Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr mice

Abstract

Metabolic syndrome is a collection of abnormalities, including obesity, dyslipidemia, hypertension, and insulin resistance, all of which contribute to the development of type 2 diabetes and atherosclerosis. Insulin resistance, dyslipidemia, and atherosclerosis are amplifi ed by the development of a chronic low-grade infl ammatory response ( 1 ). In insulin-resistant states, monocyte-derived macrophages infi ltrate visceral adipose tissue, resulting in proinfl ammatory cytokine synthesis, either from adipocytes or resident macrophages, which impairs insulin sensitivity ( 2, 3 ). Administration of diets rich in saturated fats to Ldlr Ϫ / Ϫ mice represents a model with many characteristics of the metabolic syndrome ( 4-6 ). Recent studies in this Abstract Obesity-associated chronic infl ammation contributes to metabolic dysfunction and propagates atherosclerosis. Recent evidence suggests that increased dietary cholesterol exacerbates infl ammation in adipose tissue and liver, contributing to the proatherogenic milieu. The ability of the citrus fl avonoid naringenin to prevent these cholesterol-induced perturbations is unknown. To assess the ability of naringenin to prevent the amplifi ed infl ammatory response and atherosclerosis induced by dietary cholesterol, male Ldlr ؊ / ؊ mice were fed either a cholesterol-enriched high-fat or low-fat diet supplemented with 3% naringenin for 12 weeks. Naringenin, through induction of hepatic fatty acid (FA) oxidation and attenuation of FA synthesis, prevented hepatic steatosis, hepatic VLDL overproduction, and hyperlipidemia induced by both cholesterol-rich diets. Naringenin attenuated hepatic macrophage infi ltration and infl ammation stimulated by dietary cholesterol. Insulin resistance, adipose tissue expansion, and infl ammation were alleviated by naringenin. Naringenin attenuated the cholesterol-induced formation of both foam cells and expression of infl ammatory markers in peritoneal macrophages. Naringenin signifi cantly decreased atherosclerosis and inhibited the formation of complex lesions, which was associated with normalized aortic lipids and a reversal of aortic infl ammation. We demonstrate that in mice fed cholesterolenriched diets, naringenin attenuates peripheral and systemic infl ammation, leading to protection from atherosclerosis. These studies offer a therapeutically relevant alternative for the prevention of cholesterol-induced metabolic dysregulation. -Assini, J. M., E. E. Mulvihill, B. G. Sutherland, D. E. Telford, C. G. Sawyez, S. L. Felder, S. Chhoker, J. Y. Edwards, R. Gros, and M. W. Huff. Naringenin prevents cholesterol-induced systemic infl ammation, This work was supported by Heart and Stroke Foundation of Ontario (HSFO)Grants , Canadian Foundation for Innovation and Ontario Research Fund (to R.G.), a HSFO Masters Award (to J.M.A.), and a Canadian Institutes of Health Research-Canada Graduate Scholarship Doctoral Award (to E.E.M.). 14 December 2012. Published, JLR Papers in Press, December 19, 2012 DOI 10.1194 Abbreviations: ABCG, ATP-binding...

Extracts of <i>citrus Sudachi</i> peel attenuate body weight gain in C57BL/6 mice fed a high-fat diet

“…Naringenin has been shown to have antioxidant, anti-inflammatory and anti-proliferative activities (11). Furthermore, naringenin improves obesity-related diseases in mice (12,13). The results of these studies and our study using sudachitin suggest that citrus fruit peel contains useful components for an anti-obesitic effect.…”

PPARδ activation attenuates hepatic steatosis in Ldlr mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity

“…In addition to unregulated lipogenesis, decreased fat oxidation exacerbates hepatic lipid accumulation during insulin resistance (8)(9)(10). The AMP-activated protein kinase (AMPK) controls cellular and whole-body energy metabolism ( 11,12 ).…”

“…Blood samples were obtained as previously described ( 9,32 ). Body weights and caloric consumption were determined as described previously ( 8 ).…”

“…Mice were provided free access to food and water and acclimatized to the system for 24 h prior to a 24 h data collection period, during which data on O 2 consumption and CO 2 production were collected every 10 min. EE and RER were calculated as described previously ( 8 ). (Neomarkers, Fremont, CA), stripped, and reprobed with either the ␤ -actin antibody for the postnuclear fraction or a polyclonal lamin A/C antibody (Santa Cruz Biotechnology, Santa Cruz, CA) for the nuclear fraction ( 41 ).…”

“…In the induction/intervention studies (week 11), analyses of energy expenditure (EE) and respiratory exchange ratio (RER) were performed using the Oxymax Comprehensive Lab Animal Monitoring System (CLAMS, Columbus Instruments, Columbus, OH) ( 8 ). Mice were provided free access to food and water and acclimatized to the system for 24 h prior to a 24 h data collection period, during which data on O 2 consumption and CO 2 production were collected every 10 min.…”