Adiponectin agonist treatment in diabetic pregnant rats

in Journal of Endocrinology
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  • 1 Department of Physiology, CEIR Campus Mare Nostrum, University of Murcia, Biomedical Research Institute of Murcia, Murcia, Spain
  • | 2 Department of Clinical Analysis, Biomedical Research Institute of Murcia, Santa Lucia General University Hospital, Murcia, Spain
  • | 3 Department of Plant Biology (Plant Physiology), University of Murcia, Murcia, Spain
  • | 4 Department of Clinical Psychology, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain

Correspondence should be addressed to E Larque: elvirada@um.es

*(A Gázquez and F Rodríguez contributed equally to this work)

Open access

Gestational diabetes mellitus (GDM) reduces maternal adiponectin and docosahexaenoic acid (DHA) materno-fetal transfer, which may have negative consequences for the offspring. Our aim was to evaluate the effects of the administration of a novel adiponectin agonist (AdipoRon) to GDM rats on the long-term consequences in glycaemia and fatty acids (FA) profile in the offspring. Pregnant rats were randomized to three groups: GDM rats (GDM, n = 8), GDM rats treated with AdipoRon (GDM + ADI, n = 9), and control rats (n = 10). Diabetes was induced with streptozotocin (50 mg/kg) on day 12 of gestation. GDM+ADI received 50 mg/kg/day AdipoRon from day 14 until delivery. Glycaemia and FA profile were determined in mothers and adult offspring (12 weeks old). AdipoRon tended to reduce fasting glucose in diabetic mothers. Diabetic rats presented the foetus with intrauterine growth restriction and higher adiposity, which tried to be counteracted by AdipoRon. In the adult offspring, both GDM + ADI and control animals showed better glucose recovery after oral glucose overload with respect to GDM. DHA in offspring plasma was significantly reduced in both GDM and GDM + ADI compared to controls (P = 0.043). Nevertheless, n-6/n-3 polyunsaturated FA (PUFA) ratio improved in plasma of GDM + ADI adult offspring (GDM: 14.83 ± 0.85a%; GDM + ADI: 11.49 ± 0.58b%; control: 10.03 ± 1.22b%, P = 0.034). Inflammatory markers and oxidative stress were reduced in the adult offspring of AdipoRon-treated mothers. In conclusion, AdipoRon administration to pregnant diabetic rats improved glycaemia in the mothers and long-term glucose tolerance in the offspring. In addition, it tended to reduce excessive foetal fat accumulation and improved n-6/n-3 PUFA ratio significantly in offspring at the adult state.

Abstract

Gestational diabetes mellitus (GDM) reduces maternal adiponectin and docosahexaenoic acid (DHA) materno-fetal transfer, which may have negative consequences for the offspring. Our aim was to evaluate the effects of the administration of a novel adiponectin agonist (AdipoRon) to GDM rats on the long-term consequences in glycaemia and fatty acids (FA) profile in the offspring. Pregnant rats were randomized to three groups: GDM rats (GDM, n = 8), GDM rats treated with AdipoRon (GDM + ADI, n = 9), and control rats (n = 10). Diabetes was induced with streptozotocin (50 mg/kg) on day 12 of gestation. GDM+ADI received 50 mg/kg/day AdipoRon from day 14 until delivery. Glycaemia and FA profile were determined in mothers and adult offspring (12 weeks old). AdipoRon tended to reduce fasting glucose in diabetic mothers. Diabetic rats presented the foetus with intrauterine growth restriction and higher adiposity, which tried to be counteracted by AdipoRon. In the adult offspring, both GDM + ADI and control animals showed better glucose recovery after oral glucose overload with respect to GDM. DHA in offspring plasma was significantly reduced in both GDM and GDM + ADI compared to controls (P = 0.043). Nevertheless, n-6/n-3 polyunsaturated FA (PUFA) ratio improved in plasma of GDM + ADI adult offspring (GDM: 14.83 ± 0.85a%; GDM + ADI: 11.49 ± 0.58b%; control: 10.03 ± 1.22b%, P = 0.034). Inflammatory markers and oxidative stress were reduced in the adult offspring of AdipoRon-treated mothers. In conclusion, AdipoRon administration to pregnant diabetic rats improved glycaemia in the mothers and long-term glucose tolerance in the offspring. In addition, it tended to reduce excessive foetal fat accumulation and improved n-6/n-3 PUFA ratio significantly in offspring at the adult state.

Introduction

Gestational diabetes mellitus (GDM) prevalence is increasing in women due to the obesity epidemic; however, the ideal management of GDM remains controversial (Mack & Tomich 2017). It is estimated that one out of six live births is affected by hyperglycaemia in pregnancy, most of those due to GDM (International Diabetes Federation 2017). GDM is associated with neonatal adverse outcomes such as large for gestational age infants and increased risk of obesity and cardiometabolic disease later in life (Boney et al. 2005, Lawlor et al. 2010), contributing to the perpetuation of the vicious cycle of obesity, diabetes, and metabolic syndrome. There is also growing evidence of the GDM long-term consequences for mothers, who have a higher risk of developing type 2 diabetes and cardiovascular disease (Bellamy et al. 2009, Kramer et al. 2019).

Several cohort studies reported decreased adiponectin concentrations in GDM women compared to their peers without diabetes (Fasshauer et al. 2014). Adiponectin is an insulin-sensitizing adipokine that promotes FA oxidation (liver and muscle) and lowers the expression of genes involved in hepatic gluconeogenesis via activation of AMP-activated protein kinase (AMPK) and via peroxisome proliferator-activated receptor α (PPARα) (Yamauchi et al. 2001, Kadowaki & Yamauchi 2005). Low adiponectin levels combined with high insulin resistance in GDM might contribute to enhance GDM-associated macrosomia (Fasshauer et al. 2014). Moreover, hypoadiponectinemia in pregnancy is a predictor of postpartum insulin resistance, beta-cell dysfunction, and elevated fasting glycaemia and may play a role in the subsequent development of type 2 diabetes (Retnakaran et al. 2010). These observations raised the question about the utilization of adiponectin as a new therapeutic target for insulin resistance in diabetic subjects.

There are two strategies to reverse hypoadiponectinemia, one is to increase adiponectin concentration itself through the injection of adiponectin which presents some methodological problems due to its very high concentration in blood and the high molecular weight of the active form (Pajvani et al. 2004). Other option is the use of adiponectin receptors (AdipoR1 and AdipoR2) agonists that mimic adiponectin effects. Adiponectin administration in mice models has shown positive effects on insulin sensitivity (Yamauchi et al. 2001, Combs et al. 2004) as well as using adiponectin agonists (AdipoRon) in high-fat diet obese mice (Okada-Iwabu et al. 2013). However, little is known about the effects of AdipoRon administration during gestation, especially in those pregnancies affected by GDM.

Several studies have shown impaired placental transport of docosahexaenoic acid (22:6 n-3, DHA) by GDM (Herrera & Ortega-Senovilla 2010, Leveille et al. 2018), likely as a consequence of alterations in fatty acids (FA) transport proteins related to phospholipids transfer such as the major facilitator superfamily domain-containing 2a (MFSD2a) and FA transport protein 4 (FATP-4) (Prieto-Sanchez et al. 2017, Segura et al. 2017). Insufficient supply of long-chain polyunsaturated FA (LC-PUFA) to the foetus might compromise adequate growth and later on visual and cognitive development (Innis 2007).

The aim of the present study was to investigate the effects of AdipoRon administration during gestation on glycaemia and lipid profile in both mothers and adult offspring using a rat model of GDM.

Materials and methods

Animals and study design

All procedures were approved by the Institutional Animal Care and Use Committee of the University of Murcia (Murcia, Spain) and conformed to the ARRIVE guidelines for animal research (Kilkenny et al. 2010). Animals received humane treatment in accordance with the European Union guidelines for the care and use of laboratory animals. Female adult Sprague Dawley rats (12 weeks of age) were supplied by the Animal Laboratory Service of the University of Murcia. Average weight of rats was 225 ± 5 g. Animals were housed individually with access to food and water ad libitum in a humidity and temperature-controlled (22 ± 1°C) room on a 12 h light:12 h darkness cycle.

