Peri-conceptional obesogenic exposure induces sex-specific programming of disease susceptibilities in adult mouse offspring

Abstract

Vulnerability of the fetus upon maternal obesity can potentially occur during all developmental phases. We aimed at elaborating longer-term health outcomes of fetal overnutrition during the earliest stages of development. We utilized Naval Medical Research Institute (NMRI) mice to induce pre-conceptional and gestational obesity and followed offspring outcomes in the absence of any postnatal obesogenic influences. Male adult offspring developed overweight, insulin resistance, hyperleptinemia, hyperuricemia and hepatic steatosis; all these features were not observed in females. Instead, they showed impaired fasting glucose and a reduced fat mass and adipocyte size. Influences of the interaction of maternal diet∗sex concerned offspring genes involved in fatty liver disease, lipid droplet size regulation and fat mass expansion. These data suggest that a peri-conceptional obesogenic exposure is sufficient to shape offspring gene expression patterns and health outcomes in a sex- and organ-specific manner, indicating varying developmental vulnerabilities between sexes towards metabolic disease in response to maternal overnutrition.

Keywords: ANOVA; ATP citrate lyase; AUC; Acaca; Acetyl-Coenzyme A carboxylase 1; Acly; Actb; Analysis of variance; Area under the curve; B cell leukemia/lymphoma 2; BW; Bax; Bcl2; Bcl2-associated X protein; Berardinelli–Seip congenital lipodystrophy 2 (also known as seipin); Beta-actin; Body weight; Bscl2; CD; CET; CT; Carbon dioxide production; Carnitine palmitoyltransferase 1; Cd36; Cd36 antigen; Cell death-inducing DNA fragmentation factor, alpha subunit-like effector A; Central European Time; Cidea; Computed tomography; Control diet; Cpt1; Day post coitum; EEC; European Economic Commission; Exposure to maternal control diet; Exposure to maternal high-fat, high-calorie diet; FA; Fabp4; Fasn; Fatty acid; Fatty acid binding protein 4; Fatty acid synthase; GR; GTT; Glucocorticoid receptor; Glucose tolerance test; H&E; HFD; HMW; HOMA-IR; HP; Hairy and enhancer of split 1; Heat production; Hematoxylin–eosin; Hes1; High-fat, high-calorie diet; High-molecular-weight; Homeostatic model assessment of insulin resistance; Lep; Leptin; MD; MDA; MRI; Magnetic resonance imaging; Maintenance diet; Malic enzyme 1; Malondialdehyde; Me1; Mesoderm-specific transcript/imprinted paternally expressed gene 1 (also known as Peg1); Mest; N; NAFLD; NEFA; NMRI; NRL; Naval Medical Research Institute; Nitrogen; Non-alcoholic fatty liver disease; Non-esterified fatty acid; Nose–rump-length; Nr1h3; Nr3c1; Nuclear receptor subfamily 1, group H, member 3 (also known as Lxra, liver X receptor alpha); Nuclear receptor subfamily 3, group C, member 1 (also known as Gr, glucocorticoid receptor); Obesity; Offspring; Oxygen consumption; PFA; Paraformaldehyde; Patatin-like phospholipase domain-containing protein 2 (also known as Atgl, adipose triglyceride lipase); Peptidylprolyl isomerase A; Peri-conceptional; Perilipin 2; Peroxisome proliferator activated receptor alpha; Peroxisome proliferator activated receptor gamma; Plin2; Pnpla2; Ppara; Pparg; Ppia; Pregnancy; Programming; RER; ROI; Region of interest; Respiratory exchange ratio; S.e.m.; Scd2; Secreted frizzled-related sequence protein 5; Sex-specificity; Sfrp5; Srebf1; Standard error of the mean; Stearoyl-Coenzyme A desaturase 2; Sterol regulatory element binding transcription factor 1; TBARS; Thiobarbituric acid-reactive substances; Ube2d2; Ubiquitin-conjugating enzyme E2D 2; VCO(2); VO(2); dpc; mat-CD; mat-HFD.