Efficacy of Metreleptin in Obese Patients With Type 2 Diabetes: Cellular and Molecular Pathways Underlying Leptin Tolerance

Objective: Metreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes. Research Design and Methods: We studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo–controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro. Results: In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA$_{1c}$ marginally (8.01 $\pm$ 0.93–7.96 $\pm$ 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of $\sim$50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at $\sim$50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling. Conclusions: In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA$_{1c}$ marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes

Carnegie Supernova Project: The First Homogeneous Sample of Super-Chandrasekhar-mass/2003fg-like Type Ia Supernovae

We present a multiwavelength photometric and spectroscopic analysis of 13 super-Chandrasekhar-mass/2003fg-like Type Ia supernovae (SNe Ia). Nine of these objects were observed by the Carnegie Supernova Project. The 2003fg-like SNe have slowly declining light curves (Δm 15(B) < 1.3 mag), and peak absolute B-band magnitudes of -19 < M B < -21 mag. Many of the 2003fg-like SNe are located in the same part of the luminosity-width relation as normal SNe Ia. In the optical B and V bands, the 2003fg-like SNe look like normal SNe Ia, but at redder wavelengths they diverge. Unlike other luminous SNe Ia, the 2003fg-like SNe generally have only one i-band maximum, which peaks after the epoch of the B-band maximum, while their near-IR (NIR) light-curve rise times can be ⪆40 days longer than those of normal SNe Ia. They are also at least 1 mag brighter in the NIR bands than normal SNe Ia, peaking above M H = -19 mag, and generally have negative Hubble residuals, which may be the cause of some systematics in dark-energy experiments. Spectroscopically, the 2003fg-like SNe exhibit peculiarities such as unburnt carbon well past maximum light, a large spread (8000-12,000 km s-1) in Si ii λ6355 velocities at maximum light with no rapid early velocity decline, and no clear H-band break at +10 days. We find that SNe with a larger pseudo-equivalent width of C ii at maximum light have lower Si ii λ6355 velocities and more slowly declining light curves. There are also multiple factors that contribute to the peak luminosity of 2003fg-like SNe. The explosion of a C-O degenerate core inside a carbon-rich envelope is consistent with these observations. Such a configuration may come from the core-degenerate scenario.Fil: Ashall, C.. University Hawaii Institute For Astronomy; Estados UnidosFil: Lu, J.. Florida State University; Estados UnidosFil: Hsiao, E. Y.. Florida State University; Estados UnidosFil: Hoeflich, P.. Florida State University; Estados UnidosFil: Phillips, M. M.. Las Campanas Observatory; ChileFil: Galbany, Lluís. Instituto de Ciencias del Espacio; EspañaFil: Burns, C. R.. Las Campanas Observatory; ChileFil: Contreras, C.. Las Campanas Observatory; ChileFil: Krisciunas, K.. Texas A&M University; Estados UnidosFil: Morrell, Nidia Irene. Las Campanas Observatory; ChileFil: Stritzinger, M. D.. University Aarhus; DinamarcaFil: Suntzeff, Nicholas B.. Texas A&M University; Estados UnidosFil: Taddia, F.. University Aarhus; DinamarcaFil: Anais, J.. Las Campanas Observatory; ChileFil: Baron, E.. Oklahoma State University; Estados Unidos. Universitat Hamburg; AlemaniaFil: Brown, P. J.. Texas A&M University; Estados UnidosFil: Busta, L.. Las Campanas Observatory; ChileFil: Campillay, A.. Universidad de La Serena; ChileFil: Castellón, S.. Las Campanas Observatory; ChileFil: Corco, C.. Las Campanas Observatory; Chile. Soar Telescope; ChileFil: Davis, S.. University of California at Davis; Estados UnidosFil: Folatelli, Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Förster, F.. Universidad de Chile; Chile. Instituto Milenio de Astrofísica; ChileFil: Freedman, W. L.. University of Chicago; Estados UnidosFil: Gonzaléz, C.. Las Campanas Observatory; ChileFil: Hamuy, M.. Universidad de Chile; ChileFil: Holmbo, S.. University Aarhus; DinamarcaFil: Kirshner, R. P.. Harvard-Smithsonian Center for Astrophysics; Estados UnidosFil: Kumar, S.. Florida State University; Estados UnidosFil: Marion, G. H.. University of Texas at Austin; Estados UnidosFil: Mazzali, P.. Liverpool John Moores University; Reino UnidoFil: Morokuma, T.. The University Of Tokyo; JapónFil: Nugent, P. E.. Lawrence Berkeley National Laboratory; Estados Unidos. University of California at Berkeley; Estados UnidosFil: Persson, S. E.. Las Campanas Observatory; ChileFil: Piro, A. L.. Las Campanas Observatory; ChileFil: Roth, M.. Las Campanas Observatory; ChileFil: Salgado, F.. Las Campanas Observatory; ChileFil: Sand, D.J.. University of Arizona; Estados UnidosFil: Seron, J.. Las Campanas Observatory; ChileFil: Shahbandeh, M.. Florida State University; Estados UnidosFil: Shappee, B. J.. University Hawaii Institute For Astronomy; Estados Unido