Female rats were mated (1:1), and the first day of gestation was estimated by the presence of a mating plug in the cage. They were randomly assigned to three groups of 15 animals each: diabetic rats (GDM), diabetic rats treated with adiponectin agonist (AdipoRon, Biorbyt, UK) (GDM + ADI), and healthy controls without diabetes (control). Diabetes was induced on day 12 of gestation by a single injection of streptozotocin (STZ) (50 mg/kg i.p.) (Sigma–Aldrich) dissolved in citrate buffer (10 mM, pH 4.5), control animals received vehicle only. Once the diabetes was established, GDM+ADI animals received AdipoRon (50 mg/kg/day by gavage) freshly dissolved in ethanol for days 14–20 of gestation. All diabetic rats (GDM and GDM + ADI) were given exogenous neutral protamine Hagedorn insulin (Novo Nordisk) every morning in order to maintain glycaemia values of mothers between 100 and 400 mg/mL. The units of insulin administered to pregnant rats varied depending on daily glucose values but were similar in both GDM and GDM + ADI groups (GDM: 3.44 ± 0.30 IU/d, GDM + ADI: 3.63 ± 0.33 IU/d, P = 0.653).

On day 20 of gestation, ten pregnant rats per group were anesthetized with a mixture (per 100 g) of 5 mg ketamine hydrochloride, 0.25 mg chlorobutanol, and 1 mg xylazine. Maternal blood was extracted by heart puncture in EDTA-coated tubes and centrifugated at 1400 g for 10 min at 4°C to obtain plasma. Foetal plasma was not possible to collect due to methodological difficulties related to the small size of the foetus at delivery. Placentas, whole foetus, and foetal brain were also collected (four foetus and placentas were pooled per rat), frozen in liquid nitrogen and stored at −80°C until analysis.

Three to four pregnant rats per group were allowed to breed their pups until weaning (21 days). Sex-matched offspring animals were maintained on a standard chow diet until adult state (12 weeks of age) when they were sacrificed, and plasma and brain samples collected (GDM n = 16 (8 males/8 females), GDM + ADI n = 14 (6 males/8 females), control n = 11 (6 males/5 females)). Rats were allocated during 4 days in individual metabolic cages for the collection of urine samples. Oral glucose tolerance test was performed in the offspring at 3 months of age (2 g/kg), blood was collected by a tail puncture at basal, 30, 60, and 90 min postchallenge.

Biochemical analysis

Plasma biochemical parameters (glucose, total cholesterol, HDL cholesterol, and triglycerides were quantified by an automatic analyser (Roche–Hitachi Modular PyD Autoanalyzer, Mannheim, Germany). Daily monitoring of glucose in diabetic mothers was performed with Ascensia Breeze 2 blood glucose monitoring system (Bayer AG). HbAlc was measured with A1C Now+ Multi-test System (Bayer AG).

Fatty acids analyses

Total lipids were extracted from 125 μL plasma and tissues (150 mg placenta, 600 mg whole foetus, and 80 mg brain) into chloroform:methanol (2:1 v/v) according to Folch et al. method (Folch et al. 1957). Previous to the extraction, 0.05 mg pentadecanoic acid was added to the samples as internal standard. FA methyl esters were produced according to Stoffel et al. (Stoffel et al. 1959) by adding 1 mL of 3 N methanolic HCl (Supelco, Sigma–Aldrich) and heating at 90°C for 1 h. The derivatives were extracted into hexane and stored at −20°C until gas chromatographic analysis.

FA methyl esters were analysed by gas chromatography using a SP-2560 capillary column (100 m × 0.25 mm i.d. × 20 µm) (Supelco, Sigma–Aldrich) in a Hewlett-Packard 6890 gas chromatograph (Agilent Technologies) equipped with a flame ionization detector (Larque et al. 2003). The temperature of the detector and the injector was 240°C. The oven temperature was programmed at 175°C for 30 min and increased at 2°C/min to 230°C and held at this temperature for 17 min. Helium was used as the carrier gas at a pressure of 45 psi. Peaks were identified by comparison of their retention times with appropriate FA methyl esters standards (Sigma–Aldrich), and FA concentrations were determined in relation to the peak area of internal standard.

Foetal adiposity was estimated by dividing the whole foetus total FA content by the foetal weight.

Protein extracts for Western blotting

Placental tissue of 30 mg was homogenized in 0.3 mL ice-cold lysis buffer (20 mM Tris-HCl pH 7.5, 150 mM NaCl, 5 mM Na2EDTA, 1 mM EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM beta-glycerophosphate, 1 mM Na3VO4, 1 μg/mL leupeptin) from Cell Signaling Technology. Phenylmethanesulfonyl fluoride solution of 1 mM was added to the lysis buffer before homogenization (Ruiz-Alcaraz et al. 2005). Samples were homogenized using a Tissue Lyser LT device (Qiagen Iberia SL). Protein lysates were obtained from the supernatant after 15 min centrifugation at 10,000 g 4°C. Protein was quantified by Bradford assay (Bradford 1976), and samples were stored at −80°C until Western blot analysis.

Western blot analysis

The primary antibodies used were rabbit polyclonal antibody against the orphan transporter called MFSD2a (Abcam), rabbit monoclonal against FA translocase (FAT) (Abcam), rabbit monoclonal against FATP-4 (Abcam), rabbit polyclonal antibody against adipocyte FA binding protein (A-FABP) (Sigma–Aldrich), rabbit monoclonal against phosphorylated AKT (Abcam), rabbit polyclonal against extracellular signal-regulated kinase (ERK) (Proteintech, Manchester, UK) and mouse monoclonal anti-beta-actin (Sigma–Aldrich). Anti-mouse and anti-rabbit secondary antibodies conjugated with horseradish peroxidase were obtained from Santa Cruz Biotechnology. Protein extracts (15 μg protein) diluted in sample buffer were resolved on 10% polyacrylamide gels and transferred onto PVDF membranes (Merck Millipore). Membranes were then blocked in phosphate saline buffer with 0.05% Tween 20 (PBS-T) containing 2% BSA for 1 h at room temperature. Thereafter, membranes were incubated with primary antibodies overnight at 4°C. Blots were then washed with PBS-T and probed for 1 h at room temperature with the correspondent secondary antibodies conjugated with horseradish peroxidase. Finally, membranes were stripped with Tris/HCl buffer pH 2.3 containing beta-mercaptoethanol 0.1 M and re-probed with anti-beta-actin to perform loading controls. Proteins were detected using a chemioluminescence kit according to the manufacture’s instruction (Pierce ECL 2 Western Blotting Substrate; Thermo Fisher Scientific) (Prieto-Sanchez et al. 2017). Density of all bands was determined by densitometry using Image Quant LAS 500 software (GE Healthcare). Relative protein expression data were normalized for beta-actin expression.

Levels of inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), and nitrated proteins

Renal cortex was homogenized in ice-cold 50 mmol/L Tris–HCl buffer pH 7.4 containing 1% NP-40, 0.25% sodium deoxycholate, 1 mmol/L EDTA, and 10% protease inhibitor cocktail (Sigma–Aldrich). Kidney homogenates were then centrifuged (10,000 g for 30 min) and stored at −80°C until analysis.

Concentrations of IL-1β, IL-6, TNF-α in renal cortex homogenates from each group were determined using a commercially available custom 32-plex Procartaplex Multiplex Immunoassay (Thermo Fisher Scientific) according to the manufacturer’s instructions with some modifications. Twenty-five microlitre of the kit-provided 1× Universal Assay Buffer was added to each well followed by 25 μL of four-fold serial diluted standards or undiluted samples into designated wells. After the addition of detection antibody, streptavidin-PE, and resuspend the beads, the test plate was prepared for analysis on a Luminex instrument by adding 120 μL of reading buffer. Finally, the plate was analysed on the Luminex MAGPIX System (Software: xPonent 4.2; Merck KGaA). The results were expressed as picogram/milligram of protein.

