3-8-dihydroxy-6h-dibenzo(b-d)pyran-6-one and Obesity

Obesity is not only viewed as a chronic aggressive disorder but is also associated with an increased risk for various diseases. Nonetheless, new anti-obesity drugs are an urgent need since few pharmacological choices are available on the market. Natural compounds have served as templates for drug discovery, whereas modified molecules from the leads identified based on in vitro models often reveal noncorresponding bioactivity between in vitro and in vivo studies. Therefore, to provide inspiration for the exploration of innovative anti-obesity agents, recent discoveries of natural anti-obesity compounds with in vivo evidence have been summarized according to their chemical structures, and the comparable efficacy of these compounds is categorized using animal models. In addition, several synthetic derivatives optimized from the phytochemicals are also provided to discuss medicinal chemistry achievements guided by natural sources.

Topics: Animals; Anti-Obesity Agents; Drug Discovery; Obesity; Phytochemicals

Topics: Animals; Cardiomyopathies; Mice; Mice, Obese; Mitophagy; Myocytes, Cardiac; Obesity; Protein Kinases; Ubiquitin-Protein Ligases

Obesity is a global health concern associated with the dysbiosis of intestinal microbial composition. In this study, we investigated the potentials of urolithin A (Uro-A) and urolithin B (Uro-B), two gut microbiota-derived metabolites of ellagitannins, in reducing body weight gain through the modulation of the gut microbiota. We established a high-fat diet (HFD)-induced obesity model in rats that were later administered with either 2.5 mg/kg of Uro-A or Uro-B. Serum biochemical parameters were quantified, and changes in the composition of the gut microbial community were analysed using 16S rDNA gene sequencing. Our results showed that the urolithins significantly decreased the body weight in HFD-fed rats and restored serum lipid profile. The taxonomic analysis showed that both Uro-A and Uro-modulated gut microbes related to body weight, dysfunctional lipid metabolism and inflammation. Overall, our results suggest that Uro-A and Uro-B possess anti-obesity properties, which may be related to the modulation of the gut microbial composition.

Topics: Animals; Body Weight; Coumarins; Diet, High-Fat; Dysbiosis; Gastrointestinal Microbiome; Mice; Mice, Inbred C57BL; Obesity; Rats

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.

Topics: Adipocytes, Brown; Adipocytes, White; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Coumarins; Diet, High-Fat; Energy Metabolism; Fatty Liver; Glucose Intolerance; Insulin Resistance; Maillard Reaction; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Propylthiouracil; Thermogenesis; Triiodothyronine; Weight Gain

Urolithin A (UroA) is a major metabolite of ellagic acid produced following microbial catabolism in the gut. Emerging evidence has suggested that UroA modulates energy metabolism in various cells. However, UroA's physiological functions related to obesity and insulin resistance remain unclear.. Male mice were intraperitoneally administrated either UroA or dimethyl sulfoxide (vehicle) along with a high-fat diet for 12 weeks. Insulin sensitivity was evaluated via glucose and insulin tolerance tests and acute insulin signaling. The effects of UroA on hepatic triglyceride accumulation, adipocyte size, mitochondrial DNA content, and proinflammatory gene expressions were determined. The impact of UroA on macrophage polarization and mitochondrial respiration were assessed in bone marrow-derived macrophages.. Administration of UroA (1) improved systemic insulin sensitivity, (2) attenuated triglyceride accumulation and elevated mitochondrial biogenesis in the liver, (3) reduced adipocyte hypertrophy and macrophage infiltration into the adipose tissue, and (4) altered M1/M2 polarization in peritoneal macrophages. In addition, UroA favored macrophage M2 polarization and mitochondrial respiration in bone marrow-derived macrophages.. UroA plays a direct role in improving systemic insulin sensitivity independent of its parental compounds. This work supports UroA's role in the metabolic benefits of ellagic acid-rich foods and highlights the significance of its microbial transformation in the gut.

Topics: Adipocytes; Adipose Tissue; Animals; Cells, Cultured; Coumarins; Diet, High-Fat; Glucose; Inflammation; Insulin; Insulin Resistance; Liver; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mitochondria; Obesity; Organelle Biogenesis; Triglycerides

Urolithins are microbial metabolites produced after consumption of ellagitannin-containing foods such as pomegranates and walnuts. Parallel to isoflavone-metabolizing phenotypes, ellagitannin-metabolizing phenotypes (urolithin metabotypes A, B and 0; UM-A, UM-B and UM-0, respectively) can vary among individuals depending on their body mass index (BMI), but correlations between urolithin metabotypes (UMs) and cardiometabolic risk (CMR) factors are unexplored. We investigated the association between UMs and CMR factors in individuals with different BMI and health status.. UM was identified using UPLC-ESI-qToF-MS in individuals consuming pomegranate or nuts. The associations between basal CMR factors and the urine urolithin metabolomic signature were explored in 20 healthy normoweight individuals consuming walnuts (30 g/d), 49 healthy overweight-obese individuals ingesting pomegranate extract (450 mg/d) and 25 metabolic syndrome (MetS) patients consuming nuts (15 g-walnuts, 7.5 g-hazelnuts and 7.5 g-almonds/d).. Correlations between CMR factors and urolithins were found in overweight-obese individuals. Urolithin-A (mostly present in UM-A) was positively correlated with apolipoprotein A-I (P ≤ 0.05) and intermediate-HDL-cholesterol (P ≤ 0.05) while urolithin-B and isourolithin-A (characteristic from UM-B) were positively correlated with total-cholesterol, LDL-cholesterol (P ≤ 0.001), apolipoprotein B (P ≤ 0.01), VLDL-cholesterol, IDL-cholesterol, oxidized-LDL and apolipoprotein B:apolipoprotein A-I ratio (P ≤ 0.05). In MetS patients, urolithin-A only correlated inversely with glucose (P ≤ 0.05). Statin-treated MetS patients with UM-A showed a lipid profile similar to that of healthy normoweight individuals while a poor response to lipid-lowering therapy was observed in MB patients.. UMs are potential CMR biomarkers. Overweight-obese individuals with UM-B are at increased risk of cardiometabolic disease, whereas urolithin-A production could protect against CMR factors. Further research is warranted to explore these associations in larger cohorts and whether the effect of lipid-lowering drugs or ellagitannin-consumption on CMR biomarkers depends on individuals' UM.. NCT01916239 (https://clinicaltrials.gov/ct2/show/NCT01916239) and ISRCTN36468613 (http://www.isrctn.com/ISRCTN36468613).

Topics: Adult; Biomarkers; Body Mass Index; Body Weight; Cardiovascular Diseases; Coumarins; Female; Fruit; Gastrointestinal Microbiome; Humans; Hydrolyzable Tannins; Juglans; Lipids; Lythraceae; Male; Metabolic Syndrome; Middle Aged; Nuts; Obesity; Overweight; Plant Extracts; Risk Factors