TY - JOUR
T1 - Plasma insulin levels predict atherosclerotic lesion burden in obese hyperlipidemic mice
AU - Gruen, Marnie L.
AU - Saraswathi, Viswanathan
AU - Nuotio-Antar, Alli M.
AU - Plummer, Michelle R.
AU - Coenen, Kimberly R.
AU - Hasty, Alyssa H.
N1 - Funding Information:
This work was supported by Pilot and Feasibility Awards to AH Hasty from the Diabetes Research and Training Center at Vanderbilt University (DK20593) and the Clinical Nutrition Research Unit (DK26657). A.H. Hasty is also supported by the American Heart Association (0330011N) and the American Diabetes Association (1-04-JF-20). The lipid profiles were performed in the Lipid Core Laboratory of the Mouse Metabolic Phenotyping Center at Vanderbilt University (U24 DK59637). Plasma insulin levels were determined in the Hormone Assay Core Laboratory (DK20593). We acknowledge the expertise of Vanderbilt's Immunohistochemistry Core funded by U24 DK59637, P30 CA68485-08, and P30 AR41943. We would like to thank Robin Atkinson, Carla Harris, and Shan Zhou for their technical assistance. We would also like to thank Bonnie Wasson as well as Drs. Sergio Fazio and Larry Swift for their careful review and insightful comments regarding this manuscript.
PY - 2006/5
Y1 - 2006/5
N2 - Despite a clear association between obesity, insulin resistance and atherosclerosis in humans, to date, no animal models have been described in which insulin resistance is associated with atherosclerotic lesion burden. Using two mouse models of obesity-induced hyperlipidemia:leptin deficient (ob/ob) mice on an apolipoprotein E deficient (apoE-/-) or low density lipoprotein receptor deficient (LDLR-/-) background, we sought to determine metabolic parameters most closely associated with atherosclerotic lesion burden. Total plasma cholesterol (TC) levels in ob/ob;apoE-/- mice and ob/ob;LDLR-/- mice were indistinguishable (682 ± 48 versus 663 ± 16, respectively). Analysis of lipoprotein profiles showed that cholesterol was carried primarily on VLDL in the ob/ob;apoE-/- mice and on LDL in the ob/ob;LDLR-/- mice. Plasma triglycerides (TG) were 55% lower (P < 0.001), non-esterified fatty acids (NEFA) were 1.5-fold higher (P < 0.01), and insulin levels were 1.7-fold higher (NS) in ob/ob;apoE-/- mice compared to ob/ob;LDLR-/- mice. Other parameters such as body weight, fat pad weight, and glucose levels were not different between the groups. Aortic sinus lesion area of ob/ob;apoE-/- mice was increased 3.2-fold above ob/ob;LDLR-/- mice (102,455 ± 8565 μm2/section versus 31,750 ± 4478 μm2/section, P < 0.001). Lesions in ob/ob;apoE-/- mice were also more complex as evidenced by a 7.7-fold increase in collagen content (P < 0.001). Atherosclerotic lesion area was positively correlated with body weight (P < 0.005), NEFA (P = 0.007), and insulin (P = 0.002) levels in the ob/ob;LDLR-/- mice and with insulin (P = 0.014) in the ob/ob;apoE-/- mice. In contrast, lesion burden was neither associated with TC and TG, nor with individual lipoprotein pools, in either animal model. These data provide a direct demonstration of the pathophysiologic relevance of hyperinsulinemia, NEFA, and increased body weight to atherosclerotic lesion formation.
AB - Despite a clear association between obesity, insulin resistance and atherosclerosis in humans, to date, no animal models have been described in which insulin resistance is associated with atherosclerotic lesion burden. Using two mouse models of obesity-induced hyperlipidemia:leptin deficient (ob/ob) mice on an apolipoprotein E deficient (apoE-/-) or low density lipoprotein receptor deficient (LDLR-/-) background, we sought to determine metabolic parameters most closely associated with atherosclerotic lesion burden. Total plasma cholesterol (TC) levels in ob/ob;apoE-/- mice and ob/ob;LDLR-/- mice were indistinguishable (682 ± 48 versus 663 ± 16, respectively). Analysis of lipoprotein profiles showed that cholesterol was carried primarily on VLDL in the ob/ob;apoE-/- mice and on LDL in the ob/ob;LDLR-/- mice. Plasma triglycerides (TG) were 55% lower (P < 0.001), non-esterified fatty acids (NEFA) were 1.5-fold higher (P < 0.01), and insulin levels were 1.7-fold higher (NS) in ob/ob;apoE-/- mice compared to ob/ob;LDLR-/- mice. Other parameters such as body weight, fat pad weight, and glucose levels were not different between the groups. Aortic sinus lesion area of ob/ob;apoE-/- mice was increased 3.2-fold above ob/ob;LDLR-/- mice (102,455 ± 8565 μm2/section versus 31,750 ± 4478 μm2/section, P < 0.001). Lesions in ob/ob;apoE-/- mice were also more complex as evidenced by a 7.7-fold increase in collagen content (P < 0.001). Atherosclerotic lesion area was positively correlated with body weight (P < 0.005), NEFA (P = 0.007), and insulin (P = 0.002) levels in the ob/ob;LDLR-/- mice and with insulin (P = 0.014) in the ob/ob;apoE-/- mice. In contrast, lesion burden was neither associated with TC and TG, nor with individual lipoprotein pools, in either animal model. These data provide a direct demonstration of the pathophysiologic relevance of hyperinsulinemia, NEFA, and increased body weight to atherosclerotic lesion formation.
KW - Apolipoprotein E
KW - Atherosclerosis
KW - Insulin
KW - Leptin
KW - Low density lipoprotein receptor
KW - Non-esterified fatty acids
KW - Obesity
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U2 - 10.1016/j.atherosclerosis.2005.07.007
DO - 10.1016/j.atherosclerosis.2005.07.007
M3 - Article
C2 - 16102772
AN - SCOPUS:33645883532
SN - 0021-9150
VL - 186
SP - 54
EP - 64
JO - Atherosclerosis
JF - Atherosclerosis
IS - 1
ER -