stilbenes and Obesity--Morbid

Increased visceral fat, rather than subcutaneous fat, during the onset of obesity is associated with a higher risk of developing metabolic diseases. The inherent adipogenic properties of human adipose-derived stem cells (ASCs) from visceral depots are compromised compared with those of ASCs from subcutaneous depots, but little is known about the underlying mechanisms. Using ontological analysis of global gene expression studies, we demonstrate that many genes involved in retinoic acid (RA) synthesis or regulated by RA are differentially expressed in human tissues and ASCs from subcutaneous and visceral fat. The endogenous level of RA is higher in visceral ASCs; this is associated with upregulation of the RA synthesis gene through the visceral-specific developmental factor WT1. Excessive RA-mediated activity impedes the adipogenic capability of ASCs at early but not late stages of adipogenesis, which can be reversed by antagonism of RA receptors or knockdown of WT1. Our results reveal the developmental origin of adipocytic properties and the pathophysiological contributions of visceral fat depots.

Topics: Active Transport, Cell Nucleus; Adipogenesis; Adult Stem Cells; Bariatric Surgery; Benzoates; Cells, Cultured; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Ontology; Humans; Intra-Abdominal Fat; Middle Aged; Naphthalenes; Obesity, Morbid; Receptors, Retinoic Acid; Response Elements; RNA Interference; Signal Transduction; Stilbenes; Subcutaneous Fat, Abdominal; Tretinoin; Up-Regulation; WT1 Proteins

Alcoholic and nonalcoholic fatty liver disease (ALD and NAFLD) are the predominant causes of liver-related mortality in Western countries. We have shown that limiting classical (M1) Kupffer cell (KC) polarization reduces alcohol-induced liver injury. Herein, we investigated whether favoring alternatively activated M2 KCs may protect against ALD and NAFLD. Ongoing alcohol drinkers and morbidly obese patients, with minimal hepatic injury and steatosis, displayed higher hepatic expression of M2 genes, as compared to patients with more severe liver lesions; individuals with limited liver lesions showed negligible hepatocyte apoptosis but significant macrophage apoptosis. Experiments in mouse models of ALD or NAFLD further showed that BALB/c or resveratrol-treated mice fed alcohol or a high-fat diet displayed preponderant M2 KC polarization, M1 KC apoptosis, and resistance to hepatocyte steatosis and apoptosis, as compared to control C57BL6/J mice. In vitro experiments in isolated KC, peritoneal, and Raw264.7 macrophages demonstrated that M1 macrophage apoptosis was promoted by conditioned medium from macrophages polarized into an M2 phenotype by either interleukin (IL)4, resveratrol, or adiponectin. Mechanistically, IL10 released from M2 cells promoted M1 death, and anti-IL10 antibodies blunted the proapoptic effects of M2-conditioned media. IL10 secreted by M2 KCs promoted selective M1 death by a mechanism involving activation of arginase in high inducible nitric oxide synthase-expressing M1 KCs. In alcohol-exposed mice, neutralization of IL10 impaired M1 apoptosis.. These data uncover a novel mechanism regulating the M1/M2 balance that relies on apoptotic effects of M2 KCs towards their M1 counterparts. They suggest that promoting M2-induced M1 KC apoptosis might prove a relevant strategy to limit alcohol- and high fat-induced inflammation and hepatocyte injury.

Topics: Adult; Animals; Apoptosis; Arginase; Biomarkers; Diet, High-Fat; Enzyme Activation; Ethanol; Fatty Liver; Female; Humans; Interleukin-10; Kupffer Cells; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; Obesity, Morbid; Paracrine Communication; Resveratrol; Stilbenes

The SIRT1 enzyme is involved in adipose tissue (AT) lipolysis. FOXO1 is a protein that plays a significant role in regulating metabolism. Adiponectin is an adipokine, secreted by the AT, which has been considered to have an antiobesity function. PPARγ is one of the key actors in adipocytes differentiation. This study was undertaken to investigate whether resveratrol can regulate SIRT1, FOXO1, adiponectin, PPARγ1-3, and PPARβ/δ in human AT.. The effects of resveratrol were analyzed in freshly isolated adipocytes prepared from visceral fat tissue samples obtained during bariatric surgery. Genes messenger ribonucleic acid (mRNA) levels were determined by qRT-PCR.. Ours results show that resveratrol modulates the studied genes, increasing SIRT1 (p = 0.021), FOXO1 (p = 0.001), and adiponectin (p = 0.025) mRNA expression and decreasing PPARγ1-3 (p = 0.003) mRNA in human visceral adipocytes.. Resveratrol, in vitro and at low concentration, modulates genes that are related to lipid metabolism, possibly preventing metabolic disease in human visceral adipose tissue (VAT).

Topics: Adipocytes; Adiponectin; Adult; Down-Regulation; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Intra-Abdominal Fat; Lipid Metabolism; Lipid Regulating Agents; Obesity, Morbid; PPAR gamma; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirtuin 1; Stilbenes; Up-Regulation