Adult Metabolism Research Articles

Pharmacological activation of LXR in utero directly influences ABC transporter expression and function in mice but does not affect adult cholesterol metabolism

Cholesterol is critical for several cellular functions and essential for normal fetal development. Therefore, its metabolism is tightly controlled during all life stages. The liver X receptors-alpha (LXRalpha; NR1H3) and -beta (LXRbeta; NR1H2) are nuclear receptors that are of key relevance in coordinating cholesterol and fatty acid metabolism. The aim of this study was to elucidate whether fetal cholesterol metabolism can be influenced in utero via pharmacological activation of LXR and whether this would have long-term effects on cholesterol homeostasis. Administration of the LXR agonist T0901317 to pregnant mice via their diet (0.015% wt/wt) led to induced fetal hepatic expression levels of the cholesterol transporter genes Abcg5/g8 and Abca1, higher plasma cholesterol levels, and lower hepatic cholesterol levels compared with controls. These profound changes during fetal development did not affect cholesterol metabolism in adulthood nor did they influence coping with a high-fat/high-cholesterol diet. This study shows that the LXR system is functional in fetal mice and susceptible to pharmacological activation. Despite massive changes in fetal cholesterol metabolism, regulatory mechanisms involved in cholesterol metabolism return to a "normal" state in offspring and allow coping with a high-fat/high-cholesterol diet.

Dexamethasone Exposure of Neonatal Rats Modulates Biliary Lipid Secretion and Hepatic Expression of Genes Controlling Bile Acid Metabolism in Adulthood Without Interfering With Primary Bile Acid Kinetics

Literature suggests that glucocorticoid (GC) exposure during early life may have long-term consequences into adult life. GCs are known to influence hepatic bile acid synthesis and their transport within the enterohepatic circulation. This study addresses effects of early postnatal exposure to GC on hepatic expression of key genes in bile acid metabolism and bile acid kinetics in adult rats. Male rats were treated with either dexamethasone (DEX) or saline at days 1-3 d after birth. Liver tissue and blood were collected from 2 d to 50 wk of age. Bile acid kinetics were determined at week 8. DEX acutely induced hepatic mRNA levels of cholesterol 7alpha-hydroxylase (Cyp7a1), cholesterol 27-hydroxylase (Cyp27), and in particular sterol 12alpha-hydroxylase (Cyp8b1), whereas expression of the bile acid transporters bile salt export pump (Bsep) and sodium taurocholate cotransporting polypeptide (Ntcp) was moderately affected. Neonatal DEX administration led to increased bilary lipid secretion, decreased Cyp8B1 mRNA expression and a 3-fold higher Cyp7a1/Cyp8b1 mRNA ratio in rats at week 8 compared with age-matched controls without alterations in bile acid kinetics. Therefore, neonatal DEX administration causes altered gene expressions later in life that are not translated into quantitative changes in bile acid kinetics.

Negative predictive adaptive response of a high protein weaning diet in rats exposed to a high fat/sugar diet in adulthood

Strong evidence suggests that the risk of developing diseases such as type 2 diabetes and obesity may be programmed by early environmental influences. Dietary factors may specifically influence the programming of glucose and lipid metabolism. The aim was to examine the long‐term effects of early postnatal dietary programming by diets high in protein and fiber on lipid and glucose metabolism in adulthood. Wistar dams were mated and given free access to standard chow and water. At parturition, litters were culled to 10 pups. Pups were weaned at 21 days onto control or a diet high in protein (40%) or fiber (30%) and consumed these diets until adulthood (4 months). Rats were then challenged with a high fat/high sugar diet for 6 weeks. At the end of this period body composition was assessed and an oral glucose tolerance test (OGGT) performed. Organs were removed for mRNA analysis and blood drawn for analysis of satiety hormones. A long‐term high protein diet, when followed by one high in fat and sugar, resulted in significantly higher body fat percentage. Area under the glucose curve during OGTT was approximately 56% higher in protein fed rats. The protein diet also resulted in significantly lower levels of cholesterol 7‐α hydroxylase, sodium linked transporter‐1 and glucose transporter‐5 mRNA. This suggests that a long‐term diet high in protein may have negative consequences if it is not matched by subsequent adult diet.CIHR, NSERC

