Note: for non-commercial purposes only Women’s Health Academic Centre Maternal Obesity and the Developmental Programming of Offspring Appetite and obesity: A role for leptin? Paul D Taylor, Anne-Maj Samuelsson, Clive W Coen and Lucilla Poston.
Transgenerational ‘Acceleration ‘ of Obesity? Maternal Obesity Glucose, insulin, leptin, lipids, inflammatory response Fetal macrosomia, increased adiposity Persistently altered energy balance Childhood and Adulthood Obesity
Maternal pre-pregnancy BMI and gestational weight gain Risk of offspring obesity: Hochner 2012 Jerusalem study • Adjusted means of offspring obesity outcomes at age 32 by quartiles of maternal pp BMI and GWG • Greater mppBMI, independently of GWG, was significantly associated with higher offspring BMI, and WC. • The observed associations were independent of characteristics reflecting the pre- peri- and post-natal environment, including current measures of SES and lifestyle. • A similar associations of mppBMI and GWG for DBP and SBP was observed, but this disappeared after controlling for offspring current BMI.
Why use animal models to study mechanisms of Developmental Programming? • Mice, rats, and humans share all but 1% of each other's genes • Reduce possible genetic influence • Relatively quick life cycle • Environment can be tightly controlled • Enable different diets to be tested • Investigate critical periods in development “Future studies that explore mechanisms underlying the intergenerational cycle of obesity are warranted to identify potentially novel targets for cardiometabolic risk-reduction interventions”. Hochner et al 2012
Breeding Offspring of Obese Rats and Mice (OffOb) Control Diet Highly Palatable Obesogenic Diet: Pellets with 20% FAT + Sweetened Condensed Milk Mating Weaning 6 week Gestation & Lactation 6 week Gestation & Lactation DAMS OFFSPRING Day 30 Day 90 Characterization of pre-Obese Characterization of Obese Phenotype Phenotype
Maternal Characteristics Page 5 A B 40 40 Calorific intake (kcal animal -1 day -1 ) Calorific intake (kcal animal -1 day -1 ) 50 50 * * * * * * ** ** 30 30 40 40 Body weight (g) Body weight (g) 20 20 30 30 10 10 20 20 0 0 10 10 -5-4-3-2-1 -5-4-3-2-1 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 18 18 20 20 -5-4-3-2-1 -5-4-3-2-1 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 18 18 20 20 Time (weeks) Time (weeks) Time (Gestational days) Time (Gestational days) Time (weeks) Time (weeks) Time (Gestational days) Time (Gestational days) C D E 0.3 0.3 7 7 7 6 6 6 BAT mass (g) BAT mass (g) WAT mass (g) WAT mass (g) WAT mass (g) *** *** 5 5 5 0.2 0.2 * * 4 4 4 3 3 3 0.1 0.1 2 2 2 1 1 1 Control Dam Obese Dam 0 0 0 0 0 CONTROL CONTROL OBESE OBESE Control Control Control Obese Obese Obese Control Control Obese Obese Lean mass (g) Lean mass (g) 20.5 20.5 18.8 18.8 Fat mass (g) Fat mass (g) 3.6 3.6 9.8 9.8 % Fat % Fat 14.8 14.8 34.4 34.4