Extracted proteins from renal cortex homogenates (700 µg) were assayed for the quantitative measurement of nitrated proteins as an index of oxidative stress by using the Nitrotyrosine ELISA test kit (Hycult Biotechnology, Uden, The Netherlands) as previously published (Rodriguez et al. 2011).

Total antioxidant activity

Total antioxidant activity (TAA) was determined in plasma and kidney of adult offspring rats according to Arnao et al. method (Arnao et al. 1999). The method is based on the ability of the antioxidants in the sample to reduce the radical cation of 2,2′-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), determined by the decolouration of the ABTS cation radical (ABTS·+). ABTS·+ was generated in media containing 240 µL phosphate buffer (50 mM pH 7.5), ABTS 2 mM, H2O2 60 µM, and horseradish peroxidase 0.25 µM. At stable ABTS·+ solutions, 10 µL of plasma or protein homogenate (kidney) were added, measuring the quenching of the absorbance at 730 nm after 6 min of reaction. Antioxidant activity was calculated by comparing the values of the sample with a standard curve of Trolox and expressed as Trolox millimoles equivalents by grams of albumin/protein (eq. Trolox millimoles/grams albumin or protein).

Eicosanoids analysis in urine samples

n-6 and n-3 LC-PUFA metabolites 8-iso-prostaglandin F2α (8-iso-PGF2α), PGD2, PGE2, PGF2, PGD3, PGF3, Lipoxin A4 (LxA4), 15R-LxA4, Lx-B4, 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE), 12-hydroxyicosa-5Z,8Z,10E,14Z-tetraenoic acid (12-HETE), 15-hydroxyicosa-5Z,8Z,11Z,13E-tetraenoic acid (15-HETE), and the deuterated internal standard PGE2-d4 were purchased from Cayman Chemical Co. (Ann Arbor, MI, USA). All solvents and reagents used were HPLC grade.

Solid-phase extraction procedure of eicosanoids using Strata™ X-AW cartridges 200 mg/3mL (Phenomenex, Torrance, CA, USA) was performed in urine samples as previously described by Taylor et al. (2008). In brief, urine samples were centrifuged at 1400 g for 5 min at room temperature. The supernatant (4 mL) was mixed with ultra-pure water (4 mL) and internal standard (PGE2-d4 50 ng in methanol). The sample pH was adjusted to 6.0 ± 0.05. Cartridges were preconditioned with 4 mL of methanol containing 2% formic acid (v/v) and subsequently equilibrated with 4 mL water. The diluted urine sample (8 mL) was then loaded onto the cartridge. The cartridge was washed with 4 mL water, followed by 8 mL methanol 25% (in water, v/v) and 4 mL methanol 50% (in water, v/v). Elution was subsequently performed with 3 mL of methanol containing 2% formic acid (v/v), 3 mL of methanol, and followed by 2 mL of methanol containing 50% acetonitrile (v/v). Cartridges were then dried under nitrogen gas and reconstituted in 50 μL methanol containing 0.1% formic acid (v/v) and injected onto the UHPLC-MS.

Chromatographic separation was carried out using a UPLC 1290 Infinity Series system (Agilent Technologies) equipped with a triple quadrupole mass spectrometer (6460 Jet Stream Series, Agilent Technologies) based on the methodology described by Le Faouder et al. (2013). An Excel C18 column (100 mm × 3.0 mm i.d., 1.7 µm) (ACE, Aberdeen, UK) was used. Limits of quantification and detection were also previously reported (Le Faouder et al. 2013). The relative standard deviation for peak area was in the range of 0.5–4.7% in the intraday test and 1.3–3.5% in the case of the inter-day test.

Standard curves were constructed at five concentrations for all compounds (0.025–0.5 µg/mL). The metabolite concentrations in urine were corrected for creatinine, which was measured using a commercial kit (CREATININE-J, Spinreact, Girona, Spain).

Statistical analysis

Sample size was estimated based on HbAlc percentages in diabetic mice treated with AdipoRon published by Choi et al. (2018). Type I error was set at α = 0.05 and type II error β = 0.2 (power 80%), obtaining a minimum sample size of 11 animals per group. The software used for this estimation was nQuery 7.0 (Statsols HQ, Cork, Ireland).

The three experimental groups were compared using one-way ANOVA followed by a post hoc Bonferroni test. P < 0.05 was considered statistically significant. The results are expressed as the mean ± s.e.m. Statistical analysis was performed using SPSS, version 24.0 (IBM Corp.).

Results

Pregnant diabetic rats (GDM) had significantly higher glycaemic levels than controls for both glucose (Fig. 1A) and HbAlc (Table 1). Adiponectin agonist (AdipoRon) administration tended to reduce glycaemia in diabetes-treated mothers compared to non-treated dams (Fig. 1A), following HbAlc the same non-significant trend (P = 0.073 GDM vs GDM + ADI). Maternal serum lipids (total cholesterol, HDL and LDL cholesterol, and TG) were similar in the three groups of animals (Table 1). Foetus from diabetic dams (GDM and GDM + ADI) presented intrauterine growth restriction compared to controls (Table 1). However, foetal fat content/foetal weight ratio indicated higher foetal adiposity in offspring of diabetic mothers, and AdipoRon tried to counteract this foetal fat accumulation (Fig. 1B).

Figure 1
Figure 1

(A) Fasting glucose values at day 20 of gestation in rats with gestational diabetes (GDM), GDM rats treated with adiponectin agonist (AdipoRon) (GDM + ADI), and healthy control animals. (B) Total fat content/weight ratio of foetus at delivery. GDM n = 8, GDM + ADI n = 9, control n = 10. Results are expressed as means ± s.e.m. Different letters indicate significant differences between experimental groups (P < 0.05).

Citation: Journal of Endocrinology 251, 1; 10.1530/JOE-20-0617

Table 1

Maternal, foetal, and adult offspring parameters.

GDM (n = 8)GDM+ADI (n = 9)Control (n = 10)P
Maternal parameters (day 20 of gestation)
 Weight (g)298.50 ± 7.74316.40 ± 7.18317.90 ± 12.820.350
 HbA1c (%)5.03 ± 0.12a4.68 ± 0.13a4.21 ± 0.11b0.001
 Cholesterol (mg/dL)90.50 ± 7.47101.78 ± 6.5194.89 ± 6.830.481
 HDL cholesterol (mg/dL)31.50 ± 5.9829.67 ± 6.1019.56 ± 3.610.209
 LDL cholesterol (mg/dL)61.63 ± 11.0267.78 ± 10.5775.33 ± 8.330.598
 TG (mg/dL)448.88 ± 81.84458.00 ± 61.63493.22 ± 78.330.893
 Albumin (g/dL)2.45 ± 0.182.62 ± 0.102.38 ± 0.230.570
 TAA (eq. Trolox mM/g albumin)1.04 ± 0.060.89 ± 0.101.22 ± 0.340.567
 Placental weight (g)0.45 ± 0.01a0.51 ± 0.02b0.49 ± 0.02ab0.010
Foetal parameters(n = 8)(n = 9)(n = 10)
 Weight (g)1.95 ± 0.06a2.10 ± 0.05a2.84 ± 0.27b0.002
 Foetus number14.75 ± 0.5913.60 ± 0.7814.20 ± 0.840.590
 Total fat (mg/g)6.83 ± 0.336.43 ± 0.246.02 ± 0.210.102
Adult offspring (3 months old)(n = 16)(n = 14)(n = 11)
 Weight (g)300.44 ± 16.35304.29 ± 16.87293.55 ± 16.950.600
 Glucose (mg/dL)77.45 ± 3.2580.23 ± 4.0175.21 ± 1.960.777
 Cholesterol (mg/dL)82.55 ± 1.6780.50 ± 4.0269.13 ± 2.370.291
 HDL Cholesterol (mg/dL)57.18 ± 2.1058.93 ± 3.5848.31 ± 2.30.685
 LDL Cholesterol (mg/dL)12.64 ± 1.24a9.50 ± 1.01ab8.00 ± 0.92b0.026
 TG (mg/dL)62.45 ± 5.1160.07 ± 2.5564.44 ± 4.720.846
 Albumin (g/dL)3.75 ± 0.11a2.88 ± 0.24b3.80 ± 0.06a0.002

Results are expressed as means ± s.e.m.

