scholarly journals Dysregulation of the adipoinsular axis -- a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming

2001 ◽  
Vol 170 (2) ◽  
pp. 323-332 ◽  
Author(s):  
MH Vickers ◽  
S Reddy ◽  
BA Ikenasio ◽  
BH Breier

Obesity and its related disorders are the most prevalent health problems in the Western world. Using the paradigm of fetal programming we developed a rodent model which displays the phenotype of obesity and metabolic disorders commonly observed in human populations. We apply maternal undernutrition throughout gestation, generating a nutrient-deprived intrauterine environment to induce fetal programming. Maternal undernutrition results in fetal growth retardation and in significantly decreased body weight at birth. Programmed offspring develop hyperphagia, obesity, hypertension, hyperleptinemia and hyperinsulinism during adult life and postnatal hypercaloric nutrition amplifies the metabolic abnormalities induced by fetal programming. The adipoinsular axis has been proposed as a primary candidate for linking the status of body fat mass to the function of the pancreatic beta-cells. We therefore investigated the relationship between circulating plasma concentrations of leptin and insulin and immunoreactivity in the endocrine pancreas for leptin and leptin receptor (OB-R) in genetically normal rats that were programmed to become obese during adult life. Virgin Wistar rats were time mated and randomly assigned to receive food either available ad libitum (AD group) or at 30% of the ad libitum available intake (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring (AD 6.13+/-0.04 g, UN 4.02+/-0.03 g, P<0.001). At weaning, offspring were assigned to one of two diets (a standard control diet or a hypercaloric diet consisting of 30% fat) for the remainder of the study. At the time of death (125 days of age), UN offspring had elevated (P<0.005) fasting plasma insulin (AD control 1.417+/-0.15 ng/ml, UN control 2.493+/-0.33 ng/ml, AD hypercaloric 1.70+/-0.17 ng/ml, UN hypercaloric 2.608+/-0.41 ng/ml) and leptin (AD control 8.8+/-1.6 ng/ml, UN control 14.32+/-1.9 ng/ml, AD hypercaloric 15.11+/-1.8 ng/ml, UN hypercaloric 30.18+/-5.3 ng/ml) concentrations, which were further increased (P<0.05) by postnatal hypercaloric nutrition. The elevated plasma insulin and leptin concentrations were paralleled by increased immunolabeling for leptin in the peripheral cells of the pancreatic islets. Dual immunofluorescence histochemistry for somatostatin and leptin revealed that leptin was co-localized in the pancreatic delta-cells. OB-R immunoreactivity was evenly distributed throughout the pancreatic islets and was not changed by programming nor hypercaloric nutrition. Our data suggest that reduced substrate supply during fetal development can trigger permanent dysregulation of the adipoinsular feedback system leading to hyperleptinemia, hyperinsulinism and compensatory leptin production by pancreatic delta-cells in a further attempt to reduce insulin hypersecretion in the progression to adipogenic diabetes.

2003 ◽  
Vol 285 (1) ◽  
pp. R271-R273 ◽  
Author(s):  
M. H. Vickers ◽  
B. H. Breier ◽  
D. McCarthy ◽  
P. D. Gluckman

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is now increasing evidence that alterations in the fetal environment have long-term consequences on metabolic and endocrine pathophysiology in adult life. This process has been termed “fetal programming,” and we have shown that undernutrition of the mother during gestation leads to obesity, hypertension, hyperphagia, hyperinsulinemia, and hyperleptinemia in offspring. Using this model of maternal undernutrition throughout pregnancy, we investigated whether prenatal influences may lead to alterations in postnatal locomotor behavior, independent of postnatal nutrition. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (ad libitum group) or at 30% of ad libitum intake (undernourished group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [control or hypercaloric (30% fat)]. At ages of 35 days, 145 days, and 420 days, voluntary locomotor activity was assessed. At all ages studied, offspring from undernourished mothers were significantly less active than offspring born of normal birth weight for all parameters measured, independent of postnatal nutrition. Sedentary behavior in programmed offspring was exacerbated by postnatal hypercaloric nutrition. This work is the first to clearly separate prenatal from postnatal effects and shows that lifestyle choices themselves may have a prenatal origin. We have shown that predispositions to obesity, altered eating behavior, and sedentary activity are linked and occur independently of postnatal hypercaloric nutrition. Moreover, the prenatal influence may be permanent as offspring of undernourished mothers were still significantly less active compared with normal offspring at an advanced adult age, even in the presence of a healthy diet throughout postnatal life.


