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utpal pajvani

KyeongJin Kim, Ira J Goldberg, Mark J Graham, Meenakshi Sundaram, Enrico Bertaggia, Samuel X Lee, Li Qiang, Rebecca A Haeusler, Daniel Metzger, Pierre Chambon, Zemin Yao, Henry N Ginsberg, Utpal B Pajvani
Excess plasma triglycerides (TGs) are a key component of obesity-induced metabolic syndrome. We have shown that γ-secretase inhibitor (GSI) treatment improves glucose tolerance due to inhibition of hepatic Notch signaling but found additional Notch-independent reduction of plasma TG-rich lipoproteins (TRLs) in GSI-treated, as well as hepatocyte-specific, γ-secretase knockout (L-Ncst) mice, which suggested a primary effect on hepatocyte TRL uptake. Indeed, we found increased VLDL and LDL particle uptake in L-Ncst hepatocytes and Ncst-deficient hepatoma cells, in part through reduced γ-secretase-mediated low-density lipoprotein receptor (LDLR) cleavage and degradation...
April 3, 2018: Cell Metabolism
Jacob S Ballon, Utpal B Pajvani, Laurel Es Mayer, Zachary Freyberg, Robin Freyberg, Ignacio Contreras, Michael Rosenbaum, Rudolph L Leibel, Jeffrey A Lieberman
Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions...
May 2018: Journal of Psychopharmacology
Alberto Bartolomé, Ana García-Aguilar, Shun-Ichiro Asahara, Yoshiaki Kido, Carlos Guillén, Utpal B Pajvani, Manuel Benito
The mechanistic target of rapamycin complex 1 (MTORC1) is a critical negative regulator of general autophagy. We hypothesized that MTORC1 may specifically regulate autophagic clearance of damaged mitochondria. To test this, we used cells lacking tuberous sclerosis complex 2 (TSC2 -/-), which show constitutive MTORC1 activation. TSC2 -/- cells show MTORC1-dependent impaired autophagic flux after chemical uncoupling of mitochondria, increased mitochondrial protein aging and accumulation of p62/SQSTM1 positive mitochondria...
September 11, 2017: Molecular and Cellular Biology
KyeongJin Kim, Dongryeol Ryu, Paola Dongiovanni, Lale Ozcan, Shruti Nayak, Beatrix Ueberheide, Luca Valenti, Johan Auwerx, Utpal B Pajvani
BACKGROUND & AIMS: Obesity-induced nonalcoholic fatty liver disease (NAFLD) develops, in part, via excess insulin-stimulated hepatic de novo lipogenesis, which increases, paradoxically, in patients with obesity-induced insulin resistance. Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) terminates insulin signaling by dephosphorylating Akt; levels of PHLPP2 are reduced in livers from obese mice. We investigated whether loss of hepatic PHLPP2 is sufficient to induce fatty liver in mice, mechanisms of PHLPP2 degradation in fatty liver, and expression of genes that regulate PHLPP2 in livers of patients with NAFLD...
December 2017: Gastroenterology
Leroy C Joseph, Emanuele Barca, Prakash Subramanyam, Michael Komrowski, Utpal Pajvani, Henry M Colecraft, Michio Hirano, John P Morrow
[This corrects the article DOI: 10.1371/journal.pone.0145750.].
2017: PloS One
Luca Valenti, Elisabetta Bugianesi, Utpal Pajvani, Giovanni Targher
Growing epidemiological evidence suggests that nonalcoholic fatty liver disease (NAFLD) is an early predictor of and determinant for the development of type 2 diabetes and other features of the metabolic syndrome. This finding may have important clinical implications for the diagnosis, prevention and treatment of type 2 diabetes and its chronic complications. However, given the complex and bi-directional relationships between NAFLD, insulin resistance and chronic hyperglycaemia, it is extremely difficult to distinguish whether NAFLD is a cause or a consequence of insulin resistance and type 2 diabetes...
November 2016: Liver International: Official Journal of the International Association for the Study of the Liver
KyeongJin Kim, Utpal B Pajvani
No abstract text is available yet for this article.
