Publications by authors named "Jun Yoshino"

89 Publications

Importance of Adipose Tissue NAD+ Biology in Regulating Metabolic Flexibility.

Endocrinology 2021 Mar;162(3)

Center for Human Nutrition, Washington University School of Medicine, St Louis, Missouri, USA.

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme that regulates cellular energy metabolism in many cell types. The major purpose of the present study was to test the hypothesis that NAD+ in white adipose tissue (WAT) is a regulator of whole-body metabolic flexibility in response to changes in insulin sensitivity and with respect to substrate availability and use during feeding and fasting conditions. To this end, we first evaluated the relationship between WAT NAD+ concentration and metabolic flexibility in mice and humans. We found that WAT NAD+ concentration was increased in mice after calorie restriction and exercise, 2 enhancers of metabolic flexibility. Bariatric surgery-induced 20% weight loss increased plasma adiponectin concentration, skeletal muscle insulin sensitivity, and WAT NAD+ concentration in people with obesity. We next analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) mice, which have markedly decreased NAD+ concentrations in WAT. ANKO mice oxidized more glucose during the light period and after fasting than control mice. In contrast, the normal postprandial stimulation of glucose oxidation and suppression of fat oxidation were impaired in ANKO mice. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT increases inflammation, and impairs insulin sensitivity, glucose oxidation, lipolysis, branched-chain amino acid catabolism, and mitochondrial function in WAT, which are features of metabolic inflexibility. These results demonstrate a novel function of WAT NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility, and provide new insights into the role of adipose tissue NAD+ biology in metabolic health.
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http://dx.doi.org/10.1210/endocr/bqab006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853299PMC
March 2021

Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity.

J Clin Invest 2020 12;130(12):6688-6699

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, and.

BACKGROUNDData from studies conducted in rodent models have shown that decreased adipose tissue (AT) oxygenation is involved in the pathogenesis of obesity-induced insulin resistance. Here, we evaluated the potential influence of AT oxygenation on AT biology and insulin sensitivity in people.METHODSWe evaluated subcutaneous AT oxygen partial pressure (pO2); liver and whole-body insulin sensitivity; AT expression of genes and pathways involved in inflammation, fibrosis, and branched-chain amino acid (BCAA) catabolism; systemic markers of inflammation; and plasma BCAA concentrations, in 3 groups of participants that were rigorously stratified by adiposity and insulin sensitivity: metabolically healthy lean (MHL; n = 11), metabolically healthy obese (MHO; n = 15), and metabolically unhealthy obese (MUO; n = 20).RESULTSAT pO2 progressively declined from the MHL to the MHO to the MUO group, and was positively associated with hepatic and whole-body insulin sensitivity. AT pO2 was positively associated with the expression of genes involved in BCAA catabolism, in conjunction with an inverse relationship between AT pO2 and plasma BCAA concentrations. AT pO2 was negatively associated with AT gene expression of markers of inflammation and fibrosis. Plasma PAI-1 increased from the MHL to the MHO to the MUO group and was negatively correlated with AT pO2, whereas the plasma concentrations of other cytokines and chemokines were not different among the MHL and MUO groups.CONCLUSIONThese results support the notion that reduced AT oxygenation in individuals with obesity contributes to insulin resistance by increasing plasma PAI-1 concentrations and decreasing AT BCAA catabolism and thereby increasing plasma BCAA concentrations.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants K01DK109119, T32HL130357, K01DK116917, R01ES027595, P42ES010337, DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK052574 (Digestive Disease Research Center), and UL1TR002345 (Clinical and Translational Science Award); NIH Shared Instrumentation Grants S10RR0227552, S10OD020025, and S10OD026929; and the Foundation for Barnes-Jewish Hospital.
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http://dx.doi.org/10.1172/JCI141828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685757PMC
December 2020

Effects of Diet versus Gastric Bypass on Metabolic Function in Diabetes.

N Engl J Med 2020 08;383(8):721-732

From the Center for Human Nutrition (M.Y., B.D.K., J.Y., R.I.S., D.R., K.S., B.W.P., S.K.) and the Department of Surgery (J.C.E., S.R.E.), Washington University School of Medicine, St. Louis; and the Departments of Medicine (J.D.W., M.J.), Pharmacology (J.D.W., M.J.), Pediatrics (R.K.), and Computer Science and Engineering (R.K.), University of California San Diego, San Diego.

Background: Some studies have suggested that in people with type 2 diabetes, Roux-en-Y gastric bypass has therapeutic effects on metabolic function that are independent of weight loss.

Methods: We evaluated metabolic regulators of glucose homeostasis before and after matched (approximately 18%) weight loss induced by gastric bypass (surgery group) or diet alone (diet group) in 22 patients with obesity and diabetes. The primary outcome was the change in hepatic insulin sensitivity, assessed by infusion of insulin at low rates (stages 1 and 2 of a 3-stage hyperinsulinemic euglycemic pancreatic clamp). Secondary outcomes were changes in muscle insulin sensitivity, beta-cell function, and 24-hour plasma glucose and insulin profiles.

