Chemical Characterization and Protective Effects of a Subcritical Water Extract from Olive Pomace Against Dyslipidemia and Hepatic Steatosis in High-Fat/High-Sugar Diet-Fed Mice.

Objective To investigate the protective effect of n-3 polyunsaturated fatty acids(n-3 PUFAs) on non-alcoholic fatty liver disease caused by high fat diet-induced obese(DIO) mice. Methods Three to four-week-old male C57BL/6J mice were randomly divided into 3 groups with 15 cases in each group.These mice were fed with 2 types of high-fat diet(34.9% fat providing 60% of total energy) with n-6 PUFAs(sunflower oil) and n-3 PUFAs(fish oil) respectively to induce obesity for 20 weeks, with a normal-fat diet(4.3% fat providing 10% of total energy) as lean control group.After being fasted for 12 hours, blood samples were drawn, and livers were collected.Plasma markers, insulin, glucose, lipids, alanine aminotransferase(ALT), aspartate aminotransferase(AST), and the lipids of liver were measured by biochemical methods.The mRNA expressions of hepatic genes associated with lipid metabolism, oxidative stress, inflammation and fibrosis were examined by real-time PCR. Results As compared to the control lean mice, the plasma glucose, insulin, total cholesterol(TCH), low density lipoprotein cholesterol(LDL-C) and ALT in the DIO mice with the n-6 PUFA diet were all increased(P<0.05), and also the mRNA expressions of the hepatic genes reflecting hepatic damage, oxidative stress, inflammation and fibrosis were higher(P<0.05). As compared to the DIO mice with the n-6 PUFA diet, the above markers in the plasma and the related genes' expressions in the liver were reduced in DIO mice with the n-3 PUFA diet(P<0.05). Conclusions Dietary fish oil n-3 PUFAs may play some positive roles by antagonizing the abnormal expression of the genes associated with hepatic lipid metabolism, oxidative stress, inflammation and fibrosis in the DIO mice. Key words: N-3 polyunsaturated fatty acids; Non-alcoholic fatty liver disease; Obesity; Mouse

Endocannabinoids, CB1 Receptors, and Liver Disease: Hitting More Than One Bird With the Same Stone

Adipose tissue inflammation induced by macrophage infiltration through the MCP-1/CCR2 pathway is considered to play a pivotal role in the development of visceral obesity and insulin resistance. In the present study, therefore, we examined whether pharmacological inhibition of CCR2 is effective against the development of diet-induced metabolic disorders. C57BL/6 mice were fed a high fat and sucrose diet with or without propagermanium (CCR2 inhibitor, 5 or 50 mg/kg BW/day) for 12 weeks from 6 weeks of age. Then we analyzed lipid and glucose metabolism and tissue inflammation in the liver and adipose tissues along with serum markers in those mice. Propagermanium treatment slightly decreased body weight gain and visceral fat accumulation in diet-induced obese (DIO) mice. Further, propagermanium suppressed macrophage accumulation and shifted adipose tissue macrophage polarization from the pro-inflammatory (M1) state to anti-inflammatory (M2) state in DIO mice. Expressions of TNF-alpha and MCP-1 mRNA in adipose tissue were reduced by propagermanium treatment, indicating that propagermanim suppressed inflammation in adipose tissue. Propagermanium treatment also ameliorated glucose tolerance, insulin sensitivity, and decreased hepatic triglyceride in DIO mice. Thus, propagermanium improved diet-induced obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing inflammation in adipose tissue. Our data indicate that inhibition of CCR2 could improve diet-induced metabolic disorders, and that propagermanium may be a beneficial drug for the treatment of metabolic syndrome.

Asparaginase is an anti-leukemic agent that triggers severe adverse metabolic events. Obesity is a known risk factor for asparaginase-associated liver steatosis. To better understand why, we first compared the liver metabolome of lean versus diet-induced obese (DIO) mice exposed to native asparaginase and observed a substantially altered liver metabolome in DIO mice only. To explore the basis for the altered liver metabolome in DIO mice, we designed experiments to clarify the relative contributions of obesity versus feeding excessive fat during asparaginase on liver triglycerides. Lean mice and DIO mice were fed a high-fat, obesogenic diet (OD) or low fat, maintenance diet (MD) during exposure to pegylated (PEG)-asparaginase. In lean mice, feeding OD during PEG-asparaginase modestly (2-fold) increased liver steatosis. Obese mice fed OD during PEG-asparaginase showed the lowest food intake alongside the lowest liver triglyceride secretion rates, resulting in the largest (6-fold) increase in liver triglycerides and emergent endoplasmic reticulum (ER) stress. Switching obese mice to a MD during PEG-asparaginase did not rescue liver steatosis nor alleviate ER stress. In a separate study, DIO mice globally lacking albumin (AlbKO) were fed OD during exposure to PEG-asparaginase to examine if loss of the major plasma free fatty acid carrier could lessen liver steatosis, but loss of circulating albumin did not mitigate elevated liver triglycerides. In total, the results revealed that body weight loss enables asparaginase-associated liver steatosis and ER stress. Mitigating asparaginase-induced weight loss may be a meaningful strategy in preventing liver stress during treatment.

