Abstract.In the present work, we demonstrate that treatment with 1,25-dihydroxyvitamin D3 for 24 hours increased in a dose-dependent manner the levels of the two major insulin receptor (IR) mRNAs (11 and 8.5 Kb) present in U-937 human promonocytic cells. These levels reached maximum values (1.8-fold 11 Kb; 1.4-fold 8.5 Kb) with the addition of 108 M 1,25-dihydroxyvitamin D3. In these optimal conditions the stimulatory effect of 1,25-dihydroxyvitamin D3 was accompanied by increases in both IR capacity, and insulin responsiveness for glucose transport in these cells. Moreover, such increases appear to be mediated by an enhanced expression of the receptor for 1,25-dihydroxyvitamin D3, measured at the level of both RNA and protein. These results provide evidence of 1,25-dihydroxyvitamin D3 acting as genomic stimulator of the insulin response in the control of glucose transport.

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Importance of the field: The increasing prevalence of type 2 diabetes mellitus and the negative clinical outcomes observed with the commercially available anti-diabetic drugs have led to the investigation of new therapeutic approaches focused on controlling postprandrial glucose levels. The use of carbohydrate digestive enzyme inhibitors from natural resources could be a possible strategy to block dietary carbohydrate absorption with less adverse effects than synthetic drugs. Areas covered in this review: This review covers the latest evidence regarding in vitro and in vivostudies in relation to pancreatic alpha-amylase inhibitors of plant origin, and presents bioactive compounds of phenolic nature that exhibit anti-amylase activity.What the reader will gain: The state of the art of the search for new pancreatic alpha amylase inhibitors of plant origin for the treatment of type 2 diabetes mellitus.Take home message: Pancreatic alpha-amylase inhibitors from traditional plant extracts are a promising tool for diabetes treatment. Many studies have confirmed the alpha-amylase inhibitory activity of plants and their bioactive compounds in vitro, but few studies corroborate these findings in rodents and very few in humans. Thus, despite some encouraging results, more research is required for developing a valuable anti-diabetic therapy using pancreatic alpha-amylase inhibitors of plant origin.Keywords: alpha-amylase; flavonoids; proanthocyanidins; tannins; type 2 diabetes mellitus 2 IntroductionDiabetes mellitus is one of the world´s major diseases, with an estimation of 347 million adults affected in 2011 (1). Type 2 diabetes mellitus, by far the most common type, is a metabolic disorder of multiple etiology characterized by carbohydrate, lipid and protein metabolic disorders that includes defects in insulin secretion, almost always with a major contribution of insulin resistance (2). These abnormalities could lead to lesions such as retinopathy, nephropathy, neuropathy, and angiopathy (3).In this context, the inhibition of carbohydrate digestive enzymes is considered a therapeutic tool for the treatment of type 2 diabetes (4). The most important digestive enzyme is pancreatic alpha-amylase (EC 3.2.1.1), a calcium metalloenzyme that catalyzes the hydrolysis of the alpha-1,4 glycosidic linkages of the starch, amylose, amylopectin, glycogen, and various maltodextrins and is responsible of most of starch digestion in humans. A second enzyme named alpha-glucosidase or maltase (EC 3.2.1.20) catalyzes the final step of the digestive process of carbohydrates acting upon 1,4-alpha bonds and giving as a result glucose (4).A positive correlation between human pancreatic alpha-amylase (HPA) activity and the increase in postprandial glucose levels has been shown, demonstrating the relevance of suppressing postprandial hyperglycemia (PPHG) in the treatment of type 2 diabetes (5). The ability of the alpha-amylase enzyme inhibitors to avoid dietary starch to be digested and absorbed in the organism has allowed to designat...

SummaryExcessive weight gain arises from the interactions among environmental factors, genetic predisposition and the individual behavior. However, it is becoming evident that interindividual differences in obesity susceptibility depend also on epigenetic factors. Epigenetics studies the heritable changes in gene expression that do not involve changes to the underlying DNA sequence. These processes include DNA methylation, covalent histone modifications, chromatin folding and, more recently described, the regulatory action of miRNAs and polycomb group complexes. In this review, we focus on experimental evidences concerning dietary factors influencing obesity development by epigenetic mechanisms, reporting treatment doses and durations. Moreover, we present a bioinformatic analysis of promoter regions for the search of future epigenetic biomarkers of obesity, including methylation pattern analyses of several obesity-related genes (epiobesigenes), such as FGF2, PTEN, CDKN1A and ESR1, implicated in adipogenesis, SOCS1/ SOCS3, in inflammation, and COX7A1 LPL, CAV1, and IGFBP3, in intermediate metabolism and insulin signalling. The identification of those individuals that at an early age could present changes in the methylation profiles of specific genes could help to predict their susceptibility to later develop obesity, which may allow to prevent and follow-up its progress, as well as to research and develop newer therapeutic approaches.