Results: Weight loss was associated with increases in mean suppression of glucose production from baseline, by 7.04 μmol per kilogram of fat-free mass per minute (95% confidence interval [CI], 4.74 to 9.33) in the diet group and by 7.02 μmol per kilogram of fat-free mass per minute (95% CI, 3.21 to 10.84) in the surgery group during clamp stage 1, and by 5.39 (95% CI, 2.44 to 8.34) and 5.37 (95% CI, 2.41 to 8.33) μmol per kilogram of fat-free mass per minute in the two groups, respectively, during clamp stage 2; there were no significant differences between the groups. Weight loss was associated with increased insulin-stimulated glucose disposal, from 30.5±15.9 to 61.6±13.0 μmol per kilogram of fat-free mass per minute in the diet group and from 29.4±12.6 to 54.5±10.4 μmol per kilogram of fat-free mass per minute in the surgery group; there was no significant difference between the groups. Weight loss increased beta-cell function (insulin secretion relative to insulin sensitivity) by 1.83 units (95% CI, 1.22 to 2.44) in the diet group and by 1.11 units (95% CI, 0.08 to 2.15) in the surgery group, with no significant difference between the groups, and it decreased the areas under the curve for 24-hour plasma glucose and insulin levels in both groups, with no significant difference between the groups. No major complications occurred in either group.

Conclusions: In this study involving patients with obesity and type 2 diabetes, the metabolic benefits of gastric bypass surgery and diet were similar and were apparently related to weight loss itself, with no evident clinically important effects independent of weight loss. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02207777.).
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http://dx.doi.org/10.1056/NEJMoa2003697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456610PMC
August 2020

Reply to: Absence of evidence that Slc12a8 encodes a nicotinamide mononucleotide transporter.

Nat Metab 2019 07 12;1(7):662-665. Epub 2019 Jul 12.

Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.

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http://dx.doi.org/10.1038/s42255-019-0086-zDOI Listing
July 2019

Author Correction: Slc12a8 is a nicotinamide mononucleotide transporter.

Nat Metab 2019 Jul;1(7):743

Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s42255-019-0088-xDOI Listing
July 2019

Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction.

Sci Rep 2020 02 25;10(1):3417. Epub 2020 Feb 25.

Merck & Co., Inc., South San Francisco, CA, USA.

Insulin resistance increases patients' risk of developing type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH) and a host of other comorbidities including cardiovascular disease and cancer. At the molecular level, insulin exerts its function through the insulin receptor (IR), a transmembrane receptor tyrosine kinase. Data from human genetic studies have shown that Grb14 functions as a negative modulator of IR activity, and the germline Grb14-knockout (KO) mice have improved insulin signaling in liver and skeletal muscle. Here, we show that Grb14 knockdown in liver, white adipose tissues, and heart with an AAV-shRNA (Grb14-shRNA) improves glucose homeostasis in diet-induced obese (DIO) mice. A previous report has shown that germline deletion of Grb14 in mice results in cardiac hypertrophy and impaired systolic function, which could severely limit the therapeutic potential of targeting Grb14. In this report, we demonstrate that there are no significant changes in cardiac function as measured by echocardiography in the Grb14-knockdown mice fed a high-fat diet for a period of four months. While additional studies are needed to further confirm the efficacy and to de-risk potential negative cardiac effects in preclinical models, our data support the therapeutic strategy of inhibiting Grb14 to treat diabetes and related conditions.
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http://dx.doi.org/10.1038/s41598-020-60290-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042267PMC
February 2020

Dysregulation of Amyloid Precursor Protein Impairs Adipose Tissue Mitochondrial Function and Promotes Obesity.

Nat Metab 2019 12 13;1(12):1243-1257. Epub 2019 Dec 13.

Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Mitochondrial function in white adipose tissue (WAT) is an important yet understudied aspect in adipocyte biology. Here, we report a role for amyloid precursor protein (APP) in compromising WAT mitochondrial function through a high-fat diet (HFD)-induced, unconventional mis-localization to mitochondria that further promotes obesity. In humans and mice, obese conditions significantly induce APP production in WAT and its enrichment in mitochondria. Mechanistically, a HFD-induced dysregulation of signal recognition particle subunit 54c is responsible for the mis-targeting of APP to adipocyte mitochondria. Mis-localized APP blocks the protein import machinery, leading to mitochondrial dysfunction in WAT. Adipocyte-specific and mitochondria-targeted APP overexpressing mice display increased body mass and reduced insulin sensitivity, along with dysfunctional WAT due to a dramatic hypertrophic program in adipocytes. Elimination of adipocyte APP rescues HFD-impaired mitochondrial function with significant protection from weight gain and systemic metabolic deficiency. Our data highlights an important role of APP in modulating WAT mitochondrial function and obesity-associated metabolic dysfunction.
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http://dx.doi.org/10.1038/s42255-019-0149-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980705PMC
December 2019

Secure insertion of the i-gel supraglottic airway device in children: A cohort study.

Eur J Anaesthesiol 2020 Feb;37(2):145-147

From the Department of Anaesthesia, St. Mary's Hospital, Fukuoka (SS, JY, NF), Department of Anaesthesiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan (HK).

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http://dx.doi.org/10.1097/EJA.0000000000001042DOI Listing
February 2020

A single bout of resistance exercise improves postprandial lipid metabolism in overweight/obese men with prediabetes.

