SGLT2 inhibitors are beneficial in halting diabetic kidney disease; complete mechanisms is unknown. The epithelial to mesenchymal transition (EMT) is associated with Sirt3 suppression and aberrant glycolysis. Here, we hypothesized that the SGLT2 inhibitor restores normal kidney histology/function associated with the inhibition of aberrant glycolysis in diabetic kidneys. CD-1 mice with streptozotocin-induced diabetes displayed kidney fibrosis associated with the EMT at 4-months after diabetes induction. Empagliflozin intervention for one month restored all changes; adjustment of blood glucose by insulin did not. Empagliflozin normalized suppressed Sirt3 levels and aberrant glycolysis (characterized by hypoxia-inducible factor-1α accumulation, hexokinase 2 induction and pyruvate kinase isozyme M2 dimer formation) in diabetic kidneys. Empagliflozin also suppressed the accumulation of glycolysis byproducts in diabetic kidneys. Another SGLT2 inhibitor, canagliflozin, demonstrated similar in vivo effects. High-glucose media induced the EMT, which was associated with Sirt3 suppression and aberrant glycolysis induction, in the HK2 proximal tubule cell line; SGLT2 knockdown suppressed the EMT with restoration of all aberrant functions. SGLT2 suppression in tubular cells also inhibited the mesenchymal transition of neighboring endothelial cells. Taken together, SGLT2 inhibitors exhibit renoprotective potential that is partially dependent on the inhibition of glucose reabsorption and subsequent aberrant glycolysis in kidney tubules.
Jinpeng Li, Haijie Liu, Susumu Takagi, Kyoko Nitta, Munehiro Kitada, Swayam Prakash Srivastava, Yuta Takagaki, Keizo Kanasaki, Daisuke Koya
Severe obesity (SO) affects about 6% of youth in US, augmenting the risks for cardiovascular disease and Type 2 diabetes.Herein, we obtained paired omental (omVAT) and abdominal subcutaneous (SAT) adipose tissue biopsies from obese girls with SO, undergoing sleeve gastrectomy (SG), to test whether differences in cellular and transcriptomic profiles between omVAT and SAT depots affect insulin sensitivity differentially. Following weight loss, these analyses were repeated in a subgroup of subjects having a second SAT biopsy.We found that omVAT displayed smaller adipocytes compared to SAT, increased lipolysis through adipose triglyceride lipase (ATGL) phosphorylation, reduced inflammation and increased expression of browning/beige markers. Contrary to omVAT, SAT adipocyte diameter correlated with insulin resistance. Following SG, both weight and insulin sensitivity improved markedly in all subjects. SAT adipocytes size became smaller showing an increased lipolysis through perilipin-1 phosphorylation, decreased inflammation and increased expression in browning/beige markers.In summary, in adolescent girls with SO, both omVAT and SAT depots showed distinct cellular and transcriptomic profiles. Following weight loss, the SAT depot changed its cellular morphology and transcriptomic profiles into a more favorable one. These changes in the SAT depot may play a fundamental role in the resolution of insulin resistance.
Elena Tarabra, Jessica Nouws, Alla Vash-Margita, Geoffrey S. Nadzam, Rachel Goldberg-Gell, Michelle Van Name, Bridget Pierpont, James Knight, Gerald I. Shulman, Sonia Caprio
Immune checkpoint inhibitor (ICI) therapy has shown a significant benefit in the treatment of a variety of cancer entities. However, immune-related adverse events (irAEs) occur frequently and can lead to ICI treatment termination. MicroRNA-146a (miR-146a) has regulatory functions in immune cells. We observed that mice lacking miR-146a developed significantly more severe irAEs compared to wildtype mice in several irAE target organs in two different murine models. MiR-146a-/- mice exhibited increased T cell activation and effector function upon ICI treatment. Moreover, neutrophil numbers in the spleen and the inflamed intestine were highly increased in ICI-treated miR-146a-/- mice. Therapeutic administration of a miR-146a mimic reduced irAE severity. To validate our preclinical findings in patients, we analyzed the impact of a SNP in the MIR146A gene on irAE severity in 167 patients treated with ICIs. We found that the SNP rs2910164 leading to reduced miR-146a expression was associated with an increased risk to develop severe irAEs, reduced progression-free survival and increased neutrophil counts both at baseline and during ICI therapy.In conclusion, we characterized miR-146a as a novel molecular target to prevent ICI mediated autoimmune dysregulation. Furthermore, we identified the MIR146A SNP rs2910164 as a biomarker to predict severe irAE development in ICI-treated patients.
Dominik Marschner, Martina Falk, Nora Rebeka Javorniczky, Kathrin Hanke-Müller, Justyna Rawluk, Annette Schmitt-Graeff, Federico Simonetta, Eileen Haring, Severin Dicks, Manching Ku, Sandra Duquesne, Konrad Aumann, David Rafei-Shamsabadi, Frank Meiss, Patrick Marschner, Melanie Boerries, Robert S. Negrin, Justus Duyster, Robert Zeiser, Natalie Köhler
We hypothesized that skeletal muscle contraction produces a cellular stress signal triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying novel exercise-regulated myokines, also known as exerkines, able to promote lipolysis.Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. Conditioned media and human plasma samples were analyzed using unbiased proteomic and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples.CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes (1.3 to 8 fold, p<0.001). Growth and Differentiation Factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was up-regulated in CM from both acute and chronic exercise-stimulated myotubes. We further show that physiological concentrations of recombinant GDF15 protein increase lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogates EPS CM-mediated lipolysis.We herein provide the first evidence that GDF15 is a novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.
