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Journal of Biomolecular Screening
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SIRT1 Modulating Compounds from High-Throughput Screening as Anti-Inflammatory and Insulin-Sensitizing Agents

Vasantha M. Nayagam

S*BIO PTE LTD, Singapore

Xukun Wang

S*BIO PTE LTD, Singapore

Yong Cheng Tan

S*BIO PTE LTD, Singapore

Anders Poulsen

S*BIO PTE LTD, Singapore

Kee Chuan Goh

S*BIO PTE LTD, Singapore

Tony Ng

S*BIO PTE LTD, Singapore

Haishan Wang

S*BIO PTE LTD, Singapore

Hong Yan Song

S*BIO PTE LTD, Singapore

Binhui Ni

S*BIO PTE LTD, Singapore

Michael Entzeroth

S*BIO PTE LTD, Singapore

Walter Stünkel

S*BIO PTE LTD, Singapore

The nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase SIRT1 has been linked to fatty acid metabolism via suppression of peroxysome proliferator-activated receptor gamma (PPAR-{gamma}) and to inflammatory processes by deacetylating the transcription factor NF-{kappa}B. First, modulation of SIRT1 activity affects lipid accumulation in adipocytes, which has an impact on the etiology of a variety of human metabolic diseases such as obesity and insulin-resistant diabetes. Second, activation of SIRT1 suppresses inflammation via regulation of cytokine expression. Using high-throughput screening, the authors identified compounds with SIRT1 activating and inhibiting potential. The biological activity of these SIRT1-modulating compounds was confirmed in cell-based assays using mouse adipocytes, as well as human THP-1 monocytes. SIRT1 activators were found to be potent lipolytic agents, reducing the overall lipid content of fully differentiated NIH L1 adipocytes. In addition, the same compounds have anti-inflammatory properties, as became evident by the reduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-{alpha}). In contrast, a SIRT1 inhibitory compound showed a stimulatory activity on the differentiation of adipocytes, a feature often linked to insulin sensitization.

Key Words: SIRT1 • small-molecule activators • HTS • adipocyte differentiation assay

This version was published on December 1, 2006

Journal of Biomolecular Screening, Vol. 11, No. 8, 959-967 (2006)
DOI: 10.1177/1087057106294710
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