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.
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.
|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