a rate of 3 mm Hg/sec, and reappearance of a pulse
was used to determine SBP. A minimum of three clear SBP recordings per
animal was taken, and the coefficient of variation for repeated
measurements was <5%.
IGF-I infusion
At day 175, rats were weight matched (n = 6 per group) and
received either rh-IGF-I (Genentech, Inc., San
Francisco, CA, code no. G117AZ, batch c9831AY) or saline by
osmotic minipump (model 2002, Alzet Corp.). The dose was 3 µg/g per
day for 14 days with a pump delivery rate of 5 µl/h. The mean pump
rate for the batch (lot no. 167258) of pumps used was 5.23 ±
0.2 µl/h. Pumps containing the IGF-I or saline solution were
incubated in sterile saline for 4 h at 37 C before implantation.
The osmotic pumps were implanted sc, under halothane anesthesia, using
a small incision made in the skin between the scapulae. Using a
hemostat, a small pocket was formed by spreading apart the sc
connective tissues. The pump was inserted into the pocket with the flow
moderator pointing away from the incision. The skin incision was then
closed with sutures. All animals (n = 48) were housed individually
for the duration of the study.
Endocrine analyses
IGF-I in rat blood plasma was measured using an IGFBP-blocked
RIA described previously (27). The
ED50 was 0.1 ng/tube, and the intra- and
interassay coefficients of variation were <5% and <10%
respectively.
Rat insulin was measured by RIA as described previously
(4). Blood plasma was diluted 1:4 in assay buffer (0.01
M PBS containing 0.37% Na EDTA and 0.5% BSA, pH 6.2). In
brief, the primary antibody (guinea pig antiovine insulin) was diluted
in assay buffer to an initial working dilution of 1:80,000. After 0.1
ml diluted sample, control, or standard (rat insulin, 0.01–10 ng/ml,
Crystal Chem, Chicago, IL) was incubated with 0.2 ml
primary antibody for 24 h at room temperature, 0.2 ml
125I-rh-Insulin (lot no. 615–707-208, Eli Lilly, Indianapolis, IN) was added at 15–20,000 counts per
tube. Equilibrium conditions were established after 24-h incubation at
4 C. A second antibody was used to separate bound from free ligand as
outlined previously (28) and the pellet counted by 
counter. Rat plasma samples showed parallel displacement to the
standard curve, and recovery of unlabeled rat insulin was 96.5 ±
4.4% (mean ± SEM, n = 11). The
ED50 was 0.5 ng/ml.
A double-antibody RIA was developed for measurement of leptin in rat plasma. An antibody was raised in rabbits against a fragment (aa 30–45) of bovine leptin. Standard preparation was rm-leptin (Crystal Chem, #CR-6781) used in concentrations ranging from 0.5 to 20 ng/ml. Samples were assayed neat or diluted 1:2–1:4 in assay buffer (0.05 M PBS, pH 7.4 containing 0.1 M NaCl, 0.5% BSA, 10 mM EDTA, 0.05% NaN3). In brief, 100-µl primary antibody (1:25,000) was added to tubes containing 100-µl sample or standard. Following incubation for 24 h at 4 C, 100 µl tracer (125I-rm-leptin, 20 000 cpm per tube) was added to all tubes followed by a further incubation for 24 h at 4 C. A second antibody technique to separate bound from free ligand was used as outlined previously (28). Rat plasma samples showed parallel displacement to the standard curve, and recovery of unlabeled rm-leptin was 101.4 ± 2.7% (mean ± SEM, n = 26). The ED50 was 0.37 ng/ml, and the intra-assay coefficient of variation was < 5% (all samples measured within a single assay).
Fasting plasma glucose concentrations from samples taken at the time of sacrifice were measured using a glucose analyzer (model 2300, Yellow Springs Instrument Co., Yellow Springs, OH). Blood plasma FFA were measured by diagnostic kit (no. 1383175, Roche Molecular Biochemicals, Indianapolis, IN). All other plasma analytes were measured by a BM 737 analyzer (Hitachi, Roche Diagnostics, Indianapolis, IN) by Auckland Healthcare Laboratory Services.
