Systems pharmacology of adiposity reveals inhibition of EP300 as a common therapeutic mechanism of caloric restriction and resveratrol for obesity

Abstract

Both caloric restriction (CR) and resveratrol (RSV) have beneficial effects on obesity. However, the biochemical pathways that mediate these beneficial effects might be complex and interconnected and have not been fully elucidated. To reveal the common therapeutic mechanism of CR and RSV, we performed a comparative transcriptome analysis of adipose tissues from diet-induced obese (DIO) zebrafish and obese humans. We identified nine genes in DIO zebrafish and seven genes in obese humans whose expressions were regulated by CR and RSV. Although the gene lists did not overlap except for one gene, the gene ontologies enriched in the gene lists were highly overlapped, and included genes involved in adipocyte differentiation, lipid storage and lipid metabolism. Bioinformatic analysis of cis-regulatory sequences of these genes revealed that their transcriptional regulators also overlapped, including EP300, HDAC2, CEBPB, CEBPD, FOXA1, and FOXA2. We also identified 15 and 46 genes that were dysregulated in the adipose tissue of DIO zebrafish and obese humans, respectively. Bioinformatics analysis identified EP300, HDAC2, and CEBPB as common transcriptional regulators for these genes. EP300 is a histone and lysyl acetyltransferase that modulates the function of histone and various proteins including CEBPB, CEBPD, FOXA1, and FOXA2. We demonstrated that adiposity in larval zebrafish was significantly reduced by C646, an inhibitor of EP300 that antagonizes acetyl-CoA. The reduction of adiposity by C646 was not significantly different from that induced by RSV or co-treatment of C646 and RSV. These results indicate that the inhibition of EP300 might be a common therapeutic mechanism between CR and RSV in adipose tissues of obese individuals.

Diurnal rhythms in the white adipose tissue transcriptome are disturbed in obese individuals with type 2 diabetes compared with lean control individuals

“…Among the potential upstream regulators with increased activity that may represent adipocyte treatment targets was SYVN1, which has a role in the regulation of endoplasmic reticulum protein degradation, and was shown to increase body weight by interacting with peroxisome proliferatoractivated receptor γ, coactivator 1β (PGC1β) in mice [48]. Potential upstream regulators with decreased activity were FOXA1, a transcription factor that has been implicated in the development of obesity [49], and the energy sensor AMPK. These potential treatment targets warrant further investigation, since our study design cannot distinguish whether altered expression levels are due to obesity or type 2 diabetes.…”

Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review

“…Obesity has become a severe health issue globally. Resveratrol significantly decreased the body weight and fat mass in mice with HFD-induced obesity, showing reduced leptin and lipids in plasma, modulated metabolism of glucose and insulin, and restored immune dysfunction, via the activation of PI3K/SIRT1 and Nrf2 signaling pathways, and the inhibition of transcriptional regulators (e.g., EP300 gene), which are involved in the differentiation of adipocytes as well as lipid storage and metabolism [95,96]. Moreover, besides a significant dose-dependent decrease of weight gain and lipid deposition in the liver and adipose tissues of HFD-induced obese mice, low concentrations of resveratrol (1-10 µM) suppressed adipogenic differentiation in pre-adipocytes, downregulated the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and perilipin protein in differentiated adipocytes, and inhibited TNF-α-induced lipolysis in mature adipocytes [97].…”

Efficacy of an orlistat‐resveratrol combination for weight loss in subjects with obesity: A randomized controlled trial

“…This reduction in body weight and BMI was accompanied by preservation of lean mass. Orlistat inactivates gastric and pancreatic lipases, reducing fat absorption and, thus, total calorie intake , and resveratrol activates cellular pathways involved in lipid utilization and energy expenditure in metabolically active tissues . Both compounds have been used to manage body weight in subjects who have obesity ; however, we observed that the synergic activity of the O‐R combination enhanced their beneficial effects, resulting in a higher percentage of body weight loss.…”

“…In vitro and in vivo studies have demonstrated that resveratrol acts directly on adipose tissue, decreasing adiposity during obesity through a mechanism similar to that activated by calorie restriction . Moreover, the anti‐obesity action of resveratrol also involves modulation of lipid metabolism in the liver and skeletal muscle, preventing lipid accumulation and enhancing fatty acid oxidation .…”