1974 ◽  
Vol 61 (3) ◽  
pp. 465-477 ◽  
Author(s):  
J. M. BASSETT ◽  
DENISE MADILL

SUMMARY Merino ewes whose foetuses had surgically-implanted, indwelling vascular cannulae were used to determine the influence of maternal nutritional status on foetal plasma hormone levels during the last month of gestation. Observations were made during feeding of the ewes on a lucerne chaff diet ad libitum, during restricted feeding on the same diet and during fasting. Foetuses survived for an average of 31 days after the operation and seven out of the ten ewes lambed normally. In both ewes and foetuses, plasma concentrations of insulin were significantly higher 3–12 h after feeding than in prefeeding samples. Similar changes were seen with restricted and ad-libitum feeding. Fasting for 48 h caused significant decreases in insulin levels of both ewes and foetuses, but the decrease in foetal plasma insulin concentration was less than that in ewes. In agreement with earlier studies, foetal and maternal glucose concentrations were closely correlated and foetal fructose concentrations were closely related to foetal glucose concentrations. Foetal plasma insulin concentrations were closely correlated with glucose and fructose concentrations. Plasma growth hormone (GH) levels increased significantly in both ewes and foetuses during fasting. There were also significant increases during fasting in the plasma corticosteroid levels of the ewes, but not in those of their foetuses. Feeding did not cause significant changes in foetal plasma GH or corticosteroid concentrations although maternal GH concentrations were significantly increased and corticosteroid concentrations decreased 3–12 h after feeding on the restricted diet. The results suggest that alterations in foetal plasma hormone concentrations could play an important role in foetal adaptation to fluctuations in maternal nutrient supply during the last month of gestation.


1997 ◽  
Vol 273 (1) ◽  
pp. R113-R120 ◽  
Author(s):  
B. Ahren ◽  
S. Mansson ◽  
R. L. Gingerich ◽  
P. J. Havel

Mechanisms regulating circulating leptin are incompletely understood. We developed a radioimmunoassay for mouse leptin to examine the influence of age, dietary fat content, and fasting on plasma concentrations of leptin in the background strain for the ob/ob mouse, the C57BL/6J mouse. Plasma leptin increased with age [5.3 +/- 0.6 ng/ml at 2 mo (n = 23) vs. 14.2 +/- 1.6 ng/ml at 11 mo (n = 15), P < 0.001]. Across all age groups (2-11 mo, n = 160), log plasma leptin correlated with body weight (r = 0.68, P < 0.0001), plasma insulin (r = 0.38, P < 0.001), and amount of intra-abdominal fat (r = 0.90, P < 0.001), as revealed by magnetic resonance imaging. Plasma leptin was increased by a high-fat diet (58% fat for 10 mo) and reduced by fasting for 48 h. The reduction of plasma leptin was correlated with the reduction of plasma insulin (r = 0.43, P = 0.012) but not with the initial body weight or the change in body weight. Moreover, the reduction in plasma leptin by fasting was impaired by high-fat diet. Thus plasma leptin in C57BL/6J mice 1) increases with age or a high-fat diet; 2) correlates with body weight, fat content, and plasma insulin; and 3) is reduced during fasting by an action inhibited by high-fat diet and related to changes of plasma insulin.


2014 ◽  
Vol 54 (3) ◽  
pp. 319 ◽  
Author(s):  
Ronald E. Newman ◽  
Jeffery A. Downing ◽  
Peter C. Thomson ◽  
Cherie L. Collins ◽  
David J. Henman ◽  
...  