Metabolic syndrome is a lifestyle-related disease caused by high nutrient condition and lack of exercise. The insulin resistance due to obesity has attracted attention as an underlying mechanism of metabolic syndrome. Insulin resistance refers to reduced insulin sensitivity in insulin target tissues. In this case, in order to maintain normal blood glucose levels, a compensatory large amount of insulin is released, leading to the occurrence of hyperinsulinemia. Taurine is widely distributed in animal tissues. Although it is not involved in protein synthesis, taurine plays an important role in maintaining the body's physiological function. In this experiment, insulin resistance model was induced by high fat and high sugar diet. Two percent taurine was added in drinking water to explore the mechanism of taurine in insulin resistance and to provide theoretical basis for using taurine to improve insulin resistance. The result showed that high-fat and high-sugar diet could decrease insulin sensitivity, and taurine could improve it by oral glucose tolerance test. Moreover, serum TG, TC were higher, while HDL-C in rats fed with high sugar and high fat diet was lower than normal rats, the changes of which can be significantly relieved by 2% taurine administration. mRNA and protein expressions of IRS1, and GLUT4 which were significantly changed by high sugar and high fat diet can also be regulated by 2% taurine. The results indicated that taurine can improve insulin sensitivity through remediating lipid metabolism disorder and regulating the expressions of IRS and GLUT4.

Gallic acid, a phenolic phytochemical, has been shown to exert a variety of effects, including anti-oxidative, anti- carcinogenic, anti-allergic, and anti-inflammatory effects. In this study, we attempted to determine whether gallic acid affects metabolic syndrome such as obesity and diabetes. Diet-induced obesity mice were treated intraperitoneally once per day with gallic acid (10 mg/kg/day). After 2 weeks of treatment, the mice were sacrificed to collect the blood for metabolic parameter assessments, and the adipose tissues and liver to weigh and analyze. The triglyceride concentrations were significantly improved in the gallic acid group relative to those measured in the control group. And most importantly, the blood glucose concentrations in the gallic acid group were significantly improved. In the epididymal white adipose tissue of the gallic acid group, adipocyte size was reduced, PPARγ expression was induced, and the Akt signaling pathway was activated. Our results demonstrate that gallic acid improves glucose tolerance and lipid metabolism in the obesity mice, thereby showing evidence of anti-hyperglycemic activity. The findings of an upregulation of PPARγ expression and Akt activation also contribute to our current understanding of the mechanisms underlying the effects of gallic acid on glucose metabolism.

We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain. In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice. Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high-fat, high-sugar diet. A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure. We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets. Obesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched-chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin-resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet-induced obese mice with pre-existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet-induced obesity and improves glucoregulatory control in diet-induced obese mice. Most dramatically, mice eating an otherwise unhealthy high-calorie, high-sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance.

Cancer is a worldwide epidemic and a leading cause of death. There is a need to find natural solutions for therapy to prevent that outcome. Olive pomace is a known source of bioactive compounds. This work aimed to obtain an olive pomace extract, using an innovative green method, and to assess its chemical composition and the effect of its application in different cancer cell lines. The extract was composed of sugars (28%), minerals (11%), lipids (8%), mostly oleic acid (72%), protein (1%), phenolics (3 g gallic acid equivalents/100 g), hydroxytyrosol (215 mg/100 g), flavonoids (2 g catechin equivalents/100 g), and α-tocopherol (2 mg/100 g). Moreover, 68 phenolics were tentatively identified by UHPLC-ESI-QTOF-MS. The extract significantly reduced the proliferation of the studied cancer cell lines (breast: MCF-7; pancreatic: AsPC-1; and colorectal: HT-29 and Caco-2). It was able to reduce angiogenesis in AsPC-1 cells, presented a cytotoxic effect and increased malondialdehyde levels in HT-29 cells, and decreased growth of Caco-2 cells. These results suggest that this extract can be a source of several compounds which can be used in the formulation of dietary supplements or as a structural basis for antitumoral drugs, but their mechanistic actions still need to be assessed.

Perillyl alcohol ameliorates high-fat diet-induced obesity in mice by modulating gut microbiota and activating IRF4-mediated brown fat thermogenesis.

