ORCID Profile
0000-0002-3113-7072
Current Organisations
The University of Auckland
,
Massey University - Albany Campus
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Publisher: The Endocrine Society
Date: 09-1994
DOI: 10.1210/ENDO.135.3.8070387
Abstract: The GH receptor (GHR) plays a key role in postnatal growth regulation. Although plasma concentrations of GH are high during fetal life, its role during fetal development is not well understood. Recent data suggest that GHR are present in fetal hepatic tissue as early as 51 days gestation. However, the levels of GHR expression are markedly lower in fetal hepatic tissue compared to postnatal values, and there are conflicting data suggesting that ovine placental lactogen (oPL) and oGH share a common receptor. Given the uncertainty about whether oPL acts via the oGHR or a distinct receptor, we performed ligand binding and affinity cross-linking studies on hepatic microsomal membranes from adult castrated male, pregnant female, and fetal sheep. Ligand binding assays at a constant concentration of membranes showed that [125I]oPL yielded consistently higher (P < 0.001) specific binding (59.5 +/- 6.4%, 30.5 +/- 5.7%, and 7.6 +/- 2.4% for castrated male, pregnant female, and fetal sheep, respectively) compared to [125I]oGH (17.8 +/- 4.7%, 5.0 +/- 1.6%, and 1.2 +/- 0.4% for castrated male, pregnant female, and fetal sheep, respectively). Cross-reactivity studies showed that unlabeled oPL was consistently more potent than unlabeled oGH in displacing either of the labeled ligands. The dissociation constant (Kd) for oPL binding ranged from 0.16-0.40 nM and was not changed by solubilization with Triton X-100. Equilibrium binding analysis for oGH showed lower affinity for hepatic microsomal membranes (Kd, 1.7-3.2 nM) in each of the three groups of animals. Affinity cross-linking of microsomal membranes from castrated male and pregnant female sheep liver showed four major cross-linked complexes with both [125I]oPL and [125I]oGH, with mol wt of 150, 97, 75, and 60 kilodaltons. All four bands were identified with both ligands. Unlabeled oPL showed markedly higher potency than unlabeled oGH in reducing the signal of the [125I]oPL cross-linked complexes, whereas unlabeled oGH and oPL showed comparable potencies in reducing the signal of the [125I]oGH complexes. Immunoprecipitation of detergent-solubilized hepatic microsomal membranes from pregnant and fetal sheep using a panel of monoclonal antibodies raised against the extracellular region of the rabbit GHR showed potent immunological recognition of the [125I]oPL-receptor complexes. We suggest that oGH and oPL bind to a common or a related receptor protein(s). It is possible that differences in receptor dimerization or association with other membrane proteins are the basis of the differences in affinity and biological actions of the two hormones.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2014
Publisher: Oxford University Press (OUP)
Date: 12-2004
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.NUTRES.2011.09.015
Abstract: Two important lines of research have enhanced our understanding of the molecular role of nutrition in influencing behavior. First, exposure to an adverse environment during early life can influence the long-term behavior of the offspring. Second, regulation of the nervous system development and functioning appears to involve epigenetic mechanisms that require a continuous supply of methyl group donors in food. We hypothesized that a maternal diet during pregnancy deficient in methyl donors (MDD) may lead to altered behavior in offspring through permanent changes in hippoc al DNA methylation. We used a rat model of prenatal dietary MDD to test this hypothesis in female offspring as they aged. Prenatal MDD reduced birth weight, litter size, and newborn viability. Aged female offspring of MDD mothers showed increased anxiety and increased learning ability in comparison with control diet group offspring. To explore the role of MDD on epigenetic mechanisms in the brain of adult offspring, we studied expression and methylation of 4 selected genes coding for glucocorticoid receptor, hydroxysteroid dehydrogenase 11 type 2, neuronatin, and reelin proteins in the hippoc us. No major group differences in methylation or expression of the studied genes were detected, except for a significant down-regulation of the reelin gene in the MDD female offspring. The prenatal MDD diet caused intrauterine growth restriction, associated with long-term effects on the behavior of the offspring. However, the observed behavioral differences between the MDD and control diet offspring cannot be explained by epigenetic regulation of the specific genes investigated in this study.
