A5001500351- Metabolism, Diabetes, and Cancer
- Pancreatic function and diabetes
- Adipose Tissue and Metabolism
- Diabetes Treatment and Management
- Peroxisome Proliferator-Activated Receptors
- Liver Disease Diagnosis and Treatment
- Cancer, Lipids, and Metabolism
- Lipid metabolism and biosynthesis
- Cholesterol and Lipid Metabolism
- Genetic Neurodegenerative Diseases
- Drug Transport and Resistance Mechanisms
- Diet, Metabolism, and Disease
- FOXO transcription factor regulation
- Diet and metabolism studies
- Parkinson's Disease Mechanisms and Treatments
- Eicosanoids and Hypertension Pharmacology
- Signaling Pathways in Disease
- Hepatitis C virus research
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Receptor Mechanisms and Signaling
Massanutten Regional Library
2019
Merck & Co., Inc., Rahway, NJ, USA (United States)
2013-2017
Washington University in St. Louis
2017
The University of Texas Southwestern Medical Center
2009
University of Pennsylvania
2002-2007
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades investigation, the biological roles AMPK and its potential as drug target remain incompletely understood, largely because lack optimized pharmacological tools. We developed MK-8722, potent, direct, allosteric activator all 12 mammalian complexes. In rodents rhesus monkeys, MK-8722-mediated activation skeletal muscle induced robust, durable,...
Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipogenesis as well target thiazolidinedione (TZD) antidiabetic drugs. Many PPARγ genes are induced during adipogenesis, but others, such glycerol kinase (GyK), expressed at low levels in adipocytes and dramatically up-regulated by TZDs. Here, we have explored mechanism whereby an exogenous ligand selectively required for adipocyte gene expression. The GyK contains a functional PPARγ-response element to which...
Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates adipocyte genes involved in adipogenesis and lipid metabolism is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) a recently described triglyceride-specific that induced during remains highly expressed mature adipocytes. This study evaluates ability of PPARgamma to directly regulate ATGL expression adipocytes vitro vivo. In fully differentiated 3T3-L1 adipocytes,...
In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated the adipocyte, but little is known about mechanisms regulating metabolism fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) other ligands for nuclear receptor PPARgamma dramatically upregulate oxidized LDL 1 (OLR1) adipocytes by facilitating exchange coactivators corepressors on OLR1 gene cultured mouse adipocytes....
Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes mellitus (T2DM), plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis hyperglycemia. Therefore, receptor (GCGR) antagonism has been proposed as a pharmacologic approach treat T2DM. support of this concept, potent small-molecule GCGR antagonist (GRA), MK-0893, demonstrated dose-dependent efficacy reduce hyperglycemia, with an HbA1c reduction 1.5% at the 80 mg...
The accumulation of triglycerides (TG) in the liver, designated hepatic steatosis, is characteristically associated with obesity and insulin resistance, but it can also develop after fasting. Here, we show that fasting-induced steatosis under genetic control inbred mice. After a 24-h fast, C57BL/6J mice SJL/J both lost more than 20% body weight approximately 60% total TG. In mice, TG accumulated producing frank steatosis. striking contrast, failed to accumulate any even though they nearly as...
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many the beneficial effects exercise weight loss including lipid glucose trafficking. As such, enzyme long interest as target for treatment Type 2 Diabetes Mellitus. We describe optimization β1-selective, liver-targeted AMPK activators their evolution into systemic pan-activators capable acutely lowering mouse models. Identifying surrogates acid...
Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise occur within skeletal muscle other organs. There is interest discovering a pharmacologic mimetic could imbue wellness alleviate disease burden. However, molecular physiology by which signals response highly complex, making it challenging identify single target for pharmacological mimicry. The current studies evaluated transcriptome muscle, heart, liver,...
Hepatic glucose overproduction is a major characteristic of type 2 diabetes. Because glucagon key regulator for homeostasis, antagonizing the receptor (GCGR) possible therapeutic strategy treatment diabetes mellitus. To study effect hepatic GCGR inhibition on regulation lipid metabolism, we generated siRNA-mediated knockdown (si-GCGR) in db/db mouse. The markedly reduced plasma levels; however, total cholesterol was increased. detailed analysis showed an increase LDL fraction, and no change...
Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2NI) and R531G (AMPKγ2RG), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression human AMPKγ2NI or AMPKγ2RG leads to constitutive AMPK activation WPW phenotype mice. However, these mutant proteins also caused profound, non-physiological increase glycogen, which might abnormally alter true...
Objectives Platensimycin (PTM) is a natural antibiotic produced by Streptomyces platensis that selectively inhibits bacterial and mammalian fatty acid synthase (FAS) without affecting synthesis of other lipids. Recently, we reported oral administration PTM in mouse models (db/db db/+) with high de novo lipogenesis (DNL) tone inhibited DNL enhanced glucose oxidation, which turn led to net reduction liver triglycerides (TG), reduced ambient glucose, improved insulin sensitivity. The present...