Our longterm goal is to elucidate how maternal obesity alters the intrauterine metabolic environment and programs offspring obesity. Adiponectin is an adipocyte-secreted hormone with a predominant function in maintaining energy homeostasis. During late pregnancy, maternal adiponectin levels decrease steadily, while fetal adiponectin levels increase rapidly. Adiponectin cannot pass through the placenta barrier. At delivery, a huge difference (~4-7-fold) in blood adiponectin levels between fetal and maternal blood exists. We call this difference the maternal-fetal adiponectin differential (MFAD). In contrast to adults, neonatal blood adiponectin levels are positively correlated with anthropometric parameters of adiposity. Adiponectin enhances lipid accumulation in adipocytes and increase fat tissue mass in mice. Our preliminary study showed that maternal obesity increases fetal mouse fat tissue mass with a significant elevation of adiponectin in fetal blood. However, in adiponectin gene knockout (Adipoq-/-) mice, maternal obesity failed to increase fetal body weight and fat tissue mass, which suggests that adiponectin plays an important role in fetal fat deposition. Using another fetal mouse model with controlled maternal adiponectin levels, we further studied the regulatory effects of adiponectin on fetal lipid metabolism. We found that Adipoq-/+ fetuses have significantly higher levels of: 1) body fat;2) liver triglycerid content and expression of de novo lipogenic genes and 3) lipoprotein lipase (LPL) in fat tissue, compared with Adipoq-/- fetuses. Therefore, we hypothesize that during late gestation;the MFAD coordinates both maternal and fetal lipid metabolism, and enhances fetal fat deposition by increasing fetal hepatic de novo lipogenesis and lipid accumulation. Maternal obesity further increases the MFAD, which induces more fetal fat deposition. A series of in vivo studies will be carried out using mouse models with various levels of the MFAD.
Specific aim 1 will compare the adiposity of offspring from infancy to adulthood who are either exposed in utero or not to the MFAD. The role of increased MFAD in maternal obesity-enhanced fetal fat deposition will also be studied.
Specific Aim 2 is designed to determine whether maternal obesity induces fetal liver de novo lipogenesis, and to examine the regulatory effects of adiponectin on fetal liver de novo lipogenesis. Two studies will be carried out in Specific Aim 3 to investigate if elevated fetal adiponectin stimulates triglyceride hydrolysis and fatty acid uptake in fetal fat tissues. The role of LPL in these processes will be studied using inducible adipocyte-specific LPL knockout mice. The findings of this project should identify adiponectin as a key hormone that regulates the intrauterine metabolic environment favoring fetal fat deposition via opposite changes of adiponectin levels in maternal and fetal circulation. Importantly, this project will significantly improve our understanding of maternal obesity-induced offspring adiposity.

Public Health Relevance

This project will investigate the role of the maternal-fetal adiponectin differential (MFAD) in fetal fat deposition and maternal obesity-programmed offspring adiposity. The designed studies will reveal new mechanisms of fetal lipid metabolism and may lead to new therapeutic approaches to stop the maternal- offspring obesity vicious cycle.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK095132-01A1
Application #
8446106
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Silva, Corinne M
Project Start
2012-09-30
Project End
2016-07-31
Budget Start
2012-09-30
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$329,375
Indirect Cost
$116,875
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Qiao, Liping; Lee, Samuel; Nguyen, Amanda et al. (2018) The Regulatory Effects of Brown Adipose Tissue Thermogenesis on Maternal Metabolic Adaptation, Placental Efficiency, and Fetal Growth in Mice. Am J Physiol Endocrinol Metab :
Qiao, Liping; Wattez, Jean-Sebastien; Lee, Samuel et al. (2017) Adiponectin Deficiency Impairs Maternal Metabolic Adaptation to Pregnancy in Mice. Diabetes 66:1126-1135
Qiao, Liping; Wattez, Jean-Sebastien; Lee, Samuel et al. (2016) Knockout maternal adiponectin increases fetal growth in mice: potential role for trophoblast IGFBP-1. Diabetologia 59:2417-2425
Qiao, Liping; Guo, Zhuyu; Bosco, Chris et al. (2015) Maternal High-Fat Feeding Increases Placental Lipoprotein Lipase Activity by Reducing SIRT1 Expression in Mice. Diabetes 64:3111-20
Lee, Bonggi; Qiao, Liping; Kinney, Brice et al. (2014) Macrophage depletion disrupts immune balance and energy homeostasis. PLoS One 9:e99575
Lee, Bonggi; Qiao, Liping; Lu, Min et al. (2014) C/EBP? regulates macrophage activation and systemic metabolism. Am J Physiol Endocrinol Metab 306:E1144-54
Yoo, Hyung Sun; Qiao, Liping; Bosco, Chris et al. (2014) Intermittent cold exposure enhances fat accumulation in mice. PLoS One 9:e96432
Qiao, Liping; Yoo, Hyung sun; Bosco, Chris et al. (2014) Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice. Diabetologia 57:1027-36
Lee, Bonggi; Shao, Jianhua (2014) Adiponectin and energy homeostasis. Rev Endocr Metab Disord 15:149-56