Diabetologia 2020 03 23;63(3):611-623. Epub 2019 Dec 23.

Program in Physical Therapy, Washington University, St Louis, Campus Box 8502, 4444 Forest Park Ave., St Louis, MO, 63110, USA.

Aims/hypothesis: Prediabetes is associated with postprandial hypertriacylglycerolaemia. Resistance exercise acutely lowers postprandial plasma triacylglycerol (TG); however, the changes in lipid metabolism that mediate this reduction are poorly understood. The aim of this study was to identify the constitutive metabolic mechanisms underlying the changes in postprandial lipid metabolism after resistance exercise in obese men with prediabetes.

Methods: We evaluated the effect of a single bout of whole-body resistance exercise (seven exercises, three sets, 10-12 repetitions at 80% of one-repetition maximum) on postprandial lipid metabolism in ten middle-aged (50 ± 9 years), overweight/obese (BMI: 33 ± 3 kg/m), sedentary men with prediabetes (HbA >38 but <48 mmol/mol [>5.7% but <6.5%]), or fasting plasma glucose >5.6 mmol/l but <7.0 mmol/l or 2 h OGTT glucose >7.8 mmol/l but <11.1 mmol/l). We used a randomised, crossover design with a triple-tracer mixed meal test (ingested [(C)]tripalmitin, i.v. [U-C]palmitate and [H]glycerol) to evaluate chylomicron-TG and total triacylglycerol-rich lipoprotein (TRL)-TG kinetics. We used adipose tissue and skeletal muscle biopsies to evaluate the expression of genes regulating lipolysis and lipid oxidation, skeletal muscle respirometry to evaluate oxidative capacity, and indirect calorimetry to assess whole-body lipid oxidation.

Results: The single bout of resistance exercise reduced the lipaemic response to a mixed meal in obese men with prediabetes without changing chylomicron-TG or TRL-TG fractional clearance rates. However, resistance exercise reduced endogenous and meal-derived fatty acid incorporation into chylomicron-TG and TRL-TG. Resistance exercise also increased whole-body lipid oxidation, skeletal muscle mitochondrial respiration, oxidative gene expression in skeletal muscle, and the expression of key lipolysis genes in adipose tissue.

Conclusions/interpretation: A single bout of resistance exercise improves postprandial lipid metabolism in obese men with prediabetes, which may mitigate the risk for cardiovascular disease and type 2 diabetes.
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http://dx.doi.org/10.1007/s00125-019-05070-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002271PMC
March 2020

Adipose tissue NAD biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice.

Proc Natl Acad Sci U S A 2019 11 6;116(47):23822-23828. Epub 2019 Nov 6.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO 63110;

Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase () knockout (ANKO) and brown adipocyte-specific knockout (BANKO) mice because NAMPT is the rate-limiting NAD biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD-SIRT1-caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.
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http://dx.doi.org/10.1073/pnas.1909917116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876243PMC
November 2019

Loss of ARID1A induces a stemness gene ALDH1A1 expression with histone acetylation in the malignant subtype of cholangiocarcinoma.

Carcinogenesis 2020 07;41(6):734-742

Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo.

Genomic analyses have recently discovered the malignant subtype of human intrahepatic cholangiocarcinoma (ICC) characterized by frequent mutations of chromatin remodeling gene ARID1A; however, the biological and molecular functions still remain obscure. We here examined the clinical and biological significances of ARID1A deficiency in human ICC. Immunohistochemical analysis demonstrated that the loss of ARID1A was an independent prognostic factor for overall survival of ICC patients (P = 0.023). We established ARID1A-knockout (KO) cells by using the CRISPR/Cas9 system from two human cholangiocarcinoma cell lines. ARID1A-KO cells exhibited significantly enhanced migration, invasion, and sphere formation activity. Microarray analysis revealed that ALDH1A1, a stemness gene, was the most significantly elevated genes in ARID1A-KO cells. In addition, ALDH enzymatic activity as a hallmark of cancer stem cells was markedly high in the KO cells. ARID1A and histone deacetylase 1 were directly recruited to the ALDH1A1 promoter region in cholangiocarcinoma cells with undetectable ALDH1A1 expression by chromatin immunoprecipitation assay. The histone H3K27 acetylation level at the ALDH1A1 promoter region was increased in cells when ARID1A was disrupted (P < 0.01). Clinically, inverse correlation between ARID1A and ALDH1A1 expression was also identified in primary ICC (P = 0.018), and ARID1A-negative and ALDH1A1-positve ICCs showed worse prognosis than only ARID1A-negative cases (P = 0.002). In conclusion, ARID1A may function as a tumor suppressor in ICC through transcriptional downregulation of ALDH1A1 expression with decreasing histone H3K27 acetylation. Our studies provide the basis for the development of new epigenetic approaches to ARID1A-negative ICC. Immunohistochemical loss of ARID1A is an independent prognostic factor in intrahepatic cholangiocarcinoma patients. ARID1A recruits HDAC1 to the promoter region of ALDH1A1, a stemness gene, and epigenetically suppresses ALDH1A1 expression with decreasing histone H3K27 acetylation in cholangiocarcinoma cells.
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http://dx.doi.org/10.1093/carcin/bgz179DOI Listing
July 2020

Slc12a8 is a nicotinamide mononucleotide transporter.

