Natural inhibitors of pancreatic lipase as new players in obesity treatment.

Obesity is a multifactorial disease characterized by an excessive weight for height due to an enlarged fat deposition such as adipose tissue, which is attributed to a higher calorie intake than the energy expenditure. The key strategy to combat obesity is to prevent chronic positive impairments in the energy equation. However, it is often difficult to maintain energy balance, because many available foods are high-energy yielding, which is usually accompanied by low levels of physical activity. The pharmaceutical industry has invested many efforts in producing antiobesity drugs; but only a lipid digestion inhibitor obtained from an actinobacterium is currently approved and authorized in Europe for obesity treatment. This compound inhibits the activity of pancreatic lipase, which is one of the enzymes involved in fat digestion. In a similar way, hundreds of extracts are currently being isolated from plants, fungi, algae, or bacteria and screened for their potential inhibition of pancreatic lipase activity. Among them, extracts isolated from common foodstuffs such as tea, soybean, ginseng, yerba mate, peanut, apple, or grapevine have been reported. Some of them are polyphenols and saponins with an inhibitory effect on pancreatic lipase activity, which could be applied in the management of the obesity epidemic

Shifts in microbiota species and fermentation products in a dietary model enriched in fat and sucrose

The gastrointestinal tract harbours a “superorganism” called the gut microbiota, which is known to play a crucial role in the onset and development of diverse diseases. This internal ecosystem, far from being a static environment, could be willingly manipulated by diet and dietary components. Feeding animals with high-fat sucrose diets entails diet-induced obesity, a model which is usually used in research to mimic the obese phenotype of Western societies. The aim of the present study was to identify gut microbiota dysbiosis and associated metabolic changes produced in 5 male Wistar rats fed a high-fat sucrose (HFS) diet for six weeks and to compare it with the basal microbial composition. For this purpose, DNA extracted from faeces at baseline and after the treatment was analysed by amplification of the V4-V6 region of the 16S ribosomal DNA (rDNA) gene using 454 pyrosequencing. Short-chain fatty acids (SCFA), acetate, propionate and butyrate, were also evaluated by gas chromatography-mass spectrometry (GC-MS). At the end of the treatment, gut microbiota composition significantly differed at phylum level (Firmicutes, Bacteroidetes and Proteobacteria) and class level (Erisypelotrichi, Deltaproteobacteria, Bacteroidia and Bacilli). Interestingly, Clostridia class showed a significant decrease after the HFS-diet treatment, which correlated with visceral adipose tissue, and is likely mediated by dietary carbohydrates. Of particular interest, Clostridium cluster XIVa species were significantly reduced and changes were identified in the relative abundance of other specific bacterial species (Mitsuokella jalaludinii, Eubacterium ventriosum, Clostridium sp. FCB90-3, Prevotella nanceiensis, Clostridium fusiformis, Clostridium sp. BNL1100 and Eubacterium cylindroides) that, in some cases, showed opposite trends to their relative families. These results highlight the relevance of characterizing gut microbial population differences at species level and contribute to understand the plausible link between the 1 diet and specific gut bacterial species that are able to influence the inflammatory status, intestinal barrier function and obesity development. Keywords: gut microbiota, pyrosequencing, high-fat sucrose diet, short chain fatty acids, Erysipelotrich

Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats

Diet‐induced obesity is associated to an imbalance in the normal gut microbiota composition. Resveratrol and quercetin, widely known for their health beneficial properties, have low bioavailability and, when reach the colon, they are targets of the gut microbial ecosystem. Hence, the use of these molecules in obesity might be considered as a potential strategy to modulate intestinal bacterial composition. The purpose of this study was to determine whether trans‐resveratrol and quercetin administration could counteract gut microbiota dysbiosis produced by high‐fat sucrose diet (HFS) and in turn, improve gut health. Wistar rats were randomized into four groups fed a HFS diet supplemented or not with trans‐resveratrol (15 mg/kg BW/day), quercetin (30 mg/kg BW/day) or a combination of both polyphenols at those doses. Administration of both polyphenols together prevented body‐weight gain and reduced serum insulin levels. Moreover, individual supplementation of trans‐resveratrol and quercetin effectively reduced serum insulin levels and insulin resistance. Quercetin supplementation generated a great impact on gut microbiota composition at different taxonomic levels, attenuating Firmicutes/Bacteroidetes ratio and inhibiting the growth of bacterial species previously associated to diet‐induced obesity (Erysipelotrichaceae, Bacillus, Eubacterium 1 cylindroides). Overall, the administration of quercetin was found to be effective in lessening HFS diet‐induced gut microbiota dysbiosis. In contrast, trans‐resveratrol supplementation alone or in combination with quercetin, scarcely modified the profile of gut bacteria, but acted at intestinal level altering the mRNA expression of tight‐junction proteins (TJPs) and inflammation associated genes

Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes

Antioxidant-based treatments are emerging as an interesting approach to possibly counteract obesity fat accumulation complications, since this is accompanied by an increased systemic oxidative stress. The aim of this study was to analyze specific metabolic effects of vitamin C (VC) on epididymal primary rat adipocytes. Cells were isolated and incubated for 72 h in culture medium, in the absence or presence of 1.6 nM insulin, within a range of VC concentrations (5-1000 microM). Glucose- and lipid-related variables as well as the secretion/expression patterns of several obesity-related genes were assessed. It was observed that VC dose dependently inhibited glucose uptake and lactate production, and also reduced glycerol release in both control and insulin-treated cells. Also, VC caused a dramatic concentration-dependent fall in leptin secretion especially in insulin-stimulated cells. In addition, VC (200 microM) induced Cdkn1a and Casp8, partially inhibited Irs3, and together with insulin drastically reduced Gpdh (listed as Gpd1 in the MGI database) gene expressions. Finally, VC and insulin down-regulatory effects were observed on extracellular and intracellular reactive oxygen species production respectively. In summary, this experimental assay describes a specific effect of VC in isolated rat adipocytes on glucose and fat metabolism, and on the secretion/expression of important obesity-related proteins

Metabolic faecal fingerprinting of trans-resveratrol and quercetin following a high-fat sucrose dietary model using liquid chromatography coupled to high-resolution mass spectrometry

Faecal non‐targeted metabolomics deciphers metabolic end‐products resulting from the interactions among food, host genetics, and gut microbiota. Faeces from Wistar rats fed a high‐fat sucrose (HFS) diet supplemented with trans‐resveratrol and quercetin (separately or combined) were analysed by liquid chromatography coupled to high‐resolution mass spectrometry (LC‐HRMS). Metabolomics in faeces are categorised into four clusters based on the type of treatment. Tentative identification of significantly differing metabolites highlighted the presence of carbohydrate derivatives or conjugates (3‐phenylpropyl glucosinolate and dTDP‐D‐mycaminose) in quercetin group. The trans‐resveratrol group was differentiated by compounds related to nucleotides (uridine monophosphate and 2,4‐dioxotetrahydropyrimidine D‐ribonucleotide). Marked associations between bacterial species (Clostridium genus) and the amount of some metabolites were identified. Moreover, trans‐resveratrol and resveratrol‐derived microbial metabolites (dihydroresveratrol and lunularin) were also identified. Accordingly, this study confirms the usefulness of omics‐based techniques to discriminate individuals depending on the physiological effect of food constituents and represents an interesting tool to assess the impact of future personalized therapies

Prevention of diet-induced obesity by apple polyphenols in Wistar rats through regulation of adipocyte gene expression and DNA methylation patterns

This study was conducted to determine the mechanisms implicated in the beneficial effects of apple polyphenols (APs) against diet-induced obesity in Wistar rats, described in a previous study from our group. Supplementation of high-fat sucrose diet with AP prevented adiposity increase by inhibition of adipocyte hypertrophy. Rats supplemented with AP exhibited improved glucose tolerance while adipocytes isolated from these rats showed an enhanced lipolytic response to isoproterenol. AP intake led to reduced Lep, Plin, and sterol regulatory element binding transcription factor 1 (Srebf1) mRNA levels and increased aquaporin 7 (Aqp7), adipocyte enhancer binding protein 1 (Aebp1), and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (Ppargc1a) mRNA levels in epididymal adipocytes. In addition, we found different methylation patterns of Aqp7, Lep, Ppargc1a, and Srebf1 promoters in adipocytes from apple-supplemented rats compared to high-fat sucrose fed rats. The administration of AP protects against body weight gain and fat deposition and improves glucose tolerance in rats. We propose that AP exerts the antiobesity effects through the regulation of genes involved in adipogenesis, lipolysis, and fatty acid oxidation, in a process that could be mediated in part by epigenetic mechanisms

Investigación de extractos ricos en polifenoles con actividad protectora frente al desarrollo de la obesidad: mecanismos nutrigenómicos implicados

Polyphenols have been reported to offer protection against the development of chronic diseases such as cardiovascular diseases or diabetes. The purpose of this study was to investigate the possible effect of different extracts rich in polyphenols on diet-induced adiposity and to elucidate the mechanisms involved in this effect through nutrigenomic and epigenetic studies in rats. We first characterized different rat obesity models induced by a high-fat diet, high-fat-sucrose (HFS) diet and a high-sucrose diet. The results revealed that HFS intake led to the establishment of a good obesity model to evaluate the biological activity of plant extracts. Then, a screening of different polyphenolic extracts for anti-obesity properties was conducted in rats fed a HFS diet. Extracts rich in polyphenols from apple, cinnamon, hamamelis and birch prevented body weight gain promoted by HFS intake, while apple and cinnamon extracts reduced adiposity gain. Since apple polyphenolic (AP) extract displayed the most outstanding properties, we seeked to study the mechanisms involved in its anti-obesity action. AP supplementation prevented HFS diet-induced hyperglycemia, hyperleptinemia, insulin resistance, glucose tolerance and adipocyte hypertrophy. These findings were accompanied by a prevention of the reduced lipolytic response induced by HFS diet and changes in the expression of adipocyte genes involved in adipogenesis, lipolysis, fatty acid oxidation and glycerol release. Furthermore, some of these genes could be subjected to epigenetic regulation, since changes in DNA methylation patterns were observed in AP-supplemented rats. In summary, we have shown that AP could be a useful functional food ingredient for the prevention of diet-induced obesity and its related complications

