Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond: Fig. 1.

Given the multiple differences between mice and men, it was once thought that mice could not be used to model atherosclerosis, principally a human disease. Apolipoprotein E-deficient (apoEKO) mice have convincingly changed this view, and the ability to model human-like plaques in these mice has provided scientists a platform to study multiple facets of atherogenesis and to explore potential therapeutic interventions. In addition to its well-established role in lipoprotein metabolism, recent observations of reduced adiposity and improved glucose homeostasis in apoEKO mice suggest that apoE may also play a key role in energy metabolism in peripheral organs, including adipose tissue. Finally, along with apoEKO mice, knockin mice expressing human apoE isoforms in place of endogenous mouse apoE have provided insights into how quantitative and qualitative genetic alterations interact with the environment in the pathogenesis of complex human diseases

Association of cholesterol and oxysterols in adipose tissue with obesity and metabolic syndrome traits

Adipose tissue stores a substantial amount of body cholesterol in humans. Obesity is associated with decreased concentrations of serum cholesterol. During weight gain, adipose tissue dysfunction might be one of the causes of metabolic syndrome. The aim of this study is to evaluate cholesterol storage and oxidized metabolites in adipose tissue and their relationship with metabolic clinical characteristics

Identification of novel targets in adipose tissue involved in non-alcoholic fatty liver disease progression

Obesity is a major risk factor for the development of Nonalcoholic fatty liver disease (NAFLD). We hypothesize that a dysfunctional subcutaneous white adipose tissue (scWAT) may lead to an accumulation of ectopic fat in the liver. Our aim was to investigate the molecular mechanisms involved in the causative role of scWAT in NALFD progression. We performed a RNA-sequencing analysis in a discovery cohort (n = 45) to identify genes in scWAT correlated with fatty liver index, a qualitative marker of liver steatosis. We then validated those targets in a second cohort (n = 47) of obese patients who had liver biopsies available. Finally, we obtained scWAT mesenchymal stem cells (MSCs) from 13 obese patients at different stages of NAFLD and established in vitro models of human MSC (hMSC)-derived adipocytes. We observed impaired adipogenesis in hMSC-derived adipocytes as liver steatosis increased, suggesting that an impaired adipogenic capacity is a critical event in the development of NAFLD. Four genes showed a differential expression pattern in both scWAT and hMSC-derived adipocytes, where their expression paralleled steatosis degree: SOCS3, DUSP1, SIK1, and GADD45B. We propose these genes as key players in NAFLD progression. They could eventually constitute potential new targets for future therapies against liver steatosis

Apo E polymorphism associates with body fatness independently of plasma lipids in middle age men -the aragon workers health study

Background: The apolipoprotein E (APOE) gene is polymorphic, encoding one of 3 common alleles (e2, e3, e4) produced from combinations of 2 non-synonymous SNPs (rs429358 and rs7412). APOE plays an important role controlling plasma lipids but its association with adipocyte functionality and body fatness remains to be determined. Methods: We analyzed fasting plasma lipids and genotyped the two main APOE-SNPs (rs429358 and rs7412), both located in the fourth exon of the APOE, in 4660 Caucasian middle-aged men free of cardiovascular disease. Results: The rs7412 SNP, which determines the APOE2 isoform, was significantly associated with Body Mass Index (BMI) and Waist Girth (WG) in a multivariate model accounting for age, smoking status and plasma lipids. BMI and WG were highest in TT homozygotes and lowest in CC homozygotes. This effect was independent of the rs429358 SNP, which failed to show any association with the BMI and WG variables. The odds ratio of being obese (BMI.30) for individuals carrying the APOe2 allele, present in 14% of the cohort and defined by the rs7412 SNP, was also significant in this multivariate model, with an OR of 1.27 (95% CI: 1.01–1.59). Conclusions: This study provides an evidence of a lipid-independent association between the APOE SNP rs7412 and body fatness surrogates, BMI and WG, in a large cohort of middle-aged males

Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond

Given the multiple differences between mice and men, it was once thought that mice could not be used to model atherosclerosis, principally a human disease. Apolipoprotein E-deficient (apoEKO) mice have convincingly changed this view, and the ability to model human-like plaques in these mice has provided scientists a platform to study multiple facets of atherogenesis and to explore potential therapeutic interventions. In addition to its well-established role in lipoprotein metabolism, recent observations of reduced adiposity and improved glucose homeostasis in apoEKO mice suggest that apoE may also play a key role in energy metabolism in peripheral organs, including adipose tissue. Finally, along with apoEKO mice, knockin mice expressing human apoE isoforms in place of endogenous mouse apoE have provided insights into how quantitative and qualitative genetic alterations interact with the environment in the pathogenesis of complex human diseases

Gene Therapy Based on Mesenchymal Stem Cells Derived from Adipose Tissue for the Treatment of Obesity and Its Metabolic Complications

Obesity is a highly prevalent condition often associated with dysfunctional adipose tissue. Stem cell-based therapies have become a promising tool for therapeutic intervention in the context of regenerative medicine. Among all stem cells, adipose-derived mesenchymal stem cells (ADMSCs) are the most easily obtained, have immunomodulatory properties, show great ex vivo expansion capacity and differentiation to other cell types, and release a wide variety of angiogenic factors and bioactive molecules, such as growth factors and adipokines. However, despite the positive results obtained in some pre-clinical studies, the actual clinical efficacy of ADMSCs still remains controversial. Transplanted ADMSCs present a meager rate of survival and proliferation, possibly because of the damaged microenvironment of the affected tissues. Therefore, there is a need for novel approaches to generate more functional ADMSCs with enhanced therapeutic potential. In this context, genetic manipulation has emerged as a promising strategy. In the current review, we aim to summarize several adipose-focused treatments of obesity, including cell therapy and gene therapy. Particular emphasis will be given to the continuum from obesity to metabolic syndrome, diabetes, and underlying non-alcoholic fatty liver disease (NAFLD). Furthermore, we will provide insights into the potential shared adipocentric mechanisms involved in these pathophysiological processes and their remediation using ADMSCs

The Aragon Workers Health Study (AWHS) baseline characteristics.

<p>The Aragon Workers Health Study (AWHS) baseline characteristics.</p

Apolipoprotein E genotypes and means (SD) of circulating lipids in the Aragon Workers Health Study.

<p>*P-values for the difference within each SNP including age as covariate.</p><p>Apolipoprotein E genotypes and means (SD) of circulating lipids in the Aragon Workers Health Study.</p

Association between individual APOE SNPs, rs429358 and rs7412, with body fatness.

<p>Means and standard error of the means (SEM) of Body Mass Index (BMI) and waist girth values, adjusted for age, smoking status and lipid values.</p><p>Association between individual APOE SNPs, rs429358 and rs7412, with body fatness.</p