IGFBPs in rat plasma (2-µl sample, n = 6 per treatment group) were analyzed by ligand blotting (29) as described in detail elsewhere (30). Rat 125I-IGF-II was used as radiolabel. Nitrocellulose blots were air dried and exposed to X-Omat AR diagnostic film (Eastman Kodak Co., Rochester, NY) in hyperscreen cassettes with intensifier screens (Amersham Pharmacia Biotech, Piscataway, NJ). For quantification, nitrocellulose blots were exposed overnight to phospor imaging screens and analyzed on a Storm PhosporImager system using ImageQuant software (Molecular Dynamics, Inc., Sky Valley, CA). All values were expressed relative to a normal rat plasma pool and standardized to 100% for control group. The IGFBPs were identified on the basis of their molecular size using nomenclature previously described (31).
Statistical analyses were carried out using SigmaStat (Jandel Scientific, San Rafael, CA) and StatView (SAS Institute, Inc., Cary, NC) statistical packages. Differences between groups were determined by two-way (pre-IGF-I treatment) or three-way ANOVA (post-IGF-I treatment) followed by Bonferroni post hoc analysis, and data are shown as mean ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Body weight gain was increased in all
IGF-I-treated animals (Fig. 2), and no
difference in the response to body weight gain was observed between AD
and UN offspring. However, daily weight gain was significantly lower in
animals treated with IGF-I on hypercaloric nutrition as reflected by
the significant (P < 0.05) diet and IGF-I interaction.
At the end of the study, UN offspring were shorter than AD offspring in
each treatment group and nose-anus lengths were significantly
(P < 0.05) increased in all IGF-I-treated animals
(Table 1). UN animals showed a
significantly higher food intake on both diets, compared with AD
animals. However, food intake was reduced (P < 0.005)
by IGF-I treatment (Fig. 3). A
significant statistical interaction was observed between programming
and IGF-I treatment whereby reduction in food intake was more
pronounced in UN animals following IGF-I treatment (P
< 0.005).
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).
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). Plasma glucose was not different
between AD and UN offspring but was increased (P <
0.0001) by hypercaloric nutrition. IGF-I-treated animals showed
markedly reduced plasma glucose concentrations (P <
0.0001) (Fig. 5B). Plasma leptin concentrations were higher
(P < 0.005) in UN offspring and were increased
(P < 0.0001) by hypercaloric diet. IGF-I treatment
significantly lowered plasma leptin concentrations (P
< 0.0005). As observed with insulin, there was a strong diet and IGF-I
treatment interaction (P < 0.005, Fig. 6A) with plasma leptin levels being most
markedly reduced by IGF-I treatment in offspring fed hypercalorically.
Regression analysis revealed a strong positive relationship between
plasma leptin and fasting insulin concentrations
(r2 = 0.75, P < 0.0001).
Retroperitoneal and gonadal fat pads were significantly larger in UN
offspring (P < 0.05) and were further increased by
hypercaloric nutrition in both AD and UN offspring (P
< 0.0001). Treatment with IGF-I significantly reduced fat pad mass in
all treated animals (P < 0.0001, Fig. 6, B and C).
Regression analysis showed a highly significant positive relationship
between fat mass and fasting plasma leptin (r2 =
0.765, P < 0.001, Fig. 6D).
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). AD and UN offspring fed
hypercalorically had relatively lighter kidneys (P <
0.0001). Treatment with IGF-I significantly increased kidney weight
(P < 0.0001). Heart weight was not different between
AD and UN offspring but was reduced relative to body weight in animals
fed hypercaloric nutrition. IGF-I treatment caused an increase in heart
weight in all treated animals (P < 0.05). Liver weight
was not different between AD and UN offspring and was not affected by
diet. IGF-I-treated animals had lighter livers relative to body weight,
compared with saline controls (P < 0.005). Spleen
weight was not different between AD and UN offspring and was not
altered by diet. However, treatment with IGF-I caused a significant
increase in spleen weight in AD- and UN-treated animals
(P < 0.0001). Relative brain weight in UN offspring
was reduced, compared with AD offspring, and was lighter relative to
body weight (P < 0.0001) in animals fed
hypercalorically and/or treated with IGF-I. Adrenal weight was not
different between UN and AD animals but was significantly
(P < 0.0001) increased with IGF-I treatment (Table 1).