Three studies investigated the effect of feeding strategy on production performance and endocrine status of growing pigs. For Experiment 1, 20 entire male pigs (70.0 ± 4.6 kg) were allocated randomly to individual pens in one of four climate-controlled rooms. Pigs were fed for 23 days either ad libitum or entrained to feed bi-phasically for two 90-min periods. For Experiment 2, 20 entire male pigs (41.2 ± 3.5 kg) were housed as per Experiment 1. Pigs were fed for 49 days either ad libitum or fed bi-phasically for two 60-min periods. For Experiment 3, 100 female pigs (66.1 ± 3.5 kg) were randomly allocated to individual pens within a commercial piggery and fed for 42 days either ad libitum or bi-phasically for two 60-min periods. Ear vein catheters were inserted into 10 pigs from each group and hourly blood samples were collected for 24 h in Experiments 1 and 2 and for 11 h in Experiment 3. Plasma insulin, non-esterified fatty acid and glucose concentrations were determined in Experiments 1 and 2, and glucose and insulin concentrations in Experiment 3. Feed intake and performance were recorded in all experiments and carcass composition was assessed by computed tomography for Experiment 2. There were no differences in final liveweight between the two treatment groups for all experiments. Pigs fed for two 90-min periods (Experiment 1) showed no difference in feed intake when compared with feeding ad libitum. Pigs in Experiment 2 fed for two 60-min intervals consumed 2.49 kg/pig.day compared with those fed ad libitum that consumed 2.68 kg/day (P = 0.057). In Experiment 3, pigs fed twice daily consumed 2.82 kg/pig.day compared with 2.91 kg/pig.day in ad libitum-fed pigs (P = 0.051). Bi-phasic fed pigs in Experiment 2 had improved (P < 0.05) feed conversion efficiency compared with pigs fed ad libitum. For all experiments, there was no difference in plasma glucose concentrations between the two treatments. In all three experiments, the circulating insulin concentrations for pigs fed ad libitum remained at a constant level throughout the sampling period. However, plasma insulin concentrations for the bi-phasic fed pigs significantly increased ~1 h after both feeding periods during all three experiments. Insulin secretion of pigs fed for two 90-min periods differed from that of pigs fed for two 60-min periods. Plasma insulin concentration increased five-fold following feeding for 60 min, compared with that in pigs fed for 90 min, which increased two-fold. Bi-phasic-fed pigs from Experiment 2 had reduced (P < 0.05) total carcass fat and significantly increased muscle when compared with pigs fed ad libitum. The data showed that feeding pigs at two succinct periods aligned insulin secretion to the time of feeding. Pigs fed for 60 min, unlike those fed for 90-min intervals, had reduced feed intake in comparison to those fed ad libitum. This may suggest that the duration of the feeding bout is important for this response and this may in turn influence both energy balance and the way energy is partitioned.


2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 51-52
Author(s):  
Alice Brandão

Abstract Option 1, Fetal Programming Only: Non-lactating, pregnant, multiparous Angus × Hereford cows (n = 104) were ranked by pregnancy sire (1 of 2 sires), body weight (BW), and body condition score (BCS) on d -15 of the experiment (d 180 of gestation). Cows were then assigned to receive: (1) 195 g/cow daily of CSSO (n = 52) or 2) 170 g/cow daily of CON (n = 52). Cows received treatments individually from d 0 to calving. Calves were weaned on d 290 of the experiment, preconditioned for 35 d, and placed in a feedyard until slaughter (d 514). Cows receiving CSSO and their calves had greater (P &lt; 0.01) plasma concentrations ω-6 PUFA compared with CON after calving. Colostrum IgG and calf plasma IgG concentrations 24 h after birth were greater (P ≤ 0.02) in CSSO vs. CON cattle. Calves from CSSO cows had greater (P ≤ 0.05) expression of adipogenic and myogenic genes in the longissimus muscle compared with CON. No treatments differences in birth BW, weaning BW, and final preconditioning BW were noted (P ≥ 0.36). Average daily gain and final BW in the feedyard were greater (P ≤ 0.05) in steers from CSSO cows compared with CON. The incidence of calves diagnosed with BRD that required a second antimicrobial treatment was less (P = 0.03) in calves from CSSO cows, resulting in reduced (P = 0.05) need of treatments to regain health compared with CON. Upon slaughter, LM area was greater (P = 0.03) in calves from CSSO cows compared with CON. Collectively, these results are indicative of programming effects on postnatal offspring growth and health resultant from CSSO supplementation to late-gestating cows. Hence, supplementing CSSO to beef cows during pregnancy might be a feasible alternative to optimize offspring productivity and welfare. Option 2, Fetal Programming and Fat Tubs: Two experiments were conducted to evaluate: (1) effects of calcium salts of soybean oil (CSSO) supplementation to late gestating beef cows on the performance of the offspring; (2) the viability of utilizing low-moisture molasses-based blocks (LMB) as a delivery method for CSSO supplementation. In experiment 1, non-lactating, pregnant, multiparous Angus × Hereford cows were assigned to receive: (1) 195 g/cow daily of CSSO (n = 52) or (2) 170 g/cow daily of CON (n = 52) from d 195 of gestation until calving. CSSO cattle had greater (P &lt; 0.01) plasma concentrations ω-6 PUFA; greater (P ≤ 0.02) colostrum and calf plasma IgG concentrations; greater (P ≤ 0.05) expression of adipogenic and myogenic genes in the longissimus muscle (LM); required fewer microbial treatments for BRD (P = 0.05) and had greater LM area compared to CON cohorts. In experiment 2, non-lactating, non-pregnant, multiparous beef cows were allocated to 1 of 9 pens (n = 9 pens; 4 cows/pen) and each pen was assigned to receive: 1) NOSUPP, hay only diet; 2) LMB, self-fed LMB supplement containing 24.7% DM CSSO; 3) CONC, hand-fed supplement identical to LMB. The design was a replicated 3 x 2 Latin square with 2 periods of 42 d, and a 21-d washout interval. Supplement DM intake did not differ (P = 0.39) between LMB and CONC cows from d 14 to 42 as designed, despite a greater variation in daily intake of LMB vs. CONC (treatment × day interaction; P &lt; 0.01). No treatments effects were noted (P ≥ 0.40) for hay intake, BCS, and BW. From d 14 to 42, plasma concentrations of, ω-6 PUFA (P &lt; 0.01) in CONC and LMB vs. NOSUPP cows. Hence, the use of self-fed LMB appears to be a valid strategy to provide CSSO to forage-fed beef cattle.


