Early postnatal caloric restriction protects adult male intrauterine growth-restricted offspring from obesity.

Postnatal ad libitum caloric intake superimposed on intrauterine growth restriction (IUGR) is associated with adult-onset obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). We hypothesized that this paradigm of prenatal nutrient deprivation-induced programming can be reversed with the introduction of early postnatal calorie restriction. Ten-month-old male rats exposed to either prenatal nutrient restriction with ad libitum postnatal intake (IUGR), pre- and postnatal nutrient restriction (IPGR), or postnatal nutrient restriction limited to the suckling phase (50% from postnatal [PN]1 to PN21) (PNGR) were compared with age-matched controls (CON). Visceral adiposity, metabolic profile, and insulin sensitivity by hyperinsulinemic-euglycemic clamps were examined. The 10-month-old male IUGR group had a 1.5- to 2.0-fold increase in subcutaneous and visceral fat (P < 0.0002) while remaining euglycemic, insulin sensitive, inactive, and exhibiting metabolic inflexibility (Vo(2)) versus CON. The IPGR group remained lean, euglycemic, insulin sensitive, and active while maintaining metabolic flexibility. The PNGR group was insulin sensitive, similar to IPGR, but less active while maintaining metabolic flexibility. We conclude that IUGR resulted in obesity without insulin resistance and energy metabolic perturbations prior to development of glucose intolerance and T2DM. Postnatal nutrient restriction superimposed on IUGR was protective, restoring metabolic normalcy to a lean and active phenotype

Intra-uterine Growth Restriction Downregulates the Hepatic Toll Like Receptor-4 Expression and Function

Maternal starvation is a significant cause of intrauterine growth restriction (IUGR) in the world and increases the risk of infection in the neonate. We examined the effect of maternal starvation on Toll like receptor (TLR)4 expression in hepatic, splenic and intestinal tissues obtained from the adult IUGR offspring of prenatal calorie restricted rats. The hepatic TLR4 protein concentration was undetectable in the IUGR rats that had restricted milk intake during the suckling period (SM/SP; n = 4, p < 0.05) as compared to the normal growth controls (CM/CP; n=4), and access to ad lib milk intake during the sucking period partially corrected the hepatic TLR4 expression (SM/CP; n = 4). IUGR had no effect on the splenic (n = 4) or intestinal (n = 4) TLR4 mRNA levels. In the liver, IUGR led to a 20% increase in baseline tumor necrosis factor (TNF)-α mRNA expression ( p < 0.03) and a 70% increase in interleukin-1β (IL-1β) mRNA expression ( p < 0.008) as compared to the control rats (CM/CP; n = 7). LPS-induced hepatic TNF-α release was significantly higher in SM/SP as compared to CM/CP. We propose that IUGR dysregulates TLR4 expression and function in the offspring, which may help explain the increased risk of Gram-negative sepsis and inflammatory diseases in this population

Comparative physiology of dipeptide transport in lower vertebrates (fishes) and invertebrates (lobster)

Thesis (Ph.D.)--University of Hawaii at Manoa, 1994.Includes bibliographical references (leaves 112-114).Microfiche.xi, 117 leaves, bound ill. 29 cmIn my study I propose to undertake an investigation to characterize the brush border uptake and basolateral efflux mechanisms of a biologically stable dipeptide, glycylsarcosine in an herbivorous teleost (tilapia, Oreochromis mossambicus.). This will be the first study to characterize dieptide uptake and efflux processes of a single dipeptide in any animal. In order to extend our understanding of such a unique system, I would like to compare the characteristics of brush border uptake in the herbivorous tilapia to those of a carnivorous teleost (rock fish, Sebastes caurinus) and an omnivorous invertebrate (lobster, Homarus americanus). The lobster hepatopancreas is a diverticulum of the pyloric stomach. Over the past few years a number of studies have focused on the mechanism of sugar and amino acid transport by hepatopancreatic BBMV (4,5). These investigations showed that the hepatopancreas plays a major role in the absorption of nutrients in this animal. A novel feature of these diverticula is that the luminal pH at times of feeding may drop to as low as 4 (18). A number of studies have shown that a drop in external pH stimulates sugar and amino acid transport into hepatopancreatic BBMV. The observed stimulation was attributed either to protonation of amino acids with the protonated form being the preferred substrate, or protonation of the carrier resulting in an increase in the binding affinity for the sugars. The acidic nature of these diverticula at the absorptive site, markedly affecting nutrient transport, make this an ideal animal model since the solutes under investigation (dipeptides) are known to be coupled to protons in other types of animals. It will be of interest to investigate: (1) whether such a proton coupled dipeptide mechanism exists in the brush border membrane of lobster hepatopancreas, (2) If so, are the affinities and transport capacities of these dipeptide transporters any different than those described for mammals and fishes, (3) Does the binding affinity of this transporter show any variation at different pH values?, and (4) Is the specificity of this transporter any different from those exhibited by vertebrates

Early postnatal caloric restriction protects adult male intrauterine growth-restricted offspring from obesity.

