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Stable-isotope tracing and metabolomics analysis comparing pre-adipocytes and differentiated adipocytes revealed a shift from glucose and glutamine utilization to increased branched chain amino acid catabolic flux to generate acetyl–coenzyme A. Adipose tissue plays important roles in regulating carbohydrate and lipid homeostasis, but less is known about the regulation of amino acid metabolism in adipocytes. Here we applied isotope tracing to pre-adipocytes and differentiated adipocytes to quantify the contributions of different substrates to tricarboxylic acid (TCA) metabolism and lipogenesis. In contrast to proliferating cells, which use glucose and glutamine for acetyl–coenzyme A (AcCoA) generation, differentiated adipocytes showed increased branched-chain amino acid (BCAA) catabolic flux such that leucine and isoleucine from medium and/or from protein catabolism accounted for as much as 30% of lipogenic AcCoA pools. Medium cobalamin deficiency caused methylmalonic acid accumulation and odd-chain fatty acid synthesis. Vitamin B12 supplementation reduced these metabolites and altered the balance of substrates entering mitochondria. Finally, inhibition of BCAA catabolism compromised adipogenesis. These results quantitatively highlight the contribution of BCAAs to adipocyte metabolism and suggest that BCAA catabolism has a functional role in adipocyte differentiation.

Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves 1 , 2 . Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia 3 – 7 , aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes 8 – 10 . Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome 10 – 14 , 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 15 , 16 . 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. Serine deficiency can increase small fibre neuropathy in wild-type mice and serine replacement in diabetic mice alleviates diabetic neuropathy, directly linking amino acid metabolism to peripheral nerve disorders.

Fatty acid synthase (FASN) predominantly generates straight-chain fatty acids using acetyl-CoA as the initiating substrate. However, monomethyl branched-chain fatty acids (mmBCFAs) are also present in mammals but are thought to be primarily diet derived. Here we demonstrate that mmBCFAs are de novo synthesized via mitochondrial BCAA catabolism, exported to the cytosol by adipose-specific expression of carnitine acetyltransferase (CrAT), and elongated by FASN. Brown fat exhibits the highest BCAA catabolic and mmBCFA synthesis fluxes, whereas these lipids are largely absent from liver and brain. mmBCFA synthesis is also sustained in the absence of microbiota. We identify hypoxia as a potent suppressor of BCAA catabolism that decreases mmBCFA synthesis in obese adipose tissue, such that mmBCFAs are significantly decreased in obese animals. These results identify adipose tissue mmBCFA synthesis as a novel link between BCAA metabolism and lipogenesis, highlighting roles for CrAT and FASN promiscuity influencing acyl-chain diversity in the lipidome.

Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes. Fructose consumption has greatly increased in recent years and has been linked to the development of hepatic steatosis. Here, the authors show that fructose promotes gut-barrier deterioration and subsequent endotoxaemia that in turn induces hepatic lipogenesis by activation TLR signalling in liver macrophages.

The consequences of prenatal alcohol exposure were first described more than 40 years ago.1,2 The term \"fetal alcohol syndrome\" (FAS) was first used to describe the cluster of birth defects due to prenatal alcohol exposure (including growth restriction, craniofacial abnormalities and intellectual disabilities) with lifetime consequences.2 The term \"fetal alcohol spectrum disorder\" (FASD) has since been adopted to describe a broader spectrum of presentations and disabilities resulting from alcohol exposure in utero. The prevalence has been estimated at 1 in 100 people, which translates to more than 330 000 affected individuals in Canada.3 The development of clinical capacity for FASD diagnosis remains difficult,4 because the diagnosis requires a medical evaluation and neurodevelopmental assessment conducted by a multidisciplinary team. In 2005, an international, collaborative, evidence-based guideline for diagnoses related to prenatal alcohol exposure was published.5 Since then, the field has evolved, and additional evidence, expertise and experience have emerged to suggest that a revision was required to improve both diagnoses and outcomes. The literature has also shown that impairments in behaviour and function associated with FASD have been detected from exposure to binge drinking, even infrequently or early in pregnancy, which underscores the importance of pre-pregnancy counselling. Specific research involving infants, young children and adults with FASD, as well as further insight into the neurodevelopmental dysfunction and nomenclature, prompted the update and revision process. A literature review and broad consultation process was undertaken to revise the 2005 guideline for diagnosing FASD.5 The guideline was developed according to the Appraisal of Guidelines, Research and Evaluation (AGREE II) framework,6 which provides a rigorous, evidence-based approach. The steering committee identified the scope of the guidelines and developed the key questions. These tasks were accomplished during the first meetings, after which the scope and questions were further refined and approved by consensus. The literature review was then conducted by two committee members (J.L.C. and C.R.G.) using the following combinations of MeSH (medical subject heading) search terms to address the key questions: \"fetal alcohol,\" \"diagnosis*,\" \"infant*,\" \"prenatal alcohol\" and \"adult.\" Relevant reports published from 2005 to September 2014 were identified from the following databases: PubMed, PsychLIT, Medscape, MEDLINE, the Canadian Institutes of Health Research funding database and the Cochrane Library.