Publisher: Bioscientifica
Date: 04-1994
Abstract: While the GH receptor (GHR) plays a key role during adult life, its role during fetal development is not well understood. Recent data suggest that GHRs are present in ovine fetal hepatic tissue at mid-gestation. However, the levels of GHR expression are markedly lower in fetal hepatic tissue in comparison with postnatal values. The present study investigates whether the neonatal induction of the hepatic GHR and plasma levels of IGF-I follow a pattern of strictly age-related development or whether birth-associated processes stimulate this increase. Stereotaxic electrolytic lesioning of the fetal paraventricular nuclei was employed to prolong gestation markedly. We compared the hepatic binding of ovine placental lactogen (oPL) and oGH and plasma levels of IGF-I in these post-mature fetuses with those in pre-term fetuses, pregnant mothers and lambs which were of the same conceptional age as the post-mature fetuses. While specific binding of both 125 I-labelled oGH and 125 I-labelled oPL to hepatic microsomal membranes was fully reversible in all groups, the specific binding of 125 I-labelled oGH was significantly ( P ·001) lower than specific binding of 125 I-labelled oPL in all groups of animals. There was no difference in specific I-labelled oGH or 125 I-labelled oPL binding in livers or plasma levels of IGF-I in post-mature fetuses in comparison with pre-term fetuses. In contrast, a major increase ( P ·001) in 125 I-labelled oGH and 125 I-labelled oPL binding and plasma IGF-I levels was observed in lambs. In pregnant females, specific 125 I-labelled oGH and 125 I-labelled oPL binding and plasma IGF-I levels were significantly ( P ·01) higher compared with the two fetal groups. A significant ( P ·001) correlation was observed between specific binding with 125 I-labelled oGH and 125 I-labelled oPL ( r =0·95, intercept=4·5, slope=2·36). Detailed competitive binding studies showed that the potency of unlabelled oPL in competing with 125 I-labelled oPL or 125 I-labelled oGH was consistently higher in comparison with unlabelled oGH. The differences in cross-reactivity of oPL and oGH at the distinct developmental stages were related to the differences in affinity between the two ligands and major developmental increases in capacity. The present study shows major parallel induction of oPL and oGH binding to hepatic microsomal membranes and plasma IGF-I concentrations after birth. The postnatal increase in the hepatic GHR is inhibited if delivery is prevented by stereotaxic destruction of the fetal paraventricular nuclei. Our observation that oGH and oPL binding is co-ordinately induced after birth in hepatic tissue supports the emerging evidence that the two ligands may bind to the same membrane receptor or to related protein(s). Journal of Endocrinology (1994) 141, 101–108
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0303-7207(01)00634-7
Abstract: Obesity and related metabolic disorders are prevalent health issues in modern society and are commonly attributed to lifestyle and dietary factors. However, the mechanisms by which environmental factors modulate the physiological systems that control weight regulation and the aetiology of metabolic disorders, which manifest in adult life, may have their roots before birth. The 'fetal origins' or 'fetal programming' paradigm is based on the observation that environmental changes can reset the developmental path during intrauterine development leading to obesity and cardiovascular and metabolic disorders later in life. The pathogenesis is not based on genetic defects but on altered genetic expression as a consequence of an adaptation to environmental changes during fetal development. While many endocrine systems can be affected by fetal programming recent experimental studies suggest that leptin and insulin resistance are critical endocrine defects in the pathogenesis of programming-induced obesity and metabolic disorders. However, it remains to be determined whether postnatal obesity is a consequence of programming of appetite regulation and whether hyperphagia is the main underlying cause of the increased adiposity and the development of metabolic disorders.
