Resistant Starch Type 4-enriched Diet Lowered Blood Cholesterols and Improved Body Composition in a Double Blind Controlled Cross-over Intervention

A metabolic health crisis is evident as cardiovascular diseases (CVD) remain the leading cause of mortality in the United States. Effects of resistant starch type 4 (RS4), a prebiotic fiber, in comprehensive management of metabolic syndrome (MetS) remain unknown. This study examined the effects of a blinded exchange of RS4-enriched flour (30% v/v) with regular/control flour (CF) diet on multiple MetS comorbidities. In a double blind (participants-investigators), placebo-controlled, cluster cross-over intervention (n = 86, age≥18, 2-12 week interventions, 2-week washout) in the United States, individuals were classified as having MetS (With-MetS) or not (No-MetS) following International Diabetes Federation (IDF)-criteria. RS4 consumption compared with CF resulted in 7.2% (p = 0.002) lower mean total cholesterol, 5.5% (p = 0.04) lower non-HDL, and a 12.8% (p \u3c 0.001) lower HDL cholesterol in the With-MetS group. No-MetS individuals had a 2.6% (p = 0.02) smaller waist circumference and 1.5% (p = 0.03) lower percent body fat following RS4 intervention compared to CF. A small but significant 1% increase in fat-free mass was observed in all participants combined (p = 0.02). No significant effect of RS4 was observed for glycemic variables and blood pressures. RS4 consumption improved dyslipidemia and body composition. Incorporation of RS4 in routine diets could offer an effective strategy for public cardio-metabolic health promotion

Impact of Dietary Resistant Starch Type 4 on Human Gut Microbiota and Immunometabolic Functions

Dietary modulation of the gut microbiota impacts human health. Here we investigated the hitherto unknown effects of resistant starch type 4 (RS4) enriched diet on gut microbiota composition and short-chain fatty acid (SCFA) concentrations in parallel with host immunometabolic functions in twenty individuals with signs of metabolic syndrome (MetS). Cholesterols, fasting glucose, glycosylated haemoglobin, and proinflammatory markers in the blood as well as waist circumference and % body fat were lower post intervention in the RS4 group compared with the control group. 16S-rRNA gene sequencing revealed a differential abundance of 71 bacterial operational taxonomic units, including the enrichment of three Bacteroides species and one each of Parabacteroides, Oscillospira, Blautia, Ruminococcus, Eubacterium, and Christensenella species in the RS4 group. Gas chromatography-mass spectrometry revealed higher faecal SCFAs, including butyrate, propionate, valerate, isovalerate, and hexanoate after RS4-intake. Bivariate analyses showed RS4-specific associations of the gut microbiota with the host metabolic functions and SCFA levels. Here we show that dietary RS4 induced changes in the gut microbiota are linked to its biological activity in individuals with signs of MetS. These findings have potential implications for dietary guidelines in metabolic health management

Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of γ-glutamylcysteine ligase

γ-Glutamylcysteine ligase (GCL) is the rate-limiting enzyme in glutathione (GSH) synthesis. A GAG-repeat polymorphism in the 5′ UTR of the gene coding for the catalytic subunit of GCL ( GCLC) has been associated with altered GSH levels in vitro. Thus, we hypothesized that this polymorphism is associated with altered GCL activity and blood GSH levels in vivo. A total of 256 healthy United States black and white adults were genotyped for the GAG polymorphism and blood GSH levels were measured. In a subset of 107 individuals, blood GCL activity was determined. Five alleles with 4, 7, 8, 9, and 10 GAG repeats were observed. The most prevalent genotype was 7/9 (40%) followed by 7/7 (32%) and 9/9 (11%). GSH levels were 15% lower in 9/9 individuals than 7/9 individuals ( P = 0.05). GCL activity was 21% lower in 9/9 individuals than 7/7 individuals ( P = 0.04). A decreasing trend of GCL activity was observed in the order of 7/7 > 7/9 > 9/9 ( P = 0.04). These findings show that 9/9 individuals have lower blood GSH levels, which is likely due to a decrease in GCL activity. Such individuals might be more susceptible to oxidative stress-related diseases than individuals with other genotypes

Weight Loss and Concomitant Adipose Autophagy in Methionine-Restricted Obese Mice is Not Dependent on Adiponectin or FGF21.

OBJECTIVE: Identifying novel approaches to combat obesity is important to improve health span. It was hypothesized that methionine restriction (MR) will induce weight loss in obese mice by reducing adipose tissue mass caused by increased energy expenditure and reprogramming of adipose tissue homeostasis. The roles of adiponectin (ADIPOQ) and fibroblast growth factor 21 (FGF21) during weight loss in MR mice were also tested. METHODS: Diet-induced obese (DIO) male C57BL/6J (wild type), Adipoq-deficient (Adipoq knockout [KO]), Fgf21-KO, and Adipoq-Fgf21 double-KO mice were used. Following a switch to high-fat control (DIO-CF, 60% fat/0.86% methionine) or MR (DIO-MR, 60% fat/0.12% methionine) diet, physiological parameters were measured, and inguinal and perigonadal adipose tissues were examined. RESULTS: Obese mice subjected to MR showed loss of body weight and adiposity, increased energy expenditure, and improved glucose tolerance that were independent of the actions of ADIPOQ and FGF21. MR induced reduction of circulating lipids, glucose, insulin, leptin, and insulin like growth factor 1 and increased β-hydroxybutyrate, ADIPOQ, and FGF21 concentrations. In fat, MR upregulated protein levels of adipose triglyceride lipase, apoptosis-inducing factor, lysosomal-associated membrane proteins 1 and 2, autophagy-related protein 5, beclin-1, and light chain 3B I and II. CONCLUSIONS: MR reduction of adipose tissue mass in obese mice is associated with elevated lipolysis, apoptosis, and autophagy and occurs independently of the actions of ADIPOQ and FGF21

A GAG trinucleotide-repeat polymorphism in the gene for glutathione biosynthetic enzyme, GCLC, affects gene expression through translation

A guanine-adenine-guanine (GAG) repeat polymorphism with 5 different alleles (4, 7, 8, 9, and 10 repeats) in the 5′ untranslated region (UTR) of GCLC has been associated with altered GCL activity and glutathione (GSH) levels. We investigated whether this polymorphism affects either transcription or translation using luciferase reporter constructs containing variant GCLC 5′ UTRs. Higher luciferase activity was observed in HepG2 and human embryonic kidney 293 (HEK293) cells transfected with constructs containing either 8 or 9 repeats than in constructs containing 4, 7, or 10 repeats ( P <0.05). In cell-free lysates, GAG repeat number had no effect on luciferase mRNA yield. In vitro translation of mRNAs from luciferase constructs resulted in differences similar to those found in cell cultures ( P <0.05). A similar association of GAG repeat with GCLC phenotype was observed in vivo in healthy adults, as individuals with GAG-7/7 genotype had lower GCL activity and GSH levels in lymphocytes compared to those with GAG-9/9 ( P <0.05). Higher GCL activity and GSH levels observed in red blood cells (RBCs) from individuals with GAG-7/7 compared to GAG-9/9 are likely due to differences in GCL regulation in RBCs. Altogether, these results suggest that GAG polymorphism affects GCLC expression via translation, and thus may be associated with altered risk for GSH-related diseases and toxicities.—Nichenametla, S. N., Lazarus, P., Richie, J. P., Jr. A GAG trinucleotide-repeat polymorphism in the gene for glutathione biosynthetic enzyme, GCLC, affects gene expression through translation