Long-Term Caffeine Intake Exerts Protective Effects on Intestinal Aging by Regulating Vitellogenesis and Mitochondrial Function in an Aged Caenorhabditis Elegans Model

Caffeine, a methylxanthine derived from plants, is the most widely consumed ingredient in daily life. Therefore, it is necessary to investigate the effects of caffeine intake on essential biological activities. In this study, we attempted to determine the possible anti-aging effects of long-term caffeine intake in the intestine of an aged Caenorhabditis elegans model. We examined changes in intestinal integrity, production of vitellogenin (VIT), and mitochondrial function after caffeine intake. To evaluate intestinal aging, actin-5 (ACT-5) mislocalization, lumenal expansion, and intestinal colonization were examined after caffeine intake, and the levels of vitellogenesis as well as the mitochondrial activity were measured. We found that the long-term caffeine intake (10 mM) in the L4-stage worms at 25 °C for 3 days suppressed ACT-5 mislocalization. Furthermore, the level of autophagy, which is normally increased in aging animals, was significantly reduced in these animals, and their mitochondrial functions improved after caffeine intake. In addition, the caffeine-ingesting aging animals showed high resistance to oxidative stress and increased the expression of antioxidant proteins. Taken together, these findings reveal that caffeine may be a potential anti-aging agent that can suppress intestinal atrophy during the progression of intestinal aging.     

Maternal fish oil supplementation ameliorates maternal high-fructose diet-induced dyslipidemia in neonatal mice with suppression of lipogenic gene expression in livers of postpartum mice

Maternal fructose consumption during pregnancy and lactation is associated with metabolic dysregulation in offspring. We tested the hypothesis that fish oil (FO) supplementation during pregnancy and lactation improves fructose-induced metabolic dysregulation in postpartum dams and offspring mice. We therefore aimed to determine the effects of FO supplementation on metabolic disruption in neonatal mice and dams induced by a maternal high-fructose diet (HFrD). The weight of the offspring of dams fed with HFrD on postnatal day 5 was significantly low, but this was reversed by adding FO to the maternal diet. Feeding dams with HFrD significantly increased plasma concentrations of triglycerides, uric acid, and total cholesterol, and decreased free fatty acid concentrations in offspring. Maternal supplementation with FO significantly suppressed HFrD-induced hypertriglyceridemia and hyperuricemia in the offspring. Maternal HFrD induced remarkable mRNA expression of the lipogenic genes Srebf1, Fasn, Acc1, Scd1, and Acly in the postpartum mouse liver without affecting hepatic and plasma lipid levels. Although expression levels of lipogenic genes were higher in the livers of postpartum dams than in those of nonmated mice, HFrD feeding increased the hepatic lipid accumulation in nonmated mice but not in postpartum dams. These findings suggest that although hepatic lipogenic activity is higher in postpartum dams than nonmated mice, the lipid consumption is enhanced in postpartum dams during pregnancy and lactation. Maternal FO supplementation obviously suppressed the expression of these lipogenic genes. These findings coincide with reduced plasma triglyceride concentrations in the offspring. Therefore, dietary FO apparently ameliorated maternal HFrD-induced dyslipidemia in offspring by suppressing maternal lipogenic gene expression and/or neonatal plasma levels of uric acid.     

Effects of Lingonberry (Vaccinium vitis-idaea L.) Supplementation on Hepatic Gene Expression in High-Fat Diet Fed Mice

The prevalence of nonalcoholic fatty liver disease (NAFLD) is growing worldwide in association with Western-style diet and increasing obesity. Lingonberry (Vaccinium vitis-idaea L.) is rich in polyphenols and has been shown to attenuate adverse metabolic changes in obese liver. This paper investigated the effects of lingonberry supplementation on hepatic gene expression in high-fat diet induced obesity in a mouse model. C57BL/6N male mice were fed for six weeks with either a high-fat (HF) or low-fat (LF) diet (46% and 10% energy from fat, respectively) or HF diet supplemented with air-dried lingonberry powder (HF + LGB). HF diet induced a major phenotypic change in the liver, predominantly affecting genes involved in inflammation and in glucose and lipid metabolism. Lingonberry supplementation prevented the effect of HF diet on an array of genes (in total on 263 genes) associated particularly with lipid or glucose metabolic process (such as Mogat1, Plin4, Igfbp2), inflammatory/immune response or cell migration (such as Lcn2, Saa1, Saa2, Cxcl14, Gcp1, S100a10) and cell cycle regulation (such as Cdkn1a, Tubb2a, Tubb6). The present results suggest that lingonberry supplementation prevents HF diet-induced adverse changes in the liver that are known to predispose the development of NAFLD and its comorbidities. The findings encourage carrying out human intervention trials to confirm the results, with the aim of recommending the use of lingonberries as a part of healthy diet against obesity and its hepatic and metabolic comorbidities.     

