A Dysregulation in &lt;i&gt;CES1, APOE&lt;/i&gt; and Other Lipid Metabolism-Related Genes Is Associated to Cardiovascular Risk Factors Linked to Obesity

dOptimal lipid storage and mobilization are essential for efficient adipose tissue. Nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR␥) regulates adipocyte differentiation and lipid deposition, but its role in lipolysis and dysregulation in obesity is not well defined. This investigation aimed to understand the molecular impact of dysfunctional PPAR␥ on the lipolytic axis and to explore whether these defects are also confirmed in common forms of human obesity. For this purpose, we used the P465L PPAR␥ mouse as a model of dysfunctional PPAR␥ that recapitulates the human ppar␥ mutation (P467L). We demonstrated that defective PPAR␥ impairs catecholamine-induced lipolysis. This abnormal lipolytic response is exacerbated by a state of positive energy balance in leptin-deficient ob/ob mice. We identified the protein kinase A (PKA) network as a PPAR␥-dependent regulatory node of the lipolytic response. Specifically, defective PPAR␥ is associated with decreased basal expression of prkaca (PKAcat␣) and d-akap1, the lipase genes Pnplaz (ATGL) and Lipe (HSL), and lipid droplet protein genes fsp27 and adrp in vivo and in vitro. Our data indicate that PPAR␥ is required for activation of the lipolytic regulatory network, dysregulation of which is an important feature of obesity-induced insulin resistance in humans. P eroxisome proliferator-activated receptor ␥ (PPAR␥) is an important regulator of adipogenesis and lipogenesis. However, accumulating evidence suggests that PPAR␥ may also coordinate the balance between fat deposition and mobilization through its effects on lipolysis. To elucidate the relevance of PPAR␥ for the lipolytic response, we took advantage of a rare ppar␥ mutation that causes lipodystrophy and severe metabolic disturbances in humans (34). According to the crystal structure, the P467L PPAR␥ mutation is situated in helix 12, an important region for ligand binding and PPAR transactivation (4). Characterization of patients with genetic defects in ppar␥ has revealed metabolic inflexibility in their adipose tissue, resulting from impaired fat sequestration to lipid droplets (LDs) and decreased nonesterified fatty acid mobilization (34, 37). However, the dissection of the PPAR␥-dependent mechanisms that impair the flux of lipids in and out of adipose tissue has proven difficult, given the small number of patients affected by these mutations. In this respect, a humanized mouse model harboring a homologous mutation (P465L) offers clear experimental advantages.Initial analysis of the humanized P465L PPAR␥ mice revealed that, unlike humans, these mice exhibited normal amounts of adipose tissue and were unexpectedly insulin sensitive (13). This apparent paradox was partially resolved when the P465L PPAR␥ mouse was crossed onto an ob/ob background. Under this condition of extreme positive energy balance, the P465L PPAR␥ mutant mouse recapitulated the human phenotype characterized by insulin resistance, reduced fat mass, hypertension, and dyslipidemia. In fact, the same deleterious, synergistic dysmet...

show abstract

“…6A). Our data are in agreement with previous data identifying D-AKAP1 as a potentially downregulated gene in the human obesity data set (12,22).…”

Section: Discussionsupporting

confidence: 93%

Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility

Rodríguez‐Cuenca

Carobbio

Velagapudi

et al. 2012

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…In the current study, carboxylesterase 1 (CES1) which catalyses the hydrolysis of cholesterol esters and triacylglycerols [26], and albumin which is known to have an esterase activity [27] had a greater abundance in adipose tissue of the BQ pigs compared with LW pigs. Similarly, up-regulation of CES1 transcript in human subcutaneous adipose tissues is positively related to greater adiposity [28]. Together, our results suggest the existence of a metabolic cycle where triacylglycerols are synthesized and degraded at a greater rate in adipose tissue of fat compared with lean pigs.…”

Section: Discussionsupporting

confidence: 57%

“…Importantly, at the onset of the growing period, BQ animals already exhibited enlarged adipocytes when compared with LW pigs. Because adipocyte hypertrophy has been described to participate to altered insulin sensitivity [29], one could thus speculate that an active cycle of triacylglycerols synthesis and degradation occurred in fat pigs to protect cells against fatty acids overload, which would otherwise inhibit insulin signaling [28].…”

Section: Discussionmentioning

confidence: 99%

A comparison of subcutaneous adipose tissue proteomes in juvenile piglets with a contrasted adiposity underscored similarities with human obesity

Gondret

Guével

Com

et al. 2012

Journal of Proteomics

View full text Add to dashboard Cite

“…Two genes (CTTN, PRKAR2B) were also over-expressed (FDR < 0.10) in baseline mRNA levels among the women who were subsequently categorized as "high" versus "low" responders. Protein kinase, PRKAR2B, is involved in lipolysis and was previously shown to be down-regulated in subcutaneous adipose tissue in obese compared to lean individuals (Marrades et al, 2010). Among post-menopausal women, one of the two genes identified with lower expression in high compared to low responders was LRRFIP1, which has been implicated in regulating platelet responsiveness (Goodall et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Genomic Signatures of a Global Fitness Index in a Multi‐Ethnic Cohort of Women

Rampersaud

Nathanson

Farmer

et al. 2013

Annals of Human Genetics

View full text Add to dashboard Cite

SummaryThe rates of obesity and sedentary lifestyle are on a dramatic incline, with associated detrimental health effects among women in particular. Although exercise prescriptions are useful for overcoming these problems, success can be hampered by differential responsiveness among individuals in cardiovascular fitness indices (i.e. improvements in strength, lipids, VO 2 max). Genomic factors appear to play an important role in determining this inter-individual variation. We performed microarray analyses on mRNA in whole blood from 60 sedentary women from a multi-ethnic cohort who underwent 12 weeks of exercise, to identify gene subsets that were differentially expressed between individuals who experienced the greatest and least improvements in fitness. We identified 43 transcripts in 39 unique genes (FDR<10%; FC>1.5) whose expression increased the most in "high" versus "low" pre-menopausal female responders. These 39 genes were enriched in six biological pathways, including oxidative phosphorylation (p = 8.08 × 10 −3 ). Several of the 39 genes (i.e. TIGD7, UQCRH, PSMA6, WDR12, TFB2M, USP15) have previously reported associations with fitness-related phenotypes. In summary, we identified gene signatures based on mRNA analysis that define responsiveness to exercise in a largely minority-based female cohort. Importantly, this study validates several genes/pathways previously associated with exercise responsiveness and extends these findings with additional novel genes.

show abstract

A Dysregulation in <i>CES1, APOE</i> and Other Lipid Metabolism-Related Genes Is Associated to Cardiovascular Risk Factors Linked to Obesity

Cited by 54 publications

References 53 publications

Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility

Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility

A comparison of subcutaneous adipose tissue proteomes in juvenile piglets with a contrasted adiposity underscored similarities with human obesity

Genomic Signatures of a Global Fitness Index in a Multi‐Ethnic Cohort of Women

Contact Info

Product

Resources

About