Polyphenols and metabolism: from present knowledge to future challenges.

A diet rich in polyphenols and other types of phytonutrients can reduce the occurrence of chronic diseases. However, a well-established cause-and-effect association has not been clearly demonstrated and several other issues will need to be fully understood before general recommendations will be carried out In the present review, some of the future challenges that the research on phenolic compounds will have to face in the next years are discussed: toxicological aspects of polyphenols and safety risk assessment; synergistic effects between different polyphenols; metabotype-based nutritional advice based on a differential gut microbial metabolism of polyphenols (precision nutrition); combination of polyphenols with other bioactive compounds; innovative formulations to improve the bioavailability of phenolic compounds; and polyphenols in sports nutrition and recovery.Other aspects related to polyphenol research that will have a boost in the next years are: polyphenol and gut microbiota crosstalk, including prebiotic effects and biotransformation of phenolic compounds into bioactive metabolites by gut microorganisms; molecular docking, molecular dynamics simulation, and quantum and molecular mechanics studies on the protein-polyphenol complexes; and polyphenol-based coating films, nanoparticles, and hydrogels to facilitate the delivery of drugs, nucleic acids and proteins.In summary, this article provides some constructive inspirations for advancing in the research of the applications, risk assessment and metabolic effects of dietary polyphenols in humans.

Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health.

Glutamine and glutamate are interconverted by several enzymes and alterations in this metabolic cycle are linked to cardiometabolic traits. Herein, we show that obesity-associated insulin resistance is characterized by decreased plasma and white adipose tissue glutamine-to-glutamate ratios. We couple these stoichiometric changes to perturbed fat cell glutaminase and glutamine synthase messenger RNA and protein abundance, which together promote glutaminolysis. In human white adipocytes, reductions in glutaminase activity promote aerobic glycolysis and mitochondrial oxidative capacity via increases in hypoxia-inducible factor 1α abundance, lactate levels and p38 mitogen-activated protein kinase signalling. Systemic glutaminase inhibition in male and female mice, or genetically in adipocytes of male mice, triggers the activation of thermogenic gene programs in inguinal adipocytes. Consequently, the knockout mice display higher energy expenditure and improved glucose tolerance compared to control littermates, even under high-fat diet conditions. Altogether, our findings highlight white adipocyte glutamine turnover as an important determinant of energy expenditure and metabolic health.

Unraveling Adipose Tissue Dysfunction: Molecular Mechanisms, Novel Biomarkers, and Therapeutic Targets for Liver Fat Deposition.

Adipose tissue (AT), once considered a mere fat storage organ, is now recognized as a dynamic and complex entity crucial for regulating human physiology, including metabolic processes, energy balance, and immune responses. It comprises mainly two types: white adipose tissue (WAT) for energy storage and brown adipose tissue (BAT) for thermogenesis, with beige adipocytes demonstrating the plasticity of these cells. WAT, beyond lipid storage, is involved in various metabolic activities, notably lipogenesis and lipolysis, critical for maintaining energy homeostasis. It also functions as an endocrine organ, secreting adipokines that influence metabolic, inflammatory, and immune processes. However, dysfunction in WAT, especially related to obesity, leads to metabolic disturbances, including the inability to properly store excess lipids, resulting in ectopic fat deposition in organs like the liver, contributing to non-alcoholic fatty liver disease (NAFLD). This narrative review delves into the multifaceted roles of WAT, its composition, metabolic functions, and the pathophysiology of WAT dysfunction. It also explores diagnostic approaches for adipose-related disorders, emphasizing the importance of accurately assessing AT distribution and understanding the complex relationships between fat compartments and metabolic health. Furthermore, it discusses various therapeutic strategies, including innovative therapeutics like adipose-derived mesenchymal stem cells (ADMSCs)-based treatments and gene therapy, highlighting the potential of precision medicine in targeting obesity and its associated complications.

Isthmin-1 (ISM1), a novel adipokine that reflects abdominal adipose tissue distribution in individuals with obesity.