G/A Polymorphism at –258 of the Hepatic Glucokinase Promoter Is Not Associated with Decreased Birth Weight in Preterm Neonates

Background: A high percentage of preterm neonates are born small for gestational age (SGA). These children show a high morbidity and mortality after birth and often develop insulin resistance with ensuing impaired glucose metabolism in adulthood. Since insulin is important for intrauterine growth, fetal insulin resistance might also influence birth weight of preterm neonates. Objectives: A common polymorphism in the promoter region of the human hepatic glucokinase (–258) is associated with a decreased promoter activity, an enhanced insulin secretion, and hypertension and hepatic insulin resistance in adults. In this pilot study we wanted to investigate whether the G/A polymorphism at –258 of the hepatic glucokinase promoter has an effect on birth weight of preterm neonates and therefore might constitute a genotype leading to low birth weight and metabolic defects. Methods: We enrolled 106 preterm neonates in our study. 44 of them were SGA and 62 AGA neonates. We extracted DNA from a buccal swab and identified the polymorphism by PCR-ARMS. Results: We found no difference in the prevalence of the polymorphism in either groups. Conclusion: The polymorphism at –258 of the fetal hepatic glucokinase promoter is most probably not of a major relevance in the pathophysiology of low birth weight in preterm neonates.

Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome

Prader-Willi syndrome (PWS) is an imprinted genetic obesity disorder characterized by abnormalities of growth and metabolism. Multiple mouse models with deficiency of one or more PWS candidate genes have partially correlated individual genes with aspects of the PWS phenotype, although the genetic origin of defects in growth and metabolism has not been elucidated. Gene-targeted mutation of the PWS candidate gene Magel2 in mice causes altered circadian rhythm output and reduced motor activity. We now report that Magel2-null mice exhibit neonatal growth retardation, excessive weight gain after weaning, and increased adiposity with altered metabolism in adulthood, recapitulating fundamental aspects of the PWS phenotype. Magel2-null mice provide an important opportunity to examine the physiological basis for PWS neonatal failure to thrive and post-weaning weight gain and for the relationships among circadian rhythm, feeding behavior, and metabolism.

Prenatal Exposures and Glucose Metabolism in Adulthood

Birth weight has been associated with the risk of type 2 diabetes in several studies. We investigated whether prenatal influences on birth weight (gestational age, parity, preeclampsia, prepregnancy BMI, smoking during pregnancy, and socioeconomic position [SEP]) were associated with glucose metabolism in midlife and the role of birth weight for gestational age (BGA) and adult adiposity in mediating these associations. Data from 7,518 participants of the 1958 British Birth Cohort with information on A1C at age 45 years were analyzed. Associations between prenatal exposures and A1C > or =6% were examined using a series of logistic regression models. The basic model consisted of all prenatal factors (except parity) adjusted for sex and family history of type 2 diabetes. Further adjustments included BGA only, concurrent adiposity only (BMI and waist circumference), and BGA plus adiposity. In the basic model, preeclampsia (odds ratio 1.78 [95% CI 1.14-2.80]), prepregnancy BMI > or =25 kg/m(2) (1.90 [1.45-2.47]), maternal smoking (1.33 [1.04-1.71]), and manual SEP (1.87 [1.36-2.58]) were independently associated with A1C at 45 years of age. Adjustment for BGA had little impact on the prenatal factors/A1C associations, whereas adjustment for adult adiposity at 45 years substantially reduced associations for prepregnancy BMI, smoking during pregnancy, and SEP. Prenatal exposures were related to blood glucose levels in mid-adulthood. Associations for several prenatal factors were largely mediated through adult adiposity but surprisingly not through birth weight. Prenatal exposures are likely to have the strongest effect on glucose metabolism indirectly through their influence on adiposity.

