Luteolin Attenuates Hepatic Steatosis and Insulin Resistance Through the Interplay Between the Liver and Adipose Tissue in Mice with Diet-Induced Obesity

Abstract

The flavonoid luteolin has various pharmacological activities. However, few studies exist on the in vivo mechanism underlying the actions of luteolin in hepatic steatosis and obesity. The aim of the current study was to elucidate the action of luteolin on obesity and its comorbidity by analyzing its transcriptional and metabolic responses, in particular the luteolin-mediated cross-talk between liver and adipose tissue in diet-induced obese mice. C57BL/6J mice were fed a normal, high-fat, and high-fat + 0.005% (weight for weight) luteolin diet for 16 weeks. In high fatfed mice, luteolin improved hepatic steatosis by suppressing hepatic lipogenesis and lipid absorption. In adipose tissue, luteolin increased PPARg protein expression to attenuate hepatic lipotoxicity, which may be linked to the improvement in circulating fatty acid (FA) levels by enhancing FA uptake genes and lipogenic genes and proteins in adipose tissue. Interestingly, luteolin also upregulated the expression of genes controlling lipolysis and the tricarboxylic acid (TCA) cycle prior to lipid droplet formation, thereby reducing adiposity. Moreover, luteolin improved hepatic insulin sensitivity by suppressing SREBP1 expression that modulates Irs2 expression through its negative feedback and gluconeogenesis. Luteolin ameliorates the deleterious effects of diet-induced obesity and its comorbidity via the interplay between liver and adipose tissue.Obesity is characterized by excessive fat accumulation and is associated with metabolic complications such as adiposity, dyslipidemia, insulin resistance, and steatohepatitis. The liver is one of the major organs responsible for metabolizing fats from the diet. Dysregulation of lipid metabolism in the liver induces abnormal accumulation of lipids and the subsequent formation of lipid droplets (LDs), known as hepatic steatosis. Hepatic steatosis is common in obese individuals and is strongly linked to insulin resistance (1,2). Adipose tissue is also a critical component of metabolic control and is an endocrine organ that secretes a number of adipokines known to mediate lipid metabolism, inflammation, and insulin sensitivity (3). Although the complex relationship between adiposity and hepatic steatosis has not been completely elucidated, dysregulation of lipid metabolism in the liver and adipose tissue may be involved in the pathogenesis of adiposity as well as its associated metabolic complications. One hypothesis for the explanation of a link between visceral adiposity and hepatic steatosis and insulin resistance is the "portal hypothesis," which proposes that a high rate of lipolysis of the visceral adipose tissue can lead to an increased delivery of free fatty acids (FFAs) to the liver via the portal vein, and that chronic exposure of the liver to elevated FFAs can promote hepatic steatosis and hepatic insulin resistance (4,5). However, it is still unclear how visceral adiposity is associated with hepatic steatosis and insulin resistance, in particular at the level of transcriptional changes that occur in ...

Soy Leaf Extract Containing Kaempferol Glycosides and Pheophorbides Improves Glucose Homeostasis by Enhancing Pancreatic β-Cell Function and Suppressing Hepatic Lipid Accumulation in db/db Mice

“…40 From these results, we found that the action mechanism of ESL in the liver and adipose tissue is similar to that of luteolin. In the same vein, we speculate that the improvement of glucose homeostasis by KGs in ESL-treated db/db mice may be associated with IRS-mediated insulin signaling and lipid accumulation in liver via inhibition of adipogenesis and stimulation of fat oxidation in WAT.…”

Identification of the Flavonoid Luteolin as a Repressor of the Transcription Factor Hepatocyte Nuclear Factor 4α

“…Kwon et al (42) also reported that dietary luteolin improves hepatic insulin sensitivity by suppressing the expression of sterol regulatory element-binding protein 1, which modulates Irs2 expression through negative feedback and gluconeogenesis. In addition, dietary luteolin increases PPAR␥ protein expression, which may be linked to the improvement in circulating fatty acid levels by enhancing fatty acid uptake genes in adipose tissue (42). These results suggest that dietary luteolin functions at multiple levels to improve insulin sensitivity.…”

“…Therefore, it is likely that the suppression of fat absorption has limited contribution to the anti-obesity effect of luteolin. More recently, Kwon et al (42) reported that dietary luteolin significantly decreased body weight in HFDinduced obese mice. They reported that dietary luteolin up-regulated the expression of genes controlling lipolysis and the tricarboxylic acid cycle prior to lipid droplet formation in the adipose tissue, thereby reducing adiposity.…”

Regulation of Sirt1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity

“…Systemic administration of luteolin suppressed tumor cell growth in cancers22. It was proposed that luteolin ameliorated diet-induced obesity and related complications through interactions between liver and adipose tissue23.…”