Publisher: Bioscientifica
Date: 05-1996
Abstract: Somatostatin has been suggested to influence the somatotrophic axis outside the central nervous system, in reducing GH-induced IGF-I mRNA and IGF-I generation. This study aimed to determine whether such effects were mediated via the GH receptor (GHR). GH-deficient dwarf rats aged 45–47 days ( n =8 per group) received twice daily subcutaneous injections of octreotide (1 mg/kg) (group O), saline (group S), octreotide (1 mg/kg) plus bovine GH (0·25 mg/kg) (group OG), or bovine GH (0·25 mg/kg) plus saline (group G) for 10 days. Octreotide-treated animals had less weight gain compared with saline-treated animals, but not when GH cotreated (group OG vs G). Octreotide had an overall effect on decreasing length gain ( P ·01). Serum IGF-I (ng/ml) was reduced by octreotide (group O 171 ±11, group S 239 ± 20, P ·01 group OG 283 ± 30, group G 362 ± 10, P ·001), as was serum insulin ( P ·001). A significant decrease in hepatic and muscle IGF-I mRNA expression was found as expected, yet this was not associated with decreased hepatic GHR expression. Rather, an increase in hepatic 125 I-bovine GH specific binding was observed ( P ·001) and, in GH-cotreated animals (OG), hepatic GHR and GH binding protein (GHBP) mRNA expression were also increased by octreotide by approximately 40%. In muscle, octreotide was associated with an approximately 30% decrease in GHBP mRNA and no effect on GHR mRNA. This study suggests that the suppressive effects of octreotide on IGF-I metabolism, at least in liver, are not mediated via down-regulation of GHR expression, but more likely by direct effects on IGF-I expression. Journal of Endocrinology (1996) 149, 223–231
Publisher: Cambridge University Press (CUP)
Date: 02-09-2008
DOI: 10.1017/S0007114508043353
Abstract: Maternal nutrition during pregnancy has a significant influence in establishing patterns of metabolism and postnatal behaviours in offspring, and therefore shapes their risk of developing disorders in later life. Although it is well established that a mismatch between food consumption and energy expenditure leads to obesity and metabolic dysregulation, little research has investigated the biological origin of such behaviour. We conducted the present experiments to investigate effects of early-life nutrition on preference between wheel running and lever pressing for food during adult life. To address this issue we employed a well-established experimental approach in the rat which has shown that offspring of mothers undernourished during pregnancy develop obesity and metabolic disorders when kept under standard laboratory conditions. Using this experimental approach, two studies were conducted where offspring of ad libitum -fed dams and dams undernourished throughout pregnancy were given the choice between wheel running and pressing a response lever for food. Across subsequent conditions, the rate at which the response lever provided food was varied from 0·22 to 6·0 (study 1) and 0·19 to 3·0 (study 2) pellets per min. Compared with the control group, offspring from dams undernourished during pregnancy showed a consistently greater preference for running over lever pressing for food throughout both experiments of the study. The results of the present study provide experimental evidence that a mother's nutrition during pregnancy can result in a long-term shift in her offspring's lifestyle choices that are relevant to obesity prevention. Such a shift, if endorsed, will have substantial and wide-ranging health consequences throughout the lifespan.
Publisher: Springer Science and Business Media LLC
Date: 14-03-2015
Publisher: The Endocrine Society
Date: 05-1992
DOI: 10.1210/ENDO.130.5.1315246
Abstract: Red deer antler tips in the growing phase were removed 60 days after the recommencement of growth for autoradiographical studies and RRAs. Sections were incubated with radiolabeled GH or insulin-like growth factor-I (IGF-I), with or without excess competing unlabeled hormones, and were analyzed autoradiographically. There was negligible binding of [125I]GH in any histological zone of antler sections. [125I]IGF-I showed highest specific binding in the chondroblast zone to a receptor demonstrating binding characteristics of the type 1 IGF receptor. The lowest specific binding of [125I]IGF-I was to prechondroblasts. RRAs on antler microsomal membrane preparations RRAs on antler microsomal membrane preparations confirmed the absence of GH receptors and the presence of type 1 IGF receptors found by autoradiography. These findings suggest that IGF-I may act in an endocrine manner in antler growth through a receptor resembling the type 1 IGF receptor. The presence of type 1 receptors in the chondroblast zone implicates IGF-I involvement in cartilage formation through matrixogenesis. There is no support for IGF-I having a major role in mitosis in the antler.