Plasma FFA concentrations were reduced in hypercalorically fed
animals (P < 0.005, Table 2) but there was no effect of
programming or IGF-I treatment. Plasma urea concentrations were
markedly lower in UN offspring (P < 0.05, Table 2) and
were decreased in all hypercalorically fed offspring (P
< 0.0001). Treatment with IGF-I caused a significant reduction
(P < 0.0001) in urea concentrations in all treated
offspring. Plasma creatinine levels were not different between AD and
UN offspring and were unaffected by diet. Treatment with IGF-I lowered
(P < 0.0001) creatinine concentrations in all treated
animals (Table 2).
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). Albumin concentrations were significantly
(P < 0.05) lower in UN offspring, but there was no
effect on diet or treatment. Calcium levels were higher
(P < 0.05) in UN offspring, but there was no effect on
diet or treatment. Plasma magnesium concentrations were markedly
increased (P < 0.0001) with IGF-I treatment but were
unaffected by diet and were not different between AD and UN offspring
(Table 2).
Plasma IGFBPs were analyzed using nomenclature previously
described (5, 31). The 38- to 44-kDa, 28- to 30-kDa, and
24-kDa bands represent IGFBP-3, IGFBP-1/2, and IGFBP-4,
respectively. Analysis of plasma IGFBPs revealed that basal levels of
all IGFBPs measured by ligand blot were elevated in UN offspring,
compared with AD offspring. IGF-I treatment resulted in a 3- to 5-fold
increase (P < 0.001) in IGFBP-3 in all IGF-I-treated
animals (Fig. 7A). However, there was a
diminished up-regulation of IGFBP-3 in UN animals indicated by a
significant programming (P < 0.0001) and IGF-I
treatment interaction (P < 0.0001). Postnatal
hypercaloric nutrition significantly (P < 0.0001)
reduced the IGFBP-3 band, compared with animals on the control diet,
and reduced (P < 0.0001) the up-regulation of IGFBP-3
following IGF-I treatment; there was a significant (P
< 0.05) programming, diet, and IGF-I treatment interaction.
Interestingly although in UN animals the combined 38- to 44-kDa IGFBP-3
band showed impaired up-regulation following IGF-I treatment, analysis
of the 38-kDa band alone showed an increase (P <
0.0001) of this band in UN animals, indicating a differential pattern
of up-regulation of this form of IGFBP-3 in UN animals (Fig. 7B).
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). Similarly, hypercaloric nutrition
significantly reduced the increase in IGFBP-1/-2 following IGF-I
treatment.
The 24-kDa band representing IGFBP-4 was significantly elevated in all
UN animals (P < 0.0001, Fig. 7D) and was further
amplified in all animals fed the hypercaloric diet (P
< 0.0001). In an opposing pattern to the observation in other IGFBPs,
a significant (P < 0.0001) down-regulation of
IGFBP-4 was observed following IGF-I treatment. A significant
(P < 0.001) programming and IGF-I treatment
interaction revealed that IGFBP-4 was more markedly down-regulated in
UN animals following IGF-I treatment, compared with AD animals. A
significant diet and IGF-I treatment interaction was also observed with
IGF-I treatment resulting in a lesser reduction in IGFBP-4 in
hypercalorically fed animals, compared with those fed the control
diet.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During treatment with IGF-I, we observed no significant difference in body weight response between AD and UN offspring, although a lower body weight gain was observed in all hypercalorically fed animals treated with IGF-I, compared with control-fed animals. As shown previously, treatment with IGF-I significantly reduced fasting plasma insulin and glucose concentrations in all treated animals (20, 35). A more pronounced decrease in plasma insulin concentrations was observed with IGF-I treatment in all animals fed a hypercaloric diet. However, in UN offspring animals (which were profoundly hyperinsulinemic) fed a hypercaloric diet, IGF-I treatment resulted in a return to basal fasting plasma insulin concentrations. In the present study, UN offspring were hyperphagic on both postnatal diets, compared with AD animals, confirming our previous observations. However, the significant decrease in plasma leptin concentrations following IGF-I treatment was associated with a decrease in food intake. More importantly however, the decrease in food intake following IGF-I treatment was more pronounced in offspring that were programmed to become obese and hyperphagic in adult life, which may explain the lower body weight gain observed in IGF-I-treated offspring fed hypercaloric nutrition. Although IGF-I treatment caused a significant reduction in food intake, weight gain was significantly increased in all IGF-I-treated animals. This may be a result of increased food conversion efficiency and significant increases in nitrogen balance and carcass nitrogen content following IGF-I treatment as reported previously (36). This would suggest that increased body weight as observed in the present study may be a result of altered partitioning of nutrients from fat to lean body tissue mass.
