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Sex-specific effects of maternal metformin intervention during glucose-intolerant obese pregnancy on body composition and metabolic health in aged mouse offspring.

Published version
Peer-reviewed

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Authors

Schoonejans, Josca M  ORCID logo  https://orcid.org/0000-0003-2893-7199
Blackmore, Heather L  ORCID logo  https://orcid.org/0000-0003-0180-3852
Ashmore, Thomas J 
Pantaleão, Lucas C  ORCID logo  https://orcid.org/0000-0002-5626-8810
Pellegrini Pisani, Luciana  ORCID logo  https://orcid.org/0000-0001-6579-6167

Abstract

AIMS/HYPOTHESIS: Metformin is increasingly used to treat gestational diabetes (GDM) and pregnancies complicated by pregestational type 2 diabetes or polycystic ovary syndrome but data regarding long-term offspring outcome are lacking in both human studies and animal models. Using a mouse model, this study investigated the effects of maternal metformin intervention during obese glucose-intolerant pregnancy on adiposity, hepatic steatosis and markers of metabolic health of male and female offspring up to the age of 12 months. METHODS: C57BL/6J female mice were weaned onto either a control diet (Con) or, to induce pre-conception obesity, an obesogenic diet (Ob). The respective diets were maintained throughout pregnancy and lactation. These obese dams were then randomised to the untreated group or to receive 300 mg/kg oral metformin hydrochloride treatment (Ob-Met) daily during pregnancy. In male and female offspring, body weights and body composition were measured from 1 month until 12 months of age, when serum and tissues were collected for investigation of adipocyte cellularity (histology), adipose tissue inflammation (histology and quantitative RT-PCR), and hepatic steatosis and fibrosis (histochemistry and modified Folch assay). RESULTS: At 12 months of age, male Ob and Ob-Met offspring showed increased adiposity, adipocyte hypertrophy, elevated expression of proinflammatory genes, hyperleptinaemia and hepatic lipid accumulation compared with Con offspring. Male Ob-Met offspring failed to show hyperplasia between 8 weeks and 12 months, indicative of restricted adipose tissue expansion, resulting in increased immune cell infiltration and ectopic lipid deposition. Female Ob offspring were relatively protected from these phenotypes but Ob-Met female offspring showed increased adiposity, adipose tissue inflammation, hepatic lipid accumulation, hyperleptinaemia and hyperinsulinaemia compared with Con female offspring. CONCLUSIONS/INTERPRETATION: Maternal metformin treatment of obese dams increased offspring metabolic risk factors in a sex- and age-dependent manner. These observations highlight the importance of following up offspring of both sexes beyond early adulthood after interventions during pregnancy. Our findings illustrate the complexity of balancing short-term benefits to mother and child vs any potential long-term metabolic effects on the offspring when prescribing therapeutic agents that cross the placenta.

Description

Keywords

Developmental programming, Fatty liver, Gestational diabetes, Inflammation, Maternal obesity, Metformin, White adipose tissue, Humans, Pregnancy, Animals, Mice, Child, Male, Female, Adult, Infant, Metformin, Glucose, Diabetes Mellitus, Type 2, Mice, Inbred C57BL, Obesity, Body Composition, Diabetes, Gestational, Fatty Liver, Inflammation, Lipids, Prenatal Exposure Delayed Effects, Diet, High-Fat

Journal Title

Diabetologia

Conference Name

Journal ISSN

0012-186X
1432-0428

Volume Title

65

Publisher

Springer Science and Business Media LLC
Sponsorship
British Heart Foundation (None)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (106026/Z/14/Z)
Wellcome Trust (100574/B/12/Z)
British Heart Foundation (RG/17/12/33167)
MRC (MC_UU_00014/5)
British Heart Foundation (PG/20/11/34957)
MRC (MR/T016701/1)
MRC (MC_UU_00014/4)
Medical Research Council (MC_UU_12012/4)
Medical Research Council (MC_PC_12012)
São Paulo Research Foundation, National Institute for Health Research