Differences in survival and neonatal metabolism in lambs from flocks selected for or against staple strength

In the field, we found that lamb mortality was lower (P < 0.01) in a flock selected for wool staple strength (SS+) than in a flock selected against staple strength (SS–), or a random-bred control flock (R); mortality rates calculated from 4200 records were 17.0, 22.8, and 24.1%, respectively. The proportion of twins was similar in all flocks, but birth weights differed (P < 0.01), being 4.40, 4.25, and 4.14 kg, respectively. Biochemical profiles were measured in lambs from 20 ewes from each flock around the time of birth in an animal-house study, to define potential causes of the genetic difference in survival. In the intensive study, birth weight was similar for all groups; however, gestation length was slightly shorter in the SS+ lambs (P < 0.05 for SS+ v. R). All lambs had low plasma concentrations of the essential amino acids and glucose at birth, compared with after suckling. Plasma concentrations of glucose, non-esterified fatty acids (NEFA), and blood urea nitrogen (BUN) at birth differed between lambs from the flocks with the greatest difference in mortality (i.e. SS+ v. R); that is, SS+ lambs had higher concentrations of glucose (1.84 v. 1.23 mm; P < 0.01) and NEFA (1.52 v. 1.08 mm; P < 0.05), and lower concentrations of BUN (7.7 v. 9.7 mm; P < 0.01) at birth, and for the next 9 h. The semimembranosus and semitendinosus muscle of the SS+ lambs also had lower concentrations of ATP (7.4 v. 5.0 μmol/g, respectively) compared with lambs from the other flocks, immediately post-partum. Muscle phosphocreatinine was also slightly lower in the SS+ lambs. No differences between the genotypes were observed in reserves of glycogen, carcass fat, brown adipose tissue, or in neonatal thyroid hormones. In summary, sheep selected for high wool staple strength had lower lamb mortality than the other 2 flocks. This was accompanied by metabolic differences at birth that can be associated with greater metabolic maturity, rather than greater energy reserves.

Adult sterol metabolism is not affected by a positive sterol balance in the neonatal Golden Syrian hamster

Dietary components impact metabolism early in life. Some of the diet-induced effects are long lasting and can lead to various adult-based diseases. In the current studies, we examined the short-term effects of dietary cholesterol on neonatal hepatic sterol metabolism and the long-term effects that those early-life diets had on sterol metabolism in adulthood. Neonatal hamsters began consuming solid food as a supplement to milk by 5 days of age; diets contained 0 or 2% added cholesterol (wt/wt). By 10 days of age, plasma and liver cholesterol concentrations were 3.2- and 2.5-fold greater, respectively, in the neonates fed cholesterol. Hepatic sterol synthesis rates were suppressed 65% in cholesterol-fed neonates compared with control neonates. By 20 days of age, plasma and liver cholesterol concentrations were still greater and sterol synthesis rates were now suppressed maximally in neonates fed cholesterol compared with control neonates. The expression level of an apolipoprotein B-containing lipoprotein receptor (low-density lipoprotein receptor-related protein) was greater and the mature form of the sterol regulatory element-binding protein-2 was similar in livers of 20-day-old control neonates compared with control neonates at 10 days of age. To test whether the change in sterol balance in the neonatal period had a lasting effect on hepatic sterol metabolism, all animals were weaned on a low-cholesterol diet. At 70 days of age, hepatic sterol synthesis rates, plasma lipoprotein and liver cholesterol concentrations, and bile acid pool sizes and compositions were measured. Sterol balance in the adults was similar between animals fed either diet early in life, as demonstrated by a lack of difference in any parameter measured. Thus, even though dietary cholesterol suppressed hepatic sterol synthesis rates dramatically in the neonatal hamster, the change has little impact on sterol balance later in life.

