ORCID Profile
0000-0003-0378-2581
Current Organisation
University of Adelaide
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Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.FREERADBIOMED.2009.08.019
Abstract: Sepsis and multiple organ dysfunction syndrome (MODS) are major causes of morbidity and mortality in the intensive care unit. Recently mitochondrial dysfunction has been proposed as a key early cellular event in critical illness. A growing body of experimental evidence suggests that mitochondrial therapies are effective in sepsis and MODS. The aim of this article is to undertake a systematic review of the current experimental evidence for the use of therapies for mitochondrial dysfunction during sepsis and MODS and to classify these mitochondrial therapies. A search of the MEDLINE and PubMed databases (1950 to July 2009) and a manual review of reference lists were conducted to find experimental studies containing data on the efficacy of mitochondrial therapies in sepsis and sepsis-related MODS. Fifty-one studies were included in this review. Five categories of mitochondrial therapies were defined-substrate provision, cofactor provision, mitochondrial antioxidants, mitochondrial reactive oxygen species scavengers, and membrane stabilizers. Administration of mitochondrial therapies during sepsis was associated with improvements in mitochondrial electron transport system function, oxidative phosphorylation, and ATP production and a reduction in cellular markers of oxidative stress. Amelioration of proinflammatory cytokines, caspase activation, and prevention of the membrane permeability transition were reported. Restoration of mitochondrial bioenergetics was associated with improvements in hemodynamic parameters, organ function, and overall survival. A substantial body of evidence from experimental studies at both the cellular and the organ level suggests a beneficial role for the administration of mitochondrial therapies in sepsis and MODS. We expect that mitochondrial therapies will have an increasingly important role in the management of sepsis and MODS. Clinical trials are now required.
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: The Endocrine Society
Date: 05-2006
DOI: 10.1210/EN.2005-1422
Abstract: Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as pleiotropic modulator of erse biological functions, including energy homeostasis and, recently, reproduction. Although inhibitory actions of ghrelin on LH secretion and puberty onset have been reported previously, the receptor mechanisms mediating these actions, and the potential gonadotropic effects of the unacylated isoform of ghrelin (UAG), remain unclear. In this work, the effects of single and repeated administration of ghrelin or UAG on LH secretion were compared in pubertal and adult male rats. In addition, the effects of ghrelin were assessed in models of transient or persistent hypergonadotropism. Daily injection of ghrelin or UAG throughout puberty similarly decreased LH levels and partially delayed balanopreputial separation. Likewise, chronic infusion of ghrelin or UAG to adult males resulted in significant decreases in circulating LH and FSH concentrations. Moreover, acute injection of ghrelin induced a transient reduction in LH levels in freely moving males, an effect that was fully mimicked by administration of UAG. Yet in contrast to ghrelin, UAG failed to modify GH secretion. Finally, injection of ghrelin moderately, but significantly, reduced the duration of LH secretory responses to the potent gonadotropin secretagogue kisspeptin-10, whereas ghrelin infusion in a model of chronic elevation of serum gonadotropin levels (the transgenic growth retarded male rat) evoked a significant reduction of LH concentrations. Altogether our present results further substantiate the inhibitory effect of ghrelin on basal and stimulated LH secretion in a wide array of experimental conditions. Moreover, our data are the first to demonstrate the ability of UAG, originally considered an inert form of the molecule, to mimic the actions of acylated ghrelin on LH release. These observations reinforce the contention that ghrelin, as putative signal for energy insufficiency, may operate as negative modifier of male puberty and LH secretion, an effect that might be, at least partially, conducted through a GH secretagogue receptor type 1a-independent mechanism.
