Vanessa DeClercq

Adipose Tissue: The Link Between Obesity and Cardiovascular Disease

The ever-increasing prevalence of cardiovascular disease (CVD) associated with obesity is linked through signaling pathways within adipose tissue. Adipose tissue functions as an endocrine organ, producing and secreting a variety of bioactive molecules. In obesity, the adipose tissue itself undergoes changes in cell size which alters its normal physiological function. Altered adipocyte function changes production and secretion of adipokines, such as leptin, adiponectin, angiotensinogen, plasminogen activator inhibitor-1, resistin, and several inflammatory molecules. Adipokines interact with other tissues and cells in the body, including many pathways linked to CVD. Future research in the area of obesity-related CVD requires further investigation into a combination of lifestyle and pharmacological therapies that alter adipokine production by reducing adipocyte size.

Modulation of lipid droplet size and lipid droplet proteins by trans-10,cis-12 conjugated linoleic acid parallels improvements in hepatic steatosis in obese, insulin-resistant rats.

The isomer-specific effects of conjugated linoleic acid (CLA) on hepatic steatosis were assessed in fa/fa Zucker rats, a model for insulin resistance and the metabolic syndrome. Eight weeks of feeding trans-10,cis-12 CLA significantly improved glucose tolerance without changing body weight or visceral adipose mass. The trans-10,cis-12 isomer was also associated with reduced liver lipid content, improved liver function and reduced inflammation; these effects were not observed in rats fed the cis-9,trans-11 CLA isomer. Reduced liver lipid content did not correlate with activation of AMP-activated protein kinase or suppressed activation of sterol-regulatory element binding protein-1, two key regulators of hepatic lipid metabolism. Interestingly, rats fed cis-9,trans-11 CLA had fewer cytoplasmic lipid droplets in hepatocytes compared to rats fed control diet, but these droplets were larger in size. Conversely, fa/fa rats fed the trans-10,cis-12 CLA isomer had greater numbers of hepatic lipid droplets that were smaller in size, resulting in overall lower total lipid within these droplets. Changes in lipid droplets were associated with lower hepatic levels of PERILIPIN-2 (formerly known as adipophilin) in rats fed trans-10,cis-12 CLA, whereas amounts of other members of the PERILIPIN family of lipid droplet proteins were unaffected by dietary CLA. However, CLA isomers differentially affected the subcellular localization of these proteins. Treatment of H4IIE rat hepatoma cells with CLA isomers neither prevented nor reversed, but rather induced cytoplasmic lipid droplet formation, suggesting that the anti-steatotic effects of trans-10,cis-12 CLA are likely indirect and potentially mediated via increased lipid utilization by peripheral tissues.

Paradoxical effects of fenofibrate and nicotinic acid in apo E-deficient mice.

Atherosclerosis is a complex vascular disease initiated by abnormal accumulation of plasma lipoproteins in the subendothelial space. Elevated levels of plasma triglycerides (TG) and low-density lipoprotein (LDL)-cholesterol as well as low concentrations of high-density lipoprotein (HDL) play a causal role in the development and progression of atherosclerotic lesions. We have shown that apolipoprotein E-deficient (apo E-KO) mice have elevated triglyceride levels plus diminished HDL concentrations. Drugs such as fenofibrate and nicotinic acid are well known to reduce TG and increase HDL levels in humans. In this study, we investigated the beneficial effects of fenofibrate and niacin on lipid profile and atherogenesis in apo E-KO mice and their wild-type counterparts. Animals were fed with a cholesterol-enriched diet supplemented with fenofibrate (0.1% wt/wt, n = 8) or nicotinic acid (0.5% wt/wt, n = 8) for 14 weeks. Body weights were recorded weekly, and plasma lipid profiles were determined at 4-week intervals. The hearts and aortas were collected and fixed for histologic and morphometric evaluations of atherosclerotic lesions. Fenofibrate treatment in apo E-KO mice paradoxically increased total cholesterol and TG by 65% and 44%, respectively, and decreased HDL-cholesterol levels by 35% as compared with controls. Similar effects of fenofibrate on cholesterol levels, but not on TG concentrations, were observed in C57BL/6 mice. Fenofibrate-treated mice had lower body weight as compared with controls. Niacin had no effect on body weight gain but failed to decrease TG or to increase HDL levels in either apo E-KO mice or their wild-type counterparts. Neither fenofibrate nor niacin significantly influenced atherogenesis in apo E-KO mice as compared with controls. In conclusion, this study shows that neither niacin nor fenofibrate has beneficial lipid-modifying and antiatherosclerosis activities in mice. Identification of mechanisms underlying paradoxical effects of fenofibrate on lipoprotein metabolisms in apo E-KO mice merits further investigation.