Endogenous glucose production, insulin sensitivity, and insulin secretion in normal glucose-tolerant Pima Indians with low birth weight

Individuals with low birth weight (LBW) are at increased risk of developing type 2 diabetes in later life. Whether impairments in endogenous glucose production (EGP), insulin action, insulin secretion, or a combination thereof account for this association is unclear. We, therefore, examined these parameters in Pima Indians with normal glucose tolerance. Body composition, glucose and insulin responses during a 75-g oral glucose tolerance test (OGTT), EGP, insulin-stimulated glucose disposal during low- and high-dose insulin infusion (M-low and M-high, hyperinsulinemic glucose clamp), and acute insulin response (AIR) to a 25-g intravenous glucose challenge were measured in 230 Pima Indians (147 men and 83 women, aged 25 ± 0.4 years [mean ± SE; range, 18 to 44]) with normal glucose tolerance. A subgroup of 63 subjects additionally underwent biopsies of subcutaneous adipose tissue for determination of adipocyte cell size and lipolysis. Subjects in the lowest quartile of birth weight (birth weight: 2,891 ± 33 g, LBW, n = 58) were compared to those whose birth weight was in the upper 3 quartiles (birth weight: 3,657 ± 28 g, NBW, n = 172). Age- and sex-adjusted body mass index (BMI), percent body fat, and waist-to-thigh ratio (WTR) were similar in LBW and NBW subjects. Suppression of EGP during the clamp was less in LBW than in NBW subjects before ( P = .002) and after adjustment for age, sex, percent body fat, and M-low ( P = .02). M-low and M-high were less in LBW than in NBW subjects before ( P = .05 and P = .01) and after adjustment for age, sex, percent body fat, and WTR ( P = .04 and P = .05). AIR was not different in LBW compared to NBW subjects before adjustments ( P = .06), but it was lower in LBW than in NBW subjects after adjustment for age, sex, percent body fat, and M-low ( P = .02), suggesting that AIR did not increase appropriately for the decrease in insulin-stimulated glucose disposal (M). In addition, average adipocyte cell size ( P = .08) and basal lipolysis ( P = .02) were higher in the LBW than in the NBW group. These results show that Pima Indians with LBW manifest a variety of impairments in metabolism in adulthood. Among these, a lesser insulin-stimulated suppression of EGP and a lesser insulin secretory capacity are the predominant ones. We conclude that interaction of multiple defects may contribute to increased susceptibility to type 2 diabetes among individuals with LBW.

Maternal modulation of specific and non-specific immune components of colostrum and mature milk.

The neonates of most mammalian species cannot survive on an adult diet or exposure to an array of adult pathogens. Lactation provides a transitional period for the immature newborn to adapt to the adult environment. However, there is immense variation in the metabolic maturity of mammals at birth, as well as in the rate of postnatal growth and development during the lactation period. As a result, large differences in milk composition have evolved among mammals (Oftedal and Iverson, 1995). Furthermore, large progressive changes in milk composition occur during lactation to meet the changing metabolic needs of the young (Nicholaset al.1997). For example, the Tammar Wallaby has a relatively short gestation period, during which Phase 1 of mammary development occurs. The animal weighs only 400 mg at birth and remains permanently attached to the teat for the next 130 days, while growing to 100 g (Phase 2A). The pouch young (PY) then detaches from the teat and sucks intermittently to reach a weight of 400500 g by 200 days of age (Phase 2B). The PY then leaves the pouch intermittently until 260 days when it exits the pouch permanently, finally weaning at 300 days, at a weight of 1.6-2.5 kg (Phase 3). The increase in body weight of the young from about 0.5 g to 2000 g during lactation is associated with major changes in milk composition that define phases 2A, 2B and 3 of lactation. Both mammary gland size and milk production increase commensurate with the rate of growth of the young.

Ratios of hatchling and adult mass-independent metabolism: A physiological index to the altricial-precocial continuum

Measures of metabolism which are theoretically mass-independent (MIM values = BMR ÷ M 0.67) are calculated for non-passerine species from data in the existing literature. These MIM values are, in fact as the acronym implies, essentially mass independent, with only 8.2% of the variation in MIM values attributable to log mass. In 10 of the 12 orders for which data were analysed, the slopes of the regressions of MIM values on log body mass do not differ significantly from zero. A dimensionless index of the intensity of the energy metabolism of hatchlings relative to that of conspecific adults is derived based upon the mass-independent measures of metabolism for adults and hatchlings. This ranking of metabolic maturity at hatching, a physiological index, is compared with the most commonly used classification of the avian altricial-precocial continuum which is based upon morphological and behavioral characteristics. Several taxonomic groups appear more precocial metabolically than indicated by their ranking based upon morphological and behavioral criteria.