Non-invasive and label-free calorimetry could become a disruptive technique to study single cell metabolic heat production without altering the cell behavior, but it is currently limited by insufficient sensitivity. Here, we demonstrate microfluidic single-cell calorimetry with 0.2-nW sensitivity, representing more than ten-fold enhancement over previous record, which is enabled by (i) a low-noise thermometry platform with ultralow long-term (10-h) temperature noise (80 μK) and (ii) a microfluidic channel-in-vacuum design allowing cell flow and nutrient delivery while maintaining a low thermal conductance of 2.5 μW K −1 . Using Tetrahymena thermophila as an example, we demonstrate on-chip single-cell calorimetry measurement with metabolic heat rates ranging from 1 to 4 nW, which are found to correlate well with the cell size. Finally, we perform real-time monitoring of metabolic rate stimulation by introducing a mitochondrial uncoupling agent to the microchannel, enabling determination of the spare respiratory capacity of the cells. Calorimetrically measuring the heat of single cells is currently not possible due to the sensitivity of existing calorimeters. Here the authors present on-chip single cell calorimetry, with a sensitivity over ten-fold greater than the current gold-standard.

Current robot surgery curricula developed by industry were designed for expert surgeons. We sought to identify the robotic curricula that currently exist in general surgery residencies and describe their components. We identified 12 residency programs with robotic curricula. Using a structured coding form to identify themes including sequence, duration, emphasis and assessment, we generated a descriptive summary. Curricula followed a similar sequence: learners started with online modules and simulation exercises, followed by bedside experience during R2-R3 training years, and then operative opportunities on the console in the final years of training. Consistent portions of the curricula reflect a device-dependent training paradigm; they defined the sequence of instruction. Most curricula lacked specifics on duration and content of training activities. None clearly described cognitive or psychomotor skills needed by residents and none required a proficiency assessment before graduation. Resident-specific robotic curricula remain grounded in initial industrial efforts to train experienced surgeons, are non-specific regarding the type and nature of hands on experience, and do not include discussion of operative technique and surgical concepts.

This study evaluated how real-time continuous glucose monitoring (RT-CGM) use was associated with medication use patterns and A1c changes among people with type 2 diabetes (T2D) using non-insulin therapy (NIT), basal insulin therapy (BIT), or intensive insulin therapy (IIT). We hypothesized that RT-CGM use would be associated with more frequent medication class changes and reduction in polypharmacy, alongside greater improvements in A1c compared to CGM non-use. This retrospective study analyzed US administrative claims data from the Optum Clinformatics Data Mart database between 09/01/2016 and 06/30/2024. People with T2D were divided into NIT, BIT, or IIT cohorts. Each cohort contained two groups: Dexcom RT-CGM users or CGM non-users and 1:1 propensity score matching was performed to minimize differences between the groups. We compared changes in medication use and A1c levels between RT-CGM users and CGM non-users over 12 months. Over 1.6 million people with T2D were identified prior to matching and stratified by therapy regimen as T2D-NIT, -BIT, or -IIT. After propensity score matching, the proportion of RT-CGM users taking ≥4 medications declined significantly and RT-CGM users had more net changes in their medications than CGM non-users. In addition, greater improvements in A1c were observed among RT-CGM users compared to CGM non-users in all cohorts (difference-in-differences of -0.4%, -0.5%, and -0.4% for T2D-NIT, T2D-BIT, and T2D-IIT, respectively, all p<0.0001). More RT-CGM users also achieved a mean A1c <7.0% or <8.0% at follow-up overall and among those not meeting the target at baseline. Higher rates of medication changes were associated with RT-CGM use. RT-CGM use was associated with significantly and meaningfully improved A1c levels among all T2D cohorts. The findings indicate that RT-CGM use could help all people with T2D improve their glycemia.

Given the challenges of teaching in robotic operating rooms, we sought to investigate the language of perceptual expertise used by robotic surgeons, in an effort to improve current approaches to robotic training. Expert robotic surgeons reviewed 8 anonymous video clips portraying key portions of two robotic general surgery procedures and their comments were recorded and transcribed. Using content analysis, each transcript was double-coded and reconciled using a consensus developed codebook. Seventeen expert robotic surgeons participated and comments formed two primary themes: visual comprehension and surgical technique. Surgeons minimally used tactile language. Risk avoidance was a second-order theme dominating language used. Experts occasionally used tactile language and emphasized risk avoidance as they observed robotic surgery. Despite the need to communicate perceptual expertise to trainees in robotic surgery, tactile language was not exhibited by expert surgeons, revealing an important future area of focus for intraoperative teaching skills. •Robotic surgeons use perceptual expertise to guide intraoperative decision making.•Content analysis of surgeons' describing robotic surgery revealed 2 themes: visual comprehension and surgical technique.•Surgeons minimally used tactile language.•An emphasis on risk avoidance suggests negative knowledge (knowing what not to do) is critical for surgical expertise.•Curriculum addressing techniques, instruments or surgical approaches may promote acquisition of negative knowledge.•Acquisition of negative knowledge augments perceptual expertise in surgery.