Leslie E. Landree
Johns Hopkins University
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Featured researches published by Leslie E. Landree.
Proceedings of the National Academy of Sciences of the United States of America | 2002
Jagan N. Thupari; Leslie E. Landree; Gabriele V. Ronnett; Francis P. Kuhajda
C75, a known inhibitor of fatty acid synthase is postulated to cause significant weight loss through decreased hypothalamic neuropeptide Y (NPY) production. Peripherally, C75, an α-methylene-γ-butyrolactone, reduces adipose tissue and fatty liver, despite high levels of malonyl-CoA. To investigate this paradox, we studied the effect of C75 on fatty acid oxidation and energy production in diet-induced obese (DIO) mice and cellular models. Whole-animal calorimetry showed that C75-treated DIO mice had a 50% greater weight loss, and a 32.9% increased production of energy because of fatty acid oxidation, compared with paired-fed controls. Etomoxir, an inhibitor of carnitine O-palmitoyltransferase-1 (CPT-1), reversed the increased energy expenditure in DIO mice by inhibiting fatty acid oxidation. C75 treatment of rodent adipocytes and hepatocytes and human breast cancer cells increased fatty acid oxidation and ATP levels by increasing CPT-1 activity, even in the presence of elevated concentrations of malonyl-CoA. Studies in human cancer cells showed that C75 competed with malonyl-CoA, as measured by CPT-1 activity assays. Thus, C75 acts both centrally to reduce food intake and peripherally to increase fatty acid oxidation, leading to rapid and profound weight loss, loss of adipose mass, and resolution of fatty liver. The pharmacological stimulation of CPT-1 activity is a novel finding. The dual action of the C75 class of compounds as fatty acid synthase inhibitors and CPT-1 agonists has therapeutic implications in the treatment of obesity and type II diabetes.
Cancer Research | 2007
Weibo Zhou; Wan Fang Han; Leslie E. Landree; Jagan N. Thupari; Michael L. Pinn; Tsion Bililign; Eun Kyoung Kim; Aravinda Vadlamudi; Susan M. Medghalchi; Rajaa El Meskini; Gabriele V. Ronnett; Craig A. Townsend; Francis P. Kuhajda
Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity. As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased. Despite these attempts to conserve energy, the AMP/ATP ratio increased with worsening cellular redox status. Pretreatment of SKOV3 cells with compound C, an AMPK inhibitor, substantially rescued the cells from C93 cytotoxicity, indicating its dependence on AMPK activation. 5-(Tetradecyloxy)-2-furoic acid, an ACC inhibitor, did not activate AMPK despite inhibiting fatty acid synthesis pathway activity and was not significantly cytotoxic to SKOV3 cells. This indicates that substrate accumulation from FAS inhibition triggering AMPK activation, not end-product depletion of fatty acids, is likely responsible for AMPK activation. C93 also exhibited significant antitumor activity and apoptosis against SKOV3 xenografts in athymic mice without significant weight loss or cytotoxicity to proliferating cellular compartments such as bone marrow, gastrointestinal tract, or skin. Thus, pharmacologic FAS inhibition selectively activates AMPK in ovarian cancer cells, inducing cytotoxicity while sparing most normal human tissues from the pleiotropic effects of AMPK activation.