Epigenetics could contribute to explain individual differences in weight loss after an energy restriction intervention. Here, we identify novel potential epigenetic biomarkers of weight-loss comparing DNA methylation patterns of high and low responders to a 2 hypocaloric diet. Twenty-five overweight/obese men followed an 8-week caloric restriction intervention. DNA was isolated from peripheral blood mononuclear cells and treated with bisulfite. The basal and endpoint epigenetic differences between high and low responders were analysed by methylation microarray, which was also useful to compare the epigenetic changes due to the nutrition intervention. Subsequently, Sequenom EpiTYPER technology was used to validate several relevant CpGs and the surrounding regions.DNA methylation levels in several CpGs located in ATP10A and CD44 genes showed statistical baseline differences depending on the weight-loss outcome. At the treatment endpoint, DNA methylation levels of several CpGs on WT1 promoter were statistically more methylated in the high than in the low responders. Finally, different CpG sites from WT1 and ATP10A were significantly modified as a result of the intervention.In summary, hypocaloric diet-induced weight loss in humans could alter DNA methylation status of specific genes. Moreover, baseline DNA methylation patterns may be used as epigenetic markers that could help to predict weight loss.

MILAGRO, FERMÍN I., JAVIER CAMPIÓ N, AND J. ALFREDO MARTÍNEZ. Weight gain induced by high-fat feeding involves increased liver oxidative stress. Obesity. 2006;14:1118 -1123. Objective: To assess the effects of high-fat feeding on white adipose tissue gene expression and liver oxidative stress. Research Methods and Procedures: Male Wistar rats were fed on standard pelleted or high-fat diet to produce a dietinduced obesity model. Therefore, body composition, serum biochemical values and liver malondialdehyde (MDA) were determined after 56 days of feeding. Expression (mRNA) values of three genes were also determined by reverse transcriptase-polymerase chain reaction in white adipose tissue. Results: Animals fed on the high-fat diet showed more body weight, higher fat deposition and total liver weight, and increased energy intake compared with those on the standard-fat diet. Serum fasting measurements (glucose, insulin, leptin) and homeostasis model assessment insulin resistance index were significantly increased by the high-fat diet consumption. As an indicator of oxidative stress, peroxide decomposition in liver was analyzed, showing an increase of MDA concentrations in rats fed on high-fat diet in comparison with control rats. Interestingly, liver MDA levels correlated positively with body weight gain, serum leptin, and homeostasis model assessment. Finally, leptin and glycerol-3-phosphate dehydrogenase mRNA levels, but not fatty acid synthase, were increased by high-fat diet in comparison with the control-fed group. Discussion: These results show a link among increased fat depots, insulin resistance, and liver oxidative stress. Thus, liver oxidative stress probably contributes to hepatic disorders and aggravates the metabolic syndrome, which is accompanied by a stimulation of the esterification of fatty acids as measured by glycerol-3-phosphate dehydrogenase in the adipose tissue, providing support to the hypothesis that not only calories count in the induction of weight gain or metabolic syndrome and that other factors such as oxidative stress may be involved.

Introduction !Obesity is becoming one of the greatest threats to global health in this century, with more than 1.5 billion overweight adults and at least 400 million of clinically obese subjects [1]. Due to these increasing obesity rates, the World Health Organization (WHO) has prompted to consider it as the epidemic of XXI century and to promote strategies to prevent and control its progress [2]. The development of obesity is characterized by a chronic imbalance between energy intake and energy expenditure [3][4][5], and it is often ascribed to changing lifestyles and inadequate dietary habits [3]. Also, decreased energy expenditure is often associated with an inherited low basal metabolic rate, low energy cost of physical activity, and low capacity for fat oxidation [6]. To reduce body weight and adiposity, a change in lifestyle habits is still the crucial cornerstone [7]. Physical activity might be helpful in the prevention of obesity by elevating the average daily metabolic rate and increasing energy expenditure [3]. Unfortunately, this clinical approach is not long-term lasting, and weight regain is often seen. Drugs that prevent weight regain appear necessary in obesity treatment [7]. Thus, the development of natural products for the treatment of obesity is a challenging task, which can be launched faster and cheaper than conventional single-entity pharmaceuticals [8]. Many medicinal plants may provide safe, natural, and cost-effective alternatives to synthetic drugs [9,10]. Currently, one of the most important strategies in the treatment of obesity includes development of inhibitors of nutrient digestion and absorption. For example, acarbose is an antidiabetic drug that inhibits glycoside hydrolases, thus preventing the digestion of complex carbohydrates and decreasing postprandial hyperglycemia [11,12]. Similar compounds with alpha-amylase inhibiting activity that can be used for diabetes control are being isolated from different plants. The list includes valoneaic acid dilactone [13], obtained from banaba (Lagerstroemia speciosa), the ethanol extract obtained from chestnut astringent skin [14], or the purified pancreatic alpha-amylase inhibitor isolated from white beans (Phaseolus vulgaris), which is able to reduce glycemia in both nondiabetic and diabetic rats [15]. Abstract !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 i...

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