Maternal obesity, AMPK and fetal brown adipogenesis

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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.