Mitochondrial dysfunction increases fatty acid β-oxidation and translates into impaired neuroblast maturation

The metabolic transition from anaerobic glycolysis and fatty acid \u3b2-oxidation to glycolysis coupled to oxidative phosphorylation is a key process for the transition of quiescent neural stem cells to proliferative neural progenitor cells. However, a full characterization of the metabolic shift and the involvement of mitochondria during the last step of neurogenesis, from neuroblasts to neuron maturation, is still elusive. Here, we describe a model of neuroblasts, Neuro2a cells, with impaired differentiation capacity due to mitochondrial dysfunction. Using a detailed biochemical characterization consisting of steady-state metabolomics and metabolic flux analysis, we find increased fatty acid \u3b2-oxidation as a peculiar feature of neuroblasts with altered mitochondria. The consequent metabolic switch favors neuroblast proliferation at the expense of neuron maturation

Hepatic ERα accounts for sex differences in the ability to cope with an excess of dietary lipids

Objective: Among obesity-associated metabolic diseases, non-alcoholic fatty liver disease (NAFLD) represents an increasing public health issue due to its emerging association with atherogenic dyslipidemia and cardiovascular diseases (CVDs). The lower prevalence of NAFLD in pre-menopausal women compared with men or post-menopausal women led us to hypothesize that the female-inherent ability to counteract this pathology might strongly rely on estrogen signaling. In female mammals, estrogen receptor alpha (ER\u3b1) is highly expressed in the liver, where it acts as a sensor of the nutritional status and adapts the metabolism to the reproductive needs. As in the male liver this receptor is little expressed, we here hypothesize that hepatic ER\u3b1 might account for sex differences in the ability of males and females to cope with an excess of dietary lipids and counteract the accumulation of lipids in the liver. Methods: Through liver metabolomics and transcriptomics we analyzed the relevance of hepatic ER\u3b1 in the metabolic response of males and females to a diet highly enriched in fats (HFD) as a model of diet-induced obesity. Results: The study shows that the hepatic ER\u3b1 strongly contributes to the sex-specific response to an HFD and its action accounts for opposite consequences for hepatic health in males and females. Conclusion: This study identified hepatic ER\u3b1 as a novel target for the design of sex-specific therapies against fatty liver and its cardio-metabolic consequences

Physical Exercise Affects Adipose Tissue Profile and Prevents Arterial Thrombosis in BDNF Val66Met Mice

Adipose tissue accumulation is an independent and modifiable risk factor for cardiovascular disease (CVD). The recent CVD European Guidelines strongly recommend regular physical exercise (PE) as a management strategy for prevention and treatment of CVD associated with metabolic disorders and obesity. Although mutations as well as common genetic variants, including the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, are associated with increased body weight, eating and neuropsychiatric disorders, and myocardial infarction, the effect of this polymorphism on adipose tissue accumulation and regulation as well as its relation to obesity/thrombosis remains to be elucidated. Here, we showed that white adipose tissue (WAT) of humanized knock-in BDNFVal66Met (BDNFMet/Met) mice is characterized by an altered morphology and an enhanced inflammatory profile compared to wild-type BDNFVal/Val. Four weeks of voluntary PE restored the adipocyte size distribution, counteracted the inflammatory profile of adipose tissue, and prevented the prothrombotic phenotype displayed, per se, by BDNFMet/Met mice. C3H10T1/2 cells treated with the Pro-BDNFMet peptide well recapitulated the gene alterations observed in BDNFMet/Met WAT mice. In conclusion, these data indicate the strong impact of lifestyle, in particular of the beneficial effect of PE, on the management of arterial thrombosis and inflammation associated with obesity in relation to the specific BDNF Val66Met mutation

Ketogenic Diet : a New Light Shining on Old but Gold Biochemistry

Diets low in carbohydrates and proteins and enriched in fat stimulate the hepatic synthesis of ketone bodies (KB). These molecules are used as alternative fuel for energy production in target tissues. The synthesis and utilization of KB are tightly regulated both at transcriptional and hormonal levels. The nuclear receptor peroxisome proliferator activated receptor \u3b1 (PPAR\u3b1), currently recognized as one of the master regulators of ketogenesis, integrates nutritional signals to the activation of transcriptional networks regulating fatty acid \u3b2-oxidation and ketogenesis. New factors, such as circadian rhythms and paracrine signals, are emerging as important aspects of this metabolic regulation. However, KB are currently considered not only as energy substrates but also as signaling molecules. \u3b2-hydroxybutyrate has been identified as class I histone deacetylase inhibitor, thus establishing a connection between products of hepatic lipid metabolism and epigenetics. Ketogenic diets (KD) are currently used to treat different forms of infantile epilepsy, also caused by genetic defects such as Glut1 and Pyruvate Dehydrogenase Deficiency Syndromes. However, several researchers are now focusing on the possibility to use KD in other diseases, such as cancer, neurological and metabolic disorders. Nonetheless, clear-cut evidence of the efficacy of KD in other disorders remains to be provided in order to suggest the adoption of such diets to metabolic-related pathologies