May 2, 2016: Cell Cycle
David P Sparling, Junjie Yu, KyeongJin Kim, Changyu Zhu, Sebastian Brachs, Andreas L Birkenfeld, Utpal B Pajvani
OBJECTIVE: As the obesity pandemic continues to expand, novel molecular targets to reduce obesity-related insulin resistance and Type 2 Diabetes (T2D) continue to be needed. We have recently shown that obesity is associated with reactivated liver Notch signaling, which, in turn, increases hepatic insulin resistance, opening up therapeutic avenues for Notch inhibitors to be repurposed for T2D. Herein, we tested the systemic effects of γ-secretase inhibitors (GSIs), which prevent endogenous Notch activation, and confirmed these effects through creation and characterization of two different adipocyte-specific Notch loss-of-function mouse models through genetic ablation of the Notch transcriptional effector Rbp-Jk (A-Rbpj) and the obligate γ-secretase component Nicastrin (A-Nicastrin)...
February 2016: Molecular Metabolism
Leroy C Joseph, Emanuele Barca, Prakash Subramanyam, Michael Komrowski, Utpal Pajvani, Henry M Colecraft, Michio Hirano, John P Morrow
Obesity and high saturated fat intake increase the risk of heart failure and arrhythmias. The molecular mechanisms are poorly understood. We hypothesized that physiologic levels of saturated fat could increase mitochondrial reactive oxygen species (ROS) in cardiomyocytes, leading to abnormalities of calcium homeostasis and mitochondrial function. We investigated the effect of saturated fat on mitochondrial function and calcium homeostasis in isolated ventricular myocytes. The saturated fatty acid palmitate causes a decrease in mitochondrial respiration in cardiomyocytes...
2016: PloS One
KyeongJin Kim, Li Qiang, Matthew S Hayden, David P Sparling, Nicole H Purcell, Utpal B Pajvani
Mechanistic target of rapamycin complex 1 (mTORC1), defined by the presence of Raptor, is an evolutionarily conserved and nutrient-sensitive regulator of cellular growth and other metabolic processes. To date, all known functions of Raptor involve its scaffolding mTOR kinase with substrate. Here we report that mTORC1-independent ('free') Raptor negatively regulates hepatic Akt activity and lipogenesis. Free Raptor levels in liver decline with age and in obesity; restoration of free Raptor levels reduces liver triglyceride content, through reduced β-TrCP-mediated degradation of the Akt phosphatase, PHLPP2...
January 8, 2016: Nature Communications
Alice Abraham, Mishaela Rubin, Domenico Accili, John P Bilezikian, Utpal B Pajvani
Insulin, proinsulin, and C-peptide levels increase with sulfonylurea exposure but the acuity of increase has not been described in dialysis patients. We present a case of a dialysis patient who presented with hypoglycemia and was found to have accidental sulfonylurea ingestion. This is a 73-year-old man with ESRD on peritoneal dialysis, without history of diabetes, who presented with hypoglycemia. Past medical history includes multiple myeloma, congestive heart failure, and hypertension. At initial presentation, his blood glucose was 47 mg/dL, with concomitant elevations in the following: C-peptide 30...
2015: Case Reports in Endocrinology
Utpal B Pajvani, Domenico Accili
No abstract text is available yet for this article.
November 2015: Diabetologia
Utpal B Pajvani, Domenico Accili
Until recently, type 2 diabetes was seen as a disease caused by an impaired ability of insulin to promote the uptake and utilisation of glucose. Work on forkhead box protein O (FOXO) transcription factors revealed new aspects of insulin action that have led us to articulate a liver- and beta cell-centric narrative of diabetes pathophysiology and treatment. FOXO integrate a surprisingly diverse subset of biological functions to promote metabolic flexibility. In the liver, they controls the glucokinase/glucose-6-phosphatase switch and bile acid pool composition, directing carbons to glucose or lipid utilisation, thus providing a unifying mechanism for the two abnormalities of the diabetic liver: excessive glucose production and increased lipid synthesis and secretion...
November 2015: Diabetologia
Li Qiang, Ning Kon, Wenhui Zhao, Le Jiang, Colette M Knight, Carrie Welch, Utpal Pajvani, Wei Gu, Domenico Accili
Obesity is associated with higher incidence of cancer, but the predisposing mechanisms remain poorly understood. The NAD(+)-dependent deacetylase SirT1 orchestrates metabolism, cellular survival, and growth. However, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1. In this work, we demonstrate that genetic ablation of the endogenous inhibitor of SirT1, Deleted-in-Breast-Cancer-1 (Dbc1), unexpectedly results in obesity and insulin resistance. Dbc1 deficiency promoted SirT1-dependent gain of function of stearoyl-coenzyme A desaturase 1 (Scd1), increasing plasma and tissue levels of unsaturated fatty acids...
