Publications by authors named "Deanne H Hryciw"

58 Publications

Maternal diet high in linoleic acid alters offspring fatty acids and cardiovascular function in a rat model.

Br J Nutr 2021 Apr 16:1-14. Epub 2021 Apr 16.

Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.

Linoleic acid (LA), an essential n-6 fatty acid (FA), is critical for fetal development. We investigated the effects of maternal high LA (HLA) diet on offspring cardiac development and its relationship to circulating FA and cardiovascular function in adolescent offspring, and the ability of the postnatal diet to reverse any adverse effects. Female Wistar Kyoto rats were fed low LA (LLA; 1·44 % energy from LA) or high LA (HLA; 6·21 % energy from LA) diets for 10 weeks before pregnancy and during gestation/lactation. Offspring, weaned at postnatal day 25, were fed LLA or HLA diets and euthanised at postnatal day 40 (n 6-8). Maternal HLA diet decreased circulating total cholesterol and HDL-cholesterol in females and decreased total plasma n-3 FA in males, while maternal and postnatal HLA diets decreased total plasma n-3 FA in females. α-Linolenic acid (ALA) and EPA were decreased by postnatal but not maternal HLA diets in both sexes. Maternal and postnatal HLA diets increased total plasma n-6 and LA, and a maternal HLA diet increased circulating leptin, in both male and female offspring. Maternal HLA decreased slopes of systolic and diastolic pressure-volume relationship (PVR), and increased cardiac Col1a1, Col3a1, Atp2a1 and Notch1 in males. Maternal and postnatal HLA diets left-shifted the diastolic PVR in female offspring. Coronary reactivity was altered in females, with differential effects on flow repayment after occlusion. Thus, maternal HLA diets impact lipids, FA and cardiac function in offspring, with postnatal diet modifying FA and cardiac function in the female offspring.
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http://dx.doi.org/10.1017/S0007114521001276DOI Listing
April 2021

Maternal and Postnatal High Linoleic Acid Diet Impacts Lipid Metabolism in Adult Rat Offspring in a Sex-Specific Manner.

Int J Mol Sci 2021 Mar 14;22(6). Epub 2021 Mar 14.

Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. We aimed to investigate the effect of maternal and postnatal high LA (HLA) diet on plasma FA composition, plasma and hepatic lipids and genes involved in lipid metabolism in the liver of adult offspring. Female rats were fed with low LA (LLA; 1.44% LA) or HLA (6.21% LA) diets for 10 weeks before pregnancy, and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), fed either LLA or HLA diets and sacrificed at PN180. Postnatal HLA diet decreased circulating total n-3 PUFA and alpha-linolenic acid (ALA), while increased total n-6 PUFA, LA and arachidonic acid (AA) in both male and female offspring. Maternal HLA diet increased circulating leptin in female offspring, but not in males. Maternal HLA diet decreased circulating adiponectin in males. Postnatal HLA diet significantly decreased aspartate transaminase (AST) in females and downregulated total cholesterol, HDL-cholesterol and triglycerides in the plasma of males. Maternal HLA diet downregulated the hepatic mRNA expression of in both male and female offspring and decreased the hepatic mRNA expression of and in females. Both maternal and postnatal HLA diet decreased hepatic mRNA expression of in females. Postnatal diet significantly altered circulating fatty acid concentrations, with sex-specific differences in genes that control lipid metabolism in the adult offspring following exposure to high LA diet in utero.
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http://dx.doi.org/10.3390/ijms22062946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999727PMC
March 2021

Developmental programming of peripheral diseases in offspring exposed to maternal obesity during pregnancy.

Am J Physiol Regul Integr Comp Physiol 2020 11 2;319(5):R507-R516. Epub 2020 Sep 2.

Environmental Futures Research Institute, Griffith University, Nathan, Queensland, Australia.

Obesity is an increasing global health epidemic that affects all ages, including women of reproductive age. During pregnancy, maternal obesity is associated with adverse pregnancy outcomes that lead to complications for the mother. In addition, maternal obesity can increase the risk of poor perinatal outcomes for the infant due to altered development. Recent research has investigated the effects of maternal obesity on peripheral organ development and health in later life in offspring. In this review, we have summarized studies that investigated the programming effects of maternal obesity before and during pregnancy on metabolic, cardiovascular, immune, and microbiome perturbations in offspring. Epidemiological studies investigating the effects of maternal obesity on offspring development can be complex due to other copathologies and genetic diversity. Animal studies have provided some insights into the specific mechanisms and pathways involved in programming peripheral disease risk. The effects of maternal obesity during pregnancy on offspring development are often sex specific, with sex-specific changes in placental transport and function suggestive that this organ is likely to play a central role. We believe that this review will assist in facilitating future investigations regarding the underlying mechanisms that link maternal obesity and offspring disease risk in peripheral organs.
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http://dx.doi.org/10.1152/ajpregu.00214.2020DOI Listing
November 2020

The Role of Atypical Cannabinoid Ligands O-1602 and O-1918 on Skeletal Muscle Homeostasis with a Focus on Obesity.

Int J Mol Sci 2020 Aug 18;21(16). Epub 2020 Aug 18.

Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia.

