Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr−/− mice

Abstract

Obesity and its associated metabolic dysfunction and cardiovascular disease risk represent a leading cause of adult morbidity worldwide. Currently available pharmacological therapies for obesity have had limited success in reversing existing obesity and metabolic dysregulation. Previous prevention studies demonstrated that the citrus flavonoids, naringenin and nobiletin, protect against obesity and metabolic dysfunction in mice fed a high-fat cholesterol-containing (HFHC) diet. However, their effects in an intervention model are unknown. In this report, we show that, in mice with diet-induced obesity, citrus flavonoid supplementation to a HFHC diet reversed existing obesity and adipocyte size and number through enhanced energy expenditure and increased hepatic fatty acid oxidation. Caloric intake was unaffected and no evidence of white adipose tissue browning was observed. Reversal of adiposity was accompanied by improvements in hyperlipidemia, insulin sensitivity, hepatic steatosis, and a modest reduction in blood monocytes. Together, this resulted in atherosclerotic lesions that were unchanged in size, but characterized by reduced macrophage content, consistent with a more stable plaque phenotype. These studies further suggest potential therapeutic utility of citrus flavonoids, especially in the context of existing obesity, metabolic dysfunction, and cardiovascular disease.

Naringenin Supplementation to a Chow Diet Enhances Energy Expenditure and Fatty Acid Oxidation, and Reduces Adiposity in Lean, Pair‐Fed Ldlr−/− Mice

“…Furthermore, other therapeutics that work by promoting increased energy expenditure do so by enhancing the thermogenic capacity of brown or beige adipose tissue without effect on food intake. The results of the present studies and our previous studies suggest that it is unlikely that naringenin works through either of these mechanisms . In lean chow‐fed mice, naringenin stimulated a small increase in food intake, rather than appetite suppression and no evidence of adipose tissue browning has been consistently detected.…”

“…Reduced food consumption persisted for four weeks before becoming isocaloric thereafter, resulting in non‐different overall food consumption between the two groups over 8 weeks (Figure G). In previous mouse regression studies, we observed a taste aversion during the transfer of mice from a high‐fat diet to a naringenin supplemented chow diet (data not shown), but not with a naringenin supplemented high‐fat diet, providing a likely explanation for the initial 4‐week decrease in caloric intake (Figure G).…”

“…This is the second study in which we observed an increase in food consumption, detected via metabolic cages, in naringenin‐treated mice . In both studies, the increase in food consumption was undetectable in standard caging because it was small (≈0.5 g day −1 ), although it was statistically significant.…”

“…Additionally, the effects of naringenin are not likely mediated through leptin, as naringenin maintains efficacy in the leptin‐deficient ob/ob mouse model of obesity . Furthermore, there is no evidence that naringenin induces browning of white adipose tissue …”

Naringenin attenuates non‐alcoholic fatty liver disease by down‐regulating the NLRP3/NF‐κB pathway in mice

“…In recent years, naringenin has been shown to exert a range of biological effects, including anti‐inflammation (Jin, Zeng, Zhang, Zhang, & Liang, ), anti‐oxidation (Zhao et al, ), hypolipidaemic effects (Mulvihill et al, ), immunoregulation (Zeng et al, ), and antineoplastic activity (Ke et al, ). Moreover, naringenin ameliorated obesity (Burke et al, ), metabolic syndrome (Alam et al, ), diabetes (Al‐Dosari, Ahmed, Al‐Rejaie, Alhomida, & Ola, ), and atherosclerosis (Mulvihill et al, , a). We have found that naringenin attenuated the hepatic lipid accumulation induced by a methionine‐choline deficient (MCD) diet in mice (Chen et al, ).…”