A mouse model of gestational diabetes shows dysregulated lipid metabolism post-weaning, after return to euglycaemia

Abstract

Background Gestational diabetes is associated with increased risk of type 2 diabetes mellitus and cardiovascular disease for the mother in the decade after delivery. However, the molecular mechanisms that drive these effects are unknown. Recent studies in humans have shown that lipid metabolism is dysregulated before diagnosis of and during gestational diabetes and we have shown previously that lipid metabolism is also altered in obese female mice before, during and after pregnancy. These observations led us to the hypothesis that this persistent dysregulation reflects an altered control of lipid distribution throughout the organism. Methods We tested this in post-weaning (PW) dams using our established mouse model of obese GDM (high fat, high sugar, obesogenic diet) and an updated purpose-built computational tool for plotting the distribution of lipid variables throughout the maternal system (Lipid Traffic Analysis v2.3). Results This network analysis showed that unlike hyperglycaemia, lipid distribution and traffic do not return to normal after pregnancy in obese mouse dams. A greater range of phosphatidylcholines was found throughout the lean compared to obese post-weaning dams. A range of triglycerides that were found in the hearts of lean post-weaning dams were only found in the livers of obese post-weaning dams and the abundance of odd-chain FA-containing lipids differed locally in the two groups. We have therefore shown that the control of lipid distribution changed for several metabolic pathways, with evidence for changes to the regulation of phospholipid biosynthesis and FA distribution, in a number of tissues. Conclusions We conclude that the control of lipid metabolism is altered following an obese pregnancy. These results support the hypothesis that obese dams that developed GDM maintain dysregulated lipid metabolism after pregnancy even when glycaemia returned to normal, and that these alterations could contribute to the increased risk of later type 2 diabetes and cardiovascular disease.

Paternal nutritional programming of lipid metabolism is propagated through sperm and seminal plasma

“…The analysis of the present study used only MS data and was similar to previous studies (Furse et al, 2021b , 2022 ) but with adjustments for four rather than two groups. The tissues used were mapped to the known biological/metabolic network (Fig.…”

Lipid metabolism is dysregulated in a mouse model of diabetes

“…Lipid Traffic Analysis v2.3 was used for this study (Furse et al, 2021a ; 2022a , b ). The code was executed in RStudio(v1.2.5x).…”

“…The shorter onset time of GDM means it has been easier to research and subsequently its molecular origins have received a good deal of attention. Research into the lipid metabolism around GDM has shown that lipid metabolism is disrupted in humans at least 10 weeks before diagnosis of hyperglycaemia (Furse et al, 2019 ; Lu et al, 2016 ), that the lipid composition of maternal blood plasma is different before, during and after the onset of GDM (Furse et al, 2021a ) and that dysregulated lipid metabolism persists throughout the maternal system after weaning (Furse et al, 2022a ). This evidence strongly suggests that dysregulated lipid metabolism has a role in the pathophysiology of GDM, raising questions about a possible role for dysregulated lipid metabolism in T2DM.…”

“…Lipid Traffic Analysis (LTA) is the ideal tool for answering this question as it uses differences in the spatial distribution of metabolites, between control and experimental groups, to identify how and where control mechanisms differ between systems (Furse et al, 2021a , b ; 2022a , b ). We applied LTA to the published lipidomics data, fitted into the network shown in Fig.…”

Paternal Nutritional Programming of Lipid Metabolism is Propagated Through Sperm and Seminal Plasma

“…The analysis of the present study used only MS data and was similar to previous studies (Furse et al, 2021b(Furse et al, , 2022 but with adjustments for four rather than two groups. The tissues used were mapped to the known biological/metabolic network (Fig.…”