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000330227
Abstract: i Background/Aims: /i Early-life methyl-donor deficiency is implicated in growth restriction and later-life development of type 2 diabetes mellitus. We ascertained whether dietary methyl-donor deficiency in the mother during pregnancy or during postweaning growth in the rat would impair glucose homeostasis, insulin secretion and pancreatic endocrine development in young adults. i Methods: /i Effects of maternal methyl deficiency (90% deficiency in methionine, folate and choline) were compared with those of postweaning methyl deficiency and with control diets for effects on growth, impaired glucose tolerance, insulin secretion and pancreas development in offspring. Studies focussed on male offspring, which have been shown more susceptible to early-life influences on later disease development. i Results: /i Prenatal methyl deficiency delayed delivery, restricted birthweight by 22%, reduced litter size by 33% and increased offspring mortality to 23% shortly after birth. It reduced relative endocrine pancreatic mass in adult male offspring to 46% of endocrine mass in controls, but only mildly impaired their glucose tolerance and insulin secretion. In contrast, postweaning methyl deficiency restricted growth of male rats and reduced relative pancreatic endocrine mass (–40%), but improved their glucose tolerance, despite decreased insulin secretion. i Conclusion: /i It is clear that the global undernutrition (UN) during pregnancy in rodents alters glucose metabolism in adult offspring. It has been hypothesised that alterations in epigenetic mechanisms may underlie this phenotype. However, removing all methyl donors during pregnancy, which are essential for epigenetic processes in development, did not cause any alteration in glucose metabolism in offspring as seen in the global UN model.
Publisher: Oxford University Press (OUP)
Date: 02-2004
Publisher: Elsevier BV
Date: 05-1994
DOI: 10.1016/0303-7207(94)90249-6
Abstract: The rat IGF-I gene consists of six exons, with exons 3 and 4 forming a 'core' mature IGF-I coding region to which alternate 5' and 3' regions are spliced. Transcription occurs from four dispersed start sites (ss) approximately 382 (ss 1), approximately 343 (ss 2), approximately 245 (ss 3) and approximately 30-40 (ss 4) basepairs (bp) from the 3' end of exon 1, and from a region 50-70 bp from the 3' end of exon 2. The expression of ss mRNAs displays tissue-specific and ontogenic regulation. Alternate splicing of exon 5 produces E-peptide coding domain variants (Ea and Eb mRNAs), with the Eb form found predominantly in the liver. The regulation of IGF-I mRNA expression by GH and IGF-I in the GH-deficient dwarf (dw/dw) rat was investigated using antisense RNA probes in a solution hybridization RNase protection assay to detect leader exon and E domain variant mRNAs. GH treatment of dw/dw and normal Lewis rats increased the expression of all liver leader exon ss and E domain variants coordinately (1.6-1.9-fold increase, p < 0.01), although the increase observed in Eb transcripts was significantly higher in the dw/dw compared to the normal rat (p < 0.05). In kidney, GH treatment significantly increased exon 1 ss 3 and ss 4 transcripts by approximately 40% (p < 0.05). The expression of the other start sites was not affected by GH, suggesting that transcription factors may regulate start site usage independently. GH treatment was associated with a significant increase in IGF-I mRNA expression in skeletal muscle (p < 0.05) but not cardiac muscle or spleen. IGF-I treatment was associated with minor (approximately 20%) but significant (p < 0.05) reductions in IGF-I mRNA expression in the liver and kidney of dw/dw rats, suggesting that IGF-I can suppress IGF-I mRNA expression. IGF-I treatment did not affect IGF-I mRNA expression in cardiac and skeletal muscle of dw/dw rats. IGF-I receptor mRNA was detected in extrahepatic tissues only, and was not affected by either GH or IGF-I treatment. In summary, start site-specific regulation by GH was observed in kidney. GH increased IGF-I mRNA expression in muscle, kidney and liver, but had no effect in heart or spleen in the dw/dw rat. Our data suggest that systemic IGF-I can feedback on hepatic and renal IGF-I mRNA expression in the GH-deficient state.
