Pre-Conception Weight Loss Improves Reproductive, Metabolic and Kidney Health in Obese Mice and Their Offspring

Background and Aims: An alarming 40% of women of reproductive age have obesity and during pregnancy obesity adversely impacts metabolic health in mothers and offspring. Maternal complications include diabetes, preeclampsia and chronic kidney disease (CKD). Our previous work showed that offspring have increased risks of obesity, diabetes, and CKD. While pre-pregnancy weight optimisation is advocated, evidence of benefits for mother and offspring are lacking. We aimed to determine if weight loss prior to pregnancy, either with diet modification or liraglutide, improves maternal and offspring metabolic outcomes, and reduces kidney complications in obese mothers and the offspring. Methods: C57BL/6 female mice were fed a high-fat-diet (HFD) for 8 weeks and compared to lean chow-fed controls. HFD-fed dams were administered liraglutide (0.3mg/kg, s.c., for 4weeks) or switched to chow, to induce pre-conception weight loss. Pregnancy rates were observed after mating. Maternal anthropometry and glucose tolerance were measured before and after intervention, and at late gestation. Pregnant dams were either culled at gestational day 18–20 with blood and kidney harvested, or allowed to deliver their offspring. Offspring anthropometry, and glucose tolerance were assessed at postnatal week 12 after either HFD or chow feeding. Immunohistochemistry (IHC), western blotting and RT-PCR were used to measure kidney metabolic (FAS, SREBP) and inflammatory markers (CD-68,TGF-b). Results: HFD-fed dams had reduced glucose tolerance compared to chow-fed dams (p<0.0001), and higher expression of renal metabolic and inflammatory markers in late gestation (eg FAS <0.05, TGFb <0.05). Intervention with liraglutide or diet lowered body weight, improving glucose tolerance (both p<0.001), and fecundity. Markers of kidney damage, namely albuminuria and fibronectin (by RT-PCR and IHC) were reduced (both p<0.05). Liraglutide treated mice exhibited greater gestational weight gain than mice switched to chow (P<0.001). Markers of inflammation and oxidative stress were significantly lower in obese mice with preconception weight loss via diet compared to liraglutide (eg. MnSOD, PGC1α p<0.05). The offspring of obese mothers with pre-conception weight loss had lower body weight (p<0.001) and improved glucose tolerance (p<0.01). Kidney metabolic and inflammatory markers (MCP-1, FAS, SREBP, CD68) were significantly altered in HFD-fed offspring of obese mothers administered liraglutide pre pregnancy (p<0.05). Conclusions: Preconception weight loss improves fertility, weight and metabolic outcomes in mothers and the offspring, with benefits on reproduction, metabolic health, and chronic kidney disease risk. Therefore, obese women should be targeted for pre-conception weight loss to improve intergenerational metabolic health.