O-1602 and O-1918 are atypical cannabinoid ligands for GPR55 and GPR18, which may be novel pharmaceuticals for the treatment of obesity by targeting energy homeostasis regulation in skeletal muscle. This study aimed to determine the effect of O-1602 or O-1918 on markers of oxidative capacity and fatty acid metabolism in the skeletal muscle. Diet-induced obese (DIO) male Sprague Dawley rats were administered a daily intraperitoneal injection of O-1602, O-1918 or vehicle for 6 weeks. CC myotubes were treated with O-1602 or O-1918 and human primary myotubes were treated with O-1918. GPR18 mRNA was expressed in the skeletal muscle of DIO rats and was up-regulated in red gastrocnemius when compared with white gastrocnemius. O-1602 had no effect on mRNA expression on selected markers for oxidative capacity, fatty acid metabolism or adiponectin signalling in gastrocnemius from DIO rats or in CC myotubes, while APPL2 mRNA was up-regulated in white gastrocnemius in DIO rats treated with O-1918. In CC myotubes treated with O-1918, PGC1α, NFATc1 and PDK4 mRNA were up-regulated. There were no effects of O-1918 on mRNA expression in human primary myotubes derived from obese and obese T2DM individuals. In conclusion, O-1602 does not alter mRNA expression of key pathways important for skeletal muscle energy homeostasis in obesity. In contrast, O-1918 appears to alter markers of oxidative capacity and fatty acid metabolism in CC myotubes only. GPR18 is expressed in DIO rat skeletal muscle and future work could focus on selectively modulating GPR18 in a tissue-specific manner, which may be beneficial for obesity-targeted therapies.
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http://dx.doi.org/10.3390/ijms21165922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460607PMC
August 2020

Role for endocannabinoids in early pregnancy: recent advances and the effects of cannabis use.

Am J Physiol Endocrinol Metab 2020 09 3;319(3):E557-E561. Epub 2020 Aug 3.

Environmental Futures Research Institute, Griffith University, Nathan, Queensland, Australia.

The endocannabinoid system (ECS) is associated with several physiological processes, including reproduction. This system consists of the cannabinoid receptors, endocannabinoid ligands, and enzymes that metabolize and degrade these fatty acids. Recent evidence shows that cannabinoid receptors are expressed in cells of the reproductive system, including endometrial stromal cells, ovaries, and sperm cells. Emerging and recent research suggests that the ECS may play a significant role in reproduction. The endocannabinoid ligands anandamide and 2-arachidonoylglycerol are crucial for successful endometrium decidualization, placental development, and embryo implantation. Alteration in cannabinoid receptor expression or in endocannabinoid homeostasis by excessive intake of cannabis during pregnancy is associated with negative pregnancy outcomes, including preterm birth. The use of medicinal cannabis is becoming more widespread in Western countries, especially in people of reproductive age. Cannabis contains phytocannabinoids, which modulate the ECS, and emerging evidence suggests that phytocannabinoids, through their action on cannabinoid receptors, may have a negative impact on fertility, pregnancy outcome, and fetal health. In this mini-review, we highlight the recent advances in the field, which explore the role of endocannabinoids in early pregnancy and the effects of excessive intake of phytocannabinoids in pregnancy outcomes.
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http://dx.doi.org/10.1152/ajpendo.00210.2020DOI Listing
September 2020

Maternal High Linoleic Acid Alters Placental Fatty Acid Composition.

Nutrients 2020 Jul 23;12(8). Epub 2020 Jul 23.

Institute for Health and Sport, Victoria University, Melbourne, VIC 3000, Australia.

Fetal development is modulated by maternal nutrition during pregnancy. The dietary intake of linoleic acid (LA), an essential dietary n-6 polyunsaturated fatty acid (PUFA), has increased. We previously published that increased LA consumption during pregnancy does not alter offspring or placental weight but fetal plasma fatty acid composition; the developing fetus obtains their required PUFA from the maternal circulation. However, it is unknown if increased maternal linoleic acid alters placental fatty acid storage, metabolism, transport, and general placental function. Female Wistar-Kyoto rats were fed either a low LA diet (LLA; 1.44% of energy from LA) or high LA diet (HLA; 6.21% of energy from LA) for 10 weeks before pregnancy and during gestation. Rats were sacrificed at embryonic day 20 (E20, term = 22 days) and placentae collected. The labyrinth of placentae from one male and one female fetus from each litter were analyzed. High maternal LA consumption increased placental total n-6 and LA concentrations, and decreased total n-3 PUFA, alpha-linolenic acid (ALA), and docosahexaenoic acid (DHA). Fatty acid desaturase 1 (), angiopoietin-like 4 (), and diacylglycerol lipase beta () mRNA were downregulated in placentae from offspring from HLA dams. Maternal high LA downregulated the fatty acid transport protein 4 () and glucose transporter 1 () mRNA in placentae. IL-7 and IL-10 protein were decreased in placentae from offspring from HLA dams. In conclusion, a high maternal LA diet alters the placental fatty acid composition, inflammatory proteins, and expressions of nutrient transporters, which may program deleterious outcomes in offspring.
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http://dx.doi.org/10.3390/nu12082183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468786PMC
July 2020

Role of omega-6 and omega-3 fatty acids in fetal programming.

Clin Exp Pharmacol Physiol 2020 05 28;47(5):907-915. Epub 2020 Jan 28.

Institute for Health and Sport, Victoria University, Melbourne, Vic., Australia.

Maternal nutrition plays a critical role in fetal development and can influence adult onset of disease. Linoleic acid (LA) and alpha-linolenic acid (ALA) are major omega-6 (n-6) and n-3 polyunsaturated fatty acids (PUFA), respectively, that are essential in our diet. LA and ALA are critical for the development of the fetal neurological and immune systems. However, in recent years, the consumption of n-6 PUFA has increased gradually worldwide, and elevated n-6 PUFA consumption may be harmful to human health. Consumption of diets with high levels of n-6 PUFA before or during pregnancy may have detrimental effects on fetal development and may influence overall health of offspring in adulthood. This review discusses the role of n-6 PUFA in fetal programming, the importance of a balance between n-6 and n-3 PUFAs in the maternal diet, and the need of further animal models and human studies that critically evaluate both n-6 and n-3 PUFA contents in diets.
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http://dx.doi.org/10.1111/1440-1681.13244DOI Listing
May 2020

Pregnancy and diet-related changes in the maternal gut microbiota following exposure to an elevated linoleic acid diet.

Am J Physiol Endocrinol Metab 2020 02 17;318(2):E276-E285. Epub 2019 Dec 17.

Institute for Health and Sport, Victoria University, Melbourne, Victoria, Australia.