Publisher: Springer Science and Business Media LLC
Date: 06-2012
Abstract: Metabolic flexibility is the body's ability to adapt to changing energy demand and nutrient supply. Maternal undernutrition causes growth restriction at birth and subsequent obesity development. Intriguingly, metabolic flexibility is maintained due to adaptations of muscle tissue. The aim of the present study was to investigate developmental pathways of these adaptive changes. Wistar rats received standard chow at either ad libitum (AD) or 30% of ad libitum intake (UN) throughout pregnancy. At all ages, metabolic status indicated similar insulin sensitivity in AD and UN offspring despite the development of adiposity in UN offspring at weaning. Type IIA fiber size was reduced in soleus muscle of UN offspring at weaning and they had a higher percentage of type I fibers in adulthood with a concomitantly higher oxidative capacity. Plasticity of muscle was present during the postnatal period and proposes novel pathways for the dynamic development of metabolic flexibility throughout postnatal life.
Publisher: Bioscientifica
Date: 07-1996
Abstract: The majority of IGF-I circulates in a large (150 kDa) ternary complex with IGF-binding protein-3 (IGFBP-3) and a non-IGF-binding acid-labile subunit. The secretion of ternary complex into the circulation from liver has been considered to be GH-dependent however, recent data indicate that GH does not directly regulate hepatic IGFBP-3 synthesis. To examine the role of insulin in regulating plasma IGFBP-3 levels, postpubertal male GH-deficient ( dw / dw ) rats were treated every 8 h with injections (s.c.) of 0·9% saline, 20 μg insulin/day, 200 μg hIGF-I/day, or 20 μg insulin/day plus 200 μg hIGF-I/day, for 10 days with the animals being killed 2–3 h after the final injection. Hypoglycaemia was not observed in any of the treatment groups. hIGF-I treatment increased longitudinal growth and weight gain ( P ·05), while insulin treatment had no effect. Plasma IGF-I levels were increased in groups treated with hIGF-I ( P ·05), while insulin treatment resulted in a reduction ( P -05): saline=267·1 ± 15·6 (ng/ml ± s.e.m. ), insulin=219·3 ± 17·5, hIGF-I=391·7 ± 17·6, insulin plus hIGF-I=357·5 ± 31·8. Hepatic IGF-I mRNA expression was increased in insulin-treated dw / dw rats in comparison with hIGF-I-treated animals ( P ·05) but not in comparison with saline control or the combined treatment groups. Plasma levels of intact IGFBP-3, measured by ligand blot analysis, were increased in all treatment groups compared with saline ( P ·05): saline=100·0 ± 9·4% (% of saline ± s.e.m. ), insulin=149·9 ± 17·5%, hIGF-I= 191·4 ± 17·3%, insulin plus hIGF-I=205·4 ± 15·3%. The levels of the 28/32 kDa IGFBPs and IGFBP-4 in plasma were increased by hIGF-I treatment ( P ·05) but not by insulin treatment. Hepatic specific 125 I-bovine GH binding was not significantly different in any of the treatment groups. This study provides the first evidence in non-diabetic animals that insulin regulates hepatic IGF-I mRNA expression, plasma IGF-I and plasma IGFBP-3 levels in the GH-deficient state without changes in hepatic GH receptors. The ergent response of plasma IGF-I and IGFBP-3 levels to insulin treatment in the present study may indicate an effect of insulin on the clearance of IGF-I from the circulation. Journal of Endocrinology (1996) 150, 67–76
Publisher: The Endocrine Society
Date: 05-2007
DOI: 10.1210/EN.2006-1641