Evaluation of localization and intensity of the reactions of succinic dehydrogenase, NADH tetrazole reductase and lactate dehydrogenase in developing rat testis: I. Physiological conditions

The localization, intensity, and character of the enzymatic reactions of the following enzymes responsible for the oxygenic and nonoxygenic respiration were under examination: succinic dehydrogenase (SDH), NADH tetrazole reductase (NADH-R), and lactate dehydrogenase (LDH). The features of the enzymatic reactions enumerated above were tested in male gonads of the rats on their 1st, 4th, 7th, 15th, 30th, 45th, 60th, 90th d and 1.5 year of post-fetal life. It was estimated on the examined reactions that their metabolic maturity in the gonad was reached on the 45th d of the rat's life.

Evolution of localization of the reactions of adenosine triphosphatase (Mg ++-ATP-ase), 5′nucleotidase (5′nt), alkaline phosphatase (AP), and acid phosphatase (AcP) in developing rat testis. : I. Physiological conditions

The experiments were performed upon the rats aged 1, 4, 7, 15, 30, 45, 60, 90 d, and 1,5 a. The behavior of the following reactions was described: for adenosine triphosphatase stimulated by Mg++(Mg++-ATP-ase), for 5'nucleotidase (5'Nt), for alkaline phosphatase (AP), for acid phosphatase (AcP). The first 3 are markers of the transport enzymes in cells, and the 4th is a marker of lytic processes. It was estimated on the basis of the examined reactions that a full metabolic maturity of the gonad was revealed since the 45th d of post-fetal life.

Inhibitory effects of centrally acting drugs on the neonatal imprinting of sex differences in the hepatic metabolism of a dimethylated epoxide in the rat.

The effects of the neonatal administration of reserpine, chlorpromazine, phenobarbitone and morphine on the development of sex differences in hepatic drug metabolism in the rat have been investigated. Treatment of neonatal male rats with reserpine or chlorpromazine for the first two weeks post-partum significantly inhibited the development of sex differences in drug metabolism in adult life. Similar treatment of neonatal female rats with reserpine or chlorpromazine had no effect on the development of hepatic drug metabolism in adulthood. Morphine or phenobarbitone treatment of neonatal rats of either sex had no effect on the development of sex differences in hepatic drug metabolism in adult life.

Postnatal development of lipid-clearing enzymes in the suckling animal

Age-related changes in the enzyme activities in the storage and secretory pools of extrahepatic lipoprotein lipase and hepatic triglyceride lipase were determined during a primed/constant infusion of heparin for 2 hr in puppies between birth and 18 wk of life. Lipoprotein lipase activity was low in the first 4 wk of suckling. Its storage pool increased 6-fold in the next 14 wk, with a less dramatic rise in the secretory pool. Sustained increases in the activity of this enzyme were seen late when (1) the pup was being weaned, and (2) the insulin-dependent glucoregulatory mechanism had matured. Both phases of hepatic triglyceride lipase were well developed at birth reflecting the metabolic maturity of the liver at birth. The ability to clear intravenous lipid during a 2-hr infusion was also measured in the pups. The rate of Intralipid utilization increased from 198 +/- 43 mg/kg/hr in the first week of life to 424 +/- 20 mg/kg/hr at 12 wk. Blood Intralipid homeostasis was causally related to increased activity in the storage and secretory pools of lipoprotein lipase. The progressive increase in lipoprotein lipase activity and the maintenance of the secretory capacity was dependent on the growth of the muscle mass and its capillary bed. Endogenous insulin rather than the fat content of the feed appeared significant in the postnatal development of the heparin-releasable lipid clearing enzymes.

The storage and synthetic pools of heparin-releasable lipoprotein lipase and hepatic triacylglycerol lipase in the growing puppy.

