Maternal obesity and offspring metabolic outcomes : focus on sex differences

Sammanfattning: Obesity is a worldwide health issue affecting all ages and both sexes, and its prevalence is progressively increasing among adults and children. The predisposition to metabolic complications caused by obesity is sex dependent. Intrauterine environmental changes such as overnutrition before conception, during pregnancy and lactation, have been recognized as factors predisposing offspring to metabolic complications later in life. Interestingly, sex specific differences in the adaptation to maternal obesity have been observed, but the underlying mechanism is still unclear. The general aim of the current thesis was to investigate the sexual dimorphism in metabolism during obesity and to elucidate the sex-dependent impact of maternal obesity on offspring, with particular emphasis on liver and adipose tissue metabolism. For this purpose, we used a combination of both in vivo and ex vivo advanced techniques, including nuclear magnetic resonance, transcriptomic and lipidomic analysis in key tissues regulating lipid metabolism; namely liver, subcutaneous (SAT), visceral (VAT), and brown (BAT) adipose tissues. In PAPER I we investigated the sex-specific response to obesity-induced metabolic syndrome and aimed to identify sex-specific characteristic lipid molecular species in liver, VAT and SAT in female and male ob/ob mice. We showed that upon overfeeding, males accumulated less total fat with a distribution towards more VAT and less SAT compared to females. Males presented higher lipid accumulation in liver and circulating lipids and were more insulin resistant compared to females. Males induced inflammation in adipose tissue while females presented higher pro-inflammatory markers in liver in response to overeating. Furthermore, the fatty acid and triglyceride profile in both adipose depots were diverse between the two sexes. Males had longer chain fatty acids and triglycerides compared to females. Additionally, here we showed that the hepatic phospholipid profile was sex- dependent with more abundant lipotoxic fatty acids in males than in females. The fatty acid and triglyceride synthesis pathways was highly sex-dependent at the transcriptional level, which may contribute to the sex-dependent metabolic profile. Our results provide a unique description of sexual dimorphic lipid profile in metabolic organs corelated to obesity and could be a contribution for future and more precise treatment of obesity. In PAPER II we investigated the sex-dependent long-term adaptation to maternal obesity in offspring on control diet after weaning with focus on the liver. Males from obese mothers had higher adiposity and were more insulin resistant at short-term but on the long-term post- weaning control diet reversed these effects. Our results demonstrated that maternal obesity influenced differently the hepatic lipid synthesis pathways in female and male offspring and caused a more dysfunctional metabolic profile in males than in females. We observed a sex- specific alteration in the fatty acid, triglyceride, and phospholipid profile together with a sex- specific transcriptional regulation of metabolic pathways in liver. In PAPER III we explored how maternal obesity can predispose white and brown adipose tissue in obese offspring to metabolic dysfunctions in the long-term. We showed that in utero high fat diet environment in offspring on obesogenic diet, altered the triglyceride profile between adipose depots and sexes. Maternal obesity caused changes in triglyceride composition in SAT and BAT and increased the thermogenic activity in BAT in female offspring only. In males, maternal obesity caused whitening of BAT and increased the adipocyte number in VAT and generally impaired their metabolic profile. Our results show that maternal obesity programs the transcriptional activity in white and brown adipose tissue in a sex- and adipose depot- dependent manner. The PAPER IV is a continuation of the study in PAPER III where we investigated the sex- dependent metabolic response to maternal obesity in offspring on obesogenic diet with special focus on liver. Here we showed that maternal obesity caused hepatic insulin resistance in females, and hepatic steatosis and inflammation in males. Moreover, we observed that maternal obesity caused changes in the transcriptional activity and triglyceride profile in female offspring that might prevent the adverse effects of in utero exposure to obesity. In conclusion, our results demonstrate that there is an in utero metabolic programming in offspring born from obese mothers that is sex and tissue specific. Given that the prevalence of obesity among women of reproductive age is increasing drastically, it is crucial to better define the in utero changes in offspring and its consequences. An important outcome of studying the sex differences in offspring metabolism is to understand the underlying mechanisms and paved the way to precision medicine to develop potential interventions and tackle future diseases in subsequent generations.