Abstract: Obesity and type 2 diabetes are worldwide health issues. The present paper investigates prenatal and postnatal pathways to obesity, identifying different metabolic outcomes with different effects on insulin sensitivity and different underlying mechanisms involving key components of insulin receptor signaling pathways. Pregnant Wistar rats either were fed chow ad libitum or were undernourished throughout pregnancy, generating either control or intrauterine growth restricted (IUGR) offspring. Male offspring were fed either standard chow or a high-fat diet from weaning. At 260 d of age, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic cl , and other metabolic parameters were measured. As expected, high-fat feeding caused diet-induced obesity (DIO) and insulin resistance. Importantly, the insulin sensitivity of IUGR offspring was similar to that of control offspring, despite fasting insulin hypersecretion and increased adiposity, irrespective of postnatal nutrition. Real-time PCR and Western blot analyses of key markers of insulin sensitivity and metabolic regulation showed that IUGR offspring had increased hepatic levels of atypical protein kinase C ζ (PKC ζ) and increased expression of fatty acid synthase mRNA. In contrast, DIO led to decreased expression of fatty acid synthase mRNA and hepatic steatosis. The decrease in hepatic PKC ζ with DIO may explain, at least in part, the insulin resistance. Our data suggest that the mechanisms of obesity induced by prenatal events are fundamentally different from those of obesity induced by postnatal high-fat nutrition. The origin of insulin hypersecretion in IUGR offspring may be independent of the mechanistic events that trigger the insulin resistance commonly observed in DIO.
Publisher: The Endocrine Society
Date: 04-09-2008
DOI: 10.1210/EN.2008-1035
Abstract: Obesity and its associated comorbidities are of major worldwide concern. It is now recognized that there are a number of metabolically distinct pathways of obesity development. The present paper investigates the effect of moderate daily exercise on the underlying mechanisms of one such pathway to obesity, through interrogation of metabolic flexibility. Pregnant Wistar rats were either fed chow ad libitum or undernourished throughout pregnancy, generating control or intrauterine growth restricted (IUGR) offspring, respectively. At 250 d of age, dual-emission x-ray absorptiometry scans and plasma analyses showed that moderate daily exercise, in the form of a measured amount of wheel running (56 m/d), prevented the development of obesity consistently observed in nonexercised IUGR offspring. Increased plasma C-peptide and hepatic atypical protein kinase Cζ levels explained increased glucose uptake and increased hepatic glycogen storage in IUGR offspring. Importantly, whereas circulating levels of retinol binding protein 4 were elevated in obese, nonexercised IUGR offspring, indicative of glucose sparing without exercise, retinol binding protein 4 levels were normalized in the exercised IUGR group. These data suggest that IUGR offspring have increased flexibility of energy storage and use and that moderate daily exercise prevents obesity development through activation of distinct pathways of energy use. Thus, despite a predisposition to develop obesity under sedentary conditions, obesity development was prevented in IUGR offspring when exercise was available. These results emphasize the importance of tailored lifestyle changes that activate distinct pathways of metabolic flexibility for obesity prevention. Obesity induced by prenatal undernutrition is effectively prevented by moderate daily exercise through the activation of distinct pathways of hepatic metabolic flexibility.