Data for a role of IGF-I in appetite regulation are limited, although early work by Tannenbaum et al. (37) showed that intracerebroventricular administration of IGFs resulted in a reduction in food intake. More recent work has also shown a reduction in food intake in tumor-bearing rats following infusion with either IGF-I or LR3-IGF-I (38). It is therefore tempting to speculate that our observation of reduced food intake following IGF-I treatment may be the result of the anorectic effect of IGF-I via its insulin-sensitizing effects and reduction of chronic hyperinsulinemia. Food intake was most markedly reduced in programmed animals fed hypercaloric nutrition; the same animals that showed the most marked decrease and normalization of fasting insulin and glucose concentrations following IGF-I treatment.
Our data on the lipolytic effect of IGF-I support results published previously (33, 39, 40, 41) and suggest that the effects of prolonged IGF-I treatment on adipose tissue are not insulin-like as reflected by increased lipolysis and decreased body fat mass. We propose that IGF-I treatment may reduce body fat mass via an inhibition of the lipogenic capacity of adipocytes and reduction of lipogenesis in adipose tissue via inhibition of insulin secretion. The lipolytic effects of IGF-I treatment were also concomitant with a significant decrease in fasting plasma leptin concentrations. This agrees with recent work in normal rats showing decreased plasma leptin and fat mass following constant infusion with rh-IGF-I for 6 d (18). It is unlikely that IGF-I acts via cross-reactivity with the insulin receptor. An insulin-like action would rather stimulate lipogenesis and thus increase fat pad weight and enhance leptin expression. It is also unlikely that IGF-I acts directly on adipose tissue via the IGF-I type 1 receptor. Rat adipose tissue lacks functional type 1 IGF receptors (41, 42) and IGF-I has been shown to have no effect on leptin secretion by mature adipocytes in vitro (43). Reduction of adipose tissue mass and suppression of leptin by IGF-I may be due to a reduction in circulating insulin leading to enhanced fat mobilization and nonesterified fatty acid oxidation as well as to increased gluconeogenesis from glycerol (18). However, in our study, although IGF-I infusion reduced adipose tissue weight, we observed no significant effect on plasma FFA concentrations. This may be due to increased triglyceride deposition and utilization in muscle tissue (author’s unpublished observations).
A further explanation for the metabolic effects of IGF-I observed in the present study may relate to the interactions between the leptin and insulin signaling networks (44), which may be disrupted as a result of fetal programming and further exacerbated by postnatal hypercaloric nutrition (32). Such dysregulation of the adipoinsular axis may contribute to the progression to insulin resistance and adipogenic diabetes (45, 46). Insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) co-ordinate essential effects of insulin/IGF on peripheral metabolism and ß cell function. Recent evidence suggests that impaired IRS-1 expression and downstream signaling events in adipocytes in response to insulin are associated with insulin resistance and the pentad of hypertension, hyperinsulinemia, dyslipidemia, obesity, and cardiovascular disease, known as syndrome X (7). IGF-I has been shown to inhibit insulin secretion from ß cells through an IGF-I receptor-mediated pathway (47, 48) and the IGF-I-IRS-2 signaling pathway has been proposed to be critical for postnatal ß cell function (49). It is tempting therefore to speculate that treatment with IGF-I may restore some of the functional feedback between the insulin signaling system and leptin action via modification of IRS-1 and IRS-2 and downstream signaling events.
Insulin resistance is often accompanied by hypertension, and obesity-induced hyperinsulinemia may induce alterations in sympathetic nervous system activity to increase blood pressure via vascular constriction. Because insulin-sensitizing agents have been shown to reduce blood pressure in obese, hypertensive subjects (50), it is possible that our observation of decreased SBP following IGF-I treatment may be a result of improved insulin sensitivity and glycemic control in conjunction with the known vasodilatory effects of IGF-I treatment (34). Further support for the antihypertensive effects of IGF-I as a result of improved insulin sensitivity stems from the observation that calcium and magnesium concentrations in circulation may regulate cellular responsiveness to insulin (51). In human hypertension, basal calcium levels are significantly elevated while basal magnesium concentrations are significantly decreased. Furthermore, elevated calcium or reduced magnesium concentrations are also observed in clinical states linked to hypertension, such as obesity and type 2 diabetes (52). Our observations of elevated calcium in hypertensive UN animals and a significant increase in plasma magnesium after IGF-I treatment agrees with these findings and suggests that IGF-I treatment may alleviate insulin resistance and reduce hypertension in part by changing the calcium/magnesium ratio in plasma.
