Obesity and related metabolic pathologies represent a significant public health concern. Obesity is associated with increased oxidative stress that damages genomic and mitochondrial DNA. Oxidatively-induced lesions in both DNA pools are repaired via the base-excision repair pathway, initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). Global deletion of OGG1 and common OGG1 polymorphisms render mice and humans susceptible to metabolic disease. However, the relative contribution of mitochondrial OGG1 to this metabolic phenotype is unknown. Here, we demonstrate that transgenic targeting of OGG1 to mitochondria confers significant protection from diet-induced obesity, insulin resistance, and adipose tissue inflammation. These favorable metabolic phenotypes are mediated by an increase in whole body energy expenditure driven by specific metabolic adaptations, including increased mitochondrial respiration in white adipose tissue of OGG1 transgenic (Ogg1Tg) animals. These data demonstrate a critical role for a DNA repair protein in modulating mitochondrial energetics and whole-body energy balance.

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.

Stearoyl‐CoA desaturases are ER‐resident enzymes that convert saturated fatty acids into monounsaturated fatty acids and have been studied using whole body, liver, skin, and adipose knockout models, but their specific role in the intestine is not well understood. Stearoyl‐CoA desaturase 1 (SCD1) gene and protein expression increases along the length of the intestine and was found to be induced by fasting followed by refeeding a high sucrose very low‐fat diet, similar to what has been established in liver. In addition to SCD1, stearoyl‐CoA desaturase 2 (SCD2) was also found to be expressed and regulated in a similar manner to SCD1 in the intestine. Intestine specific SCD1 knockout (iKO) mice were generated by crossing SCD1 floxed mice with mice expressing the Cre‐recombinase gene under the villin promoter. These mice have longer intestines and increased lipid absorption compared to floxed counterparts. In addition, iKO mice have increased bile acids, a more hydrophilic bile acid pool, and have increased plasma GLP‐1 and brown adipose tissue (BAT) Iodothyronine Deiodinase 2 (Dio2) gene expression. When placed on a low‐fat diet (10% fat) or a high‐fat diet (45% fat), the iKO mice had increased food intake and energy expenditure while maintaining similar or leaner body weights as their floxed counterparts. The iKO mice showed a trend of improved glucose tolerance. Overall, these results show that stearoyl‐CoA desaturases are expressed and regulated in the intestine. Knocking out SCD1 in an intestine‐specific manner leads to increased bile acids and these increased bile acids may contribute to the increased GLP‐1 and bile acid‐induced thermogenesis in BAT. When fed a high fat diet, iKO mice demonstrated an increased basal metabolic rate, increased food intake, and improved glucose tolerance.

Objectives 7,8-Dihydroxyflavone (DHF) is a naturally occurring flavonoid that is being actively investigated as a therapeutic modality in the treatment of neurological disorders. A recent study also indicated that oral DHF supplementation protected female but not male mice from diet-induced obesity. However, the mechanisms underlying this sexually-dimorphic effects of DHF were not known. The aim of the work is to investigate the mechanisms underlying sex-specific effects of flavonoid. Methods Age-matched male and female mice were given ad libitum access to high fat-diet and drinking water containing vehicle or DHF for 12 weeks. Body weights, body composition, food, and water intake, were assessed. Immunohistological analysis, immunohistochemistry staining, plasma triglycerides, plasma bile acids, and hepatic lipids were investigated. Fresh fecal samples were collected, genomic DNA was extracted and hypervariable region V4 of the 16S rRNA gene was amplified. Gut microbiota structure was evaluated using alpha diversity indices and beta diversity distance metrices. Principal coordinates analysis (PCoA) was performed using the R “ape” package to visualize differences in gut microbiota structure between treatment groups along principal coordinates that accounted for most of the variations. Results Oral administration of DHF, remodels the intestinal microbiome of female, but not male, prior to divergence in body weight. This is concomitant with increase in brown adipose tissue thermogenesis, mediated by increased expression of UCP1 and Pgc -1α protecting the female mice from diet-induced obesity. Conclusions This study demonstrates sexually-dimorphic effects of a clinically relevant natural compound. Importantly, it points to a role for sex-dependent remodeling of the intestinal microbiome as a mechanism for weight control in females. Thus, our discoveries pave the way for personalized nutrition strategies that account for sex differences in metabolism. Funding Sources NIH.