Publisher: KARGER
Date: 2008
DOI: 10.1159/000165959
Publisher: American Physiological Society
Date: 15-10-2014
DOI: 10.1152/PHYSIOLGENOMICS.00024.2014
Abstract: Epigenomic regulation of the transcriptome by DNA methylation and posttranscriptional gene silencing by miRNAs are potential environmental modulators of skeletal muscle plasticity to chronic exercise in healthy and diseased populations. We utilized transcriptome networks to connect exercise-induced differential methylation and miRNA with functional skeletal muscle plasticity. Biopsies of the vastus lateralis were collected from middle-aged Polynesian men and women with morbid obesity (44 kg/m 2 ± 10) and Type 2 diabetes before and following 16 wk of resistance ( n = 9) or endurance training ( n = 8). Longitudinal transcriptome, methylome, and microRNA (miRNA) responses were obtained via microarray, filtered by novel effect-size based false discovery rate probe selection preceding bioinformatic interrogation. Metabolic and microvascular transcriptome topology dominated the network landscape following endurance exercise. Lipid and glucose metabolism modules were connected to: microRNA (miR)-29a promoter region hypomethylation of nuclear receptor factor ( NRF1) and fatty acid transporter ( SLC27A4), and hypermethylation of fatty acid synthase, and to exon hypomethylation of 6-phosphofructo-2-kinase and Ser/Thr protein kinase. Directional change in the endurance networks was validated by lower intramyocellular lipid, increased capillarity, GLUT4, hexokinase, and mitochondrial enzyme activity and proteome. Resistance training also lowered lipid and increased enzyme activity and caused GLUT4 promoter hypomethylation however, training was inconsequential to GLUT4, capillarity, and metabolic transcriptome. miR-195 connected to negative regulation of vascular development. To conclude, integrated molecular network modelling revealed differential DNA methylation and miRNA expression changes occur in skeletal muscle in response to chronic exercise training that are most pronounced with endurance training and topographically associated with functional metabolic and microvascular plasticity relevant to diabetes rehabilitation.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2011
Abstract: Increasing evidence suggests that diets high in polyunsaturated fatty acids (PUFA) confer health benefits by improving insulin sensitivity and lipid metabolism in liver, muscle and adipose tissue. The present study investigates metabolic responses in two different lines of mice either selected for high body weight (DU6) leading to rapid obesity development, or selected for high treadmill performance (DUhTP) leading to a lean phenotype. At 29 days of age the mice were fed standard chow (7.2% fat, 25.7% protein), or a high-fat diet rich in n -3 PUFA (n-3 HFD, 27.7% fat, 19% protein) or a high-fat diet rich in n -6 PUFA (n-6 HFD, 27.7% fat, 18.6% protein) for 8 weeks. The aim of the study was to determine the effect of these PUFA-rich high-fat diets on the fatty acid profile and on the protein expression of key components of insulin signalling pathways. Plasma concentrations of leptin and insulin were higher in DU6 in comparison with DUhTP mice. The high-fat diets stimulated a strong increase in leptin levels and body fat only in DU6 mice. Muscle and liver fatty acid composition were clearly changed by dietary lipid composition. In both lines of mice n-3 HFD feeding significantly reduced the hepatic insulin receptor β protein concentration which may explain decreased insulin action in liver. In contrast, protein kinase C ζ expression increased strongly in abdominal fat of n-3 HFD fed DUhTP mice, indicating enhanced insulin sensitivity in adipose tissue. A diet high in n -3 PUFA may facilitate a shift from fuel deposition in liver to fuel storage as fat in adipose tissue in mice. Tissue specific changes in insulin sensitivity may describe, at least in part, the health improving properties of dietary n -3 PUFA. However, important genotype-diet interactions may explain why such diets have little effect in some population groups.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2019
Publisher: S. Karger AG
Date: 1993
DOI: 10.1159/000183791
Abstract: To further evaluate the role of growth hormone (GH) in the neonatal period, the effects of GH or insulin-like growth factor 1 (IGF-1) administration were studied in the neonatal GH-deficient rat. Groups of pups from newborn litters were randomized to receive twice daily subcutaneous injections of recombinant bovine growth hormone (bGH, 5 micrograms), recombinant human IGF-1 (10 micrograms) or saline from the second to twelfth day of life. The effects on growth parameters, serum IGF-1 concentration, body composition and hepatic GH receptor binding were assessed. bGH-treated animals showed increases in body weight gain (p = 0.01), serum IGF-1 (p < 0.01), carcass nitrogen (p < 0.001) and carcass water (p < 0.001) compared to IGF-1 or saline-treated animals. No differences in these parameters were noted between IGF-1 and saline-treated groups. bGH-treated animals showed a significantly lower hepatic GH receptor binding (p < 0.01) compared to the other two groups. The demonstration of anabolic responses to GH administration in the neonatal period has implications for the possible role of GH in fetal and neonatal growth.