The banff 2019 kidney meeting report (I): updates on and clarification of criteria for T cell- and antibody-mediated rejection.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation

Gender Dimorphism in Skeletal Muscle Leptin Receptors, Serum Leptin and Insulin Sensitivity

To determine if there is a gender dimorphism in the expression of leptin receptors (OB-R170, OB-R128 and OB-R98) and the protein suppressor of cytokine signaling 3 (SOCS3) in human skeletal muscle, the protein expression of OB-R, perilipin A, SOCS3 and alpha-tubulin was assessed by Western blot in muscle biopsies obtained from the m. vastus lateralis in thirty-four men (age = 27.1±6.8 yr) and thirty-three women (age = 26.7±6.7 yr). Basal serum insulin concentration and HOMA were similar in both genders. Serum leptin concentration was 3.4 times higher in women compared to men (P<0.05) and this difference remained significant after accounting for the differences in percentage of body fat or soluble leptin receptor. OB-R protein was 41% (OB-R170, P<0.05) and 163% (OB-R128, P<0.05) greater in women than men. There was no relationship between OB-R expression and the serum concentrations of leptin or 17β-estradiol. In men, muscle OB-R128 protein was inversely related to serum free testosterone. In women, OB-R98 and OB-R128 were inversely related to total serum testosterone concentration, and OB-R128 to serum free testosterone concentration. SOCS3 protein expression was similar in men and women and was not related to OB-R. In women, there was an inverse relationship between the logarithm of free testosterone and SCOS3 protein content in skeletal muscle (r = −0.46, P<0.05). In summary, there is a gender dimorphism in skeletal muscle leptin receptors expression, which can be partly explained by the influence of testosterone. SOCS3 expression in skeletal muscle is not up-regulated in women, despite very high serum leptin concentrations compared to men. The circulating form of the leptin receptor can not be used as a surrogate measure of the amount of leptin receptors expressed in skeletal muscles

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell–mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation

Interaction of the Deubiquitinating Enzyme Ubp2 and the E3 Ligase Rsp5 Is Required for Transporter/Receptor Sorting in the Multivesicular Body Pathway

Protein ubiquitination is essential for many events linked to intracellular protein trafficking. We sought to elucidate the possible involvement of the S. cerevisiae deubiquitinating enzyme Ubp2 in transporter and receptor trafficking after we (this study) and others established that affinity purified Ubp2 interacts stably with the E3 ubiquitin ligase Rsp5 and the (ubiquitin associated) UBA domain containing protein Rup1. UBP2 interacts genetically with RSP5, while Rup1 facilitates the tethering of Ubp2 to Rsp5 via a PPPSY motif. Using the uracil permease Fur4 as a model reporter system, we establish a role for Ubp2 in membrane protein turnover. Similar to hypomorphic rsp5 alleles, cells deleted for UBP2 exhibited a temporal stabilization of Fur4 at the plasma membrane, indicative of perturbed protein trafficking. This defect was ubiquitin dependent, as a Fur4 N-terminal ubiquitin fusion construct bypassed the block and restored sorting in the mutant. Moreover, the defect was absent in conditions where recycling was absent, implicating Ubp2 in sorting at the multivesicular body. Taken together, our data suggest a previously overlooked role for Ubp2 as a positive regulator of Rsp5-mediated membrane protein trafficking subsequent to endocytosis