Dietary cholesterol worsens adipose tissue macrophage accumulation and atherosclerosis in obese LDL receptor-deficient mice.
OBJECTIVE
Chronic systemic inflammation accompanies obesity and predicts development of cardiovascular disease. Dietary cholesterol has been shown to increase inflammation and atherosclerosis in LDL receptor-deficient (LDLR(-/-)) mice. This study was undertaken to determine whether dietary cholesterol and obesity have additive effects on inflammation and atherosclerosis.


RESULTS
LDLR(-/-) mice were fed chow, high-fat, high-carbohydrate (diabetogenic) diets without (DD) or with added cholesterol (DDC) for 24 weeks. Effects on adipose tissue, inflammatory markers, and atherosclerosis were studied. Despite similar weight gain between DD and DDC groups, addition of dietary cholesterol increased insulin resistance relative to DD. Adipocyte hypertrophy, macrophage accumulation, and local inflammation were observed in intraabdominal adipose tissue in DD and DDC, but were significantly higher in the DDC group. Circulating levels of the inflammatory protein serum amyloid A (SAA) were 4.4-fold higher in DD animals and 15-fold higher in DDC animals than controls, suggesting chronic systemic inflammation. Hepatic SAA mRNA levels were similarly elevated. Atherosclerosis was increased in the DD-fed animals and further increased in the DDC group.


CONCLUSIONS
Obesity-induced macrophage accumulation in adipose tissue is exacerbated by dietary cholesterol. These local inflammatory changes in adipose tissue are associated with insulin resistance, systemic inflammation, and increased atherosclerosis in this mouse model.
Subramanian
Savitha
S
Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-6426, USA.
Han
Chang Yeop
CY
Chiba
Tsuyoshi
T
McMillen
Timothy S
TS
Wang
Shari A
SA
Haw
Antonio
A
Kirk
Elizabeth A
EA
O'Brien
Kevin D
KD
Chait
Alan
A
D050153:Abdominal Fat / Q000378:metabolism / Q000473:pathology; D017667:Adipocytes / Q000473:pathology; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism; D001483:Base Sequence; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000009:adverse effects*; D017931:DNA Primers / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D008264:Macrophages / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism
D002791:Cholesterol, Dietary; D017931:DNA Primers; D018836:Inflammation Mediators; D012333:RNA, Messenger; D011973:Receptors, LDL; D000685:Serum Amyloid A Protein