Different superscript letters indicate significant differences between experimental groups (P < 0.05) (bold face).

GDM, gestational diabetes mellitus; GDM + ADI, animals with gestational diabetes mellitus treated with AdipoRon; TAA, total antioxidant activity.

No major differences were observed in maternal FA plasma, placenta, or foetal tissues (Table 2). In maternal plasma, eicosapentaenoic acid (20:5 n-3, EPA) was reduced in GDM mothers compared to control while DHA did not change significantly (Table 2). In placenta, DHA tended to increase by GDM (P = 0.107) while EPA again decreased significantly. However, no differences were observed in foetal brain (Table 2). Placental MFSD2a expression did not show differences between groups (GDM: 0.78 ± 0.12; GDM + ADI: 0.73 ± 0.10; control: 0.89 ± 0.15 arbitrary units, P = 0.636). Likewise, other FA transport proteins (FAT, FATP-4, and A-FABP) or proteins involved in insulin signalling (p-AKT and ERK) analysed in the placenta showed similar results between groups (Supplementary Fig. 1, see section on supplementary materials given at the end of this article).

Table 2

Maternal plasma, placenta, total foetus, and foetal brain fatty acid profile at day 20 of gestation.

Fatty acids (g/100 g fatty acids)GDM (n = 8)GDM+ADI (n = 9)Control (n = 10)P
Maternal plasma
 16:021.07 ± 0.9120.29 ± 0.4020.87 ± 0.520.605
 18:08.73 ± 0.779.24 ± 0.618.98 ± 0.360.807
 18:1 n-914.26 ± 1.2115.35 ± 0.7514.07 ± 0.780.498
 18:2 n-621.32 ± 1.1920.26 ± 0.7620.55 ± 1.020.723
 20:4 n-615.04 ± 0.8516.59 ± 0.8117.49 ± 1.040.173
 20:5 n-3 (EPA)0.15 ± 0.05a0.27 ± 0.06ab0.39 ± 0.05b0.016
 22:6 n-3 (DHA)6.70 ± 0.715.84 ± 0.355.60 ± 0.460.268
 SFA31.72 ± 1.6331.50 ± 0.5831.97 ± 0.530.923
 MUFA18.55 ± 1.4420.13 ± 0.8118.55 ± 0.950.417
 PUFA49.65 ± 1.4948.21 ± 0.8149.34 ± 1.010.576
 n-6/n-35.41 ± 0.516.00 ± 0.306.30 ± 0.480.336
 LC-PUFA n-619.91 ± 0.9720.34 ± 0.7321.13 ± 1.040.615
 LC-PUFA n-37.81 ± 0.806.88 ± 0.386.78 ± 0.530.355
Placenta
 16:021.49 ± 0.28ab20.98 ± 0.31a21.98 ± 0.18b0.020
 18:016.87 ± 0.2316.87 ± 0.3716.01 ± 0.330.087
 18:1 n-99.85 ± 0.549.43 ± 0.319.34 ± 0.140.512
 18:2 n-615.27 ± 0.5214.79 ± 0.4613.82 ± 0.460.086
 20:4 n-616.50 ± 0.56a17.99 ± 0.35b17.85 ± 0.35ab0.028
 20:5 n-3 (EPA)0.08 ± 0.01a0.10 ± 0.01ab0.13 ± 0.01b0.006
 22:6 n-3 (DHA)4.55 ± 0.204.59 ± 0.104.23 ± 0.120.107
 SFA41.63 ± 0.1941.21 ± 0.3941.73 ± 0.440.538
 MUFA14.11 ± 0.6313.70 ± 0.4113.74 ± 0.210.735
 PUFA44.14 ± 0.6244.96 ± 0.3744.37 ± 0.350.390
 n-6/n-37.21 ± 0.267.30 ± 0.187.71 ± 0.170.142
 LC-PUFA n-623.16 ± 0.9424.44 ± 0.4925.17 ± 0.290.053
 LC-PUFA n-35.20 ± 0.215.24 ± 0.114.93 ± 0.120.236
Total foetus
 16:023.73 ± 0.4323.13 ± 0.2623.82 ± 0.590.491
 18:012.10 ± 0.1812.28 ± 0.1612.63 ± 0.160.072
 18:1 n-914.82 ± 0.2114.76 ± 0.2214.55 ± 0.230.631
 18:2 n-68.91 ± 0.498.20 ± 0.467.80 ± 0.250.139
 20:4 n-614.83 ± 0.2215.59 ± 0.2815.11 ± 0.350.194
 20:5 n-3 (EPA)0.11 ± 0.01ab0.11 ± 0.01a0.13 ± 0.01b0.020
 22:6 n-3 (DHA)6.12 ± 0.136.32 ± 0.136.02 ± 0.170.318
 SFA38.25 ± 0.4738.16 ± 0.3039.51 ± 0.580.069
 MUFA24.00 ± 0.3023.93 ± 0.4523.77 ± 0.370.892
 PUFA37.53 ± 0.4037.69 ± 0.5036.49 ± 0.680.225
 n-6/n-34.44 ± 0.124.34 ± 0.084.37 ± 0.060.712
 LC-PUFA n-621.30 ± 0.3022.06 ± 0.2821.51 ± 0.380.237
 LC-PUFA n-36.64 ± 0.136.78 ± 0.136.52 ± 0.190.467
Foetal brain
 16:029.97 ± 0.5131.16 ± 0.5331.65 ± 0.690.124
 18:015.08 ± 0.3714.62 ± 0.1314.80 ± 0.370.578
 18:1 n-912.45 ± 0.4411.92 ± 0.1611.99 ± 0.180.319
 18:2 n-61.33 ± 0.16a1.03 ± 0.07ab0.94 ± 0.09b0.036
 20:4 n-611.85 ± 1.8213.64 ± 0.2012.96 ± 0.310.141
 20:5 n-3 (EPA)0.09 ± 0.100.03 ± 0.030.03 ± 0.030.974
 22:6 n-3 (DHA)9.87 ± 0.3510.23 ± 0.2410.00 ± 0.400.738
 SFA45.77 ± 0.2346.38 ± 0.4747.20 ± 0.710.210
 MUFA22.89 ± 1.9420.34 ± 0.2720.53 ± 0.340.398
 PUFA31.11 ± 1.9533.04 ± 0.4832.01 ± 0.850.477
 n-6/n-32.08 ± 0.242.17 ± 0.062.14 ± 0.050.477
 LC-PUFA n-619.34 ± 2.2221.42 ± 0.3020.67 ± 0.500.412
 LC-PUFA n-310.06 ± 0.4210.32 ± 0.2710.07 ± 0.410.786

Results are expressed as means ± s.e.m. Only selected fatty acids are listed but all fatty acids analysed were considered for the calculation of percentages.

Different superscript letters indicate significant differences between experimental groups (P < 0.05) (bold face).

DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GDM, gestational diabetes mellitus; GDM + ADI, animals with gestational diabetes mellitus treated with AdipoRon; LC-PUFA, long-chain polyunsaturated fatty acids (>18 carbons); MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids.

At the adult state, offspring of diabetic and control mothers showed similar fasting glucose levels (Table 1). GDM offspring showed lower glucose concentration than GDM + ADI ones after 30 min of an oral glucose overload test (Fig. 2A). However, GDM offspring had significantly higher glucose increase between basal and 90 min post-challenge compared to controls (P = 0.009) while a positive effect of AdipoRon was observed on reducing this basal- 90 min glucose increase in the offspring (Fig. 2B). Both GDM + ADI and control were returning to basal values of glycaemia after 90 min while GDM still presented elevated values of serum glucose (Fig. 2A). Serum LDL cholesterol was also higher in the offspring of GDM mothers compared to the control group while no differences were found in LDL cholesterol or triglycerides level (Table 1). GDM + ADI showed lower serum albumin than GDM or control in adult offspring (Table 1).