Nat Metab 2019 01 7;1(1):47-57. Epub 2019 Jan 7.

Department of Developmental Biology, Washington University School of Medicine,, St. Louis, MO 63110, USA.

Nicotinamide mononucleotide (NMN) is a biosynthetic precursor of NAD known to promote cellular NAD production and counteract age-associated pathologies associated with a decline in tissue NAD levels. How NMN is taken up into cells has not been entirely clear. Here we show that the gene encodes a specific NMN transporter. We find that is highly expressed and regulated by NAD in the murine small intestine. knockdown abrogates the uptake of NMN and . We further show that Slc12a8 specifically transports NMN, but not nicotinamide riboside, and that NMN transport depends on the presence of sodium ion. deficiency significantly decreases NAD levels in the jejunum and ileum, which is associated with reduced NMN uptake as traced by doubly labeled isotopic NMN. Finally, we observe that expression is upregulated in the aged murine ileum, which contributes to the maintenance of ileal NAD levels. Our work identifies the first NMN transporter and demonstrates that Slc12a8 has a critical role in regulating intestinal NAD metabolism.
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http://dx.doi.org/10.1038/s42255-018-0009-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530925PMC
January 2019

Adipose Tissue CTGF Expression is Associated with Adiposity and Insulin Resistance in Humans.

Obesity (Silver Spring) 2019 06 19;27(6):957-962. Epub 2019 Apr 19.

Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA.

Objective: Connective tissue growth factor (CTGF) is an important regulator of fibrogenesis in many organs. This study evaluated the interrelationship among adipose tissue CTGF expression, fat mass, and insulin resistance in humans.

Methods: This study examined (1) CTGF gene expression in human subcutaneous preadipocytes before and after inducing adipogenesis; (2) relationships among abdominal subcutaneous adipose tissue CTGF gene expression, body fat mass, and indices of insulin sensitivity, including the hepatic insulin sensitivity index and the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope glucose tracer infusion, in 72 people who had marked differences in adiposity and insulin sensitivity; (3) localization of CTGF protein in subcutaneous adipose tissue; and (4) effect of progressive (5%, 11%, and 16%) weight loss on adipose tissue CTGF gene expression.

Results: CTGF was highly expressed in preadipocytes, not adipocytes. Adipose tissue CTGF expression was strongly correlated with body fat mass and both skeletal muscle and liver insulin sensitivity, and CTGF-positive cells were predominantly found in areas of fibrosis. Progressive weight loss caused a stepwise decrease in adipose tissue CTGF expression.

Conclusions: It was concluded that increased CTGF expression is associated with adipose tissue expansion, adipose tissue fibrosis, and multi-organ insulin resistance in people with obesity.
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http://dx.doi.org/10.1002/oby.22463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533148PMC
June 2019

The Clinical Implications of Peripancreatic Fluid Collection After Distal Pancreatectomy.

World J Surg 2019 08;43(8):2069-2076

Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Objectives: Pancreatic fistula after distal pancreatectomy (DP) remains an unsolved problem, and postoperative CT imaging often demonstrates fluid collection (FC) around the pancreatic remnant. This study sought to clarify the clinical implications of FC.

Methods: This study enrolled 146 patients who underwent DP. FC was defined as a cyst-like lesion ≥ 10 mm in diameter on CT imaging at postoperative day (POD) 7. FC size, irregularity of FC margin, and air bubbles in FC were investigated. In addition, clinical data were retrospectively collected, and useful predictive factors for postoperative pancreatic fistula (POPF) were analyzed.

Results: Clinically relevant POPF was observed in 26 patients (17.8%), and FC was detected in 136 patients (94.4%). Multivariate analysis identified FC size and drain amylase levels on POD3 as significant risk factors for POPF. Cutoff values were determined by ROC analyses, and the levels of the FC size and drain amylase on POD3 were determined as 41 mm and 1026 IU/L, respectively. The sensitivity and specificity of FC diameters > 41 mm were 76.9% and 75.0%, respectively, while those of drain amylase levels > 1026 IU on POD3 were 73.1% and 75.8%, respectively.

Conclusions: While treating some FCs after DP was necessary for the management of POPF, others did not require any intervention since most of them spontaneously disappeared. FC size and drain amylase levels on POD3 were found to be significantly associated with POPF and could potentially help to determine appropriate treatment.
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http://dx.doi.org/10.1007/s00268-019-05009-8DOI Listing
August 2019

ACMSD: A Novel Target for Modulating NAD Homeostasis.

Authors:
Jun Yoshino

Trends Endocrinol Metab 2019 04 21;30(4):229-232. Epub 2019 Feb 21.

Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. Electronic address:

NAD has a pivotal role in regulating many biological processes. A recent study (Palzer et al., Cell Rep. 2018, 25;1359-1370) demonstrated that alpha-amino-beta-carboxy-muconate-semialdehyde decarboxylase (ACMSD) is a key regulator of NAD metabolism and overexpression of human ACMSD leads to niacin dependency for NAD biosynthesis in mice, providing important insights into human diseases associated with niacin/NAD deficiency.
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http://dx.doi.org/10.1016/j.tem.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858840PMC
April 2019

Effectiveness of arginine vasopressin for the management of refractory hemorrhagic shock in a patient with autonomic dysreflexia caused by spinal cord injury.

