No abstract

Maternal obesity is associated with increased risk of pregnancy complications and greater risk of obesity in offspring, but studies designed to examine preconception weight loss are limited. The objective of this study was to determine if a combined dietary [oligofructose (OFS)] and pharmacological (sitagliptin) preconception intervention could mitigate poor pregnancy outcomes associated with maternal obesity and improve offspring metabolic health and gut microbiota composition. Diet-induced obese female Sprague-Dawley rats were randomized to one of four intervention groups for 8 weeks: (1) Obese-Control (consumed control diet during intervention); (2) Obese-OFS (10% OFS diet); (3) Obese-S (sitagliptin drug); (4) Obese-OFS + S (combination treatment). Two reference groups were also included: (5) Obese-HFS (untreated obese consumed high fat/sucrose diet throughout study); (6) Lean-Control (lean reference group that were never obese and consumed control diet throughout). Offspring consumed control diet until 11 weeks of age followed by HFS diet until 17 weeks of age. The Obese-OFS + S rats lost weight during the intervention phase whereas the OFS and S treatments attenuated weight gain compared with Obese-HFS (p < 0.05). Gestational weight gain was lowest in Obese-OFS + S rats and highest in Obese-HFS rats (p < 0.05). Prepregnancy intervention did not affect reproductive parameters but did affect pregnancy outcomes including litter size. Male Obese-OFS offspring had significantly lower percent body fat than Obese-HFS at 17 weeks. Female Obese-S and Obese-OFS offspring had significantly lower fasting glucose at 17 weeks compared with Obese-Control and Obese-HFS. Clostridium cluster XI was higher in Obese-HFS and Obese-S dams at birth compared with all other groups. Dams with an adverse pregnancy outcome had significantly lower (p = 0.035) Lactobacillus spp. compared with dams with normal or small litters. At weaning, male offspring of Obese-HFS had higher levels of Methanobrevibacter than all other groups except Obese-S and female Obese-HFS offspring had higher Enterobacteriaceae compared with all other groups. At 11 and 17 weeks of age, Bacteroides/Prevotella spp. was significantly lower in male and female offspring of Obese-HFS dams compared with all other groups except Obese-OFS + S. Modest weight loss induced with a diet-drug combination did not affect maternal fecundity but did have sex-specific effects on offspring adiposity and glycemia that may be linked to changes in offspring microbiota.

Maternal obesity is associated with low birth weight, type 2 diabetes and obesity risk in offspring. Diets high in oligofructose (OFS) improve glucose control through glucagon‐like‐peptide‐1 (GLP‐1). Sitagliptin inhibits the degradation of GLP‐1in vivo. The aim of this study was to determine if a combined OFS and sitagliptin pre‐pregnancy intervention in obese female Sprague‐Dawley rats can improve the metabolic health of female offspring. Obese female Sprague‐Dawley rats were randomized to 1 of 6 groups: 1) AIN‐93; 2) 10% OFS; 3) Sitagliptin; 4) AIN‐93+OFS+Sitagliptin; 5) High fat & sucrose (HFS); 6) Caloric restriction (CR). A lean reference group was also included. Pups consumed AIN‐93 until 11wk when they were given HFS diet for 6 wk. Body weight and blood glucose were assessed. At birth the offspring of combination‐treated dams were significantly heavier than offspring in all other groups (p<0.04). Following the HFS diet challenge the blood glucose area under the curve for offspring of the combination group was less than the HFS and CR groups (p<0.05). Despite higher birth weight, the combined treatment significantly improved offspring glycemic control in adulthood. Funded by CIHR and ACHRI.Grant Funding Source: CIHR and ACHRI