Dietary intakes of linoleic acid (LA) have increased, including in women of reproductive age. Changes in maternal gut microbiome have been implicated in the metabolic adaptions that occur during pregnancy. We aimed to investigate whether consumption of a diet with elevated LA altered fecal microbiome diversity before and during pregnancy. Female Wistar-Kyoto rats consumed a high-LA diet (HLA: 6.21% of energy) or a low-LA diet (LLA: 1.44% of energy) for 10 wk before mating and during pregnancy. DNA was isolated from fecal samples before pregnancy [embryonic day 0 (E0)], or during pregnancy at E10 and E20. The microbiome composition was assessed with 16S rRNA sequencing. At E0, the beta-diversity of LLA and HLA groups differed with HLA rats having significantly lower abundance of the genera , and but higher abundance of and . Over gestation, in LLA but not HLA rats, there was a reduction in alpha-diversity and an increase in beta-diversity. In the LLA group, the abundance of , and decreased over gestation, whereas increased. In the HLA group; only the abundance of decreased. At E20, there were no differences in alpha- and beta-diversity, and the abundance of was significantly increased in the HLA group. In conclusion, consumption of a HLA diet alters gut microbiota composition, as does pregnancy in rats consuming a LLA diet. In pregnancy, consumption of a HLA diet does not alter gut microbiota composition.
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http://dx.doi.org/10.1152/ajpendo.00265.2019DOI Listing
February 2020

The effect of high maternal linoleic acid on endocannabinoid signalling in rodent hearts.

J Dev Orig Health Dis 2020 12 9;11(6):617-622. Epub 2019 Dec 9.

Institute for Health and Sport, Victoria University, Melbourne, Australia.

The endocannabinoid system (ECS), modulated by metabolites of linoleic acid (LA), is important in regulating cardiovascular function. In pregnancy, LA is vital for foetal development. We investigated the effects of elevated LA in H9c2 cardiomyoblasts in vitro and of a high linoleic acid (HLA, 6.21%) or low linoleic acid (LLA, 1.44%) diet during pregnancy in maternal and offspring hearts. H9c2 cell viability was reduced following LA exposure at concentrations between 300 and 1000 µM. HLA diet decreased cannabinoid receptor type 2 (CB2) mRNA expression in foetal hearts from both sexes. However, HLA diet increased CB2 expression in maternal hearts. The mRNA expression of fatty acid amide hydrolase (FAAH) in foetal hearts was higher in females than in males irrespective of diet and N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) mRNA expression showed an interaction between diet and sex. Data indicate that a high LA diet alters cell viability and CB2 expression, potentially influencing cardiac function during pregnancy and development of the offspring's heart.
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http://dx.doi.org/10.1017/S2040174419000813DOI Listing
December 2020

Editorial: Peripheral Regulators of Obesity.

Front Endocrinol (Lausanne) 2019 4;10:357. Epub 2019 Jun 4.

Department of Kinesiology, College of Health Sciences, University of Texas at El Paso, El Paso, TX, United States.

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http://dx.doi.org/10.3389/fendo.2019.00357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557997PMC
June 2019

Elevated maternal linoleic acid reduces circulating leptin concentrations, cholesterol levels and male fetal survival in a rat model.

J Physiol 2019 07 2;597(13):3349-3361. Epub 2019 Jun 2.

School of Environment and Science, Griffith University, Nathan, QLD, Australia.

Key Points: Linoleic acid consumption is increasing in Western populations. We investigated whether elevated linoleic acid in pregnancy was deleterious to mothers or offspring. Maternal and fetal body and organ weights were not affected by elevated linoleic acid consumption. Maternal lipids and leptin were altered following elevated linoleic acid consumption. Male offspring numbers were reduced following elevated linoleic acid consumption.

Abstract: Dietary intakes of linoleic acid (LA) have increased dramatically in Western populations, including in women of reproductive age. Pro-inflammatory effects of LA may have detrimental effects on maternal and offspring outcomes. We aimed to investigate whether consumption of a maternal diet with elevated LA altered maternal inflammatory or metabolic markers during pregnancy, fetal growth and/or the sex ratio of the offspring. Female Wistar Kyoto rats consumed a diet high in LA (HLA) (6.21% of energy) or a diet low in LA (LLA) (1.44% of energy) for 10 weeks prior to mating and during pregnancy. Pregnant rats were killed at embryonic day 20 (E20). There were no differences in maternal or fetal body weights or organ weights in the HLA group compared to the LLA group. There was no difference in maternal circulating cytokine concentrations between dietary groups. In the maternal liver, IL-1α concentrations were significantly lower, and TNF-α and IL-7 significantly higher in the HLA group. Total plasma cholesterol, LDL-cholesterol, HDL cholesterol and the total:HDL cholesterol ratio were lower in dams fed the HLA diet. mRNA expression of sterol regulatory element binding transcription factor 1 (SREBF-1) and leptin in maternal adipose tissue was lower in the HLA group, as were circulating leptin concentrations. The proportion of male fetuses was lower and circulating prostaglandin E metabolite concentrations were increased in the HLA group. In conclusion, consumption of a maternal diet high in linoleic acid alters cholesterol metabolism and prostaglandin E metabolite concentrations, which may contribute to the reduced proportion of male offspring.
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http://dx.doi.org/10.1113/JP277583DOI Listing
July 2019

Linoleic Acid Increases Prostaglandin E2 Release and Reduces Mitochondrial Respiration and Cell Viability in Human Trophoblast-Like Cells.

Cell Physiol Biochem 2019 18;52(1):94-108. Epub 2019 Feb 18.

Institute for Health and Sport, Victoria University, Melbourne, Australia.

Background/aims: The omega 6 fatty acid (FA) linoleic acid (LA) is required for embryonic development; however, omega 6 FAs can alter cellular metabolism via inflammation or modulation of mitochondrial function. Fetal LA is obtained from the maternal diet, and FAs are transported to the fetus via placental FA transporters (FATPs) and binding proteins (FABPs), but specific proteins responsible for LA transport in placental trophoblasts are unknown. Dietary LA consumption is increasing, but the effect of elevated LA on trophoblast function is not clear.