Claire Laurens, Anisha Parmar, Enda Murphy, Deborah Carper, Benjamin Lair, Pauline Maes, Julie Vion, Nathalie Boulet, Coralie Fontaine, Marie-Adeline Marqués, Dominique Larrouy, Isabelle Harant, Claire Thalamas, Emilie Montastier, Sylvie Caspar-Bauguil, Virginie Bourlier, Geneviève Tavernier, Jean-Louis Grolleau, Anne Bouloumié, Dominique Langin, Nathalie Viguerie, Fabrice Bertile, Stéphane Blanc, Isabelle de Glisezinski, Donal J. O'Gorman, Cedric Moro
Patients with active acromegaly (ACRO) exhibit low hepatocellular lipids (HCL) despite pronounced insulin resistance (IR). This contrasts the strong association of IR with non-alcoholic fatty liver disease in the general population. Since low HCL in acromegaly might be caused by changes in oxidative substrate metabolism, we investigated mitochondrial activity and plasma metabolomics/lipidomics in active acromegaly. Fifteen ACRO and seventeen healthy controls (CON) matched for age, BMI, gender and body composition underwent 31P/1H-7T-MR-spectroscopy of the liver and skeletal muscle, as well as plasma metabolomic profiling and an oral glucose tolerance test. ACRO showed significant lower HCL but ATP-synthesis rate was significantly increased compared to CON. Furthermore, a decreased ratio of unsaturated to saturated intrahepatocellular fatty acids was found in ACRO. Within assessed plasma lipids, lipidomics, and metabolomics, decreased carnitine species also indicate increased mitochondrial activity. We therefore conclude that excess of growth hormone (GH) in humans counteracts hepatocellular lipid accumulation by increased hepatic ATP-synthesis. This is accompanied by a decreased ratio of unsaturated-to-saturated lipids in hepatocytes and by a metabolomic profile reflecting the increase in mitochondrial activity. Thus, these findings help to better understand GH-regulated antisteatotic pathways and provide a better insight into potential novel therapeutic targets for treating NAFLD.
Paul Fellinger, Peter Wolf, Lorenz Pfleger, Patrik Krumpolec, Martin Krssak, Kristaps Klavins, Stefan Wolfsberger, Alexander Micko, Patricia Carey, Bettina Gürtl, Greisa Vila, Wolfgang Raber, Clemens Fürnsinn, Thomas Scherer, Siegfried Trattnig, Alexandra Kautzky-Willer, Michael Krebs, Yvonne Winhofer
To define cellular mechanisms underlying kidney function and failure, the Kidney Precision Medicine Project (KPMP) analyzes biopsy tissue in a multi-center research network to build cell-level process maps of kidney. This study aimed to establish a single cell RNA sequencing strategy to use cell level transcriptional profiles from kidney biopsies in KPMP to define molecular subtypes in glomerular diseases.Using multiple sources of adult human kidney reference tissue samples, 22,268 single cell profiles passed KPMP quality control parameters. Unbiased clustering resulted in 31 distinct cell clusters that were linked to kidney and immune cell types using specific cell markers. Focusing on endothelial cell phenotypes, in silico and in situ hybridization methods assigned three discrete endothelial cell clusters to distinct renal vascular beds. Transcripts defining glomerular endothelial cell (GEC) were evaluated in biopsies from patients with ten different glomerular diseases in the NEPTUNE and ERCB cohort studies. Highest GEC scores were observed in patients with focal segmental glomerulosclerosis (FSGS). Molecular endothelial signatures suggested two distinct FSGS patient subgroups with alpha-2 macroglobulin (A2M) as a key downstream mediator of the endothelial cell phenotype. Finally, glomerular A2M transcript levels associated with lower proteinuria remission rates, linking endothelial function with long-term outcome in FSGS.
Rajasree Menon, Edgar A. Otto, Paul J. Hoover, Sean Eddy, Laura H. Mariani, Bradley Godfrey, Celine C. Berthier, Felix Eichinger, Lalita Subramanian, Jennifer L. Harder, Wenjun Ju, Viji Nair, Maria Larkina, Abhijit S. Naik, Jinghui Luo, sanjay jain, Rachel Sealfon, Olga G. Troyanskaya, Nir Hacohen, Jeffrey B. Hodgin, Matthias Kretzler
Plasma viral load (VL) and CD4+ T-cell count are widely used as biomarkers of HIV-1 replication, pathogenesis, and response to antiretroviral therapy (ART). However, the clinical potential of cell-associated (CA) HIV-1 molecular markers is much less understood. Here, we measured CA HIV-1 RNA and DNA in HIV-infected individuals treated with temporary ART initiated during primary HIV-1 infection. We demonstrate significant predictive value of CA RNA for: (a) the virological and immunological response to early ART, (b) the magnitude and time to viral rebound after discontinuation of early ART, and (c) the disease progression in the absence of treatment. Remarkably, when adjusted for CA RNA, plasma VL no longer appeared as an independent predictor of any clinical endpoint in this cohort. The potential of CA RNA as an HIV-1 clinical marker, in particular as a predictive biomarker of virological control after stopping ART, should be explored in the context of HIV-1 curative interventions.