Age-related changes in the activities of extrahepatic lipoprotein lipase and hepatic triacylglycerol lipase were determined during a primed/constant-rate infusion of heparin for 2 h in puppies between birth and 18 weeks of age. The early (storage) and late (synthetic) phases were measured. Both phases of hepatic triacylglycerol lipase activity were well developed in the first week, reflecting the metabolic maturity of the liver at birth. During the 18 weeks of study, the activity remained relatively unchanged except for a sharp peak at 12 weeks. Extrahepatic lipoprotein lipase activity was low in the first 4 weeks of suckling. Its storage pool increased 6-fold in the next 14 weeks, with a less marked rise in its late (synthetic) pool. Sustained increases in the activity of this enzyme were first noticed during weaning, when the insulin-secretory response matured. Endogenous insulin-secretory capacity rather than the fat content of the feed appeared significant in the postnatal development of lipoprotein lipase (Clearing-factor lipase) activity.

Biosynthesis of phosphatidic acid by liver and lung of maternal and fetal rabbits

1. 1. The synthesis of phosphatidic acid from labelled precursors, [ 3H]palmitic acid and [ 14C]glycerol 3-phosphate. was studied in microsomes of liver and lung from maternal and fetal rabbits. 2. 2. The rate of in vitro synthesis of phosphatidic acid by liver microsomes of pregnant rabbits was in good agreement with the levels of plasma glycerolipids. 3. 3. It agrees with previous data on the biosynthesis of phosphoglycerides and pulmonary surfactant during the perinatal development of the lung. 4. 4. On the other hand. metabolic maturity of liver in order to synthesize phosphatidic acid was achieved during the postnatal period.

Pathology with reference to the bile retention syndrome.

SummaryThe pathological significance of giant cells, inspissitated bile plugs and hepatic fibrosis in the liver of infants is critically reviewed. Evidence is presented suggesting that a wide variety of pathological change in the paediatric liver results from the interaction of the effects of growth, metabolic maturity, genetic metabolic variability and infection. Understanding of the bile retention syndromes might increase if the diagnosis of ‘Neonatal Hepatitis’ and ‘biliary atresia’ as finite conditions, were to cease and their pathogenesis considered in such a multifactorial way.

The content of vitamin B12 in adult and foetal tissue: a comparative study.

Summary. The vitamin B12 content of 17 tissues in 28 adults and 17 foetuses was measured by a Euglena gracilis bioassay. The former were taken after sudden deaths, many accidental, and the latter after therapeutic abortions for mild psychiatric reasons. In the adult, the liver had the highest level of vitamin B12 followed by the kidney, adrenal, pancreas and heart. The tissues of greatest vitamin B12 concentration in the foetus were the liver, adrenal, kidney and lung. Foetal spleen, lung and colon were significantly higher than their adult counterparts, while foetal liver, kidney, heart and brain were significantly lower in comparison with the adult. Differences in vitamin B12 levels may reflect adult and foetal differences in circulation, metabolic maturity or plasma vitamin B12 transport.

Influence of body temperature and size on experimental cyanide encephalopathy

Cyanide encephalopathy was induced in several types of laboratory animals, and the influences of body size and body temperature were investigated. Four consecutive exposures to hydrogen cyanide produced a high incidence of focal, destructive brain lesions in large rats and large hamsters, a low incidence in small rats, small hamsters and mice, and no lesions in guinea pigs. Lesions of white matter occurred much more often among large rats and large hamsters than among the others. The differences in incidence and location of lesions between large and small animals were found also after single cyanide exposure. During cyanide exposures, body temperature fell more in small than in large animals, due to greater surface-volume ratio. Artificial prevention of the temperature fall in small rats caused a small increase in the number of lesions, but no change in distribution. Artificial augmentation of the temperature fall in large rats produced a decrease in the number of lesions, but again, no change in distribution. Therefore, body temperature played a role in determining the incidence of lesions, but some other factor, eerhaps related to the metabolic maturity of the brain, determined the propensity for cyanide to damage white matter of large rats and large hamsters.