Methods: Swan71 trophoblasts were exposed to physiological and supraphysiological concentrations of LA for 24 hours. Quantification of mRNA was determined using real time PCR, and protein concentration was determined by Western blot analysis. Cell viability, citrate synthase activity and mitochondrial respiration were determined.

Results: Exposure to 300 and 500 μM LA increased FATP1 and FATP4 mRNA expression. 500 μM LA increased FATP1 and FATP4 protein expression. Exposure to 500 μM increased FABP5 mRNA expression, while exposure to 100 to 500 μM LA decreased FABP3 mRNA expression. 300 and 500 μM LA decreased FABP3 protein expression. Cell viability was decreased by exposure to LA (100 to 1000 μM). Citrate synthase activity and routine mitochondrial respiration were significantly decreased by exposure to 300 and 500 μM LA, and maximal respiration and spare respiratory capacity were decreased by exposure to 100 to 500 μM LA. 300 and 500 μM LA increased reactive oxygen species generation in human trophoblasts. Moreover, exposure to 300 and 500 μM LA decreased IL-6 secretion. Exposure to 500 μM LA increased IL-8, NF-κB and PPAR-γ mRNA expression, but decreased NF-κB protein expression. 300 μM LA decreased IL-8 protein expression. Further, exposure to 100 to 500 μM LA increased prostaglandin E2 and leukotriene B₄ release.

Conclusion: Exposure to LA decreases cell viability, alters mRNA expression of FA transport related proteins, mitochondrial respiration and function, and inflammatory responses in trophoblasts. These findings may have implications on placental function when women consume high levels of LA.
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http://dx.doi.org/10.33594/000000007DOI Listing
March 2019

Atypical cannabinoid ligands O-1602 and O-1918 administered chronically in diet-induced obesity.

Endocr Connect 2019 Mar;8(3):203-216

Institute for Health and Sport, Victoria University, St Albans campus, Melbourne, Victoria, Australia.

Atypical cannabinoid compounds O-1602 and O-1918 are ligands for the putative cannabinoid receptors G protein-coupled receptor 55 and G protein-coupled receptor 18. The role of O-1602 and O-1918 in attenuating obesity and obesity-related pathologies is unknown. Therefore, we aimed to determine the role that either compound had on body weight and body composition, renal and hepatic function in diet-induced obesity. Male Sprague-Dawley rats were fed a high-fat diet (40% digestible energy from lipids) or a standard chow diet for 10 weeks. In a separate cohort, male Sprague-Dawley rats were fed a high-fat diet for 9 weeks and then injected daily with 5 mg/kg O-1602, 1 mg/kg O-1918 or vehicle (0.9% saline/0.75% Tween 80) for a further 6 weeks. Our data demonstrated that high-fat feeding upregulates whole kidney G protein receptor 55 expression. In diet-induced obesity, we also demonstrated O-1602 reduces body weight, body fat and improves albuminuria. Despite this, treatment with O-1602 resulted in gross morphological changes in the liver and kidney. Treatment with O-1918 improved albuminuria, but did not alter body weight or fat composition. In addition, treatment with O-1918 also upregulated circulation of pro-inflammatory cytokines including IL-1α, IL-2, IL-17α, IL-18 and RANTES as well as plasma AST. Thus O-1602 and O-1918 appear not to be suitable treatments for obesity and related comorbidities, due to their effects on organ morphology and pro-inflammatory signaling in obesity.
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http://dx.doi.org/10.1530/EC-18-0535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391900PMC
March 2019

SUMO-wrestling the pre-eclamptic placenta.

Authors:
Deanne H Hryciw

J Physiol 2018 05 31;596(9):1537. Epub 2018 Mar 31.

School of Environment and Science, Griffith University, Nathan, QLD, Australia.

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http://dx.doi.org/10.1113/JP275986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924820PMC
May 2018

Peripheral modulation of the endocannabinoid system in metabolic disease.

Drug Discov Today 2018 03 10;23(3):592-604. Epub 2018 Jan 10.

Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia; School of Science, Menzies Health Institute Queensland, Griffith University, Nathan, QLD, Australia. Electronic address:

Dysfunction of the endocannabinoid system (ECS) has been identified in metabolic disease. Cannabinoid receptor 1 (CB) is abundantly expressed in the brain but also expressed in the periphery. Cannabinoid receptor 2 (CB) is more abundant in the periphery, including the immune cells. In obesity, global antagonism of overexpressed CB reduces bodyweight but leads to centrally mediated adverse psychological outcomes. Emerging research in isolated cultured cells or tissues has demonstrated that targeting the endocannabinoid system in the periphery alleviates the pathologies associated with metabolic disease. Further, peripheral specific cannabinoid ligands can reverse aspects of the metabolic phenotype. This Keynote review will focus on current research on the functionality of peripheral modulation of the ECS for the treatment of obesity.
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http://dx.doi.org/10.1016/j.drudis.2018.01.029DOI Listing
March 2018

Uteroplacental insufficiency reduces rat plasma leptin concentrations and alters placental leptin transporters: ameliorated with enhanced milk intake and nutrition.

J Physiol 2017 06 29;595(11):3389-3407. Epub 2017 Mar 29.

Department of Physiology, The University of Melbourne, Victoria, 3010, Australia.

Key Points: Uteroplacental insufficiency compromises maternal mammary development, milk production and pup organ development; this is ameliorated by cross-fostering, which improves pup growth and organ development and prevents adult diseases in growth-restricted (Restricted) offspring by enhancing postnatal nutrition. Leptin is transported to the fetus from the mother by the placenta; we report reduced plasma leptin concentrations in Restricted fetuses associated with sex-specific alterations in placental leptin transporter expression. Pup plasma leptin concentrations were also reduced during suckling, which may suggest reduced milk leptin transport or leptin reabsorption. Mothers suckled by Restricted pups had impaired mammary development and changes in milk fatty acid composition with no alterations in milk leptin; cross-fostering restored pup plasma leptin concentrations, which may be correlated to improved milk composition and intake. Increased plasma leptin and altered milk fatty acid composition in Restricted pups suckling mothers with normal lactation may improve postnatal growth and prevent adult diseases.