1999 ◽  
Vol 277 (6) ◽  
pp. R1675-R1682 ◽  
Author(s):  
Karen L. Kind ◽  
Peter M. Clifton ◽  
Arkadi I. Katsman ◽  
Maria Tsiounis ◽  
Jeffrey S. Robinson ◽  
...  

Epidemiological studies suggest that retarded growth before birth is associated with increased plasma total and low-density lipoprotein (LDL) cholesterol concentrations in adult life. Thus perturbations of prenatal growth may permanently alter cholesterol metabolism. To determine directly whether restriction of prenatal nutrition and growth alters postnatal cholesterol homeostasis, the plasma cholesterol response to cholesterol feeding (0.25% cholesterol) was examined in adult guinea pig offspring of ad libitum-fed or moderately undernourished mothers. Maternal undernutrition (85% ad libitum intake throughout pregnancy) reduced birth weight (−13%). Plasma total cholesterol was higher prior to and following 6 wk cholesterol feeding in male offspring of undernourished mothers compared with male offspring of ad libitum-fed mothers ( P< 0.05). The influence of birth weight on cholesterol metabolism was examined by dividing the offspring into those whose birth weight was above (high) or below (low) the median birth weight. Plasma total cholesterol concentrations prior to cholesterol feeding did not differ with size at birth, but plasma total and LDL cholesterol were 31 and 34% higher, respectively, following cholesterol feeding in low- compared with high-birth weight males ( P < 0.02). The response to cholesterol feeding in female offspring was not altered by variable maternal nutrition or size at birth. Covariate analysis showed that the effect of maternal undernutrition on adult cholesterol metabolism could be partly accounted for by alterations in prenatal growth. In conclusion, maternal undernutrition and small size at birth permanently alter postnatal cholesterol homeostasis in the male guinea pig.


1995 ◽  
Vol 269 (2) ◽  
pp. E283-E289 ◽  
Author(s):  
A. K. Saha ◽  
T. G. Kurowski ◽  
N. B. Ruderman

Increases in the concentration of malonyl-CoA in skeletal muscle have been observed in the KKAy mouse, an obese rodent with high plasma insulin and glucose levels [Saha et al. Am. J. Physiol. 267 (Endocrinol. Metab. 30): E95-E101, 1994]. To assess whether insulin and glucose directly regulate malonyl-CoA in muscle, soleus muscles from young rats were incubated with insulin and glucose at various concentrations, and their content of malonyl-CoA was determined. In addition, the effect on malonyl-CoA of denervation and electrically induced muscle contractions was assessed. The concentration of malonyl-CoA in the soleus, taken directly from a rat fed ad libitum, was 2.0 +/- 0.2 nmol/g. In muscles incubated for 20 min in a medium devoid of added insulin and glucose, the concentration was decreased to 0.8 +/- 0.2 nmol/g. When the medium contained 0.5, 7.5, or 30 mM glucose, malonyl-CoA levels were 1.3 +/- 0.1, 1.8 +/- 0.1, or 2.4 +/- 0.2 nmol/g, respectively, in the absence of insulin and 1.7 +/- 0.1, 4.6 +/- 0.3, or 5.5 +/- 0.6 nmol/g in its presence (10 mU/ml). Compared with its level in a control muscle, the concentration of malonyl-CoA was increased threefold in the soleus 6-8 h after denervation and remained twofold higher for > or = 48 h. In contrast, muscle contractions induced by sciatic nerve stimulation, in vivo, acutely decreased the concentration of malonyl-CoA by 30-35%. The results indicate that insulin and glucose, and probably contractile activity, regulate the concentration of malonyl-CoA in muscle.(ABSTRACT TRUNCATED AT 250 WORDS)