June 23, 2015: Cell Reports
Jacob S Ballon, Utpal Pajvani, Zachary Freyberg, Rudolph L Leibel, Jeffrey A Lieberman
Antipsychotic medications are associated with major metabolic changes that contribute to medical morbidity and a significantly shortened life span. The mechanisms for these changes provide us with a broader understanding of central nervous and peripheral organ-mediated metabolic regulation. This paper reviews an extensive literature regarding putative mechanisms for effects of antipsychotic medications on weight regulation and glucose homeostasis as well as potential inherent metabolic risks of schizophrenia itself...
November 2014: Trends in Endocrinology and Metabolism: TEM
Martina Kováčová, Marta Filková, Mária Potočárová, Soňa Kiňová, Utpal B Pajvani
OBJECTIVE: We report the presentation and novel therapy of a calcitonin-secreting pancreatic neuroendocrine tumor (PNET) and review the literature on this unusual neoplasm. METHODS: We cite the history of a 38-year-old male who presented with fatigue, weight loss, and diarrhea and was found to have a pancreatic head mass on cross-sectional imaging, as well as liver metastases. RESULTS: The patient's laboratory evaluation was notable for a >100-fold elevation of the peptide hormone calcitonin in serum...
August 2014: Endocrine Practice
Luca Valenti, Rosa M Mendoza, Raffaela Rametta, Marco Maggioni, Chris Kitajewski, Carrie J Shawber, Utpal B Pajvani
Hepatic Notch signaling is inappropriately activated in obese/insulin-resistant mouse models. Genetic or pharmacologic inhibition of hepatic Notch signaling in obese mice simultaneously improves glucose tolerance and reduces hepatic triglyceride content. As such, we predicted that Notch signaling in human liver would be positively associated with insulin resistance and hepatic steatosis. Here, we systematically survey Notch signaling in liver biopsy specimens, and show active Notch signaling in lean and obese adults, with expression of multiple Notch receptors and ligands...
December 2013: Diabetes
Utpal B Pajvani, Li Qiang, Thaned Kangsamaksin, Jan Kitajewski, Henry N Ginsberg, Domenico Accili
Increased hepatic lipid content is an early correlate of insulin resistance and can be caused by nutrient-induced activation of mammalian target of rapamycin (mTor). This activation of mTor increases basal Akt activity, leading to a self-perpetuating lipogenic cycle. We have previously shown that the developmental Notch pathway has metabolic functions in adult mouse liver. Acute or chronic inhibition of Notch dampens hepatic glucose production and increases Akt activity and may therefore be predicted to increase hepatic lipid content...
August 2013: Nature Medicine
Lale Ozcan, Catherine C L Wong, Gang Li, Tao Xu, Utpal Pajvani, Sung Kyu Robin Park, Anetta Wronska, Bi-Xing Chen, Andrew R Marks, Akiyoshi Fukamizu, Johannes Backs, Harold A Singer, John R Yates, Domenico Accili, Ira Tabas
Hepatic glucose production (HGP) is crucial for glucose homeostasis, but the underlying mechanisms have not been fully elucidated. Here, we show that a calcium-sensing enzyme, CaMKII, is activated in a calcium- and IP3R-dependent manner by cAMP and glucagon in primary hepatocytes and by glucagon and fasting in vivo. Genetic deficiency or inhibition of CaMKII blocks nuclear translocation of FoxO1 by affecting its phosphorylation, impairs fasting- and glucagon/cAMP-induced glycogenolysis and gluconeogenesis, and lowers blood glucose levels, while constitutively active CaMKII has the opposite effects...
May 2, 2012: Cell Metabolism
Utpal B Pajvani, Carrie J Shawber, Varman T Samuel, Andreas L Birkenfeld, Gerald I Shulman, Jan Kitajewski, Domenico Accili
Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate this function. Altered Notch signaling is evident in tumorigenesis, and Notch antagonists are in clinical testing for application in cancer. Here we report that FoxO1 and Notch coordinately regulate hepatic glucose metabolism. Combined haploinsufficiency of FoxO1 and Notch1 markedly raises insulin sensitivity in diet-induced insulin resistance, as does liver-specific knockout of the Notch transcriptional effector Rbp-Jκ...
July 31, 2011: Nature Medicine
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