Alexander O. Pasternak, Marlous L. Grijsen, Ferdinand W. Wit, Margreet Bakker, Suzanne Jurriaans, Jan M. Prins, Ben Berkhout
The specificity of antibodies (Abs) generated to influenza A virus (IAV) infection can significantly alter protection and viral clearance. At present, the impact of age upon this process is relatively unexplored. Here, we evaluated the Ab response in newborn and adult African green monkeys (AGM) following infection with IAV using a strain that enables us to determine the immunodominance (ID) hierarchy of the Ab response to hemagglutinin (HA), the principal target of protective Abs. This revealed altered ID patterns in the early IgM anti-HA response in newborns versus adults that converged over time. While the IgG ID profiles for HA in newborn and adult monkeys were similar, this was not the case for IgA. Importantly, HA stem-specific Abs were generated robustly and similarly in newborns and adults in terms of quality and quantity. Together these results demonstrate that newborns and adults can differ in the Ab ID pattern established following infection and that the ID pattern can vary across isotypes. In addition, newborns have the ability to generate potent HA stem-specific Ab responses. Our findings further the understanding of the newborn response to IAV antigens and inform the development of improved vaccines for this at-risk population.
Elene A. Clemens, Davide Angeletti, Beth C. Holbrook, Masaru Kanekiyo, Matthew J. Jorgensen, Barney S. Graham, Jonathan W. Yewdell, Martha A. Alexander-Miller
The blood hormone erythropoietin (EPO), upon binding to its receptor (EpoR), modulates high fat-diet (HFD)-induced obesity in mice, improves glucose tolerance, and prevents white adipose tissue inflammation. Transgenic mice with constitutive over-expression of human EPO solely in brain (Tg21) were used to assess the neuro-endocrine EPO effect without increasing the hematocrit. Male Tg21-mice resisted HFD-induced weight gain, showed lower serum ACTH, corticosterone and C-reactive protein levels, and prevented myeloid cell recruitment to hypothalamus compared with WT-males. HFD-induced hypothalamic inflammation (HI) and microglial activation were higher in male mice, and Tg21-males exhibited lower increase in HI than WT-males. Physiological EPO function in the brain also showed sexual dimorphism in regulating HFD response. Targeted deletion of EpoR gene expression in neuronal and glial cells worsened HFD-induced glucose intolerance in both male and female mice, but increased weight gain and HI in the hypothalamus in male mice only. Female estrogen production blocked reduced weight gain and HI. Both male and female Tg21-mice kept on normal-chow and HFD showed significantly improved glycemic control. Our data indicates that cerebral EPO regulates weight gain and HI in a sex-dependent response, distinct from EPO regulation of glycemic control, and independent of erythropoietic EPO response.
Soumyadeep Dey, Zhenzhong Cui, Oksana Gavrilova, XiaoJie Zhang, Max Gassmann, Constance T. Noguchi
Most prostate cancers depend on androgens for growth and therefore the mainstay treatment for advanced, recurrent or metastatic prostate cancer is androgen deprivation therapy (ADT). A prominent side effect in patients receiving ADT is an obese frailty syndrome that includes fat gain and sarcopenia, defined as the loss of muscle function accompanied by reduced muscle mass or quality. Mice bearing Pten deficient prostate cancers were examined to gain mechanistic insight into ADT-induced sarcopenic obesity. Castration induced fat gain as well as skeletal muscle mass and strength loss. Catabolic TGFß-family myokine protein levels were increased immediately prior to strength loss and pan-myokine blockade using a soluble receptor (ActRIIB-Fc) completely reversed the castration-induced sarcopenia. The onset of castration-induced strength and muscle mass loss, as well as the increase in catabolic TGFß-family myokine protein levels, were coordinately accelerated in tumor-bearing mice relative to tumor-free mice. Notably, GDF11 increased in muscle after castration only in tumor-bearing mice, but not in tumor free mice. An early surge of GDF11 in prostate tumor tissue and in the circulation suggests that endocrine GDF11 signaling from tumor to muscle is a major driver of the accelerated ADT-induced sarcopenic phenotype. In tumor-bearing mice, GDF11 blockade largely prevented castration-induced strength loss but did not preserve muscle mass, which confirms a primary role for GDF11 in muscle function and suggests an additional role for the other catabolic myokines.
Chunliu Pan, Neha Jaiswal Agrawal, Yanni Zulia, Shalini Singh, Kai Sha, James L. Mohler, Kevin H. Eng, Joe Chakkalakal, John J. Krolewski, Kent L. Nastiuk
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