Figure 2
Figure 2

(A) Glucose values after an oral glucose overload (2 g/kg) in the adult offspring of rats with gestational diabetes (GDM), GDM rats treated with adiponectin agonist (AdipoRon) (GDM + ADI), and healthy control animals. (B) Glucose increase between basal and 90 min postchallenge (2 g glucose/kg) in the adult offspring. GDM n = 16, GDM+ADI n = 14, control n = 11. Results are expressed as means ± s.e.m. *Indicates significant differences between GDM and control groups (P < 0.05). Indicates significant differences between GDM and GDM+ADI groups (P < 0.05). Different letters indicate significant differences between experimental groups (P < 0.05).

Citation: Journal of Endocrinology 251, 1; 10.1530/JOE-20-0617

Concerning to FA profile in the adult offspring, DHA was significantly reduced in plasma of GDM offspring compared to control (Fig. 3A), whereas arachidonic acid (20:4 n-6) (Table 3) and n-6/n-3 LC-PUFA ratio increased (Fig. 3B). AdipoRon normalized n-6/n-3 LC-PUFA ratio in the GDM offspring to values observed in control animals (Fig. 3B). Adult brain FA composition remained similar among groups, showing the strong regulation of its FA composition (Table 3).

Figure 3
Figure 3

(A) Docosahexaenoic acid (DHA) in plasma of adult offspring (3 months old) of rats with gestational diabetes (GDM), GDM rats treated with adiponectin agonist (AdipoRon) (GDM + ADI), and healthy control animals. (B) n-6/n-3 polyunsaturated fatty acids (PUFA) ratio in plasma of adult offspring. GDM n = 16, GDM + ADI n = 14, Control n = 11. Results are expressed as means ± s.e.m. Different letters indicate significant differences between experimental groups (P < 0.05).

Citation: Journal of Endocrinology 251, 1; 10.1530/JOE-20-0617

Table 3

Fatty acid profile in plasma and brain of 3 months old offspring.

Fatty acids (g/100 g fatty acids)GDM (n = 16)GDM+ADI (n = 14)Control (n = 11)P
 16:022.74 ± 0.5622.58 ± 0.6520.75 ± 0.770.383
 18:013.77 ± 0.6315.54 ± 0.7815.82 ± 0.790.528
 18:1 n-99.16 ± 0.43a5.95 ± 0.33b10.63 ± 0.53c<0.001
 18:2 n-615.36 ± 0.7712.02 ± 0.7111.80 ± 1.010.184
 20:4 n-629.87 ± 1.02a29.81 ± 0.70ab27.47 ± 1.33b0.045
 SFA38.60 ± 0.52a43.04 ± 0.82b39.93 ± 0.66ab0.007
 MUFA12.47 ± 0.66a9.38 ± 0.47a15.45 ± 0.86b<0.001
 PUFA48.92 ± 0.60a47.53 ± 0.62a44.61 ± 1.45b0.001
 LC-PUFA n-630.00 ± 0.98ab30.97 ± 0.71a28.09 ± 1.25b0.038
 LC-PUFA n-33.20 ± 0.193.67 ± 0.184.27 ± 0.390.110
Brain
 16:017.69 ± 0.1417.91 ± 0.1117.79 ± 0.120.464
 18:019.38 ± 0.0819.87 ± 0.1719.66 ± 0.100.150
 18:1 n-916.04 ± 0.1715.79 ± 0.1216.34 ± 0.100.119
 18:2 n-60.72 ± 0.020.70 ± 0.020.72 ± 0.020.819
 20:4 n-610.63 ± 0.1110.56 ± 0.0710.56 ± 0.110.973
 22:6 n-3 (DHA)17.18 ± 0.1717.36 ± 0.1517.15 ± 0.160.694
 SFA40.27 ± 0.13b41.17 ± 0.23a40.70 ± 0.12ab0.037
 MUFA25.21 ± 0.3124.22 ± 0.2424.79 ± 0.310.120
 PUFA34.42 ± 0.2234.55 ± 0.1734.36 ± 0.200.596
 n-6/n-30.90 ± 0.010.87 ± 0.010.90 ± 0.010.337
 LC-PUFA n-615.50 ± 0.1415.38 ± 0.1115.50 ± 0.140.820
 LC-PUFA n-317.47 ± 0.1617.67 ± 0.1517.44 ± 0.160.623

Results are expressed as means ± s.e.m. 3 months old offspring from 3 to 4 pregnant rats per group. Only selected fatty acids are listed but all fatty acids analysed were considered for the calculation of percentages. GDM n = 16 (8 males/8 females), GDM + ADI n = 14 (6 males/8 females), Control n = 11 (6 males/5 females).

Different superscript letters indicate significant differences between experimental groups (P < 0.05) (bold face).

DHA, docosahexaenoic acid; GDM, gestational diabetes mellitus; GDM + ADI, animals with gestational diabetes mellitus treated with AdipoRon; LC-PUFA, long-chain polyunsaturated fatty acids (>18 carbons); MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids.

Maternal AdipoRon treatment tended to increase total antioxidant status, determined by TAA, in the kidney of GDM + ADI offspring (P = 0.086) (Table 4). This was confirmed with the lower nitrotyrosine level (oxidative stress marker) observed in the renal cortex of these animals (Table 4). Moreover, AdipoRon significantly reduced pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in renal tissue of adult offspring with respect to both GDM and control groups (Table 4). However, PG and LC-PUFA-derived eicosanoids did not show major differences in the urine of adult offspring (Table 4).

Table 4

Oxidative stress parameters, immunological markers, prostaglandins, and LC-PUFA intermediate metabolites in adult offspring.

GDM (n = 16)GDM+ADI (n = 14)Control (n = 11)P
Plasma
 TAA (eq. Trolox mM/g albumin)1.02 ± 0.031.50 ± 0.271.04 ± 0.030.307
Renal cortex
 TAA (eq. Trolox mM/mg protein)54.01 ± 1.4362.84 ± 4.4649.13 ± 1.180.086
 IL-1β (pg/mg protein)276.16 ± 23.72a211.77 ± 18.10b270.23 ± 16.78ab0.039
 IL-6 (pg/mg protein)202.51 ± 18.98a132.57 ± 10.85b212.44 ± 16.39a0.046
 TNF-α (pg/mg protein)152.31 ± 13.99a111.45 ± 10.69b151.36 ± 11.52a0.047
 Nitrotyrosine (pmol/mg protein)6.69 ± 0.33a5.47 ± 0.23b6.60 ± 0.27a0.024
 Total protein (mg/mL)24.17 ± 0.87a33.71 ± 1.78b25.86 ± 0.93a0.001
Urine (ng/mg creatinine)
 8-Iso-15(R)-PGF2α0.03 ± 0.010.03 ± 0.010.04 ± 0.010.939
 PGD23.98 ± 0.983.91 ± 1.104.96 ± 1.300.542
 PGE22.75 ± 0.532.01 ± 0.331.89 ± 0.330.654
 PGF22.72 ± 0.552.08 ± 0.551.86 ± 0.440.400
 PGD30.11 ± 0.040.03 ± 0.010.05 ± 0.030.379
 PGF30.43 ± 0.140.13 ± 0.060.36 ± 0.130.146
 LxA40.36 ± 0.090.37 ± 0.130.38 ± 0.100.985
 15R-LxA40.43 ± 0.110.48 ± 0.160.35 ± 0.100.873
 Lx-B40.08 ± 0.020.05 ± 0.020.09 ± 0.030.702
 5-HETE0.35 ± 0.160.25 ± 0.030.17 ± 0.030.771
 12-HETE0.54 ± 0.120.34 ± 0.070.27 ± 0.050.257
 15-HETE1.05 ± 0.270.46 ± 0.090.81 ± 0.190.517

Results are expressed as means ± s.e.m. 3 months old offspring from 3 to 4 pregnant rats per group. GDM n = 16 (8 males/8 females), GDM + ADI n = 14 (6 males/8 females), control n = 11 (6 males/5 females).

Different superscript letters indicate significant differences between experimental groups (P < 0.05) (bold face).