JA Clin Rep 2018 Nov 12;4(1):79. Epub 2018 Nov 12.

Department of Anesthesiology and Critical Care Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Background: Arginine vasopressin has been used for the management of refractory vasodilatory shock. However, it is still unclear whether arginine vasopressin is useful for hypotension in patients with spinal cord injury.

Case Description: A 78-year-old man with autonomic dysreflexia and paralysis below the level corresponding to Th2 due to spinal cord injury previously underwent cholecystectomy. During the surgery, accidental hemorrhage led him to refractory hemorrhagic shock unresponsive to fluid resuscitation and catecholamine. Lasting hypotension was improved with arginine vasopressin.

Conclusion: We described a rare case report on the use of arginine vasopressin for management of refractory hemorrhagic shock in a patient with autonomic dysreflexia.
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http://dx.doi.org/10.1186/s40981-018-0216-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966762PMC
November 2018

The muscle anabolic effect of protein ingestion during a hyperinsulinaemic euglycaemic clamp in middle-aged women is not caused by leucine alone.

J Physiol 2018 10 29;596(19):4681-4692. Epub 2018 Aug 29.

Center for Human Nutrition.

Key Points: It has been suggested that leucine is primarily responsible for the increase in muscle protein synthesis after protein ingestion because leucine uniquely activates the mTOR-p70S6K signalling cascade. We compared the effects of ingesting protein or an amount of leucine equal to that in the protein during a hyperinsulinaemic-euglycaemic clamp (to eliminate potential confounding as a result of differences in the insulinogenic effect of protein and leucine ingestion) on muscle anabolic signalling and protein turnover in 28 women. We found that protein, but not leucine, ingestion increased muscle p-mTOR and p-p70S6K , although only protein, and not leucine, ingestion decreased muscle p-eIF2α and increased muscle protein synthesis.

Abstract: It has been suggested that leucine is primarily responsible for the increase in muscle protein synthesis (MPS) after protein ingestion because leucine uniquely activates the mTOR-p70S6K signalling cascade. We tested this hypothesis by measuring muscle p-mTOR , p-p70S6K and p-eIF2α , as well as protein turnover (by stable isotope labelled amino acid tracer infusion in conjunction with leg arteriovenous blood and muscle tissue sampling), in 28 women who consumed either 0.45 g protein kg fat-free mass (containing 0.0513 g leucine kg fat-free mass) or a control drink (n = 14) or 0.0513 g leucine kg fat-free mass or a control drink (n = 14) during a hyperinsulinaemic-euglycaemic clamp procedure (HECP). Compared to basal conditions, the HECP alone (without protein or leucine ingestion) suppressed muscle protein breakdown by ∼20% and increased p-mTOR and p-p70S6K by >50% (all P < 0.05) but had no effect on p-eIF2α and MPS. Both protein and leucine ingestion further increased p-mTOR and p-p70S6K , although only protein, and not leucine, ingestion decreased (by ∼35%) p-eIF2α and increased (by ∼100%) MPS (all P < 0.05). Accordingly, leg net protein balance changed from negative (loss) during basal conditions to equilibrium during the HECP alone and the HECP with concomitant leucine ingestion and to positive (gain) during the HECP with concomitant protein ingestion. These results provide new insights into the regulation of MPS by demonstrating that leucine and mTOR signalling alone are not responsible for the muscle anabolic effect of protein ingestion during physiological hyperinsulinaemia, most probably because they fail to signal to eIF2α to initiate translation and/or additional amino acids are needed to sustain translation.
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http://dx.doi.org/10.1113/JP276504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166086PMC
October 2018

Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice.

FASEB J 2019 01 20;33(1):652-667. Epub 2018 Jul 20.

Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Lipin 1 regulates glycerolipid homeostasis by acting as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride-synthesis pathway and by regulating transcription factor activity. Mutations in human lipin 1 are a common cause of recurrent rhabdomyolysis in children. Mice with constitutive whole-body lipin 1 deficiency have been used to examine mechanisms connecting lipin 1 deficiency to myocyte injury. However, that mouse model is confounded by lipodystrophy not phenocopied in people. Herein, 2 muscle-specific mouse models were studied: 1) Lpin1 exon 3 and 4 deletion, resulting in a hypomorphic protein without PAP activity, but which preserved transcriptional coregulatory function; and 2) Lpin1 exon 7 deletion, resulting in total protein loss. In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol. Additionally, lipin 1-deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy. Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed. These data suggest that mice lacking lipin 1-mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches.-Schweitzer, G. G., Collier, S. L., Chen, Z., McCommis, K. S., Pittman, S. K., Yoshino, J., Matkovich, S. J., Hsu, F.-F., Chrast, R., Eaton, J. M., Harris, T. E., Weihl, C. C., Finck, B. N. Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice.
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http://dx.doi.org/10.1096/fj.201800361RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355067PMC
January 2019

Metabolic importance of adipose tissue monoacylglycerol acyltransferase 1 in mice and humans.