Liver X receptors, nervous system, and lipid metabolism

Lipids in the nervous system are represented by cholesterol and phospholipids as constituents of cell membranes and, in particular, of myelin. Therefore, lipids are finely regulated to guarantee physiological functions. In the central nervous system, cholesterol is locally synthesized due to the presence of the blood brain barrier. In the peripheral nervous system cholesterol is either up-taken by lipoproteins and/or produced by de novo biosynthesis. Defects in lipid homeostasis in these tissues lead to structural and functional changes that often result in different pathological conditions depending on the affected pathways (i.e. cholesterol biosynthesis, cholesterol efflux, fatty acid biosynthesis etc.). Alterations in cholesterol metabolism in the central nervous system are linked to several disorders such as Alzheimer's disease, Huntington disease, Parkinson disease, Multiple sclerosis, Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and glioblastoma. In the peripheral nervous system changes in lipid metabolism are associated with the development of peripheral neuropathy that may be caused by metabolic disorders, injuries, therapeutics, and autoimmune diseases. Transcription factors, such as the Liver X receptors (LXR), regulate both cholesterol and fatty acid metabolism in several tissues including the nervous system. In the last few years several studies elucidated the biology of LXR in the nervous system due to the availability of knock-out mice and the development of synthetic ligands. Here, we review a survey of the literature focused on the central and peripheral nervous system and in physiological and pathological settings with particular attention to the roles played by LXR in both districts

po 324 interferon regulatory factor 1 irf1 regulates inflammatory and metabolic phenotypes in pancreatic ductal adenocarcinoma

Introduction Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent neoplasia of the exocrine pancreas. This tumour is and is characterised by a pervasive heterogeneity, with the coexistence of a range of histological grades, from epithelial-like to mesenchymal-like features. We previously dissected the transcriptional and epigenetic networks underlying PDAC grading. We identified the association of low grade phenotypes with a cell-autonomous interferon-related signature. Therefore, we set out to investigate the sustainment of inflammatory and interferon-related signatures in well-differentiated pancreatic cancer cells, and to determine the role of this network in PDAC biology. Material and methods We used cell-line based models of cancer differentiation, xenografts and human samples. We used CRISPR-Cas9 mediated genome editing to delete the transcription factor IRF1 (Interferon Regulatory Factor 1) in low-grade PDAC cells. RNA-seq, metabolic assays (oxygraphy, steady state metabolomics, fluxomics) and cell biology assays were carried out in IRF1 wt and knock-out cell lines. Data validation in human PDAC samples was carried out by immunohistochemistry. Results and discussions We found that IRF1 is a transcription factor differentially expressed between low- and high-grade PDACs, both in cell lines and in human tumours. IRF1 deletion in low-grade cell lines reduced the expression of genes in the antigen processing and presentation pathways, while its overexpression promoted the expression of the same genes in high-grade cells, where they are normally not expressed. Furthermore, xenografted IRF1-deficient cell lines recruited fewer immune cells in vivo . IRF1 deletion also affected epithelial phenotypes, including growth rate, cell shape, motility and collagen remodelling ability. Alongside, we unveiled a role of IRF1 in the control of the metabolism of low-grade PDAC cells, consisting in the control of mitochondrial respiration and lipogenesis as well as of the overall lipid profile of these cells. Conclusion To conclude, our results provide hints on the regulatory networks controlling cell differentiation in human PDACs. We show that IRF1 acts as a pleiotropic regulator in the low grade component of PDACs, with wide effects on immunological and metabolic features of this cancer population. Our work reinforces the body of knowledge needed for the development of those therapeutic strategies aiming at exploiting immunological or metabolic pitfalls

HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning.

White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and β-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning.Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning

Activation of a non-neuronal cholinergic system in visceral white adipose tissue of obese mice and humans

Background and objectives: Since white adipose tissue (WAT) lacks parasympathetic cholinergic innervation, the source of the acetylcholine (ACh) acting on white adipocyte cholinergic receptors is unknown. This study was designed to identify ACh-producing cells in mouse and human visceral WAT and to determine whether a non-neuronal cholinergic system becomes activated in obese inflamed WAT. Methods: Mouse epididymal WAT (eWAT) and human omental fat were studied in normal and obese subjects. The expression of the key molecules involved in cholinergic signaling was evaluated by qRT-PCR and western blotting whereas their tissue distribution and cellular localization were investigated by immunohistochemistry, confocal microscopy and in situ hybridization. ACh levels were measured by liquid chromatography/tandem mass spectrometry. The cellular effects of ACh were assessed in cultured human multipotent adipose-derived stem cell (hMADS) adipocytes. Results: In mouse eWAT, diet-induced obesity modulated the expression of key cholinergic molecular components and, especially, raised the expression of choline acetyltransferase (ChAT), the ACh-synthesizing enzyme, which was chiefly detected in interstitial macrophages, in macrophages forming crown-like structures (CLSs), and in multinucleated giant cells (MGCs). The stromal vascular fraction of obese mouse eWAT contained significantly higher ACh and choline levels than that of control mice. ChAT was undetectable in omental fat from healthy subjects, whereas it was expressed in a number of interstitial macrophages, CLSs, and MGCs from some obese individuals. In hMADS adipocytes stressed with tumor necrosis factor a, ACh, alone or combined with rivastigmine, significantly blunted monocyte chemoattractant protein 1 and interleukin 6 expression, it partially but significantly, restored adiponectin and GLUT4 expression, and promoted glucose uptake. Conclusions: In mouse and human visceral WAT, obesity induces activation of a macrophage-dependent non-neuronal cholinergic system that is capable of exerting anti-inflammatory and insulin-sensitizing effects on white adipocytes. (c) 2023 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)