Epigallocatechin-3-gallate (EGCG) is a polyphenol green tea catechin with potential health benefits and therapeutic effects in non-alcoholic fatty liver disease (NAFLD), a common liver disorder that adversely affects liver function and lipid metabolism. This systematic review surveyed the effects of EGCG or green tea extract (GTE) on NAFLD reported in studies involving rodent models or humans with a focus on clinicopathologic outcomes, lipid and carbohydrate metabolism, and inflammatory, oxidative stress, and liver injury markers. Articles involving clinical efficacy of EGCG/GTE on human subjects and rodent models were gathered by searching the PUBMED database and by referencing additional articles identified from other literature reviews. EGCG or GTE supplementation reduced body weight, adipose tissue deposits, and food intake. Mechanistically, the majority of these studies confirmed that EGCG or GTE supplementation plays a significant role in regulating lipid and glucose metabolism and expression of genes involved in lipid synthesis. Importantly, EGCG and GTE supplementation were shown to have beneficial effects on oxidative stress-related pathways that activate pro-inflammatory responses, leading to liver damage. In conclusion, green tea catechins are a potentially useful treatment option for NAFLD. More research is required to determine the ideal dosage, treatment duration, and most effective delivery method of EGCG or GTE, and to provide more definitive conclusions by performing large, randomized clinical trials.

Unique pharmacology of a novel allosteric agonist/sensitizer insulin receptor monoclonal antibody

Tirzepatide retention in iWAT with mesoporous polydopamine encapsulation enhances weight loss through leptin receptor signaling.

Visceral obesity and insulin resistance are common underlying factors of the metabolic syndrome (MetS), which is associated with a chronic low-grade inflammatory state and cardiovascular disease. C-C chemokine receptor-2 (CCR2), known as a receptor for MCP-1, plays a role in monocyte/macrophage (M φ ) recruitment and M φ -dependent inflammatory response. Recently, adipose tissue inflammation by M φ infiltration through MCP-1/CCR2 is considered to play a pivotal role in the development of visceral obesity and insulin resistance. However, the effect of postnatal inhibition of CCR2 on the development of diet-induced obesity (DIO) and insulin resistance remains unclear. To further explore the role of CCR2 in the development of visceral obesity and its associated metabolic disorders, we studied the effect of pharmacological inhibition of CCR2 before the onset of DIO in C57BL/6 mice. To study the effect of CCR2 inhibition, C57BL/6 mice were fed a high fat and high sugar diet with or without propagermanium (Pro, dose of 5mg and 50mg/kg/day), as a CCR2 inhibitor for 12 weeks from 6 weeks of age. At the end of study the gene expression of F4/80 and CD11c was reduced by 50%, while that of IL-10 and MGL-1 was increased by 2-fold in white adipose tissue (WAT), indicating that Pro suppressed adipose tissue M φ accumulation and shifted the infiltration of pro-inflammatory M1 M φ to anti-inflammatory M2 M φ . These data are consistent with a marked reduction of pro-inflammatory cytokine, TNF- α by Pro by 50% in WAT and liver. Diet-induced hypoadiponectinemia and hyperleptinemia were also improved by Pro treatment. Further, Pro treatment ameliorated insulin sensitivity and glucose tolerance, resulting in a marked reduction of plasma glucose and insulin level. Finally, Pro treatment decreased hepatic triglyceride contents by 45% in DIO mice. In conclusion, Pro improved obesity and its associated metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing infiltration of pro-inflammatory M1 M φ into WAT. Our data also implicate that CCR2 contributes to DIO and type 2 diabetes by accelerating adipose tissue inflammation, and that Pro may be a beneficial drug for the treatment of such metabolic disorders by blocking CCR2-mediated inflammation.

The circular RNA circH19 has been implicated in the regulation of gene expression and various biological processes, including obesity. Objectives: This study aimed to elucidate the metabolic changes in plasma after circH19 knockdown in a diet-induced obese (DIO) mouse model. Methods: Plasma samples were collected following the intervention and subjected to non-targeted metabolomics analysis using liquid chromatography–mass spectrometry (LC-MS). Metabolic profiling was performed to identify and quantify metabolites, followed by multivariate statistical analysis to discern differential metabolic signatures. Results: A total of 1250 features were quantified, resulting in the upregulation of 564 metabolites and the downregulation of 686 metabolites in the circH19 knockdown group compared to the control mice. Metabolic pathway analysis revealed disruptions in lipid metabolism, amino acid turnover, and energy production pathways. Notably, the intervention led to a substantial decrease in circulating lipids and alterations in the plasma amino acid profile, indicative of an impact on protein catabolism and anabolic processes. The observed shifts in lipid and amino acid metabolism suggest potential therapeutic avenues for obesity and related metabolic disorders. Conclusions: The circH19 knockdown in DIO mice led to significant alterations in plasma metabolites, highlighting its potential role in the regulation of obesity and metabolic disorders.

Effects of dietary wild bitter melon (Momordica charantia var. abbreviate Ser.) extract on glucose and lipid metabolism in HFD/STZ-induced type 2 diabetic rats.