Elderly women: Homocysteine reduction by short-term folic acid supplementation resulting in increased glucose concentrations and affecting lipid metabolism (C677T MTHFR polymorphism)

ObjectiveSerum homocysteine levels show interindividual variation and are determined by nutritional factors, such as B-vitamin intake, and by age and genetic influences, such as the genotype of the methylenetetrahydrofolate reductase (MTHFR) gene. Recently, the relation between one-carbon and lipid metabolism has been shown. Therefore, we hypothesized that folic acid supplementation would not only decrease homocysteine concentrations but also affect lipid metabolism. The aim of the present study was to evaluate the impact of short-term folic acid supplementation on homocysteine and lipid metabolism in Polish women older than 60 y with different C677T MTHFR genotypes.MethodsOne hundred twenty-two volunteers were supplemented with folic acid 400 μg/d for 8 wk. Folate intake was assessed using a food-frequency questionnaire. The serum homocysteine level was analyzed using high-performance liquid chromatography. Serum biomarkers were measured with a Vitalab Flexor biochemical analyzer. MTHFR genotyping was performed using the polymerase chain reaction restriction fragment length polymorphism method.ResultsIn the studied group, the MTHFR genotype frequencies were 0.14 for TT, 0.43 for CT, 0.43 for CC carriers. At baseline, the average folic acid and homocysteine concentrations were 12.16 ± 0.23 ng/mL and 7.94 ± 0.3 μmol/L, respectively. Folic acid supplementation lowered the serum homocysteine concentration. However, the dietary intervention also led to an increase in glucose concentrations (P < 0.01). The T-allele carriers had a larger waist circumference (P < 0.05) and a higher waist-to-hip ratio (P < 0.01).ConclusionsIn elderly women, a short-term, low-dose folic acid supplementation lowered the serum homocysteine level but also increased glucose concentrations. The C677T MTHFR polymorphism affects the waist-to-hip ratio and lipid metabolism.     

Acetyl-L-carnitine supplementation differently influences nutrient partitioning, serum leptin concentration and skeletal muscle mitochondrial respiration in young and old rats

Variations in energy balance, body composition, and nutrient partitioning induced by acetyl-L-carnitine (ALCAR) supplementation were studied in young (2 mo) and old (24 mo) Wistar rats. Changes in skeletal muscle metabolism as well as in serum free triiodothyronine and leptin levels were also evaluated. Rats were administered 0 (control) or 15 g/L ALCAR in their drinking water for 1 mo. ALCAR treatment significantly decreased body lipid percentage in young rats and significantly increased body protein percentage in old rats. The percentage of metabolizable energy (ME) intake stored as lipid was lower in ALCAR-treated young rats, whereas the percentage of ME intake stored as protein was greater in ALCAR-treated old rats compared with their age-matched controls. In addition, ALCAR supplementation significantly decreased serum leptin levels in old rats. Elevated skeletal muscle respiration was found in old rats treated with ALCAR, due to an increase in mitochondrial protein mass. In conclusion, ALCAR supplementation decreases efficiency of lipid deposition in young rats and increases efficiency of protein deposition in old rats. In addition, ALCAR supplementation partly reduces the leptin resistance that occurs in old rats, and improves ATP production in skeletal muscle mitochondria through an increase in mitochondrial protein content.     

Lipid deposition pattern and adaptive strategy in response to dietary fat in Chinese perch (<Emphasis Type="Italic">Siniperca chuatsi</Emphasis>)

Background

Previous studies in teleost have demonstrated the adaptive strategy to maintain hepatic lipid homeostasis within certain limit. The excess of fat-intake could induce abnormal lipid deposition in liver but not adipose tissue. However, the molecular mechanism between the impaired lipid homeostasis and the aggravated lipid deposition in liver has not been elucidated well in fish.

