Location: Arkansas Children's Nutrition CenterTitle: Enhanced Adipogenic and Lipogenic Signatures in White Adipose Tissue of Offspring Exposed to Maternal Obesity In Utero ) Author
Submitted to: Endocrine Reviews
Publication Type: Abstract Only
Publication Acceptance Date: 3/1/2011
Publication Date: 6/15/2011
Citation: Shankar, K., Zhong, Y., Kang, P., Borengasser, S.J., Ronis, M.J., Badger, T.M. 2011. Enhanced Adipogenic and Lipogenic Signatures in White Adipose Tissue of Offspring Exposed to Maternal Obesity In Utero. Endocrine Reviews. 32:OR31-4. Interpretive Summary: Obesity in the mother during pregnancy significantly increases the risk of obesity in the offspring later-in-life. The mechanisms of such maternal obesity-induced programming of offspring metabolism remain unclear. Using a novel model of obesity in the rat, we previously demonstrated that offspring born to obese dams, gain greater body weight and accrue greater body fat, even while consuming the same amount of calories. In the present studies, we investigated whether exposure to maternal obesity influenced, the ability of fat tissue to synthesize new fat or develop specialized cells that accumulate fat (adipocytes). Using an approach that monitors the expression of all genes, our studies suggest that pathways regulating synthesis of new lipids in the fat tissue is strongly increased in offspring born to obese dams. Further, using techniques that test the ability of resident stem cells to develop into fat-accumulating cells, we demonstrate that offspring from obese dams have an increased propensity to make fat cells. These studies highlight novel mechanisms that may predispose offspring of obese dams to gaining greater fat mass in adulthood.
Technical Abstract: The risk of obesity throughout life is subject to programming beginning early in development. Exposure to maternal obesity (MO) at conception and during gestation increases the risk of obesity in adult-life. MO was induced in female Sprague Dawley rats via overfeeding of liquid diets (30% excess calories). Exposure to MO was restricted only to gestation by cross-fostering pups to lean dams at birth. Male offspring from obese rat dams gain greater body weight (p < 0.005), fat mass and develop insulin resistance when fed high-fat diets (45% fat). Hepatic microarray analyses at postnatal day (PND) 21 revealed a reprogramming of lipogenic and lipid degradative pathways following exposure to MO. In this report we examined global gene expression changes in white adipose tissue (WAT) using microarrays, adipogenic potential of WAT stromal vascular (SV) cells and expression of insulin signaling components. Exposure to maternal obesity altered the expression of 258 transcripts in the offspring WAT at PND21. In offspring of obese dams, the expression of lipogenic transcripts regulated by SREBP-1 was up-regulated akin to the regulation in the liver. Real-time PCR confirmed increased expression of FASN (3-fold), SREBP-1 (1.7-fold), ChREBP (2.5-fold), ACLY (4.5-fold), ELOVL6 (3.6-fold), and adiponutrin (4.8-fold) in the WAT of offspring of obese dams (p < 0.05). Protein expression of lipogenic proteins including SREBP-1, FASN and GAPDH was confirmed to be elevated in obese-dam offspring, along with increased levels of Glut-4 protein (1.5-fold, p<0.05), suggesting increased glucose flux into WAT adipocytes driving lipogenesis. However, insulin-signaling components (IR-beta, pAKT and total AKT, pAS160, pERK and total ERK) were unchanged in total WAT lysates. Protein expression of adipogenic factors PPAR-, C/EBP-alpha and C/EBP-beta was increased (p < 0.05) in WAT tissues of offspring from obese dams. Ex vivo adipogenic differentiation of SV cells using hormonal cocktail revealed greater differentiation in offspring of obese dams. This was confirmed by enhanced mRNA expression of leptin, FASN, FABP4 and PPAR- and decreased expression of Pref-1 mRNA in cells cultured from offspring of obese dams. Our findings suggest that MO programs increased adipogenic potential of SV cells combined with increased lipogenic gene expression in WAT. These changes may underlie greater adiposity and obesity risk in the offspring later in life.