Maternal Characteristics Page 6 * * 6 6 Late gestation Concentrations Concentrations 5 5 4 4 3 3 *** *** 2 2 1 1 0 0 Triglyceride Triglyceride Cholesterol Cholesterol Glucose Glucose Insulin Insulin Leptin Leptin (mmol/L) (mmol/L) (mmol/L) (mmol/L) (10*mmol/L) (10*mmol/L) (100*pmol/L) (100*pmol/L) (100*pg/L) (100*pg/L) Weaning 6 6 Concentrations Concentrations 5 5 *** *** 4 4 *** *** 3 3 ** ** 2 2 ** ** 1 1 0 0 Triglyceride Triglyceride Cholesterol Cholesterol Glucose Glucose Insulin Insulin Leptin Leptin (mmol/L) (mmol/L) (mmol/L) (mmol/L) (10*mmol/L) (10*mmol/L) (100*pmol/L) (100*pmol/L) (10*pg/L) (10*pg/L)
Offspring Phenotype: hyperphagia and adult obesity Page 7 A MALE MALE FEMALE FEMALE * * * * 120 120 120 120 120 120 (kcal animal-1 week-1) (kcal animal-1 week-1) (kcal animal-1 week-1) Calorific intake Calorific intake Calorific intake 100 100 100 100 100 100 80 80 80 80 80 80 60 60 60 60 60 60 40 40 40 40 40 40 2 2 2 4 4 4 6 6 6 8 8 8 10 10 10 12 12 12 14 14 14 16 16 16 18 18 18 20 20 20 22 22 22 2 2 2 4 4 4 6 6 6 8 8 8 10 10 10 12 12 12 14 14 14 16 16 16 18 18 18 20 20 20 22 22 22 Time (weeks) Time (weeks) Time (weeks) Time (weeks) Time (weeks) Time (weeks) B 35 35 35 35 35 35 35 35 * * * * * * * * body weight (g) body weight (g) body weight (g) body weight (g) 30 30 30 30 30 30 30 30 25 25 25 25 25 25 25 25 20 20 20 20 20 20 20 20 22 22 Fat mass (mg/g BW) Fat mass (mg/g BW) *** *** 16 16 Fat mass (mg/g BW) Fat mass (mg/g BW) 15 15 15 15 20 20 15 15 15 15 14 14 ** ** 18 18 12 12 16 16 10 10 10 10 10 10 10 10 14 14 10 10 12 12 8 8 5 5 5 5 5 5 5 5 10 10 6 6 OC OC OO OO OC OC OO OO 0 0 0 0 0 0 0 0 0 0 0 0 5 5 5 5 10 10 10 10 15 15 15 15 20 20 20 20 25 25 25 25 0 0 0 0 5 5 5 5 10 10 10 10 15 15 15 15 20 20 20 20 25 25 25 25 Time (weeks) Time (weeks) Time (weeks) Time (weeks) Time (weeks) Time (weeks) Time (weeks) Time (weeks) 6 6 6 C Concentrations Concentrations Concentrations 5 5 5 4 4 4 *** *** *** 3 3 3 * * * 2 2 2 ** ** ** 1 1 1 0 0 0 Triglyceride Triglyceride Triglyceride Cholesterol Cholesterol Cholesterol Glucose Glucose Glucose Insulin Insulin Insulin Leptin Leptin Leptin (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (10*mmol/L) (10*mmol/L) (10*mmol/L) (100*pmol/L) (100*pmol/L) (100*pmol/L) (pg/L) (pg/L) (pg/L) D 6 6 6 Concentrations Concentrations Concentrations 5 5 5 * * * 4 4 4 3 3 3 2 2 2 * * * ** ** ** 1 1 1 * * * 0 0 0 Triglyceride Triglyceride Triglyceride Cholesterol Cholesterol Cholesterol Glucose Glucose Glucose Insulin Insulin Insulin Leptin Leptin Leptin (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (10*mmol/L) (10*mmol/L) (10*mmol/L) (100*pmol/L) (100*pmol/L) (100*pmol/L) (pg/L) (pg/L) (pg/L)
Summary (1): Maternal Obesity in rodents Maternal Phenotype High-fat high-sugar diet leads to hypercalorific intake & maternal obesity. Hyperleptinaemia, hyperinsulinaemia in pregnancy Further hyperglycaemia, dyslipidaemia during suckling. Offspring Phenotype Increased birthweight & weight at weaning (milk content) Hyperphagic and hypertensive from weaning Abdominal obesity, hyperleptinaemia, dyslipidaemia, hyperinsulinaemia and reduced muscle mass by 3 months. Hyperglycaemia (type 2 DM) and fatty liver disease (NAFLD) by 6 months.
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