Publisher: Wiley
Date: 21-10-2016
DOI: 10.1111/COBI.12609
Publisher: The Endocrine Society
Date: 05-1992
DOI: 10.1210/ENDO.130.5.1374015
Abstract: The somatogenic effects of recombinant ovine placental lactogen (oPL) were investigated in the GH-deficient dwarf rat and compared to those of identical doses of recombinant bovine GH (bGH) in three independent studies. Both oPL and bGH treatments resulted in an increase (P less than 0.05) in body weight gain compared to that in saline controls, with oPL treatment being more potent than bGH (P less than 0.05). In promoting linear growth, oPL was more potent (P less than 0.05) than bGH in some instances. The nitrogen content of dry carcass matter was increased with oPL treatment compared to saline (P less than 0.05), with a nonsignificant increase in bGH-treated animals. Carcass fat was similarly reduced by both oPL and bGH treatment (P less than 0.05) compared to saline. Serum insulin-like growth factor-I (IGF-I) concentrations were increased significantly (P less than 0.05) by both oPL and bGH treatments, with a significantly greater effect of oPL suggested in one study. No increase in hepatic IGF-I mRNA was evident with either treatment, suggesting that the increase in serum IGF-I is due to posttranscriptional mechanisms. The expression of IGF-binding protein-3 hepatic mRNA was increased (P less than 0.05) with bGH treatment compared to that after saline treatment, but was unaffected by oPL treatment, indicating regulation by GH at the transcriptional level. The binding of [125I]bGH to hepatic membrane preparations demonstrated no difference in specific binding compared to that in saline controls. However, [125I]oPL specific binding was greater in oPL-treated animals (P less than 0.05). Animals treated with bGH had reduced (P less than 0.05) hepatic GH receptor mRNA compared to saline controls, but oPL treatment had no effect. Thus, oPL is a potent anabolic and lipolytic agent in the dwarf rat, exerting greater somatogenic effects on some parameters than bGH. Our data suggest differences in receptor binding and effects on GH receptor and IGF-binding protein-3 expression with these two treatments, raising the possibility of actions through different pathways or differential effects at the GH receptor level.
Publisher: The Endocrine Society
Date: 28-05-2009
DOI: 10.1210/EN.2009-0125
Abstract: Effective regulation of energy metabolism is vital for the maintenance of optimal health, and an inability to make these dynamic adjustments is a recognized cause of obesity and metabolic disorders. Epidemiological and experimental studies have highlighted the role of prenatal factors in the disease process, and it is now generally accepted that maternal nutrition during pregnancy significantly influences intrauterine development, shaping postnatal health. Consequences of impaired nutrition during fetal development include intrauterine growth restriction (IUGR) and subsequent obesity development in adult life. We have previously shown that prenatal undernutrition has a lasting effect on behavior, with IUGR offspring expressing a higher preference for voluntary exercise, and moderate daily exercise preventing obesity development. The present study investigated skeletal muscle structure in IUGR offspring and how moderate daily exercise drives changes in metabolic pathways that promote obesity prevention. Pregnant Wistar rats were either fed chow ad libitum or undernourished, generating control or IUGR offspring respectively. Although red muscle structure indicated higher oxidative capacity in IUGR offspring, obesity prevention was not due to increased fatty acid oxidation, indicated by decreased peroxisomal proliferator-activated receptor-γ coactivator 1 and carnitine-palmitoyltransferase 1 expression. In contrast, increased protein kinase Cζ expression and glycogen content in white muscle of exercised IUGR offspring suggests an enhanced capacity for anaerobic utilization of glucose. Furthermore, exercise-induced lactate accumulation was effectively prevented by stimulation of a lactate shuttle, driven by the increases in monocarboxylate transporters-4 and -1 in white muscle. This enhanced metabolic flexibility in IUGR offspring may facilitate muscle contractile performance and therefore support moderate daily exercise for effective obesity prevention.
No related grants have been discovered for Bernhard Breier.