1993 ◽  
Vol 265 (2) ◽  
pp. C337-C342 ◽  
Author(s):  
S. Hayashi ◽  
M. Horie ◽  
Y. Tsuura ◽  
H. Ishida ◽  
Y. Okada ◽  
...  

An antiarrhythmic agent, disopyramide, was found to enhance the insulin secretory capacity of Wistar rat pancreatic islets with a half-maximal concentration of 23.3 microM. Employing a patch-clamp technique, disopyramide was found to inhibit ATP-sensitive K+ (KATP) channel activity in rat pancreatic beta-cells in primary culture without altering the unitary conductance. Half-maximal inhibition was achieved by the addition of 3.6 microM disopyramide to the intracellular bathing solution in the inside-out mode, 11.0 microM to the extracellular bathing solution in the outside-out mode, and 87.4 microM in the cell-attached mode. The binding of [3H]glibenclamide to pancreatic islets was inhibited by unlabeled glibenclamide but not by unlabeled disopyramide. Based on these observations, it is concluded that disopyramide blocks pancreatic KATP channels via binding to a site(s) distinct from the sulfonylurea receptor. This effect may be causatively involved in disopyramide-induced hypoglycemia.


1982 ◽  
Vol 60 (9) ◽  
pp. 2079-2084 ◽  
Author(s):  
G. F. Wagner ◽  
B. A. McKeown

An experiment was conducted to determine if the hyperglycemia that is observed in zinc-stressed fish is also accompanied by changes in the levels of plasma insulin and liver glycogen. Juvenile rainbow trout were exposed to three concentrations of zinc sulphate along with a control group over 31 days. Plasma glucose levels were monitored in each group over the course of the experiment. The group demonstrating the most acute and sustained hyperglycemia (0.352 ppm zinc) was then analyzed along with the controls for changes in plasma insulin (using a teleost insulin radioimmunoassay) and liver glycogen levels. Significant depressions in plasma insulin and liver glycogen levels were observed in the zinc-exposed fish when compared with the controls. These changes are discussed with respect to possible influences of epinephrine, which is elevated in stressed fish, and (or) a direct effect of zinc metal on the pancreatic beta cells.


2002 ◽  
Vol 80 (2) ◽  
pp. 366-371 ◽  
Author(s):  
Scott Nunes ◽  
Eva-Maria Muecke ◽  
Kay E Holekamp

We evaluated the relationship between body fat and the metabolic hormones insulin and corticosterone in free-living juvenile Belding's ground squirrels (Spermophilus beldingi). Some free-living juveniles were provisioned with extra food high in fat and calories, and unprovisioned juveniles were used as controls. Body fat (as a percentage of body mass) of squirrels was regularly evaluated using non-invasive methods. Blood samples were also regularly collected from juveniles and assayed for plasma concentrations of insulin and corticosterone. Provisioned juveniles were fatter than unprovisioned juveniles during most of the active season, but differences in body fat disappeared near the end of summer as juveniles began fattening for hibernation. Thus, our data indicate that although body fat may fluctuate with energy availability early in the active season, it is regulated at precise levels as squirrels prepare for winter. Plasma corticosterone concentrations did not differ between provisioned and unprovisioned juveniles. However, plasma insulin concentrations were greater in provisioned than in unprovisioned juveniles early in the summer. Differences in insulin concentrations disappeared later in the active season, just prior to the disappearance of differences in body fat. Moreover, plasma insulin concentrations were significantly correlated with subsequent changes in body fat. Thus, our data suggest a link between insulin and seasonal regulation of body fat in juvenile S. beldingi.


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