J Lipid Res 2018 09 31;59(9):1630-1639. Epub 2018 May 31.

Medicine, Washington University School of Medicine, St. Louis, MO 63110.

Adipocyte triglyceride storage provides a reservoir of energy that allows the organism to survive times of nutrient scarcity, but excessive adiposity has emerged as a health problem in many areas of the world. Monoacylglycerol acyltransferase (MGAT) acylates monoacylglycerol to produce diacylglycerol; the penultimate step in triglyceride synthesis. However, little is known about MGAT activity in adipocytes, which are believed to rely primarily on another pathway for triglyceride synthesis. We show that expression of the gene that encodes MGAT1 is robustly induced during adipocyte differentiation and that its expression is suppressed in fat of genetically-obese mice and metabolically-abnormal obese human subjects. Interestingly, MGAT1 expression is also reduced in physiologic contexts where lipolysis is high. Moreover, knockdown or knockout of MGAT1 in adipocytes leads to higher rates of basal adipocyte lipolysis. Collectively, these data suggest that MGAT1 activity may play a role in regulating basal adipocyte FFA retention.
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http://dx.doi.org/10.1194/jlr.M084947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121930PMC
September 2018

NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward.

Mol Psychiatry 2019 11 4;24(11):1668-1684. Epub 2018 May 4.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, 15219, USA.

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.
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http://dx.doi.org/10.1038/s41380-018-0061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215755PMC
November 2019

Percutaneous muscle biopsy-induced tissue injury causes local endoplasmic reticulum stress.

Physiol Rep 2018 04;6(8):e13679

Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

Endoplasmic reticulum (ER) stress is likely involved in the pathogenesis of metabolic dysfunction in people with obesity and diabetes. Although tissue biopsy is often used to evaluate the presence and severity of ER stress, it is not known whether acute tissue injury-induced by percutaneous muscle biopsy causes ER stress and its potential downstream effects on markers of inflammation and metabolic function. In this study, we tested the hypothesis that percutaneous biopsy-induced tissue injury causes ER stress and alters inflammatory and metabolic pathways in skeletal muscle. Vastus lateralis muscle tissue was obtained by percutaneous biopsy at 0600 h and 12 h later from either the contralateral leg (Group 1, n = 6) or at the same site as the initial biopsy (Group 2, n = 6) in women who were overweight. Muscle gene expression of selected markers of ER stress, inflammation, and regulators of glucose and lipid metabolism were determined. Compared with Group 1, muscle gene expression in the second biopsy sample obtained in Group 2 demonstrated marked increases in markers of ER stress (GRP78, XBP1, ATF6) and inflammation (IL6, TNF), and alterations in metabolic regulators (decreased expression of GLUT4 and PPARGC1A and increased expression of FASN). Our results suggest that acute tissue injury induced by percutaneous muscle biopsy causes an integrated local response that involves an induction of ER stress and alterations in markers of inflammation and regulators of glucose and lipid metabolism.
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http://dx.doi.org/10.14814/phy2.13679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913661PMC
April 2018

NAD-dependent deacetylase SIRT3 in adipocytes is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism.

Am J Physiol Endocrinol Metab 2018 10 10;315(4):E520-E530. Epub 2018 Apr 10.

Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine , St. Louis, Missouri.

Mitochondrial dysfunction in adipose tissue is involved in the pathophysiology of obesity-induced systemic metabolic complications, such as type 2 diabetes, insulin resistance, and dyslipidemia. However, the mechanisms responsible for obesity-induced adipose tissue mitochondrial dysfunction are not clear. The aim of present study was to test the hypothesis that nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin-3 (SIRT3) in adipocytes plays a critical role in adipose tissue mitochondrial biology and obesity. We first measured adipose tissue SIRT3 expression in obese and lean mice. Next, adipocyte-specific mitochondrial Sirt3 knockout (AMiSKO) mice were generated and metabolically characterized. We evaluated glucose and lipid metabolism in adult mice fed either a regular-chow diet or high-fat diet (HFD) and in aged mice. We also determined the effects of Sirt3 deletion on adipose tissue metabolism and mitochondrial biology. Supporting our hypothesis, obese mice had decreased SIRT3 gene and protein expression in adipose tissue. However, despite successful knockout of SIRT3, AMiSKO mice had normal glucose and lipid metabolism and did not change metabolic responses to HFD-feeding and aging. In addition, loss of SIRT3 had no major impact on putative SIRT3 targets, key metabolic pathways, and mitochondrial function in white and brown adipose tissue. Collectively, these findings suggest that adipocyte SIRT3 is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism. Contrary to our hypothesis, loss of SIRT3 function in adipocytes is unlikely to contribute to the pathophysiology of obesity-induced metabolic complications.
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http://dx.doi.org/10.1152/ajpendo.00057.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230701PMC
October 2018

Effect of Progressive Weight Loss on Lactate Metabolism: A Randomized Controlled Trial.