Methods

Four isonitrogenous diets with different fat levels (2, 7, 12 and 17%) were formulated, named L2, L7, L12 and L17 respectively, and fed Chinese perch (44.50?±?0.25 g) to apparent satiation for five weeks. Growth index, triglyceride concentrations and expression of genes involved in lipid metabolism were measured.

Results

The maximal growth performance and food intake were observed in L12 group. The lipid content in liver and serum were comparable in L2, L7 and L12 groups, while they were increased significantly in L17 group. Histology analysis also demonstrated that mass lipid droplets emerged in hepatocyte and then induced hepatic steatosis in L17 group. Compared to L2 group, the lipolytic genes related to fatty acids (FAs) transport (lpl & hl) and FAs β-oxidation (cpt1 & cs) were increased in L7 and L12 group. Relative mRNA levels of the gluconeogenesis (pc, pepck & g6pase) were also increased, in contrast, the lipogenic genes (srebp1, accα & fas) were decreased. Compared to L12 group, L17 group had higher mRNA levels of the FAs transport and the lipogenesis. But the lipolytic genes related to FAs β-oxidation were steady and the mRNA levels of gluconeogenesis were down-regulated instead.

Conclusions

Within certain limit, the increase of dietary fat in L7 and L12 group was propitious to reduce the consumption of protein and improve growth performance in Chinese perch. It was due to the homeostasis of hepatic triglyceride (TG) pool and serum glucose through promoting the FAs β-oxidation and gluconeogenesis respectively. Both the increase of lipogenesis and the absence of FAs β-oxidation in L17 group could trigger the esterification of FAs, indeed, the inhibition of gluconeogenesis could also aggravate triglyceride accumulation in liver and induce hepatic steatosis.

     

Chitooligosaccharide ameliorates diet-induced obesity in mice and affects adipose gene expression involved in adipogenesis and inflammation

Chitooligosaccharide (CO) has been reported to have potential antiobestic effects in a few studies, but the antiobesity properties of CO and its related mechanisms in models of dietary obesity remain unclear. We investigated the effect of CO on body weight gain, size of adipocytes, adipokines, and lipid profiles in high-fat (HF) diet-induced obese mice and on the gene expression in adipose tissue using a complementary DNA microarray approach to test the hypothesis that CO supplementation would alleviate HF diet-induced obesity by the alteration of adipose tissue-specific gene expression. Male C57BL/6N mice were fed a normal diet (control), HF diet, or CO-supplemented HF diet (1% or 3%) for 5 months. Compared with the HF diet mice, mice fed the 3% CO-supplemented diet gained 15% less weight but did not display any change in food and energy intake. Chitooligosaccharide supplementation markedly improved serum and hepatic lipid profiles. Histologic examination showed that epididymal adipocyte size was smaller in mice fed the HF + 3% CO. Microarray analysis showed that dietary CO supplementation modulated adipogenesis-related genes such as matrix metallopeptidases 3, 12, 13, and 14; tissue inhibitor of metalloproteinase 1; and cathepsin k in the adipose tissues. Twenty-five percent of the CO-responsive genes identified are involved in immune responses including the inflammatory response and cytokine production. These results suggest that CO supplementation may help ameliorate HF diet-induced weight gain and improve serum and liver lipid profile abnormalities, which are associated, at least in part, with altered adipose tissue gene expression involved in adipogenesis and inflammation.     

Adzuki Bean Alleviates Obesity and Insulin Resistance Induced by a High-Fat Diet and Modulates Gut Microbiota in Mice

