Dietary fructose as a metabolic risk factor

Over the past decades, the role of the intestinal microbiota in metabolic diseases has come forward. In this regard, both composition and function of our intestinal microbiota is highly variable and influenced by multiple factors, of which diet is one of the major elements. Between 1970 and 1990, diet composition has changed and consumption of dietary sugars has increased, of which fructose intake rose by more than 10-fold. This increased intake of sugars and fructose is considered as one of the major risk factors in the developments of obesity and several metabolic disturbances. In this review, we describe the association of dietary fructose intake with insulin resistance, nonalcoholic fatty liver disease (NAFLD) and lipid metabolism. Moreover, we will focus on the potential causality of this altered gut microbiota using fecal transplantation studies in human metabolic disease and whether fecal microbial transplant can reverse this phenotype

Evaluating causality of cellular senescence in non-alcoholic fatty liver diseaseKey points

Summary: Cellular senescence is a state of irreversible cell cycle arrest that has important physiological functions. However, cellular senescence is also a hallmark of ageing and has been associated with several pathological conditions. A wide range of factors including genotoxic stress, mitogens and inflammatory cytokines can induce senescence. Phenotypically, senescent cells are characterised by short telomeres, an enlarged nuclear area and damaged genomic and mitochondrial DNA. Secretion of proinflammatory proteins, also known as the senescence-associated secretory phenotype, is a characteristic of senescent cells that is thought to be the main contributor to their disease-inducing properties. In the past decade, the role of cellular senescence in the development of non-alcoholic fatty liver disease (NAFLD) and its progression towards non-alcoholic steatohepatitis (NASH) has garnered significant interest. Until recently, it was suggested that hepatocyte cellular senescence is a mere consequence of the metabolic dysregulation and inflammatory phenomena in fatty liver disease. However, recent work in rodents has suggested that senescence may be a causal factor in NAFLD development. Although causality is yet to be established in humans, current evidence suggests that targeting senescent cells has therapeutic potential for NAFLD. We aim to provide insights into the quality of the evidence supporting a causal role of cellular senescence in the development of NAFLD in rodents and humans. We will elaborate on key cellular and molecular features of senescence and discuss the efficacy and safety of novel senolytic drugs for the treatment or prevention of NAFLD

Autocrine negative feed-back regulation of lipolysis through sensing of NEFAs by FFAR4/GPR120 in WAT

Objectives: Long-chain fatty acids (LCFAs) released from adipocytes inhibit lipolysis through an unclear mechanism. We hypothesized that the LCFA receptor, FFAR4 (GPR120), which is highly expressed in adipocytes, may be involved in this feedback regulation. Methods and results: Liquid chromatography mass spectrometry (LC-MS) analysis of conditioned media from isoproterenol-stimulated primary cultures of murine and human adipocytes demonstrated that most of the released non-esterified free fatty acids (NEFAs) are known agonists for FFAR4. In agreement with this, conditioned medium from isoproterenol-treated adipocytes stimulated signaling strongly in FFAR4 transfected COS-7 cells as opposed to non-transfected control cells. In transfected 3T3-L1 cells, FFAR4 agonism stimulated Gi- and Go-mini G protein binding more strongly than Gq, effects which were blocked by the selective FFAR4 antagonist AH7614. In primary cultures of murine white adipocytes, the synthetic, selective FFAR4 agonist CpdA inhibited isoproterenol-induced intracellular cAMP accumulation in a manner similar to the antilipolytic control agent nicotinic acid acting through another receptor, HCAR2. In vivo, oral gavage with the synthetic, specific FFAR4 agonist CpdB decreased the level of circulating NEFAs in fasting lean mice to a similar degree as nicotinic acid. In agreement with the identified anti-lipolytic effect of FFAR4, plasma NEFAs and glycerol were increased in FFAR4-deficient mice as compared to littermate controls despite having elevated insulin levels, and cAMP accumulation in primary adipocyte cultures was augmented by treatment with the FFAR4 antagonist conceivably by blocking the stimulatory tone of endogenous NEFAs on FFAR4. Conclusions: In white adipocytes, FFAR4 functions as an NEFA-activated, autocrine, negative feedback regulator of lipolysis by decreasing cAMP though Gi-mediated signaling

Faecal Microbiota transplantation affects liver DNA methylation in Non-alcoholic fatty liver disease: a multi-omics approach

ABSTRACTIndividuals with nonalcoholic fatty liver disease (NAFLD) have an altered gut microbiota composition. Moreover, hepatic DNA methylation may be altered in the state of NAFLD. Using a fecal microbiota transplantation (FMT) intervention, we aimed to investigate whether a change in gut microbiota composition relates to altered liver DNA methylation in NAFLD. Moreover, we assessed whether plasma metabolite profiles altered by FMT relate to changes in liver DNA methylation. Twenty-one individuals with NAFLD underwent three 8-weekly vegan allogenic donor (n = 10) or autologous (n = 11) FMTs. We obtained hepatic DNA methylation profiles from paired liver biopsies of study participants before and after FMTs. We applied a multi-omics machine learning approach to identify changes in the gut microbiome, peripheral blood metabolome and liver DNA methylome, and analyzed cross-omics correlations. Vegan allogenic donor FMT compared to autologous FMT induced distinct differential changes in I) gut microbiota profiles, including increased abundance of Eubacterium siraeum and potential probiotic Blautia wexlerae; II) plasma metabolites, including altered levels of phenylacetylcarnitine (PAC) and phenylacetylglutamine (PAG) both from gut-derived phenylacetic acid, and of several choline-derived long-chain acylcholines; and III) hepatic DNA methylation profiles, most importantly in Threonyl-TRNA Synthetase 1 (TARS) and Zinc finger protein 57 (ZFP57). Multi-omics analysis showed that Gemmiger formicillis and Firmicutes bacterium_CAG_170 positively correlated with both PAC and PAG. E siraeum negatively correlated with DNA methylation of cg16885113 in ZFP57. Alterations in gut microbiota composition by FMT caused widespread changes in plasma metabolites (e.g. PAC, PAG, and choline-derived metabolites) and liver DNA methylation profiles in individuals with NAFLD. These results indicate that FMTs might induce metaorganismal pathway changes, from the gut bacteria to the liver

Type 2 diabetes is associated with increased circulating levels of 3-hydroxydecanoate activating GPR84 and neutrophil migration

Obesity and diabetes are associated with inflammation and altered plasma levels of several metabolites, which may be involved in disease progression. Some metabolites can activate G protein-coupled receptors (GPCRs) expressed on immune cells where they can modulate metabolic inflammation. Here, we find that 3-hydroxydecanoate is enriched in the circulation of obese individuals with type 2 diabetes (T2D) compared with nondiabetic controls. Administration of 3-hydroxydecanoate to mice promotes immune cell recruitment to adipose tissue, which was associated with adipose inflammation and increased fasting insulin levels. Furthermore, we demonstrate that 3-hydroxydecanoate stimulates migration of primary human and mouse neutrophils, but not monocytes, through GPR84 and Gαi signaling in vitro. Our findings indicate that 3-hydroxydecanoate is a T2D-associated metabolite that increases inflammatory responses and may contribute to the chronic inflammation observed in diabetes