Obesity (Silver Spring) 2018 04 24;26(4):683-688. Epub 2018 Feb 24.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Objective: Lactate is an intermediate of glucose metabolism that has been implicated in the pathogenesis of insulin resistance. This study evaluated the relationship between glucose kinetics and plasma lactate concentration ([LAC]) before and after manipulating insulin sensitivity by progressive weight loss.

Methods: Forty people with obesity (BMI = 37.9 ± 4.3 kg/m ) were randomized to weight maintenance (n = 14) or weight loss (n = 19). Subjects were studied before and after 6 months of weight maintenance and before and after 5%, 11%, and 16% weight loss. A hyperinsulinemic-euglycemic clamp procedure in conjunction with [6,6- H ]glucose tracer infusion was used to assess glucose kinetics.

Results: At baseline, fasting [LAC] correlated positively with endogenous glucose production rate (r = 0.532; P = 0.001) and negatively with insulin sensitivity, assessed as the insulin-stimulated glucose disposal (r = -0.361; P = 0.04). Progressive (5% through 16%) weight loss caused a progressive decrease in fasting [LAC], and the decrease in fasting [LAC] after 5% weight loss was correlated with the decrease in endogenous glucose production (r = 0.654; P = 0.002) and the increase in insulin sensitivity (r = -0.595; P = 0.007).

Conclusions: This study demonstrates the interrelationships among weight loss, hepatic and muscle glucose kinetics, insulin sensitivity, and [LAC], and it suggests that [LAC] can serve as an additional biomarker of glucose-related insulin resistance.
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http://dx.doi.org/10.1002/oby.22129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866193PMC
April 2018

Retinal de novo lipogenesis coordinates neurotrophic signaling to maintain vision.

JCI Insight 2018 01 11;3(1). Epub 2018 Jan 11.

Division of Endocrinology, Metabolism, and Lipid Research.

Membrane lipid composition is central to the highly specialized functions of neurological tissues. In the retina, abnormal lipid metabolism causes severe forms of blindness, often through poorly understood neuronal cell death. Here, we demonstrate that deleting the de novo lipogenic enzyme fatty acid synthase (FAS) from the neural retina, but not the vascular retina, results in progressive neurodegeneration and blindness with a temporal pattern resembling rodent models of retinitis pigmentosa. Blindness was not rescued by protection from light-evoked activity; by eating a diet enriched in palmitate, the product of the FAS reaction; or by treatment with the PPARα agonist fenofibrate. Vision loss was due to aberrant synaptic structure, blunted responsiveness to glial-derived neurotrophic factor and ciliary neurotrophic factor, and eventual apoptotic cell loss. This progressive neurodegeneration was associated with decreased membrane cholesterol content, as well as loss of discrete n-3 polyunsaturated fatty acid- and saturated fatty acid-containing phospholipid species within specialized membrane microdomains. Neurotrophic signaling was restored by exogenous cholesterol delivery. These findings implicate de novo lipogenesis in neurotrophin-dependent cell survival by maintaining retinal membrane configuration and lipid composition, and they suggest that ongoing lipogenesis may be required to prevent cell death in many forms of retinopathy.
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http://dx.doi.org/10.1172/jci.insight.97076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821215PMC
January 2018

Diurnal Variation in PDK4 Expression Is Associated With Plasma Free Fatty Acid Availability in People.

J Clin Endocrinol Metab 2018 03;103(3):1068-1076

Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

Context: Many biological pathways involved in regulating substrate metabolism display rhythmic oscillation patterns. In rodents, clock genes regulate circadian rhythms of metabolic genes and substrate metabolism. However, the interrelationships among substrate metabolism, metabolic genes, and clock genes have not been fully explored in people.

Objective: We tested the hypothesis that the diurnal expression pattern of pyruvate dehydrogenase kinase 4 (PDK4), a key metabolic enzyme involved in fuel switching between glucose and free fatty acids (FFAs), is associated with plasma FFA concentration and clock genes.

Design And Methods: We analyzed peripheral blood mononuclear cells (PBMCs), subcutaneous adipose tissue, and plasma samples obtained serially during 24 hours from metabolically healthy women (n = 10) and evaluated the interrelationships among PDK4, plasma FFA, and clock genes. We also determined the potential mechanisms responsible for PDK4 transcriptional regulation by using primary human PBMCs and adipocytes.

Results: We found that PDK4 diurnal expression patterns were similar in PBMCs and adipose tissue (ρ = 0.84, P < 0.001). The diurnal variation in PBMC PDK4 expression correlated more strongly with plasma FFA and insulin (ρ = 0.86 and 0.63, respectively, both P < 0.001) concentrations than clock genes. Data obtained from primary culture experiments demonstrated that FFAs directly induced PDK4 gene expression, at least in part through activation of peroxisome proliferator-activated receptor α.

Conclusions: Our results suggest that plasma FFA availability is an important regulator of diurnal expression patterns of PDK4, and we identify a novel interaction between plasma FFA and cellular diurnal rhythms in regulating substrate metabolism.
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http://dx.doi.org/10.1210/jc.2017-02230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283414PMC
March 2018

The role of breakfast in adipose tissue biology.

Authors:
Jun Yoshino

J Physiol 2018 02 15;596(4):551-552. Epub 2018 Jan 15.

Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.