American Journal of Physiology-regulatory Integrative and Comparative Physiology | 2011
Francis P. Kuhajda; Susan Aja; Yajun Tu; Wan Fang Han; Susan M. Medghalchi; Rajaa El Meskini; Leslie E. Landree; Jonathan M. Peterson; Khadija Daniels; Kody Wong; Edward A. Wydysh; Craig A. Townsend; Gabriele V. Ronnett
Storage of excess calories as triglycerides is central to obesity and its associated disorders. Glycerol-3-phosphate acyltransferases (GPATs) catalyze the initial step in acylglyceride syntheses, including triglyceride synthesis. We utilized a novel small-molecule GPAT inhibitor, FSG67, to investigate metabolic consequences of systemic pharmacological GPAT inhibition in lean and diet-induced obese (DIO) mice. FSG67 administered intraperitoneally decreased body weight and energy intake, without producing conditioned taste aversion. Daily FSG67 (5 mg/kg, 15.3 μmol/kg) produced gradual 12% weight loss in DIO mice beyond that due to transient 9- to 10-day hypophagia (6% weight loss in pair-fed controls). Continued FSG67 maintained the weight loss despite return to baseline energy intake. Weight was lost specifically from fat mass. Indirect calorimetry showed partial protection by FSG67 against decreased rates of oxygen consumption seen with hypophagia. Despite low respiratory exchange ratio due to a high-fat diet, FSG67-treated mice showed further decreased respiratory exchange ratio, beyond pair-fed controls, indicating enhanced fat oxidation. Chronic FSG67 increased glucose tolerance and insulin sensitivity in DIO mice. Chronic FSG67 decreased gene expression for lipogenic enzymes in white adipose tissue and liver and decreased lipid accumulation in white adipose, brown adipose, and liver tissues without signs of damage. RT-PCR showed decreased gene expression for orexigenic hypothalamic neuropeptides AgRP or NPY after acute and chronic systemic FSG67. FSG67 given intracerebroventricularly (100 and 320 nmol icv) produced 24-h weight loss and feeding suppression, indicating contributions from direct central nervous system sites of action. Together, these data point to GPAT as a new potential therapeutic target for the management of obesity and its comorbidities.
Central nervous system agents in medicinal chemistry | 2006
Leslie E. Landree; Eun Kyoung Kim; Louise D. McCullough; Francis P. Kuhajda; Gabriele V. Ronnett
The regulation of cellular energy homeostasis within the CNS is crucial not only to neuronal survival, but to the brains function as an integrator of hormonal and neural inputs that regulate many functions, such as feeding behavior. The sensing and regulation of CNS cellular energy balance is altered in many diseases. Recent studies have suggested that fatty acid metabolism plays a significant role in regulating cellular energy balance in the brain. This hypothesis is supported by observations that the pharmacological manipulation of fatty acid metabolism alters food intake and causes weight loss. Fatty acid levels are determined by fatty acid synthase (FAS), which catalyzes the de novo synthesis of longchain fatty acids that are stored as triglycerides during energy surplus, and carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme for entry of long-chain acyl-CoAs into the mitochondria for fatty acid oxidation during energy deficit. Most recently, it has been reported that pharmacological manipulation of fatty acid metabolism can also alter cellular energy balance in a stroke model, thus providing neuroprotection. While the physiological contribution of fatty acid metabolism is a hypothesis that awaits further testing, here, we review studies from a number of laboratories investigating fatty acid metabolism as a therapeutic approach for obesity and disorders of CNS energy balance such as stroke.
Journal of Biological Chemistry | 2005
Louise D. McCullough; Zhiyuan Zeng; Hong Li; Leslie E. Landree; Jill M. McFadden; Gabriele V. Ronnett
Journal of Biological Chemistry | 2004
Eun Kyoung Kim; Ian Miller; Susan Aja; Leslie E. Landree; Michael L. Pinn; Jill M. McFadden; Francis P. Kuhajda; Timothy H. Moran; Gabriele V. Ronnett
American Journal of Physiology-endocrinology and Metabolism | 2002
Eun Kyoung Kim; Ian Miller; Leslie E. Landree; Felice F. Borisy-Rudin; Pierre Brown; Tarik Tihan; Craig A. Townsend; Lee A. Witters; Timothy H. Moran; Francis P. Kuhajda; Gabriele V. Ronnett
Journal of Biological Chemistry | 2004
Leslie E. Landree; Andrea L. Hanlon; David W. Strong; Gavin Rumbaugh; Ian Miller; Jagan N. Thupari; Erin C. Connolly; Richard L. Huganir; Christine A. Richardson; Lee A. Witters; Francis P. Kuhajda; Gabriele V. Ronnett
American Journal of Physiology-regulatory Integrative and Comparative Physiology | 2008
Susan Aja; Leslie E. Landree; Amy M. Kleman; Susan M. Medghalchi; Aravinda Vadlamudi; Jill M. McFadden; Andrea Aplasca; Jayson Hyun; Erica Plummer; Khadija Daniels; Matthew H. Kemm; Craig A. Townsend; Jagan N. Thupari; Francis P. Kuhajda; Timothy H. Moran; Gabriele V. Ronnett
Archive | 2005
Gabrielle V. Ronnett; Frankcis P. Kuhajda; Jagan N. Thupari; Leslie E. Landree; Timothy H. Moran; Eun Kyoung Kim