Xanthohumol Pyrazole Derivative Improves Diet-Induced Obesity and Induces Energy Expenditure in High-Fat Diet-Fed Mice

Abstract

The energy intake exceeding energy expenditure (EE) results in a positive energy balance, leading to storage of excess energy and weight gain. Here, we investigate the potential of a newly synthesized compound as an inducer of EE for the management of diet-induced obesity and insulin resistance. Xanthohumol (XN), a prenylated flavonoid from hops, was used as a precursor for the synthesis of a pyrazole derivative tested for its properties on high-fat diet (HFD)-induced metabolic impairments. In a comparative study with XN, we report that 4-(5-(4-hydroxyphenyl)-1-methyl-1H-pyrazol-3-yl)-5-methoxy-2-(3-methylbut-2-en-1-yl)­benzene-1,3-diol (XP) uncouples oxidative phosphorylation in C2C12 cells. In HFD-fed mice, XP improved glucose tolerance and decreased weight gain by increasing EE and locomotor activity. Using an untargeted metabolomics approach, we assessed the effects of treatment on metabolites and their corresponding biochemical pathways. We found that XP and XN reduced purine metabolites and other energy metabolites in the plasma of HFD-fed mice. The induction of locomotor activity was associated with an increase in inosine monophosphate in the cortex of XP-treated mice. Together, these results suggest that XP, better than XN, affects mitochondrial respiration and cellular energy metabolism to prevent obesity in HFD-fed mice.

Establishment of a novel obesity mouse model: the induction of intestinal microbiota dysbiosis

“…In recent years, studies have shown that the intestinal microbiota plays an important role in the development and regulation of obesity 4 , 5 . Researchers in China and around the world have used high-fat and high-sugar methods to establish mouse models of obesity and have successfully carried out a number of studies on this basis 5 – 7 . However, there have been few studies on mouse models of obesity induced by intestinal microbiota dysbiosis.…”

Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

“…Accumulating studies indicate these prenylated flavonoids may mediate their beneficial effects via polypharmacological mechanisms of action, which could increase their effectiveness in treating disease. Previous studies link the anti-obesity and MetS benefits of XN and its derivatives to possibly increasing energy expenditure through mild mitochondrial uncoupling and increasing locomotor activity [ 13 , 35 , 36 ]. XN improves diet-induced obesity and hepatosteatosis by inhibiting expression of and inactivating maturation of sterol regulatory element-binding proteins, thus reducing the expression of genes involved in fatty acid and cholesterol biosynthesis [ 14 , 37 ].…”

Reversing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

“…Accumulating studies indicate these prenylated flavonoids may mediate their beneficial effects via polypharmacological mechanisms of action, which could increase their effectiveness in treating disease. Previous studies link the anti-obesity and MetS benefits of XN and its derivatives to possibly increasing energy expenditure through mild mitochondrial uncoupling and increasing locomotor activity [43, 48, 49]. Xanthohumol improves diet-induced obesity and hepatosteatosis by inhibiting expression of and inactivating maturation of sterol regulatory element-binding proteins, thus reducing the expression of genes involved in fatty acid and cholesterol biosynthesis [14, 50].…”