Proteomics Analysis of Human Obesity Reveals the Epigenetic Factor HDAC4 as a Potential Target for Obesity

Abstract

Sedentary lifestyle and excessive energy intake are prominent contributors to obesity; a major risk factors for the development of insulin resistance, type 2 diabetes and cardiovascular diseases. Elucidating the molecular mechanisms underlying these chronic conditions is of relevant importance as it might lead to the identification of novel anti-obesity targets. The purpose of the current study is to investigate differentially expressed proteins between lean and obese subjects through a shot-gun quantitative proteomics approach using peripheral blood mononuclear cells (PBMCs) extracts as well as potential modulation of those proteins by physical exercise. Using this approach, a total of 47 proteins showed at least 1.5 fold change between lean and obese subjects. In obese, the proteomic profiling before and after 3 months of physical exercise showed differential expression of 38 proteins. Thrombospondin 1 (TSP1) was among the proteins that were upregulated in obese subjects and then decreased by physical exercise. Conversely, the histone deacetylase 4 (HDAC4) was downregulated in obese subjects and then induced by physical exercise. The proteomic data was further validated by qRT-PCR, Western blot and immunohistochemistry in both PBMCs and adipose tissue. We also showed that HDAC4 levels correlated positively with maximum oxygen consumption (VO2 Max) but negatively with body mass index, percent body fat, and the inflammatory chemokine RANTES. In functional assays, our data indicated that ectopic expression of HDAC4 significantly impaired TNF-α-dependent activation of NF-κB, establishing thus a link between HDAC4 and regulation of the immune system. Together, the expression pattern of HDAC4 in obese subjects before and after physical exercise, its correlation with various physical, clinical and metabolic parameters along with its inhibitory effect on NF-κB are suggestive of a protective role of HDAC4 against obesity. HDAC4 could therefore represent a potential therapeutic target for the control and management of obesity and presumably insulin resistance.

Significance of CXCL12 in Type 2 Diabetes Mellitus and Its Associated Complications

“…The finding that a homozygous form of the SDF-1 3′A genotype is more frequent in T2D patients with proliferative retinopathy by Djuric [61]. Due to the fact that reports exist to show that this genetic variation increases the CXCL12 protein expression, this may meant that some of circulatory CXCL12 is secreted by PBMCS as the main source of this chemokine which was previously supported by several lines of evidences [62,63].…”

The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction: A Scientific Statement From the American Heart Association

“…The investigators found that among obese patients, there were increases in proinflammatory signals such as thrombospondin-1, a glycoprotein with proinflammatory and antiangiogenic properties. 127 On the other hand, histone deacetylase 4, an epigenetic antiinflammatory regulatory protein, was downregulated among obese patients. Intriguingly, these abnormal protein profiles, although suggesting an overactive inflammatory response, could be significantly reversed by exercise.…”

The Omics of Obesity

“…Sixteen-week old wild type (WT) and the leptin-deficient ob/ob mice, a genetic model of obesity that becomes overweight due to hyperphagia, were studied for their hepatic lipidomic profiles using non-targeted analysis via ultra-performance liquid chromatography (UPLC) coupled to quadrupole mass spectrometry (MS). The obese mice had an increased level of TAG and DAG lipid species in the liver as well as diacylphosphoglycerols and ceramide species, while there was a decrease in the sphingomyelins [50]. Using high-fat feeding to induce obesity, Turner et al performed a tissue lipid profiling study over a course of time of the high-fat dietary intervention [51].…”