BACKGROUND: The assessment of obesity-related health risks has traditionally relied on the Body Mass Index and waist circumference, but their limitations have propelled the need for a more comprehensive approach. The differentiation between visceral (VIS) and subcutaneous (SC) fat provides a finer-grained understanding of these risks, yet practical assessment methods are lacking. We hypothesized that combining the SC-VIS fat ratio with non-invasive biomarkers could create a valuable tool for obesity-related risk assessment. METHODS AND RESULTS: A clinical study of 125 individuals with obesity revealed significant differences in abdominal fat distribution measured by CT-scan among genders and distinct models of obesity, including visceral, subcutaneous, and the SC/VIS ratio. Stratification based on these models highlighted various metabolic changes. The SC/VIS ratio emerged as an excellent metric to differentiate metabolic status. Gene expression analysis identified candidate biomarkers, with ISM1 showing promise. Subsequent validation demonstrated a correlation between ISM1 levels in SC and plasma, reinforcing its potential as a non-invasive biomarker for fat distribution. Serum adipokine levels also correlated with the SC/VIS ratio. The Receiver Operating Characteristic analysis revealed ISM1's efficacy in discriminating individuals with favorable metabolic profiles based on adipose tissue distribution. Correlation analysis also suggested that ISM1 was involved in glucose regulation pathways. CONCLUSION: The study's results support the hypothesis that the SC-VIS fat ratio and its derived non-invasive biomarkers can comprehensively assess obesity-related health risks. ISM1 could predict abdominal fat partitioning and be a potential biomarker for evaluating obesity-related health risks.

CRISPR/Cas9-mediated deletion of adipocyte genes associated with NAFLD alters adipocyte lipid handling and reduces steatosis in hepatocytes in vitro.

Obesity is a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD), and the subcutaneous white adipose tissue (scWAT) is the primary lipid storage depot and regulates lipid fluxes to other organs. Our previous work identified genes upregulated in scWAT of patients with NAFLD: SOCS3, DUSP1, and SIK1. Herein, we knocked down (KD) their expression in human adipose-derived mesenchymal stem cells (hADMSCs) using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology and characterized their phenotype. We found that SOCS3, DUSP1, and SIK1 expression in hADMSC-derived adipocytes was not critical for adipogenesis. However, the metabolic characterization of the cells suggested that the genes played important roles in lipid metabolism. Reduction of SIK1 expression significantly increased both de novo lipogenesis (DNL) and palmitate-induced lipogenesis (PIL). Editing out SOCS3 reduced DNL while increasing isoproterenol-induced lipolysis and insulin-induced palmitate accumulation. Conversely, DUSP1 reduced PIL and DNL. Moreover, RNA-sequencing analysis of edited cells showed that these genes not only altered lipid metabolism but also other biological pathways related to inflammatory processes, in the case of DUSP1, extracellular matrix remodeling for SOCS3, or cellular transport for SIK1. Finally, to evaluate a possible adipocyte-hepatocyte axis, human hepatoma HepG2 cells were cocultured with edited hADMSCs-derived adipocytes in the presence of [3H]-palmitate. All HepG2 cells cultured with DUSP1-, SIK1-, or SOCS3-KD adipocytes decreased [3H]-palmitate accumulation compared with control adipocytes. These results support our hypotheses that SOCS3, DUSP1, and SIK1 regulate multiple aspects of adipocyte function, which may play a role in the progression of obesity-associated comorbidities, such as NAFLD.NEW & NOTEWORTHY Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology successfully edited genomic DNA of human adipose-derived mesenchymal stem cells (hADMSC). SOCS3, SIK1, and DUSP1 regulate adipocyte lipid handling. Silencing SOCS3, SIK1, and DUSP1 expression in hADMSC-derived adipocytes reduces hepatocyte lipid storage in vitro.

Triglyceride-rich lipoproteins and insulin resistance in patients with chronic hepatitis C receiving direct-acting antivirals.

