Role of NAD+ Signaling through Poly(ADP-ribose) Polymerase 1 in Adipogenesis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 649-677-Adipocyte Biology
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-660
Keun Woo Ryu*, Xin Luo and W Lee Kraus
UT Southwestern Medical Center, Dallas, TX
Adipose tissue plays a central role in the development of obesity and insulin resistance. Adipogenesis is tightly regulated by the sequential regulation of a set of key adipogenic transcription factors. Although the major transcription cascades and protein factors that regulate this process have been identified, our understanding of the precise molecular mechanisms of adipogenesis, particularly during the early stages of differentiation, is incomplete.

Recent studies have shown that enzymes involved in nuclear nicotinamide adenine dinucleotide (NAD+) signaling pathways play important roles in adipogenesis. Poly(ADP-ribose) polymerase 1 (PARP-1) is a major nuclear NAD+ consuming enzyme which catalyze the covalent attachment of poly(ADP-ribose) (PAR) chains on target proteins. PARP-1 has been shown to play key roles in gene regulation during a wide array of physiological processes, including adipogenesis, but molecular mechanism remains unclear.

To elucidate the transcriptional regulatory functions of NAD+ signaling in adipogenesis, we are using a well-established model of adipogenesis: the murine 3T3-L1 preadipocyte cell line. Using a variety of cell-based and molecular assays, we have found that (1) poly(ADP- ribosyl)ation activity of PARP-1fluctuate during adipogenesis, (2) RNAi-mediated depletion of PARP-1 alters adipogenesis-related gene expression and modulates the 3T3-L1 cell differentiation program, (3) reducing nuclear NAD+ pools by RNAi depleted nicotinamide mononucleotide adenyltransferase 1 (NMNAT-1), a nuclear NAD+ synthase which plays a key role in supplying NAD+ for PARP-1, downregulates PARP-1 enzymatic activity enhances the differentiation of 3T3-L1 cells, and (4) PARP-1 bind to the genomic regions of regulated adipogenic target genes in a pattern that partially overlaps with the peroxisome proliferator activated receptor (PPAR), a key transcriptional regulator of adipogenesis. We are now conducting additional experiments to elucidate the exact role and regulatory mechanisms of NAD+ signaling in adipogenesis.

Collectively, these studies will help to elucidate the adipogenic regulatory network, as well as shed light on the mechanisms by how nuclear NAD+ signal can regulate transcription to affect cell proliferation and differentiation. These studies have the potential to reveal new aspects of the pathogenesis of obesity and the potential therapeutic benefits of inhibitors for the NAD+ dependent enzymes.

Nothing to Disclose: KWR, XL, WLK

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Sources of Research Support: This work is supported by grants from the NIH/NIDDK to W.L.K.