Sex-Dependent Effects of 7,8-Dihydroxyflavone on Metabolic Health Are Associated with Alterations in the Host Gut Microbiome

Abstract

7,8-Dihydroxyflavone (DHF) is a naturally occurring flavonoid that has been reported to protect against a variety of pathologies. Chronic administration of DHF prevents high-fat diet (HFD)-induced obesity in female, but not male, mice. However, the mechanisms underlying this sexual dimorphism have not been elucidated. We have discovered that oral DHF supplementation significantly attenuates fat mass, hepatic lipid accumulation, and adipose tissue inflammation in female mice. In contrast, male mice were not protected from adiposity, and had a paradoxical worsening of hepatic lipid accumulation and adipose tissue inflammation upon DHF supplementation. Consistent with these sexually dimorphic effects on body weight and metabolic health, 7,8-DHF induced early and stable remodeling of the female intestinal microbiome. DHF supplementation significantly increased gut microbial diversity, and suppressed potentially detrimental bacteria, particularly Desulfovibrionaceae, which are pro-inflammatory and positively associated with obesity and inflammation. Changes in the female gut microbiome preceded alterations in body weights, and in silico analyses indicated that these early microbial changes were highly predictive of subsequent weight gain in female mice. While some alterations in the intestinal microbiome were also observed in male DHF-supplemented mice, these changes were distinct from those in females and, importantly, were not predictive of subsequent body weight changes in male animals. The temporality of microbial changes preceding alterations in body weight in female mice suggests a role for the gut microbiome in mediating the sexually dimorphic effects of DHF on body weight. Given the significant clinical interest in this flavonoid across a wide range of pathologies, further elucidation of these sexually dimorphic effects will aid the development of effective clinical therapies.

Metabolic protection by the dietary flavonoid 7,8-dihydroxyflavone requires an intact gut microbiome

“…We and others have previously reported that oral DHF administration protects female but not male mice from HFDinduced obesity (38,39). We also reported that paradoxically, DHF supplementation exacerbates some of the metabolic pathologies associated with HFD-feeding in male mice, including increasing hepatic lipid accumulation and adipose tissue inflammation (38). In our previous study, we discovered a novel role for DHF in modulating the gut microbiome of female, but not male, mice at an early time point, prior to any divergence in body weights between DHF-treated and control groups.…”

“…In addition, members of Rikenella are also associated with obesity and gut epithelial injury (96,102). More importantly, these changes in the gut microbiome were highly predictive of subsequent protection from HFD-induced weight gain in female mice, while no such association was observed in male DHF-supplemented animals (38). Given these previous associations between the gut microbiome and the metabolic effects of oral DHF supplementation, the current study was designed to determine whether the gut microbiome is causally linked to the effects of DHF.…”

“…Following this, mice were randomly assigned to Abx-control or Abx-DHF groups and received Abx throughout the 12-week HFD-feeding. Body weights and food intake were measured weekly, and water intake was measured twice a week (38). Body composition was determined by NMR (Echo MRI, Columbus, OH, United States), at the start and end of HFD-feeding (38).…”

“…DHF supplementation has been explored as a therapeutic strategy against neurodegeneration, cognitive decline, and depression (32,(35)(36)(37). Recently, we and others have shown that oral DHF supplementation can also protect against high-fat diet (HFD) induced obesity, adiposity, and glucose intolerance (38,39). Interestingly, this protection was only observed in female but not in male mice, where DHF paradoxically exacerbated lipid accumulation and adipose tissue inflammation.…”

Retinoic acid regulates pyruvate dehydrogenase kinase 4 (Pdk4) to modulate fuel utilization in the adult heart: Insights from wild‐type and β‐carotene 9′,10′ oxygenase knockout mice

“…Heart (LV) lipid extracts were also prepared by Folch extraction 45 to be analyzed by TLC GC-MS as described previously. 46,47 Briefly, tissue extracts were dissolved in chloroform, 2% Triton X100 solution and subsequently evaporated under nitrogen and dissolved in water. Lipids were then separated by thin-layer chromatography (TLC) on silica gel-60 plates (Millipore Sigma, St. Louis, MO, USA) in heptane-isopropyl ether-glacial acetic acid (60:40:3, v/v/v) with authentic standards.…”