Abstract: Uteroplacental insufficiency reduces birth weight and adversely affects fetal organ development, increasing adult disease risk. Cross-fostering improves postnatal nutrition and restores these deficits. Mothers with growth-restricted pups have compromised milk production and composition; however, the impact cross-fostering has on milk production and composition is unknown. Plasma leptin concentrations peak during the completion of organogenesis, which occurs postnatally in rats. Leptin is transferred to the fetus via the placenta and to the pup via the lactating mammary gland. This study investigated the effect of uteroplacental insufficiency on pup plasma leptin concentrations and placental leptin transporters. We additionally examined whether cross-fostering improves mammary development, milk composition and pup plasma leptin concentrations. Fetal growth restriction was induced by bilateral uterine vessel ligation surgery on gestation day 18 in Wistar Kyoto rats (termed uteroplacental insufficiency surgery mothers). Growth-restricted (Restricted) fetuses had reduced plasma leptin concentrations, persisting throughout lactation, and sex-specific alterations in placental leptin transporters. Mothers suckled by Restricted pups had impaired mammary development, altered milk fatty acid composition and increased plasma leptin concentrations, despite no changes in milk leptin. Milk intake was reduced in Restricted pups suckling uteroplacental insufficiency surgery mothers compared to Restricted pups suckling sham-operated mothers. Cross-fostering Restricted pups onto a sham-operated mother improved postnatal growth and restored plasma leptin concentrations compared to Restricted pups suckling uteroplacental insufficiency surgery mothers. Uteroplacental insufficiency alters leptin homeostasis. This is ameliorated with cross-fostering and enhanced milk fatty acid composition and consumption, which may protect the pups from developing adverse health conditions in adulthood.
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http://dx.doi.org/10.1113/JP273825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451707PMC
June 2017

Uptake of leptin and albumin via separate pathways in proximal tubule cells.

Int J Biochem Cell Biol 2016 10 1;79:194-198. Epub 2016 Sep 1.

Centre For Chronic Disease, College of Health and Biomedicine, Victoria University, St. Albans, VIC 3021, Australia; Department of Physiology, The University of Melbourne, Parkville, Melbourne, VIC 3010, Australia. Electronic address:

The adipokine leptin and oncotic protein albumin are endocytosed in the proximal tubule via the scavenger receptor megalin. Leptin reduces megalin expression and activates cell signalling pathways that upregulate fibrotic protein expression. The aim of this study was to investigate if leptin uptake in proximal tubule cells was via the albumin-megalin endocytic complex. In immortalised proximal tubule Opossum kidney cells (OK) fluorescent leptin and albumin co-localised following 5min exposure, however there was no co-localisation at 10, 20 and 30min exposure. In OK cells, acute exposure to leptin for 2h did not alter NHE3, ClC-5, NHERF1 and NHERF2 mRNA. However, acute leptin exposure increased NHERF2 protein expression in proximal tubule cells. In OK cells, immunoprecipitation experimentation indicated leptin did not bind to ClC-5. Leptin uptake in OK cells was enhanced by bafilomycin and ammonium chloride treatment, demonstrating that uptake was not dependent on lysosomal pH. Thus, it is likely that two pools of megalin exist in proximal tubule cells to facilitate separate uptake of leptin and albumin by endocytosis.
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http://dx.doi.org/10.1016/j.biocel.2016.08.031DOI Listing
October 2016

Cannabinoid receptors in the kidney.

Curr Opin Nephrol Hypertens 2016 09;25(5):459-64

aDepartment of Physiology, The University of Melbourne bCentre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, Australia.

Purpose Of Review: The endocannabinoid system modulates cell signaling targets that are essential for energy homeostasis. Endocannabinoids bind to G protein-coupled receptors in the central nervous system and periphery, including the kidney. Modulation of cannabinoid receptor 1 (CB1) and CB2 activity in the kidney in diabetes and obesity has been identified as potential therapeutic target to reduce albuminuria and renal fibrosis. This review will highlight the results of recent studies that have identified a role for CB1 and CB2 in normal and pathological renal conditions.

Recent Findings: CB1 and CB2 have been reported to play key roles in renal function and dysfunction. Recent studies have determined that antagonism of CB1 and agonism of CB2 in diabetic nephropathy and obesity associated kidney disease can reduce albuminuria, potentially by acting on both the glomeruli and tubules. Emerging studies have also identified a role for CB1 in renal diseases associated with fibrosis, with CB1 upregulated in multiple models of human nephropathies.

Summary: Emerging studies using isolated cells, rodent models, and human studies have identified a critical role for the endocannabinoid system in renal function and disease. Thus, therapeutics that modulate the activity of CB1 and CB2 in renal disease could become clinically relevant.
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http://dx.doi.org/10.1097/MNH.0000000000000249DOI Listing
September 2016

Linoleic acid and the pathogenesis of obesity.

Prostaglandins Other Lipid Mediat 2016 09 24;125:90-9. Epub 2016 Jun 24.

Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, PO Box 14428, Melbourne, Victoria 8001, Australia. Electronic address:

The modern Western diet has been consumed in developed English speaking countries for the last 50 years, and is now gradually being adopted in Eastern and developing countries. These nutrition transitions are typified by an increased intake of high linoleic acid (LA) plant oils, due to their abundance and low price, resulting in an increase in the PUFA n-6:n-3 ratio. This increase in LA above what is estimated to be required is hypothesised to be implicated in the increased rates of obesity and other associated non-communicable diseases which occur following a transition to a modern Westernised diet. LA can be converted to the metabolically active arachidonic acid, which has roles in inducing inflammation and adipogenesis, and endocannabinoid system regulation. This review aims to address the possible implications of excessive LA and its metabolites in the pathogenesis of obesity.
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http://dx.doi.org/10.1016/j.prostaglandins.2016.06.003DOI Listing
September 2016

Uteroplacental insufficiency leads to hypertension, but not glucose intolerance or impaired skeletal muscle mitochondrial biogenesis, in 12-month-old rats.