The highly significant increase in kidney weight with IGF-I treatment may also be an important factor in reduction of SBP via changes in renal plasma flow and glomerular filtration rate. Given recent in vitro observations (22, 53), it is tempting to speculate that IGF-I treatment may also reduce blood pressure by down-regulating the local RAS and limiting angiotensin II formation through mediation of the angiotensin type 1 receptor (23). Heart weight in all IGF-I-treated animals was significantly increased, which may reflect myocyte growth and improved contractility. Others have shown cardiac hypertrophy and increased left ventricular mass following IGF-I treatment (20, 54, 55). Importantly, IGF-I treatment reduced SBP only in animals that were hypertensive as a result of fetal programming or postnatal hypercaloric nutrition, and systolic blood pressure in normotensive animals remained unaltered.
Some effects of IGF-I treatment on improving insulin sensitivity and ameliorating the postnatal pathophysiology following fetal programming may be mediated by changes in circulating IGFBPs. Previous work by our group (5) has shown that circulating IGFBPs are differentially regulated as a result of fetal programming. However, data on the effect of IGF-I therapy on IGFBPs in postnatal life following fetal programming are limited. In the present study, fetal programming led to an increase in circulating levels of IGFBP-1/-2 and -4 concentrations as shown by Western ligand blotting. Similar results have been observed before in the serum of growth-retarded fetuses, compared with control fetuses (25, 26). The IGFBP-1/-2 doublet has also been previously shown to be increased in growth-retarded fetuses using a model of uterine artery ligation in the rat; because serum immunoreactive IGFBP-2 was unchanged among the groups, it was suggested that IGFBP-1 accounted for the increase in doublet intensity (56). Elevated IGFBP-1 is normally associated with poor glycemic control and implicated in the pathogenesis of type 2 diabetes because a rise in IGFBP-1 has been related to inadequate portal delivery of insulin (57, 58, 59). Previous work by our group (60) has shown that plasma levels of IGFBP-3 are increased 2-fold following treatment with h-IGF-I in the GH-deficient dwarf rat. Work by others (61) has shown a highly significant increase in IGFBP-3 following IGF-I therapy in the normal rat. The mechanism underlying the preferential up-regulation of the 38-kDa IGFBP-3 band in UN animals following IGF-I treatment is still to be elucidated but may relate to changes in phosphorylation or glycosylation of IGFBP-3 (62).
Fetal programming resulted in a significant elevation in circulating IGFBP-4 levels, which were amplified by postnatal hypercaloric nutrition. Treatment with IGF-I decreased circulating IGFBP-4 in all treated animals; moreover, IGF-I treatment was more effective in reducing IGFBP-4 concentrations in those animals that had become obese as a result of fetal programming and hypercaloric nutrition. This observation is not surprising because IGFBP-4 appears to inhibit IGF-I action under most, if not all, experimental conditions (63). It is tempting to speculate that IGF-I treatment causes activation of IGFBP-4 proteases and may result in the degradation and inactivation of IGFBP-4 as reported by others (64, 65, 66). The increase in circulating IGFBP-1, -2, and -3 and the decrease in IGFBP-4 with IGF-I treatment may represent a mechanism of increasing IGF-I activity at the different target tissues discussed above.
In conclusion, our animal model of fetal programming by maternal undernutrition during pregnancy results in profound hyperphagia, obesity, hypertension, hyperinsulinemia, and hyperleptinemia during adult life. Postnatal hypercaloric nutrition amplifies the metabolic and cardiovascular pathophysiology consistent with the clinical setting of syndrome X (7). Treatment with IGF-1 at an adult age showed a significant increase in body length, a marked reduction in food intake and body fat mass, and normalization of blood pressure. Further intriguing findings include reduction of fasting plasma insulin and leptin concentrations. Thus, IGF-1 treatment may alleviate insulin and leptin resistance and improve obesity, hyperphagia, and hypertension by differential effects on IGF-I receptor-signaling pathways or downstream signaling networks including the IRS and RAS. IGF-I treatment may also restore functional interactions between insulin and leptin following perturbations of the hypothalamic circuitry that controls food intake and of the adipoinsular axis as a result of fetal programming.
