Supplemental wheat germ modulates phosphorylation of STAT3 in the gut and NF-κBp65 in the adipose tissue of mice fed a Western diet.

Background: Commensal gut bacteria, including Lactobacillus, can produce metabolites that stimulate the release of gut antimicrobial peptides (AMPs) via the signal transducer and activator of transcription (STAT)3 pathway and prevent obesity-associated leaky gut and chronic inflammation. We have previously reported that wheat germ (WG) selectively increased cecal Lactobacillus in obese mice. Objectives: This study investigated the effects of WG on gut STAT3 activation and AMPs (Reg3γ and Reg3ß) as well as the potential of WG to inhibit nuclear Nf-κB-activation and immune cell infiltration in the visceral adipose tissue (VAT) of mice fed a Western diet (i.e., high-fat and sucrose diet [HFS]). Methods: Six-wk-old male C57BL/6 mice were randomly assigned to 4 groups (n = 12/group): control (C, 10% fat and sucrose kcal) or HFS (45% fat and 26% sucrose kcal) diet with or without 10% WG (wt/wt) for 12 wk. Assessments include serum metabolic parameters jejunal AMPs genes, inflammatory markers, and phosphorylation of STAT3 as well as VAT NF-κBp65. Independent and interaction effects of HFS and WG were analyzed with a 2-factor ANOVA. Results: WG significantly improved markers of insulin resistance and upregulated jejunal Il10 and Il22 genes. The HFS + WG group had a 15-fold increase in jejunal pSTAT3 compared with the HFS group. Consequently, WG significantly upregulated jejunal mRNA expression of Reg3γ and Reg3ß. The HFS group had a significantly higher VAT NF-κBp65 phosphorylation than the C group, while the HFS + WG group suppressed this to the level of C. Moreover, VAT Il6 and Lbp genes were downregulated in the HFS + WG group compared with HFS. Genes related to macrophage infiltration in the VAT were repressed in the WG-fed mice. Conclusion: These findings show the potential of WG to influence vital regulatory pathways in the gut and adipose tissue which may reduce the chronic inflammatory burden on these tissues that are important targets in obesity and insulin resistance.

Montmorencytart cherry supplementation improved markers of glucose homeostasis but has modest effects on indicators of gut health in mice fed a Western diet.

The gut microbiota plays an important role in the pathophysiology of obesity and type 2 diabetes. Emerging evidence suggests that anthocyanin-rich foods such as US Montmorency tart cherry (TC) can promote health by influencing the gut microbiota and maintaining gut integrity. This study investigated the effects of TC supplementation on the gut microbiota, markers of gut health, and metabolic parameters in mice fed a western diet (WD). Seventy-two C57BL/6 male mice were assigned to dietary treatments in a 2 × 3 factorial design with diet (control, WD) and TC (0, 5, 10% wt/wt) as factors. After 12 weeks of dietary treatment, tissues were collected to evaluate metabolic parameters and markers of gut health including cecal content microbiota and fecal short chain fatty acids (SCFAs). TC supplementation significantly increased the bacterial phylum, Actinobacteria, cecal weight, and fecal SCFAs and reduced the Proteobacteria and Deferribacteres phyla. However, gut histological parameters and expression of genes related to gut integrity were unaffected by TC. Body weight, serum cholesterol, triglyceride, leptin, plasminogen activator inhibitor-1 and resistin were increased with WD and TC had no effect on these parameters. Fasting blood glucose and the surrogate marker of insulin resistance, homeostatic model assessment of insulin resistance (HOMA-IR), was significantly increased by WD which was improved by TC particularly the 5% dose. In conclusion, TC supplementation, particularly the 5% dose, improved markers of glucose homeostasis but has modest effects on gut microbial population and SCFAs production. The mechanism by which TC improved markers of glucose homeostasis needs to be further investigated.

Deficiency of ß-carotene oxygenase 2 induces mitochondrial fragmentation and activates the STING-IRF3 pathway in the mouse hypothalamus.

Hypothalamic inflammation has been linked to various aspects of central metabolic dysfunction and diseases in humans, including hyperphagia, altered energy expenditure, and obesity. We previously reported that loss of ß-carotene oxygenase 2 (BCO2), a mitochondrial inner membrane protein, causes the alteration of the hypothalamic metabolome, low-grade inflammation, and an increase in food intake in mice at an early age, e.g., 3-6 weeks. Here, we determined the extent to which the deficiency of BCO2 induces hypothalamic inflammation in BCO2 knockout mice. Mitochondrial proteomics, electron microscopy, and immunoblotting were used to assess the changes in hypothalamic mitochondrial dynamics and mitochondrial DNA sensing and signaling. The results showed that deficiency of BCO2 altered hypothalamic mitochondrial proteome and respiratory supercomplex assembly by enhancing the expression of NADH:ubiquinone oxidoreductase subunit A11 protein and improved cardiolipin synthesis. BCO2 deficiency potentiated mitochondrial fission but suppressed mitophagy and mitochondrial biogenesis. Furthermore, deficiency of BCO2 resulted in inactivation of mitochondrial MnSOD enzyme, excessive production of reactive oxygen species, and elevation of protein levels of stimulator of interferon genes (STING) and interferon regulatory factor 3 (IRF3) in the hypothalamus. The data suggest that BCO2 is essential for hypothalamic mitochondrial dynamics. BCO2 deficiency induces mitochondrial fragmentation and mitochondrial oxidative stress, which may lead to mitochondrial DNA release into the cytosol and subsequently sensing by activation of the STING-IRF3 signaling pathway in the mouse hypothalamus.