Physiol Rep 2015 Sep;3(9)

Departments of Physiology, The University of Melbourne, Parkville, Victoria, Australia School of Exercise and Nutrition Sciences, Centre for Physical Activity and Nutrition Research, Deakin University, Burwood, Victoria, Australia.

Growth restriction impacts on offspring development and increases their risk of disease in adulthood which is exacerbated with "second hits." The aim of this study was to investigate if blood pressure, glucose tolerance, and skeletal muscle mitochondrial biogenesis were altered in 12-month-old male and female offspring with prenatal or postnatal growth restriction. Bilateral uterine vessel ligation induced uteroplacental insufficiency and growth restriction in offspring (Restricted). A sham surgery was also performed during pregnancy (Control) and some litters from sham mothers had their litter size reduced (Reduced litter), which restricted postnatal growth. Growth-restricted females only developed hypertension at 12 months, which was not observed in males. In Restricted females only homeostasis model assessment for insulin resistance was decreased, indicating enhanced hepatic insulin sensitivity, which was not observed in males. Plasma leptin was increased only in the Reduced males at 12 months compared to Control and Restricted males, which was not observed in females. Compared to Controls, leptin, ghrelin, and adiponectin were unaltered in the Restricted males and females, suggesting that at 12 months of age the reduction in body weight in the Restricted offspring is not a consequence of circulating adipokines. Skeletal muscle PGC-1α levels were unaltered in 12-month-old male and female rats, which indicate improvements in lean muscle mass by 12 months of age. In summary, sex strongly impacts the cardiometabolic effects of growth restriction in 12-month-old rats and it is females who are at particular risk of developing long-term hypertension following growth restriction.
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http://dx.doi.org/10.14814/phy2.12556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600396PMC
September 2015

G protein coupled receptor 18: A potential role for endocannabinoid signaling in metabolic dysfunction.

Mol Nutr Food Res 2016 Jan 22;60(1):92-102. Epub 2015 Sep 22.

Centre for Chronic Disease Prevention and Management, College of Health & Biomedicine, Victoria University, Melbourne, VIC, Australia.

Endocannabinoids are products of dietary fatty acids that are modulated by an alteration in food intake levels. Overweight and obese individuals have substantially higher circulating levels of the arachidonic acid derived endocannabinoids, anandamide and 2-arachidonoyl glycerol, and show an altered pattern of cannabinoid receptor expression. These cannabinoid receptors are part of a large family of G protein coupled receptors (GPCRs). GPCRs are major therapeutic targets for various diseases within the cardiovascular, neurological, gastrointestinal, and endocrine systems, as well as metabolic disorders such as obesity and type 2 diabetes mellitus. Obesity is considered a state of chronic low-grade inflammation elicited by an immunological response. Interestingly, the newly deorphanized GPCR (GPR18), which is considered to be a putative cannabinoid receptor, is proposed to have an immunological function. In this review, the current scientific knowledge on GPR18 is explored including its localization, signaling pathways, and pharmacology. Importantly, the involvement of nutritional factors and potential dietary regulation of GPR18 and its (patho)physiological roles are described. Further research on this receptor and its regulation will enable a better understanding of the complex mechanisms of GPR18 and its potential as a novel therapeutic target for treating metabolic disorders.
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http://dx.doi.org/10.1002/mnfr.201500449DOI Listing
January 2016

Puberty onset is delayed following uteroplacental insufficiency and occurs earlier with improved lactation and growth for pups born small.

Reprod Fertil Dev 2017 Feb;29(2):307-318

Department of Physiology, The University of Melbourne, Vic. 3010, Australia.

Being born small programs adult diseases later in life, with the early postnatal growth rate in growth-restricted offspring playing a role in the reduction of the risk of disease in adulthood. In addition, early postnatal growth is critical for puberty onset (PO). Using cross-fostering, we determined the effects of growth restriction and prenatal and postnatal environments on PO and sex steroids. Bilateral uterine vessel ligation (Restricted) or sham surgery (Control), performed on Gestational Day 18 in Wistar-Kyoto rats induced fetal growth restriction. Control, Reduced (Control litter size reduced to five pups) and Restricted pups were cross-fostered onto different Control (normal lactation) or Restricted (impaired lactation) mothers on Day 1. The day of vaginal opening (females) and balanopreputial separation (males) characterised PO. Blood was sampled for sex steroid and leptin analysis. Restricted pups were born lighter than Controls (P<0.05). PO was delayed by 3.4-4 days in Restricted-on-Restricted males and females (P<0.05). Plasma leptin concentrations at PO were lower in both sexes in all groups compared with Restricted-on-Control and Control-on-Control (P<0.05). PO occurred earlier in Restricted-on-Control (~2 days) with normal leptin concentrations and accelerated growth compared with Restricted-on-Restricted (P<0.05). Testosterone concentrations were lower in male Restricted-on-Restricted than Control-on-Control at 6 months (P<0.05). Restricted-on-Restricted females had lower progesterone at PO compared with Control-on-Control (P<0.05). Female Restricted-on-Restricted had lower oestradiol, with Restricted-on-Control having higher testosterone concentrations at 6 months than Control-on-Control (P<0.05). Growth restriction reduced postnatal growth and leptin concentrations, delaying PO in both sexes and programming altered sex steroids. This highlights the importance of the interaction between prenatal and postnatal growth in the programming of adult reproductive status.
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http://dx.doi.org/10.1071/RD15151DOI Listing
February 2017

Maternal obesity in females born small: Pregnancy complications and offspring disease risk.

Mol Nutr Food Res 2016 Jan 6;60(1):8-17. Epub 2015 Aug 6.

Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia.