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Acknowledgments |
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Footnotes |
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Abbreviations: AD, Ad libitum; IGFBP, IGF-binding protein; IRS, insulin receptor substrate; RAS, renin-angiotensin system; rh-IGF-1, recombinant human IGF-1; SBP, systolic blood pressure; UN offspring, offspring from mothers that were undernourished throughout pregnancy.
Received December 15, 2000.
Accepted for publication May 24, 2001.
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C. S. Wyrwoll, P. J. Mark, T. A. Mori, I. B. Puddey, and B. J. Waddell Prevention of Programmed Hyperleptinemia and Hypertension by Postnatal Dietary {omega}-3 Fatty Acids Endocrinology, January 1, 2006; 147(1): 599 - 606. [Abstract] [Full Text] [PDF]
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 G. Riviere, A. Michaud, C. Breton, G. VanCamp, C. Laborie, M. Enache, J. Lesage, S. Deloof, P. Corvol, and D. Vieau Angiotensin-Converting Enzyme 2 (ACE2) and ACE Activities Display Tissue-Specific Sensitivity to Undernutrition-Programmed Hypertension in the Adult Rat Hypertension, November 1, 2005; 46(5): 1169 - 1174. [Abstract] [Full Text] [PDF]
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M. H. Vickers, P. D. Gluckman, A. H. Coveny, P. L. Hofman, W. S. Cutfield, A. Gertler, B. H. Breier, and M. Harris Neonatal Leptin Treatment Reverses Developmental Programming Endocrinology, October 1, 2005; 146(10): 4211 - 4216. [Abstract] [Full Text] [PDF]
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 S. A Bayol, B. H Simbi, and N. C Stickland A maternal cafeteria diet during gestation and lactation promotes adiposity and impairs skeletal muscle development and metabolism in rat offspring at weaning J. Physiol., September 15, 2005; 567(3): 951 - 961. [Abstract] [Full Text] [PDF]
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 I. C. Mcmillen and J. S. Robinson Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming Physiol Rev, April 1, 2005; 85(2): 571 - 633. [Abstract] [Full Text] [PDF]
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E Zambrano, G. L Rodriguez-Gonzalez, C Guzman, R Garcia-Becerra, L Boeck, L Diaz, M Menjivar, F Larrea, and P. W Nathanielsz A maternal low protein diet during pregnancy and lactation in the rat impairs male reproductive development J. Physiol., February 15, 2005; 563(1): 275 - 284. [Abstract] [Full Text] [PDF]
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J. A Armitage, I. Y Khan, P. D Taylor, P. W Nathanielsz, and L. Poston Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? J. Physiol., December 1, 2004; 561(2): 355 - 377. [Abstract] [Full Text] [PDF]
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A. Varma, J. He, B.-C. Shin, L. A. Weissfeld, and S. U. Devaskar Postnatal intracerebroventricular exposure to leptin causes an altered adult female phenotype Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1132 - E1141. [Abstract] [Full Text] [PDF]
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M. Desai, C. Guerra, S. Wang, and M. G. Ross Programming of Hypertonicity in Neonatal Lambs: Resetting of the Threshold for Vasopressin Secretion Endocrinology, October 1, 2003; 144(10): 4332 - 4337. [Abstract] [Full Text] [PDF]
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M. H. Vickers, B. H. Breier, D. McCarthy, and P. D. Gluckman Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R271 - R273. [Abstract] [Full Text] [PDF]
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A. Varma, J. He, L. Weissfeld, and S. U. Devaskar Postnatal intracerebroventricular exposure to neuropeptide Y causes weight loss in female adult rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2003; 284(6): R1560 - R1566. [Abstract] [Full Text] [PDF]
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 N. WINN, A. PAUL, A. MUSARO, and N. ROSENTHAL Insulin-like Growth Factor Isoforms in Skeletal Muscle Aging, Regeneration, and Disease Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 507 - 518. [Abstract] [PDF]
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),
AD hypercaloric diet (
), UN control diet (
), UN hypercaloric diet
(
)]. Note the marked effect of hypercaloric nutrition on body
weight of UN offspring and apparent catch-up growth to control-fed AD
offspring by postnatal day 100 (n = 6 per group, data are
mean ± SEM).