HETE, hydroxyicosa-tetraenoic acid; IL, interleukin; Lx, lipoxin; PG, prostaglandin; TAA, total antioxidant activity; TNF-α, tumor necrosis factor α.

Discussion

Here we report the effects of the orally active adiponectin agonist termed AdipoRon on glycaemia and lipid profile in both mother and adult offspring, after its administration during gestation to diabetic rats. As expected, diabetic animals presented higher glucose and HbAlc than non-diabetic control animals. However, AdipoRon treatment tended to reduce glycaemia, indicating a positive effect of the adiponectin agonist on glucose control in the mothers and offspring. It is worth to mention that diabetic animals received daily exogenous insulin which might have affected the results observed. Okada-Iwabu et al. reported a significant reduction in fasting plasma glucose and insulin levels of high-fat diet-induced obese mice after the administration of AdipoRon for 10 days (Okada-Iwabu et al. 2013). They found increased exercise endurance and increased expression of genes involved in FA oxidation in muscle (e.g. medium-chain acyl-CoA dehydrogenase) and lower activation of gluconeogenesis pathways in the liver (e.g. glucose-6-phosphatase) of animals treated with AdipoRon (Okada-Iwabu et al. 2013). Low levels of serum adiponectin are negatively and independently associated with metabolic syndrome-related disorders such as insulin resistance, diabetes, and dyslipidaemia (Kishida et al. 2012). Thus, administration of AdipoRon during gestation may be a useful strategy to improve glycaemic control in GDM subjects, reducing the risk of later glucose intolerance and insulin resistance in the offspring (Scholtens et al. 2019).

Diabetes can result in intrauterine growth restriction in animals. STZ-induced diabetes in rats can be associated with mild diabetes and macrosomia or with insulin-deficient diabetes and foetal growth restriction,the latter being the more common situation (Eriksson et al. 1984, Canavan & Goldspink 1988, Holemans et al. 1997, Ergaz et al. 2005). Despite intrauterine growth restriction, GDM foetus showed higher adiposity than controls, which tried to be mitigated by AdipoRon treatment. As no differences were detected in FA carriers expression in placenta, changes in foetal adiposity could be driven by maternal glucose transfer. There are some evidences of increased glucose transporters expression in diabetes-complicated pregnancies (Stanirowski et al. 2018). The independent-insulin glucose transporter 1 (GLUT-1) may be responsible for excessive glucose transfer and acceleration of foetal adiposity in the GDM foetus. Aye and colleagues reported reduced insulin receptors activity (IR-β and IRS-1), p-AKT, and mTORC1 activity in the placenta of obese pregnant mice after adiponectin administration while no differences in ERK expression (Aye et al. 2015). mTORC1 is a placental nutrient sensor activated by insulin that promotes nutrient transport across the placenta (especially amino acids) contributing to foetal growth (Jansson et al. 2012, Dimasuay et al. 2016). We were not able to quantify placental mTORC1 because of technical problems, but we did not find differences in p-AKT or ERK expression (Supplementary Fig. 1). Thus, AdipoRon may serve as a therapeutic treatment against negative foetal outcomes of GDM related to foetal adiposity. Growth-restricted foetus (GDM and GDM + ADI) showed higher levels of serum LDL cholesterol in adulthood (3 months old) while similar concentrations were observed for total and HDL cholesterol. Tenhola et al. (2000) reported negative associations between birthweight of small for gestational age infants and later total cholesterol concentration in blood during childhood, supporting the relevance of foetal nutrition to adult disease (Ornoy 2011).

Our group previously reported impaired placental transfer of 13C-DHA in GDM women compared to healthy women (Pagan et al. 2013). MFSD2a is postulated as one of the major transporters of Lyso-DHA across the blood–brain barrier (Nguyen et al. 2014) and also in the placenta (Prieto-Sanchez et al. 2017). In the present study, no differences were observed in MFSD2a expression in the placenta or DHA in the total foetus. However, DHA percentage was estimated in the whole foetus and not in cord blood, which could have mask differences in FA foetal plasma profile.

We demonstrated for the first time that GDM+ADI offspring presented an improved response to glucose overload than GDM offspring, indicating the effectiveness of the maternal treatment with AdipoRon on the long-term glucose tolerance in the next generation. However, it was surprising that GDM offspring showed better glucose tolerance than GDM + ADI offspring at 30 min post-challenge, which may be related to an alteration in gastric emptying (Goyal et al. 2019, Wu et al. 2020). Impaired insulin response and altered pancreatic β-cell function are thought to be responsible for the transgenerational transmission of GDM (Aerts & van Assche 2006). The use of AdipoRon in the treatment of GDM may lead to a lower incidence of metabolic syndrome and diabetes in future generations. Our results in pregnant rats agree with those recently published by Scholtens et al. (2019) which showed, across the maternal glucose spectrum, associations between the exposure to hyperglycaemia in utero and elevated glucose values and insulin resistance during childhood (HAPO follow-up cohort). In summary, both studies corroborate the long-term health consequences of maternal hyperglycaemia during pregnancy for the offspring. Reduced tolerance to glucose in adult offspring of GDM may contribute to the pathogenesis of metabolic syndrome and pre-diabetes or diabetes mellitus type 2 (Clausen et al. 2008).

Inflammatory cytokines and oxidative stress markers were measured in the renal cortex as kidneys’ function is usually impaired by diabetes. GDM + ADI offspring showed decreased pro-inflammatory cytokines (IL-1, IL-6, and TNF-α) in the renal cortex compared to GDM and control, which can be due in part to the higher protein content in the tissue. Our results are consistent with those reported by Okada-Iwabu et al. who showed a reduction in the expression levels of the genes encoding pro-inflammatory cytokines (e.g. IL-6 and TNF-α) in the liver and white adipose tissue of high-fat diet obese mice after AdipoRon administration (Okada-Iwabu et al. 2013). Oxidative stress status in kidneys of adult offspring was also reduced by AdipoRon treatment (higher TAA and lower nitrotyrosine). Nevertheless, no significant differences were observed in plasma TAA or urinary eicosanoids. Several studies have recently reported a reduction in renal oxidative stress, apoptosis, lipotoxicity, and inflammation after AdipoRon administration in animal models, which could be especially beneficial in the pathophysiology of diabetic nephropathy and other related disorders (Choi et al. 2018, Xiong et al. 2020, Qiu et al. 2021). This is probably mediated by activating the AMPK pathway (Kim et al. 2018, Gu et al. 2020). Thus, AdipoRon seems to promote positive effects on antioxidant and immune systems that could protect against the renal injury associated to diabetes and other pathologies in long term.

DHA was strongly reduced in plasma of GDM and GDM + ADI adult offspring. Reduced DHA status has been extensively described in the cord blood of GDM women (Min et al. 2005, Pagan et al. 2013, Ortega-Senovilla et al. 2020), but here we report the long-term deleterious consequences of GDM on the FA in the offspring. AdipoRon treatment during pregnancy did not improve the DHA level of GDM + ADI but was effective to reduce the unbalanced n-6/n-3 PUFA ratio observed in GDM offspring. In the present study, we cannot discard that this situation of lower DHA in GDM offspring was likely established already at delivery since cord blood samples were not available. Zhao et al. showed associations between low circulating DHA levels and compromised foetal insulin sensitivity, and this may be involved in the early programming of the susceptibility to type 2 diabetes in offspring of GDM women (Zhao et al. 2014). The AdipoRon administration during pregnancy may also have additional effects in the offspring under different metabolic challenges (e.g. high-fat diet) and this should be explored in future studies.

The strengths of the present study are the administration for the first time of the novel adiponectin agonist AdipoRon in pregnant diabetic animals and the evaluation of its effect for the offspring at both birth and adult state. Our study also presents some limitations since the animal model of diabetes induced by STZ used has some physiopathological differences with human GDM that may include insulin treatment requirement, absence of increased insulin resistance, or foetal growth restriction among others. We cannot exclude that these physiological differences in the rat model could have biased the results reported and the extrapolation to the human GDM condition.