Adzuki bean consumption has many health benefits, but its effects on obesity and regulating gut microbiota imbalances induced by a high-fat diet (HFD) have not been thoroughly studied. Mice were fed a low-fat diet, a HFD, and a HFD supplemented with 15% adzuki bean (HFD-AB) for 12 weeks. Adzuki bean supplementation significantly reduced obesity, lipid accumulation, and serum lipid and lipopolysaccharide (LPS) levels induced by HFD. It also mitigated liver function damage and hepatic steatosis. In particular, adzuki bean supplementation improved glucose homeostasis by increasing insulin sensitivity. In addition, it significantly reversed HFD-induced gut microbiota imbalances. Adzuki bean significantly reduced the ratio of Firmicutes/Bacteroidetes (F/B); enriched the occurrence of Bifidobacterium, Prevotellaceae, Ruminococcus_1, norank_f_Muribaculaceae, Alloprevotella, Muribaculum, Turicibacter, Lachnospiraceae_NK4A136_group, and Lachnoclostridium; and returned HFD-dependent taxa (Desulfovibrionaceae, Bilophila, Ruminiclostridium_9, Blautia, and Ruminiclostridium) back to normal status. PICRUSt2 analysis showed that the changes in gut microbiota induced by adzuki bean supplementation may be associated with the metabolism of carbohydrates, lipids, sulfur, and cysteine and methionine; and LPS biosynthesis; and valine, leucine, and isoleucine degradation.     

Lipid metabolism in trained rats: effect of guarana (Paullinia cupana Mart.) supplementation

BACKGROUND AND AIMS: Guarana is widely consumed by athletes, either in supplements or in soft drinks, under the belief that it presents ergogenic and "fat burning" effects. We examined the effect of guarana supplementation (14 days) upon aspects of lipid metabolism in sedentary (C) and trained rats (T). METHODS: To isolate the effect of caffeine from that of other components of guarana, we adopted two different doses of whole extract (G1-0.130 g/kg; G2-0.325 g/kg) or decaffeinated extract (DG1, DG2). Body weight, food and water intake; muscle fat content, oleate incorporation, glycogen content, and carnitine palmitoyltransferase I (CPT I) activity and mRNA expression; along with plasma lactate concentration, were assessed. RESULTS: Muscle oleate incorporation was decreased in rats receiving decaffeinated guarana in relation to G1 and G2; as was CPT I mRNA expression in the gastrocnemius. Whole extract supplementation, but not DG induced reduced plasma lactate concentration in trained rats. G1 showed higher muscle glycogen content compared with all other groups. The results show an effect of guarana on aspects of lipid metabolism, which is abolished by decaffeination. CONCLUSION: The changes in lipid metabolism of supplemented rats herein reported are associated with the methylxanthine content of guarana.     

Acute and timing effects of beta-hydroxy-beta-methylbutyrate (HMB) on indirect markers of skeletal muscle damage

Background

The effects of dairy on energy metabolism appear to be mediated, in part, by leucine and calcium which regulate both adipocyte and skeletal muscle energy metabolism. We recently demonstrated that leucine and calcitriol regulate fatty acid oxidation in skeletal muscle cells in vitro, with leucine promoting and calcitriol suppressing fatty acid oxidation. Moreover, leucine coordinately regulated adipocyte lipid metabolism to promote flux of lipid to skeletal muscle and regulate metabolic flexibility. We have now investigated the role of mitochondrial biogenesis in mediating these effects.

Methods

We tested the effect of leucine, calcitriol and calcium in regulation of mitochondrial mass using a fluorescence method and tested mitochondrial biogenesis regulatory genes as well mitochondrial component genes using real-time PCR. We also evaluated the effect of leucine on oxygen consumption with a modified perfusion system.

Results

Leucine (0.5 mM) increased mitochondrial mass by 30% and 53% in C2C12 myocytes and 3T3-L1 adipocytes, respectively, while calcitriol (10 nM) decreased mitochondrial abundance by 37% and 27% (p < 0.02). Leucine also stimulated mitochondrial biogenesis genes SIRT-1, PGC-1α and NRF-1 as well as mitochondrial component genes UCP3, COX, and NADH expression by 3–5 fold in C2C12 cells (p < 0.003). Adipocyte-conditioned medium reduced mitochondrial abundance (p < 0.001) and decreased UCP3 but increased PGC-1α expression in myocytes, suggesting a feedback stimulation of mitochondrial biogenesis. Similar data were observed in C2C12 myocytes co-cultured with adipocytes, with co-culture markedly suppressing mitochondrial abundance (p < 0.02). Leucine stimulated oxygen consumption in both C2C12 cells and adipocytes compared with either control or valine-treated cells. Transfection of C2C12 myocytes with SIRT-1 siRNA resulted in parallel suppression of SIRT-1 expression and leucine-induced stimulation of PGC-1α and NRF-1, indicating that SIRT-1 mediates leucine induced mitochondrial biogenesis in muscle cells.

