3-OH Phloretin Inhibits High-Fat Diet-Induced Obesity and Obesity-Induced Inflammation by Reducing Macrophage Infiltration into White Adipose Tissue

Abstract

Phloretin and its glycoside phlorizin have been reported to prevent obesity induced by high-fat diet (HFD), but the effect of 3-OH phloretin, a catechol metabolite of phloretin, has not been investigated. In this study, we investigated the anti-obesity effects of phloretin and 3-OH phloretin in HFD-fed mice. The body weight gain induced by HFD was more inhibited by administration of 3-OH phloretin than by phloretin. The increases in fat mass, white adipose tissue (WAT) weight, adipocyte size, and lipid accumulation by HFD were also remarkably inhibited by 3-OH phloretin and, to a lesser extent, by phloretin. The HFD-induced upregulation of chemokines and pro-inflammatory cytokines was suppressed by 3-OH phloretin, preventing M1 macrophages from infiltrating into WAT and thereby reducing WAT inflammation. 3-OH phloretin also showed a more potent effect than phloretin on suppressing the expression of adipogenesis regulator genes, such as PPARγ2, C/EBPα, FAS, and CD36. Fasting blood glucose and insulin levels increased by HFD were diminished by the administration of 3-OH phloretin, suggesting that 3-OH phloretin may alleviate obesity-induced insulin resistance. These findings suggested that 3-OH phloretin has the potential to be a natural bioactive compound that can be used in the prevention or treatment of obesity and insulin resistance.

Biosynthesis of 3-Hydroxyphloretin Using Rational Design of 4-Hydroxyphenylacetate 3-Monooxygenase

“…Dihydrochalcones (DHCs) are a major subclass of flavonoids, in which the two aromatic rings (A, B) are linked by a three saturated carbon (α, β, C4) carbonyl system (Figure ). DHCs with different substituents have diverse physiological activities and are widely used in the fields of pharmacology and food. − Phloretin is a typical DHC with multiple phenolic hydroxyl groups that endow it with strong antioxidant ability. , An increase in the number of hydroxyl groups in polyphenol compounds will have a higher preventive effect on obesity, which can be used to develop antiobesity therapies using natural products . 3-Hydroxyphloretin is the 3-hydroxylated product of phloretin, also known as eriodictyol DHC, and is found to inhibit 3T3-L1 preadipocytes from differentiating into adipocytes .…”

“…2,6 An increase in the number of hydroxyl groups in polyphenol compounds will have a higher preventive effect on obesity, which can be used to develop antiobesity therapies using natural products. 7 3-Hydroxyphloretin is the 3hydroxylated product of phloretin, also known as eriodictyol DHC, and is found to inhibit 3T3-L1 preadipocytes from differentiating into adipocytes. 8 In addition, 3-hydroxyphloretin showed a greater inhibitory effect on Gram-negative Klebsiella pneumonia than phloretin.…”