Obesity is a major public health crisis, with 1.6 billion adults worldwide being classified as overweight or obese in 2014. Therefore, it is not surprising that the number of women who are overweight or obese at the time of conception is increasing. Obesity during pregnancy is associated with the development of gestational diabetes and preeclampsia. The developmental origins of health and disease hypothesis proposes that perturbations during critical stages of development can result in adverse fetal changes that leads to an increased risk of developing diseases in adulthood. Of particular concern, children born to obese mothers are at a greater risk of developing cardiometabolic disease. One subset of the population who are predisposed to developing obesity are children born small for gestational age, which occurs in 10% of pregnancies worldwide. Epidemiological studies report that these growth-restricted children have an increased susceptibility to type 2 diabetes, obesity, and hypertension. Importantly during pregnancy, growth-restricted females have a higher risk of developing cardiometabolic disease, indicating that they may have an exacerbated phenotype if they are also overweight or obese. Thus, the development of early pregnancy interventions targeted to obese mothers may prevent their children from developing cardiometabolic disease in adulthood.
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http://dx.doi.org/10.1002/mnfr.201500289DOI Listing
January 2016

Australia's nutrition transition 1961-2009: a focus on fats.

Br J Nutr 2015 Aug 30;114(3):337-46. Epub 2015 Jun 30.

Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University,PO Box 14428,Melbourne,Victoria8001,Australia.

Since the 1960s, Australian diets have changed considerably, influenced by a burgeoning multicultural cuisine, increase in urbanisation and food technology advances. This has been described as a 'nutrition transition', resulting in the adoption of a Western diet pattern, with a shift away from unrefined foods towards a diet higher in both plant-derived high PUFA and total fats and refined carbohydrates. Utilising the 1961-2009 annual food supply data from the UN FAO, the present study investigated changes in the intake of macronutrient and specific fatty acid in the Australian population, including that of the PUFA linoleic acid (LA), due to its hypothesised role in inflammation and risk for obesity. Cumulative change over time for the contribution of specific nutrients to total available energy (TAE) was calculated, as was linearity of change. Over the time period analysed, the cumulative change in TAE from carbohydrate was -9.35 and +16.67 % from lipid. The cumulative change in TAE from LA was +120.48 %. Moreover, the cumulative change in the contribution of LA to total PUFA availability was +7.1 %. Utilising the average g/d per capita of LA from selected dietary sources, the change in the contribution of specific foodstuffs was assessed, with total plant oils having a cumulative change of +627.19 % to LA availability, equating to a cumulative change of +195.61 % in contribution to total LA availability. The results of the present study indicate that LA availability in Australia has increased over the previous five decades as a result of the availability of increased plant oils, as has total fat, possibly contributing to the increasing rates of obesity and obesity-associated co-morbidities.
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http://dx.doi.org/10.1017/S0007114515001907DOI Listing
August 2015

Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats.

J Endocrinol 2015 May 24;225(2):113-24. Epub 2015 Mar 24.

College of Health and Biomedicine Centre for Chronic Disease Prevention and Management, Victoria University, St Albans Campus, PO Box 14428, Melbourne, Victoria 8001, Australia The Florey Institute of Neuroscience and Mental Health Parkville, Melbourne, Victoria 3052, Australia Department of Physiology The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia

Modulation of the endocannabinoid system as an anti-obesity therapeutic is well established; however, the direct effects of cannabinoid receptor 1 (CB1) antagonism on renal function and structure in a model of diet-induced obesity (DIO) are unknown. The aim of this study was to characterise the renal effects of the CB1 antagonist AM251 in a model of DIO. Male Sprague-Dawley rats were fed a low- or high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks to elicit DIO (n=9). In a different cohort, rats were fed a HFD for 15 weeks. After 9 weeks consuming a HFD, rats were injected daily for 6 weeks with 3 mg/kg AM251 (n=9) or saline via i.p. injection (n=9). After 10 weeks consuming a HFD, CB1 and megalin protein expression were significantly increased in the kidneys of obese rats. Antagonism of CB1 with AM251 significantly reduced weight gain, systolic blood pressure, plasma leptin, and reduced albuminuria and plasma creatinine levels in obese rats. Importantly, there was a significant reduction in tubular cross-section diameter in the obese rats treated with AM251. An improvement in albuminuria was likely due to the reduction in tubular size, reduced leptinaemia and maintenance of megalin expression levels. In obese rats, AM251 did not alter diastolic blood pressure, sodium excretion, creatinine clearance or expression of the fibrotic proteins VEGFA, TGFB1 and collagen IV in the kidney. This study demonstrates that treatment with CB1 antagonist AM251 improves renal outcomes in obese rats.
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http://dx.doi.org/10.1530/JOE-15-0004DOI Listing
May 2015

Chloride channel ClC-5 binds to aspartyl aminopeptidase to regulate renal albumin endocytosis.

Am J Physiol Renal Physiol 2015 Apr 13;308(7):F784-92. Epub 2015 Jan 13.

School of Medical Sciences and the Bosch Institute, The University of Sydney, New South Wales, Australia