Investigación de extractos ricos en polifenoles con actividad protectora frente al desarrollo de la obesidad: mecanismos nutrigenómicos implicados

Polyphenols have been reported to offer protection against the development of chronic diseases such as cardiovascular diseases or diabetes. The purpose of this study was to investigate the possible effect of different extracts rich in polyphenols on diet-induced adiposity and to elucidate the mechanisms involved in this effect through nutrigenomic and epigenetic studies in rats. We first characterized different rat obesity models induced by a high-fat diet, high-fat-sucrose (HFS) diet and a high-sucrose diet. The results revealed that HFS intake led to the establishment of a good obesity model to evaluate the biological activity of plant extracts. Then, a screening of different polyphenolic extracts for anti-obesity properties was conducted in rats fed a HFS diet. Extracts rich in polyphenols from apple, cinnamon, hamamelis and birch prevented body weight gain promoted by HFS intake, while apple and cinnamon extracts reduced adiposity gain. Since apple polyphenolic (AP) extract displayed the most outstanding properties, we seeked to study the mechanisms involved in its anti-obesity action. AP supplementation prevented HFS diet-induced hyperglycemia, hyperleptinemia, insulin resistance, glucose tolerance and adipocyte hypertrophy. These findings were accompanied by a prevention of the reduced lipolytic response induced by HFS diet and changes in the expression of adipocyte genes involved in adipogenesis, lipolysis, fatty acid oxidation and glycerol release. Furthermore, some of these genes could be subjected to epigenetic regulation, since changes in DNA methylation patterns were observed in AP-supplemented rats. In summary, we have shown that AP could be a useful functional food ingredient for the prevention of diet-induced obesity and its related complications

Some cyclin-dependent kinase inhibitors-related genes are regulated by vitamin C in a model of diet-induced obesity

The aim of this research was to investigate differential gene expression of cyclin-dependent kinase inhibitors (CKIs) in white adipose tissue (WAT) and liver from high-fat fed male Wistar rats with or without vitamin C (VC) supplementation (750 mg/kg of body weight). After 56 d of experimentation, animals fed on a cafeteria diet increased significantly body weights and total body fat. Reverse transcription-polymerase chain reaction (RT-PCR) studies showed that cafeteria diet decreased p21 and p57 mRNA expression in subcutaneous WAT and increased p21 mRNA in liver. Overall, these data provide new information about the role of high fat intake on mRNA levels of several CKIs with implications in adipogenesis, cell metabolism and weight homeostasis. Interestingly, VC supplementation partially prevented diet-induced adiposity and increased p27 mRNA in liver without any changes in the other tissues and genes analyzed. Thus, hepatic mRNA changes induced by ascorbic acid indicate a possible role of these genes in diet-induced oxidative stress processes

Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats

Diet‐induced obesity is associated to an imbalance in the normal gut microbiota composition. Resveratrol and quercetin, widely known for their health beneficial properties, have low bioavailability and, when reach the colon, they are targets of the gut microbial ecosystem. Hence, the use of these molecules in obesity might be considered as a potential strategy to modulate intestinal bacterial composition. The purpose of this study was to determine whether trans‐resveratrol and quercetin administration could counteract gut microbiota dysbiosis produced by high‐fat sucrose diet (HFS) and in turn, improve gut health. Wistar rats were randomized into four groups fed a HFS diet supplemented or not with trans‐resveratrol (15 mg/kg BW/day), quercetin (30 mg/kg BW/day) or a combination of both polyphenols at those doses. Administration of both polyphenols together prevented body‐weight gain and reduced serum insulin levels. Moreover, individual supplementation of trans‐resveratrol and quercetin effectively reduced serum insulin levels and insulin resistance. Quercetin supplementation generated a great impact on gut microbiota composition at different taxonomic levels, attenuating Firmicutes/Bacteroidetes ratio and inhibiting the growth of bacterial species previously associated to diet‐induced obesity (Erysipelotrichaceae, Bacillus, Eubacterium 1 cylindroides). Overall, the administration of quercetin was found to be effective in lessening HFS diet‐induced gut microbiota dysbiosis. In contrast, trans‐resveratrol supplementation alone or in combination with quercetin, scarcely modified the profile of gut bacteria, but acted at intestinal level altering the mRNA expression of tight‐junction proteins (TJPs) and inflammation associated genes