Postnatal ad libitum caloric intake superimposed on intrauterine growth restriction (IUGR) is associated with adult-onset obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). We hypothesized that this paradigm of prenatal nutrient deprivation-induced programming can be reversed with the introduction of early postnatal calorie restriction. Ten-month-old male rats exposed to either prenatal nutrient restriction with ad libitum postnatal intake (IUGR), pre- and postnatal nutrient restriction (IPGR), or postnatal nutrient restriction limited to the suckling phase (50% from postnatal [PN]1 to PN21) (PNGR) were compared with age-matched controls (CON). Visceral adiposity, metabolic profile, and insulin sensitivity by hyperinsulinemic-euglycemic clamps were examined. The 10-month-old male IUGR group had a 1.5- to 2.0-fold increase in subcutaneous and visceral fat (P &lt; 0.0002) while remaining euglycemic, insulin sensitive, inactive, and exhibiting metabolic inflexibility (Vo(2)) versus CON. The IPGR group remained lean, euglycemic, insulin sensitive, and active while maintaining metabolic flexibility. The PNGR group was insulin sensitive, similar to IPGR, but less active while maintaining metabolic flexibility. We conclude that IUGR resulted in obesity without insulin resistance and energy metabolic perturbations prior to development of glucose intolerance and T2DM. Postnatal nutrient restriction superimposed on IUGR was protective, restoring metabolic normalcy to a lean and active phenotype

Intra-uterine growth restriction downregulates the hepatic toll like receptor-4 expression and function.

Maternal starvation is a significant cause of intrauterine growth restriction (IUGR) in the world and increases the risk of infection in the neonate. We examined the effect of maternal starvation on Toll like receptor (TLR)4 expression in hepatic, splenic and intestinal tissues obtained from the adult IUGR offspring of prenatal calorie restricted rats. The hepatic TLR4 protein concentration was undetectable in the IUGR rats that had restricted milk intake during the suckling period (SM/SP; n = 4. p &lt; 0.05) as compared to the normal growth controls (CM/CP; n = 4), and access to ad lib milk intake during the sucking period partially corrected the hepatic TLR4 expression (SM/CP; n = 4). IUGR had no effect on the splenic (n = 4) or intestinal (n = 4) TLR4 mRNA levels. In the liver, IUGR led to a 20% increase in baseline tumor necrosis factor (TNF)-alpha mRNA expression (p &lt; 0.03) and a 70% increase in interleukin-1beta (IL-1beta) mRNA expression (p &lt; 0.008) as compared to the control rats (CM/CP; n = 7). LPS-induced hepatic TNF-alpha release was significantly higher in SM/SP as compared to CM/CP. We propose that IUGR dysregulates TLR4 expression and function in the offspring, which may help explain the increased risk of Gram-negative sepsis and inflammatory diseases in this population

Early exposure of the pregestational intrauterine and postnatal growth-restricted female offspring to a peroxisome proliferator-activated receptor-γ agonist

Prenatal nutrient restriction with intrauterine growth restriction (IUGR) alters basal and glucose-stimulated insulin response and hepatic metabolic adaptation. The effect of early intervention with insulin-sensitizing peroxisome proliferator-activated receptor γ agonists was examined in the metabolically maladapted F1 pregestational IUGR offspring with a propensity toward pregnancy-induced gestational diabetes. The effect of rosiglitazone maleate [RG; 11 μmol/day from postnatal day (PN) 21 to PN60] vs. placebo (PL) on metabolic adaptations in 2-mo-old F1 female rats subjected to prenatal (IUGR), postnatal (PNGR), or pre- and postnatal (IUGR + PNGR) nutrient restriction was investigated compared with control (CON). RG vs. PL had no effect on body weight or plasma glucose concentrations but increased subcutaneous white and brown adipose tissue and plasma cholesterol concentrations in all three experimental groups. Glucose tolerance tests with a 1:1 mixture of [2-2H2]- and [6,6-2H2]glucose in RG IUGR vs. PL IUGR revealed glucose tolerance with a lower glucose-stimulated insulin release (GSIR) and suppressed endogenous hepatic glucose production (HGP) with no difference in glucose clearance (GC) and recycling (GR). RG PNGR, although similar to PL CON, was hyperglycemic vs. PL PNGR with reduced GR but no difference in the existent low GSIR, HGP, and GC. RG IUGR + PNGR overall was no different from the PL counterpart. Insulin tolerance tests revealed perturbed recovery to baseline from the exaggerated hypoglycemia in RG vs. the PL groups with the only exception being RG PNGR where further worsening of hypoglycemia over PL PNGR was minimal with full recovery to baseline. These observations support that early intervention with RG suppressed HGP in IUGR vs. PL IUGR, without increasing GSIR similar to that seen in CON. Although RG reversed PNGR to the PL CON metabolic state, no such insulin-sensitizing effect was realized in IUGR + PNGR