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http://dx.doi.org/10.1113/JP275576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813601PMC
February 2018

NAD Intermediates: The Biology and Therapeutic Potential of NMN and NR.

Cell Metab 2018 03 14;27(3):513-528. Epub 2017 Dec 14.

Department of Developmental Biology, Department of Medicine (Joint), Washington University School of Medicine, Campus Box 8103, 660 South Euclid Avenue, St. Louis, MO 63110, USA; Japan Agency for Medical Research and Development, Project for Elucidating and Controlling Mechanisms of Aging and Longevity, Tokyo, Japan. Electronic address:

Research on the biology of NAD has been gaining momentum, providing many critical insights into the pathogenesis of age-associated functional decline and diseases. In particular, two key NAD intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied over the past several years. Supplementing these NAD intermediates has shown preventive and therapeutic effects, ameliorating age-associated pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health.
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http://dx.doi.org/10.1016/j.cmet.2017.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842119PMC
March 2018

Alterations in 3-Hydroxyisobutyrate and FGF21 Metabolism Are Associated With Protein Ingestion-Induced Insulin Resistance.

Diabetes 2017 07 4;66(7):1871-1878. Epub 2017 May 4.

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO

Systemic hyperaminoacidemia, induced by either intravenous amino acid infusion or protein ingestion, reduces insulin-stimulated glucose disposal. Studies of mice suggest that the valine metabolite 3-hydroxyisobutyrate (3-HIB), fibroblast growth factor 21 (FGF21), adiponectin, and nonesterified fatty acids (NEFAs) may be involved in amino acid-mediated insulin resistance. We therefore measured in 30 women the rate of glucose disposal, and plasma 3-HIB, FGF21, adiponectin, and NEFA concentrations, under basal conditions and during a hyperinsulinemic-euglycemic clamp procedure (HECP), with and without concomitant ingestion of protein ( = 15) or an amount of leucine that matched the amount of protein ( = 15). We found that during the HECP without protein or leucine ingestion, the grand mean ± SEM plasma 3-HIB concentration decreased (from 35 ± 2 to 14 ± 1 µmol/L) and the grand median [quartiles] FGF21 concentration increased (from 178 [116, 217] to 509 [340, 648] pg/mL). Ingestion of protein, but not leucine, decreased insulin-stimulated glucose disposal ( < 0.05) and prevented both the HECP-mediated decrease in 3-HIB and increase in FGF21 concentration in plasma. Neither protein nor leucine ingestion altered plasma adiponectin or NEFA concentrations. These findings suggest that 3-HIB and FGF21 might be involved in protein-mediated insulin resistance in humans.
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http://dx.doi.org/10.2337/db16-1475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482083PMC
July 2017

GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients.

JCI Insight 2017 May 4;2(9). Epub 2017 May 4.

Departments of Ophthalmology.

Glaucoma is the second leading cause of blindness worldwide. Physicians often use surrogate endpoints to monitor the progression of glaucomatous neurodegeneration. These approaches are limited in their ability to quantify disease severity and progression due to inherent subjectivity, unreliability, and limitations of normative databases. Therefore, there is a critical need to identify specific molecular markers that predict or measure glaucomatous neurodegeneration. Here, we demonstrate that growth differentiation factor 15 (GDF15) is associated with retinal ganglion cell death. Gdf15 expression in the retina is specifically increased after acute injury to retinal ganglion cell axons and in a murine chronic glaucoma model. We also demonstrate that the ganglion cell layer may be one of the sources of secreted GDF15 and that GDF15 diffuses to and can be detected in aqueous humor (AH). In validating these findings in human patients with glaucoma, we find not only that GDF15 is increased in AH of patients with primary open angle glaucoma (POAG), but also that elevated GDF15 levels are significantly associated with worse functional outcomes in glaucoma patients, as measured by visual field testing. Thus, GDF15 maybe a reliable metric of glaucomatous neurodegeneration, although further prospective validation studies will be necessary to determine if GDF15 can be used in clinical practice.
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http://dx.doi.org/10.1172/jci.insight.91455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414567PMC
May 2017

An adipo-biliary-uridine axis that regulates energy homeostasis.

Science 2017 03 16;355(6330). Epub 2017 Mar 16.

Touchstone Diabetes Center, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.

Uridine, a pyrimidine nucleoside present at high levels in the plasma of rodents and humans, is critical for RNA synthesis, glycogen deposition, and many other essential cellular processes. It also contributes to systemic metabolism, but the underlying mechanisms remain unclear. We found that plasma uridine levels are regulated by fasting and refeeding in mice, rats, and humans. Fasting increases plasma uridine levels, and this increase relies largely on adipocytes. In contrast, refeeding reduces plasma uridine levels through biliary clearance. Elevation of plasma uridine is required for the drop in body temperature that occurs during fasting. Further, feeding-induced clearance of plasma uridine improves glucose metabolism. We also present findings that implicate leptin signaling in uridine homeostasis and consequent metabolic control and thermoregulation. Our results indicate that plasma uridine governs energy homeostasis and thermoregulation in a mechanism involving adipocyte-dependent uridine biosynthesis and leptin signaling.
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http://dx.doi.org/10.1126/science.aaf5375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832364PMC
March 2017