Maternal obesity, before and during pregnancy, can program obesity risk in offspring. Glucagon‐like peptide‐1 (GLP‐1) is a satiety hormone stimulated by the prebiotic fiber, oligofructose (OFS). GLP‐1 is protected against degradation by the diabetes drug, sitagliptin. Our objective was to determine if treating maternal obesity in the pre‐pregnancy period with OFS and sitagliptin is more effective at reducing adiposity and improving gut microbiota profiles than either alone. Obese female rats (n=52) were randomized to 1 of 4 treatments for 8wk: 1) AIN‐93M; 2) OFS; 3) AIN‐93M+Sitagliptin; 4) OFS+ Sitagliptin. Reference groups were: high fat, sucrose (HFS, obese control), lean control, and caloric restriction (matched weight to gp 4). Rats were mated following treatment. Results showed: 1) Consumption of the HFS diet throughout pregnancy and lactation deteriorated maternal health with significantly increased adiposity and impaired glucose tolerance (P<0.05). 2) Whereas pre‐treating obesity with OFS and sitagliptin reduced maternal weight gain during pregnancy, rats that were calorically restricted showed excessive gestational weight gain. 3) The beneficial effects of OFS consumption on bifidobacteria and C. leptum numbers persisted throughout pregnancy and lactation. The significance of this work lies in identification of novel obesity treatments that could be used prior to conception and reduce the transmission of obesity risk to offspring. Funded by CIHR.

Obesity-related cardiac lipid accumulation is associated with cardiac lipotoxicity and dysfunction. Cysteine is a sulfur-containing amino acid required for synthesis of the antioxidant glutathione. Cysteine is supplied by the transsulfuration of homocysteine by cystathionine-beta-synthase (Cbs). We previously reported mice heterozygous for targeted disruption of Cbs (Cbs +/-) with dietinduced obesity have enhanced cardiac lipotoxicity. We hypothesis that Cbs +/-mice with obesity will be more susceptible to altered myocardial fatty acid uptake, activation and oxidation. Cbs +/+ and Cbs +/-mice fed a high-fat diet (HFD) from weaning for 20 weeks to induce obesity had similar increases in body weight and visceral adiposity (P<0.01) than mice fed chow. However, Cbs +/-mice with obesity had higher fasting glucose levels (P<0.01) at baseline and greater glucose intolerance (P<0.01) than Cbs +/+ mice with obesity. Cbs +/+ and Cbs +/-mice with obesity had similar increases in fasting insulin levels (P<0.01). No effect on plasma total adiponectin concentrations were detected; however, Cbs +/-mice with obesity had higher high molecular weight (HMW) adiponectin concentrations (P<0.01) than Cbs +/+ mice fed chow. This was accompanied by increased markers of fatty acid uptake (CD36, P<0.01); activation (long-chain acyl CoA synthetase 1, P<0.01); and oxidation (carnitine palmitoyltransferase 1 and acyl CoA oxidase, P<0.01) in heart. We further observed no changes in markers of cardiac function (alpha 1, skeletal actin and beta 7, myosin heavy chain), despite cardiac lipotoxicity. 524-ORBackground: A mismatch between an organism phenotype and the environment can increase disease risk. Maternal obesity is associated an increased risk of type 2 diabetes and obesity in offspring. Improving maternal weight status may offset the risks for offspring. Diets high in the prebiotic fibre, oligofructose (OFS), improve glucose control through glucagon-like-peptide-1 (GLP-1). Sitagliptin (JanuviaTM) increases the half-life of GLP-1. Objective: To determine if a combined OFS and Sitagliptin prepregnancy intervention in obese female Sprague-Dawley rats can improve the metabolic health of their male offspring. Methods: Female Sprague-Dawley rats were randomized to 1 of 7 groups: 1) lean reference; 2) AIN-93; 3) 10% OFS; 4) Sitagliptin; 5) AIN-93+OFS+Sitagliptin; 6) Caloric restriction; 7) High fat/sucrose reference (HFS). Groups 2-7 had a period of obesity induction prior to treatment. Pups consumed AIN-93 until 11wk then switched onto HFS diet for 6 wk. Body composition and blood glucose were assessed. Results: At birth, the offspring of the combination dams were heavier than offspring of dams in the sitagliptin, caloric restriction and reference groups (p<0.04). The change in glucose total area under the curve before and after the HFS diet showed a significant decreasing trend from group 1-7(p<0.0001) wherein the lean group increased, the combination group did not change and the HFS group decreased.