Publisher: The Endocrine Society
Date: 11-2005
DOI: 10.1210/EN.2005-0335
Abstract: Profound somatotroph hypoplasia in the dwarf (dw/dw) rat is accompanied by an estrogen-dependent induction of prolactin secretion by the GH secretagogue, GHRP-6. Using electron microscopy, we demonstrated that the reduction in the somatotroph population in the dw/dw pituitary is accompanied by the presence of a morphologically distinct lactotroph subpopulation. In these cells, which did not coexpress GH, the size, shape, and number of the secretory granules were between those of the type I and type II lactotrophs. We therefore called these cells intermediate lactotrophs. The intermediate lactotrophs accounted for up to 30% of the total prolactin-positive cell population in dw/dw males and up to 12% in females. Using tannic acid to quantify the fusion of secretory granules, we have shown that the intermediate lactotrophs are unresponsive to either GH-releasing factor (GRF) or TRH but exhibit a sexually dimorphic secretory response to acute ghrelin treatment, granular fusions being 4-fold higher in females. No cell matching the morphology of the novel lactotroph subpopulation was observed in the pituitary of the GRF-insensitive lit/lit mouse. However, ablation of GRF neurons with neonatal monosodium glutamate treatment had no effect on the population of intermediate lactotrophs in the dw/dw rat. Thus, the presence of the intermediate lactotrophs in the dw/dw pituitary appears to be independent of the function of the GRF neurons.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2014
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: 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: The Endocrine Society
Date: 2004
DOI: 10.1210/EN.2003-0899
Abstract: Ghrelin promotes fat accumulation, despite potent stimulation of the lipolytic hormone, GH. The function of the major circulating isoform of ghrelin, des-octanoyl ghrelin, is unclear, because it does not activate the GH secretagogue receptor (GHS-R1a) and lacks the endocrine activities of ghrelin. We have now addressed these issues by infusing ghrelin, des-octanoyl ghrelin, or synthetic GHS-R1a agonists into three rat models with moderate, severe, or total GH deficiency. We show that in the context of significant GH secretion, the adipogenic effect of systemic ghrelin infusion is pattern dependent. However, this adipogenic action is not mediated by the pituitary hormones. Using a novel unilateral local infusion strategy, we demonstrate that ghrelin promotes bone marrow adipogenesis in vivo by a direct peripheral action. Surprisingly, this effect was also observed with des-octanoyl ghrelin, whereas a potent synthetic GHS-R1a agonist was ineffective. Thus, these adipogenic effects are mediated by a receptor other than GHS-R1a. This is the first in vivo demonstration of a direct adipogenic effect of des-octanoyl ghrelin, a major circulating form of ghrelin that lacks GH-releasing activity. We suggest that the ratio of ghrelin and des-octanoyl ghrelin production could help regulate the balance between adipogenesis and lipolysis in response to nutritional status.
Publisher: The Endocrine Society
Date: 11-2003
DOI: 10.1210/EN.2003-0423
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2010
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.PAN.2016.06.659
Abstract: Mitochondrial dysfunction occurs in vital organs in experimental acute pancreatitis (AP) and may play an important role in determining severity of AP. However, obtaining vital organ biopsies to measure mitochondrial function (MtF) in patients with AP poses considerable risk of harm. Being able to measure MtF from peripheral blood will bypass this problem. Furthermore, whether mitochondrial dysfunction is detectable in peripheral blood in mild AP is unknown. Therefore, the objective was to evaluate peripheral blood MtF in experimental and clinical AP. Mitochondrial respiration was measured using high resolution oxygraphy in an experimental study in caerulein induced AP and in a separate study, in patients with mild AP. Superoxide, cytochrome c, mitochondrial membrane potential (ΔΨ) and adenine triphosphate (ATP) were also measured as other markers of MtF. Even though some states of mitochondrial respiration were increased in both experimental and clinical AP, this did not lead to an increase in net ATP in patients with AP. The increased leak respiration in both studies was further proof of dyscoupled mitochondria. In the clinical study there were also features of mitochondrial dysfunction with increased leak flux control ratio, superoxide, ΔΨ and decreased cytochrome c. There is evidence of mitochondrial dysfunction with dyscoupled mitochondria, increased superoxide and decreased cytochrome c in patients with mild acute pancreatitis. Further studies should now determine whether mitochondrial function alters with severity in AP and whether mitochondrial dysfunction responds to treatments.
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: 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.
Publisher: Wiley
Date: 31-07-2006
DOI: 10.1111/J.1365-2826.2006.01467.X
Abstract: Growth hormone (GH) is known to regulate peripheral components of the hypothalamo-pituitary gonadal (HPG) axis, but it remains unclear whether GH exerts a significant influence on the activity of the hypothalamo-pituitary components of the HPG axis. In this study, we investigated the development of HPG axis function in the male transgenic growth retarded (Tgr) rat, a model of moderate systemic GH deficiency caused by hypothalamic expression of human (h)GH. Impaired postnatal somatotroph expansion and moderate GH deficiency in male Tgr rats were accompanied by a two- to three-fold increase in pituitary gonadotrophin content, but without a significant change in the pituitary gonadotroph population. A three- to nine-fold elevation in basal circulating luteinising hormone concentration was seen in postpubertal Tgr rats, with a smaller increase in follicle-stimulating hormone. Despite this hypergonadotrophism, there was no corresponding increase in steroidogenic (circulating testosterone and seminal vesicle weights) or gametogenic (spermatozoa counts in seminiferous tubules) activity in the postpubertal Tgr testis. Following puberty, the plasma leptin concentration also became progressively elevated in Tgr males. Circulating gonadotrophin and leptin levels were normalised in Tgr rats by peripheral physiological replacement of rat GH, but plasma testosterone concentration was unaffected. These results confirm that hGH exerts a positive influence on the central control of gonadotrophin secretion in the Tgr rat, but the absence of a corresponding elevation in the steroidogenic or gametogenic function of the Tgr testis implies that the peripheral GH/insulin-like growth factor I axis may also exert a permissive influence on testicular function. The relative contribution of somatogenic and lactogenic mechanisms and the potential influence of elevated leptin and decreased sensitivity to androgen feedback to the development of postpubertal hypergonadotrophism in Tgr males remain to be determined.
Publisher: Elsevier BV
Date: 05-2011
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Nichola Thompson.