quantitative-determination-de-novo-fatty-acid-synthesis-brown-adipose

Quantitative Determination of <em>De Novo</em> Fatty Acid Synthesis in Brown Adipose Tissue Using Deuterium Oxide

Fatty acid synthesis is a complex and highly energy demanding metabolic pathway with important functional roles in the control of whole-body metabolic ...

University College Dublin

To determine whether metabolomic analysis of follicular fluid could prove a useful noninvasive technique for the selection of viable oocytes and embryos.

An investigation into the relationship between the metabolic profile of follicular fluid, oocyte developmental potential, and implantation outcome.

The objectives of the present study were to (1) examine the effects of the phenotypic factors age, gender and BMI on the lipidomic profile and (2) investigate the relationship between the lipidome, inflammatory markers and insulin resistance. Specific ceramide, phosphatidylcholine and phosphatidylethanolamine lipids were increased in females relative to males and specific lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylcholine and phosphatidylethanolamine lipids decreased as BMI increased. However, age had a minimal effect on the lipid profile with significant differences found in only two lipid species. Network analysis revealed strong negative correlations between the inflammatory markers CRP, TNF-α, resistin and MCP-1 and lipids in the LPC, PC and PE classes, whereas IL-8 formed positive correlations with lipids from the CER and SM classes. Further analysis revealed that LPC a C18:1 and PE ae C40:6 were highly associated with insulin resistance as indicated by HOMA-IR score. The present study identified lipids that are affected by BMI and gender and identified a series of lipids which had significant relationships with inflammatory markers. LPC a C18:1 and PE ae C40:6 were found to be highly associated with insulin resistance pointing to the possibility that the alterations in these specific lipids may play a role in the development of insulin resistance.

Relationship between the lipidome, inflammatory markers and insulin resistance.

Our objective was to determine if early pregnancy urinary metabolomic profiles could predict fetal adiposity and macrosomia.

Early pregnancy maternal urinary metabolomic profile and later insulin resistance and fetal adiposity.

Metabolic balance-a masterclass in mass action.

In the Microvascular Outcomes after Metabolic Surgery randomised clinical trial (MOMS RCT, NCT01821508), combined metabolic surgery (gastric bypass) plus medical therapy (CSM) was superior to medical therapy alone (MTA) as a means of achieving albuminuria remission at 2-year follow-up in patients with obesity and early diabetic kidney disease (DKD). In the present study, we assessed the urinary H-NMR metabolome in a subgroup of patients from both arms of the MOMS RCT at baseline and 6-month follow-up. Whilst CSM and MTA both reduced the urinary excretion of sugars, CSM generated a distinctive urinary metabolomic profile characterised by increases in host-microbial co-metabolites (N-phenylacetylglycine, trimethylamine N-oxide, and 4-aminobutyrate (GABA)) and amino acids (arginine and glutamine). Furthermore, reductions in aromatic amino acids (phenylalanine and tyrosine), as well as branched-chain amino acids (BCAAs) and related catabolites (valine, leucine, 3-hydroxyisobutyrate, 3-hydroxyisovalerate, and 3-methyl-2-oxovalerate), were observed following CSM but not MTA. Improvements in BMI did not correlate with improvements in metabolic and renal indices following CSM. Conversely, urinary metabolites changed by CSM at 6 months were moderately to strongly correlated with improvements in blood pressure, glycaemia, triglycerides, and albuminuria up to 24 months following treatment initiation, highlighting the potential involvement of these shifts in the urinary metabolomic profile in the metabolic and renoprotective effects of CSM.

Urinary Metabolomic Changes Accompanying Albuminuria Remission following Gastric Bypass Surgery for Type 2 Diabetic Kidney Disease.