Conclusion

These data suggest that leucine and calcitriol modulation of muscle and adipocyte energy metabolism is mediated, in part, by mitochondrial biogenesis.     

Does Nausea and Vomiting of Pregnancy Play a Role in the Association Found Between Maternal Caffeine Intake and Fetal Growth Restriction?

The aim of this study was to explore the relationships between nausea and vomiting in pregnancy and (a) fetal growth restriction; and (b) maternal caffeine metabolism and fetal growth restriction. A cohort of 2,643 pregnant women, aged 18–45 years, attending two UK maternity units between 8 and 12 weeks gestation, was recruited. A validated tool assessed caffeine intake at different stages of pregnancy and caffeine metabolism was assessed from a caffeine challenge test. Experience of nausea and vomiting of pregnancy was self-reported for each trimester. Adjustment was made for confounders, including salivary cotinine as a biomarker of current smoking status. There were no significant associations between fetal growth restriction and nausea and vomiting in pregnancy, even after adjustment for smoking and alcohol intake. There were no significant differences in the relationship between caffeine intake and fetal growth restriction between those experiencing symptoms of nausea and vomiting and those who did not, for either the first (p = 0.50) or second trimester (p = 0.61) after adjustment for smoking, alcohol intake and caffeine half-life. There were also no significant differences in the relationship between caffeine half-life and fetal growth restriction between those experiencing symptoms of nausea and vomiting and those who did not, for either the first trimester (p = 0.91) or the second trimester (p = 0.45) after adjusting for smoking, alcohol intake and caffeine intake. The results from this study show no evidence that the relationship between maternal caffeine intake and fetal growth restriction is modified by nausea and vomiting in pregnancy.     

Taurine supplementation associated with exercise increases mitochondrial activity and fatty acid oxidation gene expression in the subcutaneous white adipose tissue of obese women

Taurine supplementation only increased the expression of fat oxidation genes (ACO2 and ACOX1). Exercise increased energy metabolism and the expression of fat oxidation genes in the subcutaneous white adipose tissue. The association between taurine supplementation and exercise promoted additional effects to exercise by increasing energy expenditure, and upregulating mitochondrial respiratory capacity and the expression of genes related to mitochondrial metabolism and fat oxidation in the subcutaneous adipose tissue (scWAT) of obese women.

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Coffee consumption prevents fibrosis in a rat model that mimics secondary biliary cirrhosis in humans

Investigations demonstrated that oxidative stress plays an important role in injury promotion in cholestatic liver disease. We hypothesized that coffee attenuates cholestasis-induced hepatic necrosis and fibrosis via its antioxidant, anti-inflammatory, and antifibrotic properties. The major aim of this study was to evaluate the hepatoprotective properties of coffee and caffeine in a model of chronic bile duct ligation (BDL) in male Wistar rats. Liver injury was induced by 28-day BDL, and conventional coffee, decaffeinated coffee, or caffeine was administered daily. After treatment, the hepatic oxidative status was estimated by measuring lipid peroxidation, the reduced to oxidized glutathione ratio, and glutathione peroxidase. Fibrosis was assessed by measuring the liver hydroxyproline content. The transforming growth factor-β, connective tissue growth factor, α-smooth muscle actin, collagen 1, and interleukin-10 proteins and mRNAs were measured by Western blot and polymerase chain reaction, respectively. Conventional coffee suppressed most of the changes produced by BDL; however, caffeine showed better antifibrotic effects. Coffee demonstrated antioxidant properties by restoring the redox equilibrium, and it also prevented the elevation of liver enzymes as well as hepatic glycogen depletion. Interestingly, coffee and caffeine administration prevented collagen increases. Western blot assays showed decreased expression levels of transforming growth factor-β, connective tissue growth factor, α-smooth muscle actin, and collagen 1 in the coffee- and caffeine-treated BDL groups. Similarly, coffee decreased the mRNA levels of these proteins. We conclude that coffee prevents liver cirrhosis induced by BDL by attenuating the oxidant processes, blocking hepatic stellate cell activation, and downregulating the main profibrotic molecules involved in extracellular matrix deposition.     