BACKGROUND & AIMS: Hepatitis C virus (HCV) interferes with carbohydrate and lipid metabolism causing cardiovascular disease and insulin resistance (IR). Direct-acting antivirals (DAAs) are highly effective for the eradication of HCV, with positive effects on metabolic health although paradoxically associated with increased total and LDL-cholesterol. The aims of this study were 1) to characterize dyslipidemia (lipoprotein content, number, and size) in naive HCV-infected individuals and 2) to evaluate the longitudinal association of metabolic changes and lipoparticle characteristics after DAA therapy. METHODS: We conducted a prospective study with one-year follow-up. 83 naive outpatients treated with DAAs were included. Those co-infected with HBV or HIV were excluded. IR was analyzed using the HOMA index. Lipoproteins were studied by fast-protein liquid chromatography (FPLC) and Nuclear Magnetic Resonance Spectroscopy (NMR). RESULTS: FPLC analysis showed that lipoprotein-borne HCV was only present in the VLDL region most enriched in APOE. There was a lack of association between HOMA and total cholesterol or cholesterol carried by LDL or HDL at baseline. Alternatively, a positive association was found between HOMA and total circulating triglycerides (TG), as well as with TG transported in VLDL, LDL, and HDL. HCV eradication with DAAs resulted in a strong and significant decrease in HOMA (-22%) and HDL-TG (-18%) after one-year follow-up. CONCLUSIONS: HCV-dependent lipid abnormalities are associated with IR and DAA therapy can reverse this association. These findings may have potential clinical implications as the HDL-TG trajectory may inform the evolution of glucose tolerance and IR after HCV eradication.

Gene Therapy Based on Mesenchymal Stem Cells Derived from Adipose Tissue for the Treatment of Obesity and Its Metabolic Complications.

Obesity is a highly prevalent condition often associated with dysfunctional adipose tissue. Stem cell-based therapies have become a promising tool for therapeutic intervention in the context of regenerative medicine. Among all stem cells, adipose-derived mesenchymal stem cells (ADMSCs) are the most easily obtained, have immunomodulatory properties, show great ex vivo expansion capacity and differentiation to other cell types, and release a wide variety of angiogenic factors and bioactive molecules, such as growth factors and adipokines. However, despite the positive results obtained in some pre-clinical studies, the actual clinical efficacy of ADMSCs still remains controversial. Transplanted ADMSCs present a meager rate of survival and proliferation, possibly because of the damaged microenvironment of the affected tissues. Therefore, there is a need for novel approaches to generate more functional ADMSCs with enhanced therapeutic potential. In this context, genetic manipulation has emerged as a promising strategy. In the current review, we aim to summarize several adipose-focused treatments of obesity, including cell therapy and gene therapy. Particular emphasis will be given to the continuum from obesity to metabolic syndrome, diabetes, and underlying non-alcoholic fatty liver disease (NAFLD). Furthermore, we will provide insights into the potential shared adipocentric mechanisms involved in these pathophysiological processes and their remediation using ADMSCs.

Identification of novel targets in adipose tissue involved in non-alcoholic fatty liver disease progression.

Obesity is a major risk factor for the development of Nonalcoholic fatty liver disease (NAFLD). We hypothesize that a dysfunctional subcutaneous white adipose tissue (scWAT) may lead to an accumulation of ectopic fat in the liver. Our aim was to investigate the molecular mechanisms involved in the causative role of scWAT in NALFD progression. We performed a RNA-sequencing analysis in a discovery cohort (n = 45) to identify genes in scWAT correlated with fatty liver index, a qualitative marker of liver steatosis. We then validated those targets in a second cohort (n = 47) of obese patients who had liver biopsies available. Finally, we obtained scWAT mesenchymal stem cells (MSCs) from 13 obese patients at different stages of NAFLD and established in vitro models of human MSC (hMSC)-derived adipocytes. We observed impaired adipogenesis in hMSC-derived adipocytes as liver steatosis increased, suggesting that an impaired adipogenic capacity is a critical event in the development of NAFLD. Four genes showed a differential expression pattern in both scWAT and hMSC-derived adipocytes, where their expression paralleled steatosis degree: SOCS3, DUSP1, SIK1, and GADD45B. We propose these genes as key players in NAFLD progression. They could eventually constitute potential new targets for future therapies against liver steatosis.

Adiponectin overexpression in C2C12 myocytes increases lipid oxidation and myofiber transition.