There is a need to transform our current food system if we are to feed the rapidly expanding global population while maintaining planetary health. Within the island of Ireland, there is an urgent need to diversify the foods that currently contribute to our populations' protein intake. A Shared Island Innovative Food System approach is required to achieve this in a manner that is sustainable and provides benefits to producers, consumers and other supply chain participants. The Protein-I project employs such an approach, with the paradigm focusing on production of plant food through to human health, while paying particular attention to the development of the rural bioeconomy. Using an interdisciplinary approach, the team will develop strategies to maximise sustainable plant protein production in a traceable/transparent fashion and assess the impact of changes to existing value chains and the development of new value chains for the rural economy. A smart supply chain technology solution tailored to the needs of the agri-food industry will be developed and tested. Additionally, we will co-design consumer-led approaches to diversify plant protein intake, model the impact of changes at the population level and perform human interventions to demonstrate efficacy in terms of achieving adequate nutrition and improved health. Comprehensive engagement with stakeholders is embedded throughout the whole project to embrace the multi-actor approach. Overall, the project will be a key step towards future-proofing our food system on the island of Ireland and moving towards protecting planetary and population health, within the context of a just transition.

An innovative food system approach to diversifying protein intake: Protein-I: Shared Island sustainable healthy nutrition.

Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves. Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes. Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome, but the mechanistic drivers and downstream consequences of this metabotype remain unclear. Low systemic serine and glycine are also emerging as a hallmark of macular and peripheral nerve disorders, correlating with impaired visual acuity and peripheral neuropathy. Here we demonstrate that aberrant serine homeostasis drives serine and glycine deficiencies in diabetic mice, which can be diagnosed with a serine tolerance test that quantifies serine uptake and disposal. Mimicking these metabolic alterations in young mice by dietary serine or glycine restriction together with high fat intake markedly accelerates the onset of small fibre neuropathy while reducing adiposity. Normalization of serine by dietary supplementation and mitigation of dyslipidaemia with myriocin both alleviate neuropathy in diabetic mice, linking serine-associated peripheral neuropathy to sphingolipid metabolism. These findings identify systemic serine deficiency and dyslipidaemia as novel risk factors for peripheral neuropathy that may be exploited therapeutically.

Insulin-regulated serine and lipid metabolism drive peripheral neuropathy.

The non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insight into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we compared patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both.

Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease.

Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and GWAS have linked MacTel to decreased circulating levels of serine and elevated levels of neurotoxic 1-deoxysphingolipids (1-dSLs). However, retina-specific, disease-contributing factors have yet to be identified. Here, we used iPSC-differentiated retinal pigmented epithelial (iRPE) cells derived from donors with or without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE cells mimicked the low serine levels observed in serum from patients with MacTel. Through RNA-Seq and gene set enrichment pathway analysis, we determined that MacTel iRPE cells are enriched in cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress testing, we functionally validated that MacTel iRPE cells had a reduction in mitochondrial function that was independent of defects in serine biosynthesis and 1-dSL accumulation. Thus, we identified phenotypes that may constitute alternative disease mechanisms beyond the known serine/sphingolipid pathway.

Article	Year
An investigation into the relationship between the metabolic profile of follicular fluid, oocyte developmental potential, and implantation outcome. Fertility and sterility\| PubMed ID: 22365382	2012
Relationship between the lipidome, inflammatory markers and insulin resistance. Molecular bioSystems\| PubMed ID: 24714806	2014
Early pregnancy maternal urinary metabolomic profile and later insulin resistance and fetal adiposity. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians\| PubMed ID: 25231596	2015
Metabolic balance-a masterclass in mass action. Nature metabolism\| PubMed ID: 35058632	2022
Urinary Metabolomic Changes Accompanying Albuminuria Remission following Gastric Bypass Surgery for Type 2 Diabetic Kidney Disease. Metabolites\| PubMed ID: 35186675	2022
An innovative food system approach to diversifying protein intake: Protein-I: Shared Island sustainable healthy nutrition. Nutrition bulletin\| PubMed ID: 36437572	2022
Insulin-regulated serine and lipid metabolism drive peripheral neuropathy. Nature\| PubMed ID: 36697822	2023
Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease. Molecular metabolism\| PubMed ID: 36997154	2023
iPSC-derived retinal pigmented epithelial cells from patients with macular telangiectasia show decreased mitochondrial function. The Journal of clinical investigation\| PubMed ID: 37115691	2023

Martina Wallace

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