Conjugated linoleic acid improves blood pressure by increasing adiponectin and endothelial nitric oxide synthase activity

Conjugated linoleic acid (CLA) has been reported to reduce blood pressure in obese insulin-resistant rats, but its mechanism of action has not been identified. The objective of this study was to determine whether CLA isomers can reduce obesity-related hypertension in the fa/fa Zucker rat in relation to adiponectin production and endothelial nitric oxide synthase (eNOS) activation. Obese fa/fa Zucker rats were randomly assigned to one of four groups: (1) cis-9,trans-11-CLA, (2) trans-10,cis-12 (t10,c12)-CLA, (3) control or (4) captopril. After 8 weeks, systolic blood pressure increased 30% in control obese rats. This increase was attenuated 11%-13% in the t10,c12-CLA isomer and captopril groups, respectively. The t10,c12-CLA isomer concurrently elevated adiponectin levels in both plasma and adipose tissue and increased phosphorylated eNOS in adipose tissue as well as the aorta. Although a direct effect of CLA was not observed in cultured endothelial cells, direct adiponectin treatment increased phosphorylation of eNOS. Endothelial nitric oxide synthase phosphorylation was also increased in adipose of fa/fa Zucker rats infused with adiponectin in parallel with improvements in blood pressure. Our results suggest that the t10,c12-CLA isomer attenuates development of obesity-related hypertension, at least in part, by stimulating adiponectin production, which subsequently activates vascular eNOS.

Modulation of Cardiovascular Function by Adipokines

Cardiovascular disease (CVD) and associated risk factors such as obesity remain at the forefront of health concerns. Adipose tissue has been well established as an endocrine organ that becomes dysfunctional with increased adipose tissue mass. The secretion of several adipokines is altered in subjects with abdominal adiposity and these changes to the endocrine balance may contribute to increased CVD risk. The identification and characterization of disease-specific proteins within the adipose tissue offers a novel therapeutic target for prevention or treatment of cardiovascular complications. This review will discuss the latest developments on therapeutic targets within the context of adipokines, such as adiponectin, C1q/ tumor necrosis factor (TNF) related proteins (CTRPs), visfatin, vaspin, chemerin and omentin, and their involvement in obesity-related cardiovascular complications.

Isomer-specific effects of conjugated linoleic acid on blood pressure, adipocyte size and function.

Obesity-related hypertension may be caused by activation of the local adipose tissue renin-angiotensin system, resulting in exaggerated production of the vasoconstrictor angiotensin II. Additionally, secretion of adiponectin from adipose tissue, which prevents endothelial dysfunction, is altered in obesity. Consumption of conjugated linoleic acid (CLA) has been shown to modulate cytokine release from adipocytes and positively influence blood pressure in younger rats, but its physiological actions in older models with established hypertension and isomer-specific effects on adipocyte size remain to be determined. Therefore, we investigated the effects of CLA isomers on adipocyte size in relation to blood pressure and adipokine production by hypertrophic adipocytes in older fa/fa Zucker rats with established hypertension. fa/fa Zucker rats were fed with cis(c)9, trans(t)11-CLA or t10, c12-CLA isomers for 8 weeks and compared with lean and obese rats fed with the control diet. Blood pressure and adipocyte size were subsequently measured. Collagenase-isolated adipocytes were size-separated and angiotensinogen and adiponectin protein levels quantified by Western blotting. The t10, c12-CLA group had reduced blood pressure, fewer large adipocytes and increased serum adiponectin. Angiotensinogen was present at higher levels in the large adipocytes, whereas the converse was observed for adiponectin. The beneficial effects of the t10, c12-CLA isomer on blood pressure and adipocyte size in vivo may be due to its ability to reduce the number of large adipocytes, which alters the levels of vasoactive molecules secreted from adipose tissue.

Trans-10,cis-12-conjugated linoleic acid worsens renal pathology and alters cyclooxygenase derived oxylipins in obesity-associated nephropathy

Dietary conjugated linoleic acid (CLA) reduces indicators of early renal disease progression and the associated elevated cyclooxygenase (COX) levels in young obese rats with obesity-associated nephropathy (OAN). Therefore, renal function and injury and COX and its metabolites were assessed in obese fa/fa Zucker rats with more advanced renal disease. Obese rats at 16 weeks of age were provided with either cis(c)9, trans(t)11 (fa/fa-9,11) or t10,c12 (fa/fa-10,12) CLA for 8 weeks, and compared to lean (lean-CTL) and obese (fa/fa-CTL) rats provided the control diet without CLA. Obese rats displayed significantly reduced renal function and increased renal injury compared to lean rats. In the obese rat groups, glomerular hypertrophy was reduced in both CLA-supplemented groups. While all other measures of renal function or injury were not different in fa/fa-9,11 compared to fa/fa-CTL rats, the fa/fa-10,12 rats had greater renal hypertrophy, glomerular fibrosis, fibrosis, tubular casts and macrophage infiltration compared to the fa/fa-CTL and fa/fa-9,11 groups. The fa/fa-10,12 group also had elevated levels of renal COX1, which was associated with increased levels of two oxylipins produced by this enzyme, 6-keto-prostaglandin F(1α), and thromboxane B₂. Renal linoleic acid and its lipoxygenase products also were lower in obese compared to lean rats, but CLA supplementation had no effect on these or any other lipoxygenase oxylipins. In summary, supplementation with c9,t11 CLA did not improve more advanced OAN and t10,c12 CLA worsened the renal pathology. Altered production of select COX1 derived oxylipins was associated with the detrimental effect of the t10,c12 isomer.