Adiponectin and fetal programming

Summary

Principal Investigator: Jianhua Shao
Abstract: DESCRIPTION (provided by applicant): The prevalence of childhood obesity in the United States has tripled to 17% since 1980. Recent human and animal studies have demonstrated that maternal obesity increases the risk of offspring obesity, which indicate that fetal programming plays an important role in the obesity epidemic. The ultimate goal of this project is to elucidate the underlying mechanisms through which maternal obesity alters the intrauterine metabolic environment and programs offspring obesity. Adiponectin is an adipocyte-derived hormone that sensitizes insulin and regulates energy homeostasis. Blood adiponectin levels of newborns are 4-7 folds higher than that in maternal circulation. In contrast to adults, neonatal blood adiponectin concentrations positively correlate with infant body weight. Studies have shown that adiponectin enhances adipocyte differentiation, inhibits lipolysis and increases adipose tissue mass in mice. Consistent with human studies, our preliminary mouse studies showed that maternal obesity significantly increased fetal body weight. Although there was no change in placenta mass, remarkably increased lipoprotein lipase (LPL) gene expressions were observed in placentas from obese dams. Blood adiponectin concentrations were also significantly increased in fetuses from obese dams. Importantly, adiponectin gene deletion attenuated maternal obesity-induced high birthweight and placental LPL expression. Furthermore, mouse embryonic fibroblasts (MEFs) from obese dams exhibited remarkable high efficiency in adipocyte differentiation, while protein levels of transcription factor C/EBP2 was significantly elevated. A methylation region was identified in the promoter of C/EBP2 gene. The methylation levels of C/EBP2 promoter were significantly low in MEFs from obese dams. Adiponectin treatment increased C/EBP2 gene expression while reduced its DNA methylation in MEFs. Therefore, we hypothesize that elevated fetal adiponectin mediates maternal obesity-induced high birthweight and offspring obesity by increasing placental fatty acid transport and reducing C/EBP2 gene methylation. Studies of Specific Aim 1 are designed to determine the role of fetal adiponectin in maternal obesity-induced high birthweight and adult obesity using a series of mouse models, which take the advantage of the in-transportablility of adiponectin through placenta and create a unique model with intrauterine adiponectin deficiency. Specific Aim 2 will study the effects of fetal adiponectin on placental fatty acid transport. A placenta-specific LPL knockout mouse model will be employed to verify the role of placental LPL in maternal obesity-induced high birthweight and adiponectin-enhanced fetal lipid accumulation. By using high fat diet-induced obese dams and adiponectin knockout mice, Specific Aim 3 will study the effects of maternal obesity and the role of fetal adiponectin on C/EBP2 promoter methylation. Overall, this project will investigate the role of fetal adiponectin in maternal obesity-programmed offspring adiposity. These studies will reveal new pathways of fetal programming that will lead to new therapeutic approaches to stop the vicious cycle of maternal-offspring obesity.
Funding Period: 2012-02-22 - 2017-01-31
more information: NIH RePORT

Top Publications

  1. pmc Adiponectin enhances mouse fetal fat deposition
    Liping Qiao
    Department of Pediatrics, University of California San Diego, La Jolla, California, USA
    Diabetes 61:3199-207. 2012
  2. pmc Adiponectin and energy homeostasis
    Bonggi Lee
    Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0983, La Jolla, CA, 92093, USA
    Rev Endocr Metab Disord 15:149-56. 2014
  3. pmc Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice
    Liping Qiao
    Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0983, La Jolla, CA, 92093, USA
    Diabetologia 57:1027-36. 2014
  4. pmc C/EBPα regulates macrophage activation and systemic metabolism
    Bonggi Lee
    Department of Pediatrics, University of California San Diego, La Jolla, California
    Am J Physiol Endocrinol Metab 306:E1144-54. 2014
  5. pmc Intermittent cold exposure enhances fat accumulation in mice
    Hyung Sun Yoo
    Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America
    PLoS ONE 9:e96432. 2014

Research Grants

Detail Information

Publications5

  1. pmc Adiponectin enhances mouse fetal fat deposition
    Liping Qiao
    Department of Pediatrics, University of California San Diego, La Jolla, California, USA
    Diabetes 61:3199-207. 2012
    ..Together, our study indicates that adiponectin enhances fetal fat deposition and plays an important role in maternal obesity-induced high birth weight...
  2. pmc Adiponectin and energy homeostasis
    Bonggi Lee
    Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0983, La Jolla, CA, 92093, USA
    Rev Endocr Metab Disord 15:149-56. 2014
    ..In this review, we summarize the progress of research about 1) the causal relationship of adiposity, energy intake, and adiponectin gene expression; and 2) the regulatory role of adiponectin in systemic energy metabolism. ..
  3. pmc Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice
    Liping Qiao
    Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0983, La Jolla, CA, 92093, USA
    Diabetologia 57:1027-36. 2014
    ..The main objective of this study was to investigate whether or not adiponectin regulates brown adipose tissue (BAT) activation and thermogenesis...
  4. pmc C/EBPα regulates macrophage activation and systemic metabolism
    Bonggi Lee
    Department of Pediatrics, University of California San Diego, La Jolla, California
    Am J Physiol Endocrinol Metab 306:E1144-54. 2014
    ..Together, these results imply that C/EBPα is required for macrophage activation, which plays an important role in maintaining skeletal muscle energy metabolism. ..
  5. pmc Intermittent cold exposure enhances fat accumulation in mice
    Hyung Sun Yoo
    Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America
    PLoS ONE 9:e96432. 2014
    ..Together, our results indicate that despite enhancing BAT recruitment, ICE in mice increases fat accumulation by stimulating de novo lipogenesis. ..

Research Grants30

  1. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  2. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  3. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..