Conclusions

In conclusion, AdipoRon administration to pregnant diabetic rats led to improved maternal glycaemia and reduced foetal adiposity associated with GDM. At the adult state, GDM offspring presented impaired glucose response compared to control, and it was counteracted by AdipoRon treatment. In addition, AdipoRon improved the plasma n-6/n-3 ratio in the offspring and showed some positive effects on antioxidant and inflammatory status. Adiporon seems to be a promising therapeutic drug for the control of glycaemia in the diabetic mother and the offspring in long term.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/JOE-20-0617.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was financially supported by the Spanish Government (GD-BRAIN, SAF2015-69265-C2-1-R), the Maternal and Child Health and Development Research Network (RED SAMID III, RD 16/0022/0009) and the Research Excellence Group CHRONOHEALTH (Séneca Foundation, 19899/GERM/15, Murcia).

Data availability

The datasets generated during and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Author contribution statement

A G, F R, and E L designed and conducted the study, performed experiments, and wrote the manuscript. A G, F R, M S-C, L E M-G, and M D A-O performed laboratory analyses. P S-G and M B A acquired data. A G, F R, M S-C, M B A, and E L interpreted data. All authors have read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgements

The authors thank Fernando Vallejo and José E Yuste (CEBAS-CSIC, Murcia) for technical support with metabolomic analysis of urine samples. The authors also thank Ms Mari Carmen Pérez (Department of Physiology) for her technical assistance.

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  • Min Y, Lowy C, Ghebremeskel K, Thomas B, Bitsanis D & Crawford MA 2005 Fetal erythrocyte membrane lipids modification: preliminary observation of an early sign of compromised insulin sensitivity in offspring of gestational diabetic women. Diabetic Medicine 22 9149 20. (https://doi.org/10.1111/j.1464-5491.2005.01556.x)

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  • Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, Wenk MR, Goh EL & Silver DL 2014 Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509 50350 6. (https://doi.org/10.1038/nature13241)

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  • Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura-Someya T & Shirouzu M et al.2013 A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503 49349 9. (https://doi.org/10.1038/nature12656)

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  • Ornoy A 2011 Prenatal origin of obesity and their complications: gestational diabetes, maternal overweight and the paradoxical effects of fetal growth restriction and macrosomia. Reproductive Toxicology 32 2052 12. (https://doi.org/10.1016/j.reprotox.2011.05.002)

    • Search Google Scholar
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  • Ortega-Senovilla H, Schaefer-Graf U & Herrera E 2020 Pregnant women with gestational diabetes and with well controlled glucose levels have decreased concentrations of individual fatty acids in maternal and cord serum. Diabetologia 63 864874. (https://doi.org/10.1007/s00125-019-05054-x)

    • Search Google Scholar
    • Export Citation
  • Pagan A, Prieto-Sanchez MT, Blanco-Carnero JE, Gil-Sanchez A, Parrilla JJ, Demmelmair H, Koletzko B & Larque E 2013 Materno-fetal transfer of docosahexaenoic acid is impaired by gestational diabetes mellitus. American Journal of Physiology: Endocrinology and Metabolism 305 E826E8 33. (https://doi.org/10.1152/ajpendo.00291.2013)

    • Search Google Scholar
    • Export Citation
  • Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A & Xiang AH et al.2004 Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. Journal of Biological Chemistry 279 12152121 62. (https://doi.org/10.1074/jbc.M311113200)

    • Search Google Scholar
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  • Prieto-Sanchez MT, Ruiz-Palacios M, Blanco-Carnero JE, Pagan A, Hellmuth C, Uhl O, Peissner W, Ruiz-Alcaraz AJ, Parrilla JJ & Koletzko B et al.2017 Placental MFSD2a transporter is related to decreased DHA in cord blood of women with treated gestational diabetes. Clinical Nutrition 36 513521. (https://doi.org/10.1016/j.clnu.2016.01.014)

    • Search Google Scholar
    • Export Citation
  • Qiu W, Wu H, Hu Z, Wu X, Tu M, Fang F, Zhu X, Liu Y, Lian J & Valverde P et al.2021 Identification and characterization of a novel adiponectin receptor agonist adipo anti-inflammation agonist and its anti-inflammatory effects in vitro and in vivo. British Journal of Pharmacology 178 280297. (https://doi.org/10.1111/bph.15277)

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  • Retnakaran R, Qi Y, Connelly PW, Sermer M, Hanley AJ & Zinman B 2010 Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia. Diabetologia 53 2682 76. (https://doi.org/10.1007/s00125-009-1600-8)

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  • Rodriguez F, Lopez B, Perez C, Fenoy FJ, Hernandez I, Stec DE, Li Volti G & Salom MG 2011 Chronic tempol treatment attenuates the renal hemodynamic effects induced by a heme oxygenase inhibitor in streptozotocin diabetic rats. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 301 R1540R1548 (https://doi.org/10.1152/ajpregu.00847.2010)

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  • Segura MT, Demmelmair H, Krauss-Etschmann S, Nathan P, Dehmel S, Padilla MC, Rueda R, Koletzko B & Campoy C 2017 Maternal BMI and gestational diabetes alter placental lipid transporters and fatty acid composition. Placenta 57 144151. (https://doi.org/10.1016/j.placenta.2017.07.001)

    • Search Google Scholar
    • Export Citation
  • Stanirowski PJ, Szukiewicz D, Pazura-Turowska M, Sawicki W & Cendrowski K 2018 Placental expression of glucose transporter proteins in pregnancies complicated by gestational and pregestational diabetes mellitus. Canadian Journal of Diabetes 42 209217. (https://doi.org/10.1016/j.jcjd.2017.04.008)

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  • Tenhola S, Martikainen A, Rahiala E, Herrgård E, Halonen P & Voutilainen R 2000 Serum lipid concentrations and growth characteristics in 12-year-old children born small for gestational age. Pediatric Research 48 623628. (https://doi.org/10.1203/00006450-200011000-00012)

    • Search Google Scholar
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  • Wu T, Rayner CK, Jones KL, Xie C, Marathe C & Horowitz M 2020 Role of intestinal glucose absorption in glucose tolerance. Current Opinion in Pharmacology 55 116124. (https://doi.org/10.1016/j.coph.2020.10.017)

    • Search Google Scholar
    • Export Citation
  • Xiong S, Han Y, Gao P, Zhao H, Jiang N & Sun L 2020 AdipoRon protects against tubular injury in diabetic nephropathy by inhibiting endoplasmic reticulum stress. Oxidative Medicine and Cellular Longevity 2020 6104375. (https://doi.org/10.1155/2020/6104375)

    • Search Google Scholar
    • Export Citation
  • Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K & Tsuboyama-Kasaoka N et al.2001 The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine 7 94194 6. (https://doi.org/10.1038/90984)

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  • Zhao JP, Levy E, Fraser WD, Julien P, Delvin E, Montoudis A, Spahis S, Garofalo C, Nuyt AM & Luo ZC 2014 Circulating docosahexaenoic acid levels are associated with fetal insulin sensitivity. PLoS ONE 9 e85054. (https://doi.org/10.1371/journal.pone.0085054)

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    (A) Fasting glucose values at day 20 of gestation in rats with gestational diabetes (GDM), GDM rats treated with adiponectin agonist (AdipoRon) (GDM + ADI), and healthy control animals. (B) Total fat content/weight ratio of foetus at delivery. GDM n = 8, GDM + ADI n = 9, control n = 10. Results are expressed as means ± s.e.m. Different letters indicate significant differences between experimental groups (P < 0.05).

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    (A) Glucose values after an oral glucose overload (2 g/kg) in the adult offspring of rats with gestational diabetes (GDM), GDM rats treated with adiponectin agonist (AdipoRon) (GDM + ADI), and healthy control animals. (B) Glucose increase between basal and 90 min postchallenge (2 g glucose/kg) in the adult offspring. GDM n = 16, GDM+ADI n = 14, control n = 11. Results are expressed as means ± s.e.m. *Indicates significant differences between GDM and control groups (P < 0.05). Indicates significant differences between GDM and GDM+ADI groups (P < 0.05). Different letters indicate significant differences between experimental groups (P < 0.05).

