Cholesterol, a Cell Size-dependent Signal That Regulates Glucose Metabolism and Gene Expression in Adipocytes

Abstract

Enlarged fat cells exhibit modified metabolic capacities, which could be involved in the metabolic complications of obesity at the whole body level. We show here that sterol regulatory element-binding protein 2 (SREBP-2) and its target genes are induced in the adipose tissue of several models of rodent obesity, suggesting cholesterol imbalance in enlarged adipocytes. Within a particular fat pad, larger adipocytes have reduced membrane cholesterol concentrations compared with smaller fat cells, demonstrating that altered cholesterol distribution is characteristic of adipocyte hypertrophy per se. We show that treatment with methyl-␤-cyclodextrin, which mimics the membrane cholesterol reduction of hypertrophied adipocytes, induces insulin resistance. We also produced cholesterol depletion by mevastatin treatment, which activates SREBP-2 and its target genes. The analysis of 40 adipocyte genes showed that the response to cholesterol depletion implicated genes involved in cholesterol traffic (caveolin 2, scavenger receptor BI, and ATP binding cassette 1 genes) but also adipocyte-derived secretion products (tumor necrosis factor ␣, angiotensinogen, and interleukin-6) and proteins involved in energy metabolism (fatty acid synthase, GLUT 4, and UCP3). These data demonstrate that altering cholesterol balance profoundly modifies adipocyte metabolism in a way resembling that seen in hypertrophied fat cells from obese rodents or humans. This is the first evidence that intracellular cholesterol might serve as a link between fat cell size and adipocyte metabolic activity.Depending upon physiological or pathological conditions, lipid storage within the adipocyte may vary dramatically. This is particularly obvious in the obese state in which long term disequilibria in energy balance produces massive fat cell hypertrophy. Enlarged fat cells isolated from obese animals or humans exhibit modified metabolic properties and do not respond to hormones as do adipocytes from lean controls. For example, they develop insulin resistance (1-4) and produce increased quantities of secreted products such as leptin (1) or TNF-␣ 1 (5). These characteristics could be secondary to the hormonal and metabolic changes linked to obesity but could also be due to cell hypertrophy per se and thus be part of an adaptative mechanism in relationship with the status of energy stores in adipose tissue.Results from previous studies summarized below lead us to propose a role for cholesterol as a signaling molecule for fat cell hypertrophy. Cholesterol accumulates in large quantities in a non-esterified form within the adipocyte lipid droplet (for review see Ref. 6) proportionally to the triglyceride content (7,8). Several lines of evidence also suggest that concomitantly with the enlargement of the triglyceride stores, adipocyte cholesterol is redistributed from the plasma membrane to the lipid droplet. First, a decrease in plasma membrane cholesterol, associated with increased fluidity, has been reported in hypertrophied adipocytes (9). Second, plasma membran...

Alpha2delta-1 in SF1 + Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

“…Previous investigations indicate that alterations in cholesterol levels greatly affect adipocyte metabolic activity, which can ultimately have deleterious effects on insulin sensitivity (Le Lay et al, 2001). The failure of mutants to suppress lipolysis in the fed state was surprising because NE is known to stimulate this process, and mutants exhibited decreased sympathetic tone in WAT.…”

Dietary Cholesterol Promotes Adipocyte Hypertrophy and Adipose Tissue Inflammation in Visceral, but Not in Subcutaneous, Fat in Monkeys

“…Adipose tissue is the largest free cholesterol storage site in the body, and its cholesterol content affects gene expression and cellular function 20, 21 . However, it is unclear whether dietary cholesterol has a direct impact on adipocyte size, cholesterol content, and metabolic function.…”

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

“…Ontheotherhand,theimpairedcapacityforthesensingof thereplenishmentoftheirlipidstoresbyadipocyteswhichresultsinalterationsinthebufferingcapacityofadiposetissue has been suggested as the cause of metabolic syndrome [5,35].Basedonthefactthattriacylglycerolandcholesterolstorage are closely linked in adipocytes, it has been postulated thatcholesterolmightparticipateintheintracellularsensing forfatcellsizeandtriacylglycerolcontent [36,37].OurmicroarrayandRT-PCRanalysisshowedadown-regulationofthe APOEgeneinobesesubjects.Thisisinaccordancewiththe markedsuppressionofadiposeAPOEobservedinbothdietinduced and genetic (ob/ob mice) models of obesity [38]. A recent study evidenced that excess fat accumulation via an APOE-dependentpathway mightplayaroleindevelopment of the metabolic syndrome [39].…”