ClC-5 is a chloride/proton exchanger that plays an obligate role in albumin uptake by the renal proximal tubule. ClC-5 forms an endocytic complex with the albumin receptor megalin/cubilin. We have identified a novel ClC-5 binding partner, cytosolic aspartyl aminopeptidase (DNPEP; EC 3.4.11.21), that catalyzes the release of N-terminal aspartate/glutamate residues. The physiological role of DNPEP remains largely unresolved. Mass spectrometric analysis of proteins binding to the glutathione-S-transferase (GST)-ClC-5 C terminus identified DNPEP as an interacting partner. Coimmunoprecipitation confirmed that DNPEP and ClC-5 also associated in cells. Further experiments using purified GST-ClC-5 and His-DNPEP proteins demonstrated that the two proteins bound directly to each other. In opossum kidney (OK) cells, confocal immunofluorescence studies revealed that DNPEP colocalized with albumin-containing endocytic vesicles. Overexpression of wild-type DNPEP increased cell-surface levels of ClC-5 and albumin uptake. Analysis of DNPEP-immunoprecipitated products from rat kidney lysate identified β-actin and tubulin, suggesting a role for DNPEP in cytoskeletal maintenance. A DNase I inhibition assay showed a significant decrease in the amount of G actin when DNPEP was overexpressed in OK cells, suggesting a role for DNPEP in stabilizing the cytoskeleton. DNPEP was not present in the urine of healthy rats; however, it was readily detected in the urine in rat models of mild and heavy proteinuria (diabetic nephropathy and anti-glomerular basement membrane disease, respectively). Urinary levels of DNPEP were found to correlate with the severity of proteinuria. Therefore, we have identified another key molecular component of the albumin endocytic machinery in the renal proximal tubule and describe a new role for DNPEP in stabilizing the actin cytoskeleton.
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http://dx.doi.org/10.1152/ajprenal.00322.2014DOI Listing
April 2015

Direct activation of the proposed anti-diabetic receptor, GPR119 in cardiomyoblasts decreases markers of muscle metabolic activity.

Mol Cell Endocrinol 2015 Feb 8;402:72-85. Epub 2015 Jan 8.

Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, Melbourne 8001, Australia. Electronic address:

GPR119 agonists are emerging rapidly as a pharmaceutical treatment of diabetes. Diabetes is a known risk factor for cardiovascular disease yet the cardiac-specific consequences of GPR119 activation are unknown. This study demonstrated that GPR119 agonism in cardiac myoblasts reduces metabolic activity in high and low concentrations of fatty acids, with high concentrations of palmitate largely attenuating the effects of the GPR119 agonist, PSN632408. The effects of GPR119 activation on gene and protein markers of metabolism were dependent on fatty acid exposure. Activating GPR119 did not affect cell hypertrophy of lipid accumulation regardless of lipid exposure. These results suggest that the pathways activated in response to GPR119 modulation in cardiac muscle cells differ between healthy and metabolically dysregulated states. However regardless of the pathway activated by GPR119, these effects may cause detrimental reductions to oxidative/metabolic capacity under both conditions. Thus further development of GPR119 agonists for treating metabolic diseases is warranted.
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http://dx.doi.org/10.1016/j.mce.2015.01.006DOI Listing
February 2015

Elevated cannabinoid receptor 1 and G protein-coupled receptor 55 expression in proximal tubule cells and whole kidney exposed to diabetic conditions.

Clin Exp Pharmacol Physiol 2015 Mar;42(3):256-62

Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine Victoria University, Melbourne, Vic., Australia.

Hyperglycaemia increases the risk of developing diabetic nephropathy, with primary targets in the glomerulus and proximal tubule. Importantly, glomerular damage in the kidney leads to elevated albumin levels in the filtrate, which contributes to tubular structural modifications that lead to dysfunction. Diabetes alters the endocannabinoid system in a number of target organs, with previous research characterizing tissue-specific changes in the expression of the cannabinoid receptor 1 (CB1 ) and G protein-coupled receptor 55 (GPR55), a putative cannabinoid receptor, in diabetes. Although these receptors have a functional role in the cannabinoid system in the kidney, there has been little investigation into changes in the expression of CB1 and GPR55 in the proximal tubule under diabetic conditions. In this study, CB1 and GPR55 messenger RNA and protein levels were quantified in cultured human kidney cells and then treated with either elevated glucose, elevated albumin, or a combination of glucose and albumin for 4, 6, 18, or 24 h. In addition, CB1 and GPR55 protein expression was characterized in whole-kidney lysate from streptozotocin-induced diabetic Sprague-Dawley rats. In vitro exposure to elevated glucose and albumin increased CB1 and GPR55 messenger RNA and protein expression in proximal tubule cells in a time-dependant manner. In whole kidney of streptozotocin-induced diabetic rats, CB1 protein was upregulated, whereas GPR55 protein concentration was not altered. Thus, expression of CB1 and GPR55 in proximal tubules is altered in response to elevated levels of glucose and albumin. Further investigations should determine if these receptors are effective physiological targets for the treatment and prevention of diabetic nephropathy.
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http://dx.doi.org/10.1111/1440-1681.12355DOI Listing
March 2015

Leptin in pregnancy and development: a contributor to adulthood disease?

Am J Physiol Endocrinol Metab 2015 Mar 16;308(5):E335-50. Epub 2014 Dec 16.

Department of Physiology, University of Melbourne, Parkville, Australia;

Emerging research has highlighted the importance of leptin in fetal growth and development independent of its essential role in the maintenance of hunger and satiety through the modulation of neuropeptide Y and proopiomelanocortin neurons. Alterations in maternal-placental-fetal leptin exchange may modify the development of the fetus and contribute to the increased risk of developing disease in adulthood. In addition, leptin also plays an important role in reproductive functions, with plasma leptin concentrations rising in pregnant women, peaking during the third trimester. Elevated plasma leptin concentrations occur at the completion of organogenesis, and research in animal models has demonstrated that leptin is involved in the development and maturation of a number of organs, including the heart, brain, kidneys, and pancreas. Elevated maternal plasma leptin is associated with maternal obesity, and reduced fetal plasma leptin is correlated with intrauterine growth restriction. Alterations in plasma leptin during development may be associated with an increased risk of developing a number of adulthood diseases, including cardiovascular, metabolic, and renal diseases via altered fetal development and organogenesis. Importantly, research has shown that leptin antagonism after birth significantly reduces maturation of numerous organs. Conversely, restoration of the leptin deficiency after birth in growth-restricted animals restores the offspring's body weight and improves organogenesis. Therefore, leptin appears to play a major role in organogenesis, which may adversely affect the risk of developing a number of diseases in adulthood. Therefore, greater understanding of the role of leptin during development may assist in the prevention and treatment of a number of disease states that occur in adulthood.
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http://dx.doi.org/10.1152/ajpendo.00312.2014DOI Listing
March 2015