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    (A) Docosahexaenoic acid (DHA) in plasma of adult offspring (3 months old) of rats with gestational diabetes (GDM), GDM rats treated with adiponectin agonist (AdipoRon) (GDM + ADI), and healthy control animals. (B) n-6/n-3 polyunsaturated fatty acids (PUFA) ratio in plasma of adult offspring. GDM n = 16, GDM + ADI n = 14, Control n = 11. Results are expressed as means ± s.e.m. Different letters indicate significant differences between experimental groups (P < 0.05).

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  • Min Y, Lowy C, Ghebremeskel K, Thomas B, Bitsanis D & Crawford MA 2005 Fetal erythrocyte membrane lipids modification: preliminary observation of an early sign of compromised insulin sensitivity in offspring of gestational diabetic women. Diabetic Medicine 22 9149 20. (https://doi.org/10.1111/j.1464-5491.2005.01556.x)

    • Search Google Scholar
    • Export Citation
  • Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, Wenk MR, Goh EL & Silver DL 2014 Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509 50350 6. (https://doi.org/10.1038/nature13241)

    • Search Google Scholar
    • Export Citation
  • Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura-Someya T & Shirouzu M et al.2013 A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503 49349 9. (https://doi.org/10.1038/nature12656)

    • Search Google Scholar
    • Export Citation
  • Ornoy A 2011 Prenatal origin of obesity and their complications: gestational diabetes, maternal overweight and the paradoxical effects of fetal growth restriction and macrosomia. Reproductive Toxicology 32 2052 12. (https://doi.org/10.1016/j.reprotox.2011.05.002)

    • Search Google Scholar
    • Export Citation
  • Ortega-Senovilla H, Schaefer-Graf U & Herrera E 2020 Pregnant women with gestational diabetes and with well controlled glucose levels have decreased concentrations of individual fatty acids in maternal and cord serum. Diabetologia 63 864874. (https://doi.org/10.1007/s00125-019-05054-x)

    • Search Google Scholar
    • Export Citation
  • Pagan A, Prieto-Sanchez MT, Blanco-Carnero JE, Gil-Sanchez A, Parrilla JJ, Demmelmair H, Koletzko B & Larque E 2013 Materno-fetal transfer of docosahexaenoic acid is impaired by gestational diabetes mellitus. American Journal of Physiology: Endocrinology and Metabolism 305 E826E8 33. (https://doi.org/10.1152/ajpendo.00291.2013)

    • Search Google Scholar
    • Export Citation
  • Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A & Xiang AH et al.2004 Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. Journal of Biological Chemistry 279 12152121 62. (https://doi.org/10.1074/jbc.M311113200)

    • Search Google Scholar
    • Export Citation
  • Prieto-Sanchez MT, Ruiz-Palacios M, Blanco-Carnero JE, Pagan A, Hellmuth C, Uhl O, Peissner W, Ruiz-Alcaraz AJ, Parrilla JJ & Koletzko B et al.2017 Placental MFSD2a transporter is related to decreased DHA in cord blood of women with treated gestational diabetes. Clinical Nutrition 36 513521. (https://doi.org/10.1016/j.clnu.2016.01.014)

    • Search Google Scholar
    • Export Citation
  • Qiu W, Wu H, Hu Z, Wu X, Tu M, Fang F, Zhu X, Liu Y, Lian J & Valverde P et al.2021 Identification and characterization of a novel adiponectin receptor agonist adipo anti-inflammation agonist and its anti-inflammatory effects in vitro and in vivo. British Journal of Pharmacology 178 280297. (https://doi.org/10.1111/bph.15277)

    • Search Google Scholar
    • Export Citation
  • Retnakaran R, Qi Y, Connelly PW, Sermer M, Hanley AJ & Zinman B 2010 Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia. Diabetologia 53 2682 76. (https://doi.org/10.1007/s00125-009-1600-8)

    • Search Google Scholar
    • Export Citation
  • Rodriguez F, Lopez B, Perez C, Fenoy FJ, Hernandez I, Stec DE, Li Volti G & Salom MG 2011 Chronic tempol treatment attenuates the renal hemodynamic effects induced by a heme oxygenase inhibitor in streptozotocin diabetic rats. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 301 R1540R1548 (https://doi.org/10.1152/ajpregu.00847.2010)

    • Search Google Scholar
    • Export Citation
  • Ruiz-Alcaraz AJ, Liu HK, Cuthbertson DJ, Mcmanus EJ, Akhtar S, Lipina C, Morris AD, Petrie JR, Hundal HS & Sutherland C 2005 A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration. Biochemical Journal 392 3453 52. (https://doi.org/10.1042/BJ20051194)

    • Search Google Scholar
    • Export Citation
  • Scholtens DM, Kuang A, Lowe LP, Hamilton J, Lawrence JM, Lebenthal Y, Brickman WJ, Clayton P, Ma RC & McCance D et al. 2019 Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal glycemia and childhood glucose metabolism. Diabetes Care 42 381392. (https://doi.org/10.2337/dc18-2021)

    • Search Google Scholar
    • Export Citation
  • Segura MT, Demmelmair H, Krauss-Etschmann S, Nathan P, Dehmel S, Padilla MC, Rueda R, Koletzko B & Campoy C 2017 Maternal BMI and gestational diabetes alter placental lipid transporters and fatty acid composition. Placenta 57 144151. (https://doi.org/10.1016/j.placenta.2017.07.001)

    • Search Google Scholar
    • Export Citation
  • Stanirowski PJ, Szukiewicz D, Pazura-Turowska M, Sawicki W & Cendrowski K 2018 Placental expression of glucose transporter proteins in pregnancies complicated by gestational and pregestational diabetes mellitus. Canadian Journal of Diabetes 42 209217. (https://doi.org/10.1016/j.jcjd.2017.04.008)

    • Search Google Scholar
    • Export Citation
  • Stoffel W, Chu F & Ahrens EH 1959 Analysis of long-chain fatty acids by gas liquid chromatography. Micromethod for preparation of methyl esters. Analytical Chemistry 31 30730 8. (https://doi.org/10.1021/ac60146a047)

    • Search Google Scholar
    • Export Citation
  • Taylor AW, Bruno RS & Traber MG 2008 Women and smokers have elevated urinary F(2)-isoprostane metabolites: a novel extraction and LC-MS methodology. Lipids 43 9259 36. (https://doi.org/10.1007/s11745-008-3222-1)

    • Search Google Scholar
    • Export Citation
  • Tenhola S, Martikainen A, Rahiala E, Herrgård E, Halonen P & Voutilainen R 2000 Serum lipid concentrations and growth characteristics in 12-year-old children born small for gestational age. Pediatric Research 48 623628. (https://doi.org/10.1203/00006450-200011000-00012)

    • Search Google Scholar
    • Export Citation
  • Wu T, Rayner CK, Jones KL, Xie C, Marathe C & Horowitz M 2020 Role of intestinal glucose absorption in glucose tolerance. Current Opinion in Pharmacology 55 116124. (https://doi.org/10.1016/j.coph.2020.10.017)

    • Search Google Scholar
    • Export Citation
  • Xiong S, Han Y, Gao P, Zhao H, Jiang N & Sun L 2020 AdipoRon protects against tubular injury in diabetic nephropathy by inhibiting endoplasmic reticulum stress. Oxidative Medicine and Cellular Longevity 2020 6104375. (https://doi.org/10.1155/2020/6104375)

    • Search Google Scholar
    • Export Citation
  • Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K & Tsuboyama-Kasaoka N et al.2001 The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine 7 94194 6. (https://doi.org/10.1038/90984)

    • Search Google Scholar
    • Export Citation
  • Zhao JP, Levy E, Fraser WD, Julien P, Delvin E, Montoudis A, Spahis S, Garofalo C, Nuyt AM & Luo ZC 2014 Circulating docosahexaenoic acid levels are associated with fetal insulin sensitivity. PLoS ONE 9 e85054. (https://doi.org/10.1371/journal.pone.0085054)

    • Search Google Scholar
    • Export Citation