Genetic determinants of serum lipid levels in Chinese subjects: a population-based study in Shanghai, China

We examined the associations between 21 single nucleotide polymorphisms (SNPs) of eight lipid metabolism genes and lipid levels in a Chinese population. This study was conducted as part of a population-based study in China with 799 randomly selected healthy residents who provided fasting blood and an in-person interview. Associations between variants and mean lipid levels were examined using a test of trend and least squares mean test in a general linear model. Four SNPs were associated with lipid levels: LDLR rs1003723 was associated with total cholesterol (P-trend = 0.002) and LDL (P-trend = 0.01), LDLR rs6413503 was associated with total cholesterol (P-trend = 0.05), APOB rs1367117 was associated with apoB (P-trend = 0.02), and ABCB11 rs49550 was associated with total cholesterol (P-trend = 0.01), triglycerides (P-trend = 0.01), and apoA (P-trend = 0.01). We found statistically significant effects on lipid levels for LDLR rs6413503 among those with high dairy intake, LPL rs263 among those with high allium vegetable intake, and APOE rs440446 among those with high red meat intake. We identified new associations between SNPs and lipid levels in Chinese previously found in Caucasians. These findings provide insight into the role of lipid metabolism genes, as well as the mechanisms by which these genes may be linked with disease.     

Dietary Cocoa Flavanols Enhance Mitochondrial Function in Skeletal Muscle and Modify Whole-Body Metabolism in Healthy Mice

Mitochondrial dysfunction is widely reported in various diseases and contributes to their pathogenesis. We assessed the effect of cocoa flavanols supplementation on mitochondrial function and whole metabolism, and we explored whether the mitochondrial deacetylase sirtuin-3 (Sirt3) is involved or not. We explored the effects of 15 days of CF supplementation in wild type and Sirt3^-/- mice. Whole-body metabolism was assessed by indirect calorimetry, and an oral glucose tolerance test was performed to assess glucose metabolism. Mitochondrial respiratory function was assessed in permeabilised fibres and the pyridine nucleotides content (NAD⁺ and NADH) were quantified. In the wild type, CF supplementation significantly modified whole-body metabolism by promoting carbohydrate use and improved glucose tolerance. CF supplementation induced a significant increase of mitochondrial mass, while significant qualitative adaptation occurred to maintain H₂O₂ production and cellular oxidative stress. CF supplementation induced a significant increase in NAD⁺ and NADH content. All the effects mentioned above were blunted in Sirt3^-/- mice. Collectively, CF supplementation boosted the NAD metabolism that stimulates sirtuins metabolism and improved mitochondrial function, which likely contributed to the observed whole-body metabolism adaptation, with a greater ability to use carbohydrates, at least partially through Sirt3.     

Increased hepatic de novo lipogenesis and mitochondrial efficiency in a model of obesity induced by diets rich in fructose

Purpose

To assess hepatic de novo lipogenesis and mitochondrial energetics as well as whole-body energy homeostasis in sedentary rats fed a fructose-rich diet.

Methods

Male rats of 90 days of age were fed a high-fructose or control diet for 8 weeks. Body composition, energy balance, oxygen consumption, carbon dioxide production, non-protein respiratory quotient, de novo lipogenesis and insulin resistance were measured. Determination of specific activity of hepatic enzymes of de novo lipogenesis, mitochondrial mass, oxidative capacity and degree of coupling, together with parameters of oxidative stress and antioxidant defence, was also carried out.

Results

Body energy and lipid content as well as plasma insulin and non-esterified fatty acids were significantly higher in fructose-fed than in control rats. Significantly higher rates of net de novo lipogenesis and activities of hepatic lipogenic enzymes fatty acid synthase and stearoyl CoA desaturase-1 were found in fructose-fed rats compared to controls. Mitochondrial protein mass and degree of coupling were significantly higher in fructose-fed rats compared to controls. Hepatic mitochondria showed oxidative damage, both in the lipid and in the protein component, together with decreased activity of antioxidant defence.

Conclusion

Liver mitochondrial compartment is highly affected by fructose feeding. The increased mitochondrial efficiency allows liver cells to burn less substrates to produce ATP for de novo lipogenesis and gluconeogenesis. In addition, increased lipogenesis gives rise to whole body and ectopic lipid deposition, and higher mitochondrial coupling causes mitochondrial oxidative stress.