Metabolic syndrome and obesity have detrimental effects on the metabolic function of the skeletal muscle. Mounting evidence indicates that patients with those conditions may present an increased ratio of glycolytic to oxidative fibers associated with a decrease in oxidative capacity. In this regard, adiponectin, a hormone mainly secreted by adipocytes that regulates glucose and lipid metabolism, has emerged as a myokine that could play an important role in this process. We aimed to investigate whether adiponectin overexpression in skeletal muscle might be a local protective mechanism, favoring fatty acid utilization. To that end, we generated an in vitro model of myocytes with upregulated endogenous adiponectin using a lentiviral carrier. We demonstrated that the adiponectin-transduced myocytes were able to produce and secrete fully functional adiponectin complexes. Adiponectin overexpression remarkably upregulated the mRNA level of myogenic regulatory factors as well as genes implicated in lipolysis (HSL, ATGL) and cellular and mitochondrial fatty acid transport (LPL, CD36, CPT1B). This was accompanied by increased isoproterenol-induced lipolysis and ß-oxidation and reduced lipogenesis, whereas insulin-stimulated glucose uptake was unaltered in transduced myocytes. Lastly, the relative expression of the more glycolytic myofibers (MyHC IIb) compared to the more oxidative ones (MyHC I) was notably reduced. Our results showed that the released adiponectin acted in an autocrine/paracrine manner, increasing lipid oxidation in myocytes and leading to a transition of myofibers from the glycolytic to the oxidative type. In conclusion, muscle adiponectin overexpression might be a way to relieve muscle diseases caused by oxidative muscle fiber deficiency.

Amino Acid Profile in Malnourished Patients with Liver Cirrhosis and Its Modification with Oral Nutritional Supplements: Implications on Minimal Hepatic Encephalopathy.

Low plasma levels of branched chain amino acids (BCAA) in liver cirrhosis are associated with hepatic encephalopathy (HE). We aimed to identify a metabolic signature of minimal hepatic encephalopathy (MHE) in malnourished cirrhotic patients and evaluate its modification with oral nutritional supplements (ONS) enriched with ß-Hydroxy-ß-methylbutyrate (HMB), a derivative of the BCAA leucine. Post hoc analysis was conducted on a double-blind placebo-controlled trial of 43 individuals with cirrhosis and malnutrition, who were randomized to receive, for 12 weeks, oral supplementation twice a day with either 220 mL of Ensure® Plus Advance (HMB group, n = 22) or with 220 mL of Ensure® Plus High Protein (HP group, n = 21). MHE evaluation was by psychometric hepatic encephalopathy score (PHES). Compared to the HP group, an HMB-specific treatment effect led to a larger increase in Val, Leu, Phe, Trp and BCAA fasting plasma levels. Both treatments increased Fischer's ratio and urea without an increase in Gln or ammonia fasting plasma levels. MHE was associated with a reduced total plasma amino acid concentration, a reduced BCAA and Fischer´s ratio, and an increased Gln/Glu ratio. HMB-enriched ONS increased Fischer´s ratio without varying Gln or ammonia plasma levels in liver cirrhosis and malnutrition, a protective amino acid profile that can help prevent MHE.

Regulation of p27 and Cdk2 Expression in Different Adipose Tissue Depots in Aging and Obesity.

Aging usually comes associated with increased visceral fat accumulation, reaching even an obesity state, and favoring its associated comorbidities. One of the processes involved in aging is cellular senescence, which is highly dependent on the activity of the regulators of the cell cycle. The aim of this study was to analyze the changes in the expression of p27 and cdk2 in different adipose tissue depots during aging, as well as their regulation by obesity in mice. Changes in the expression of p27 and CDK2 in visceral and subcutaneous white adipose tissue (WAT) biopsies were also analyzed in a human cohort of obesity and type 2 diabetes. p27, but not cdk2, exhibits a lower expression in subcutaneous than in visceral WAT in mice and humans. p27 is drastically downregulated by aging in subcutaneous WAT (scWAT), but not in gonadal WAT, of female mice. Obesity upregulates p27 and cdk2 expression in scWAT, but not in other fat depots of aged mice. In humans, a significant upregulation of p27 was observed in visceral WAT of subjects with obesity. Taken together, these results show a differential adipose depot-dependent regulation of p27 and cdk2 in aging and obesity, suggesting that p27 and cdk2 could contribute to the adipose-tissue depot's metabolic differences. Further studies are necessary to fully corroborate this hypothesis.