Maternal obesity, AMPK and fetal brown adipogenesis Min Du Developmental Biology Group, Washington State University, Pullman, WA 99164 ABSTRACT SIGNIFICANCE: Up to 35% of pregnant American women are clinically obese, and additional women are with gestational diabetes, conditions which affect fetal development with long-term consequences for offspring health, including pre-disposition to obesity and type 2 diabetes. The underlying mechanisms remain poorly defined. RATIONALE: Brown adipose tissue (BAT) and beige adipocytes burn lipids to generate heat; thus, enhancing BAT function prevents obesity, diabetes and metabolic disorders. We found that maternal obesity (MO) impairs fetal BAT development, which has long-term negative impacts on BAT and beige adipocyte thermogenesis in adults. Fetal BAT development involves both brown/beige adipogenesis, which requires PRDM16, an indispensable transcription factor. We found that MO inhibits AMP-activated protein kinase (AMPK) and reduces Prdm16 expression through blocking DNA demethylation in its promoter. We also found that ?-ketoglutarate (aKG) is a rate limiting factor for both histone and DNA demethylations, and histone modifications guide DNA demethylation. In addition, MO and AMPK inhibition increase cytosolic acetyl-CoA (ACoA) concentration, which should promote white adipogenesis. Because beige and white adipogenesis share a common pool of progenitor cells, we HYPOTHESIZE: AMPK inhibition due to MO attenuates aKG-mediated histone demethylation in the Prdm16 promoter, coupled with elevated ACoA level, compromising brown/beige in favor of white adipogenesis during fetal development.
SPECIFIC AIMS : 1) examine aKG in linking MO to impaired histone demethylation in the Prdm16 promoter during fetal BAT development; 2) study elevated ACoA due to MO in enhancing white adipogenesis within fetal BAT; and 3) explore the mediatory role of AMPK in linking MO, aKG/ACoA ratio and brown/beige versus white adipogenesis. INNOVATION: Proposed studies are based on our recent discovery that AMPK/aKG axis regulates DNA demethylation of the Prdm16 promoter, a process required for brown/beige adipogenesis, and will continue to explore the role of MO in histone demethylations, which governs locus-specific DNA demethylation; we will further explore the mediatory role of AMPK in determining brown/beige versus white adipogenesis affected by MO. ENVIRONMENT: All methodologies required have been established in our laboratory. The Developmental Biology Group and the Center for Reproductive Biology provide excellent academic environment, and animal and laboratory facilities. IMPACT: Proposed studies will demonstrate AMPK and aKG/ACoA ratio as key factors regulating fetal BAT development impaired due to MO, which will make it possible to use available anti-diabetic drugs, known activators of AMPK, to prevent impairment of fetal BAT development of obese mothers. Given the recent demonstration of abundant existence of brown/beige adipocytes in human adults and the long-term impact of fetal BAT and beige adipocyte development on their thermogenic function in adults, interventions to improve fetal brown/beige adipose development will help the increasing number of obese pregnant women and women with gestational diabetes to deliver healthy children.

Public Health Relevance

Brown/beige adipocytes have high efficiency in burning lipids and glucose, and are highly effective in reducing obesity and metabolic dysfunction. We propose that maternal obesity reduces brown/beige adipocyte formation via inhibiting AMPK, a key enzyme regulating cell metabolism, and AMPK is an effective target promoting brown/beige adipogenesis and thus reducing obesity and metabolic diseases in offspring born to obese mothers.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Bremer, Andrew
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington State University
Veterinary Sciences
Earth Sciences/Resources
United States
Zip Code
Zhao, Liang; Zou, Tiande; Gomez, Noe Alberto et al. (2018) Raspberry alleviates obesity-induced inflammation and insulin resistance in skeletal muscle through activation of AMP-activated protein kinase (AMPK) ?1. Nutr Diabetes 8:39
Zou, Tiande; Wang, Bo; Yang, Qiyuan et al. (2018) Raspberry promotes brown and beige adipocyte development in mice fed high-fat diet through activation of AMP-activated protein kinase (AMPK) ?1. J Nutr Biochem 55:157-164
Wang, B; Fu, Xing; Zhu, Mei-Jun et al. (2017) Retinoic acid inhibits white adipogenesis by disrupting GADD45A-mediated Zfp423 DNA demethylation. J Mol Cell Biol 9:338-349
Wang, Songbo; Liang, Xingwei; Yang, Qiyuan et al. (2017) Resveratrol enhances brown adipocyte formation and function by activating AMP-activated protein kinase (AMPK) ?1 in mice fed high-fat diet. Mol Nutr Food Res 61:
Wang, Bo; Wang, Zhixiu; de Avila, Jeanene M et al. (2017) Moderate alcohol intake induces thermogenic brown/beige adipocyte formation via elevating retinoic acid signaling. FASEB J 31:4612-4622
Wang, Bo; Zhang, Faya; Zhang, Hui et al. (2017) Alcohol intake aggravates adipose browning and muscle atrophy in cancer-associated cachexia. Oncotarget 8:100411-100420
Wang, Bo; Fu, Xing; Liang, Xingwei et al. (2017) Maternal Retinoids Increase PDGFR?+Progenitor Population and Beige Adipogenesis in Progeny by Stimulating Vascular Development. EBioMedicine 18:288-299
Griner, John D; Rogers, Carl J; Zhu, Mei-Jun et al. (2017) Lysyl oxidase propeptide promotes adipogenesis through inhibition of FGF-2 signaling. Adipocyte 6:12-19
Wang, Bo; Fu, Xing; Liang, Xingwei et al. (2017) Retinoic acid induces white adipose tissue browning by increasing adipose vascularity and inducing beige adipogenesis of PDGFR?+ adipose progenitors. Cell Discov 3:17036
Zhao, Junxing; Yang, Qiyuan; Zhang, Lupei et al. (2017) AMPK?1 deficiency suppresses brown adipogenesis in favor of fibrogenesis during brown adipose tissue development. Biochem Biophys Res Commun 491:508-514

Showing the most recent 10 out of 38 publications