Physiological mechanisms of sustained fumagillin-induced weight loss.

Current obesity interventions suffer from lack of durable effects and undesirable complications. Fumagillin, an inhibitor of methionine aminopeptidase-2, causes weight loss by reducing food intake, but with effects on weight that are superior to pair-feeding. Here, we show that feeding of rats on a high-fat diet supplemented with fumagillin (HF/FG) suppresses the aggressive feeding observed in pair-fed controls (HF/PF) and alters expression of circadian genes relative to the HF/PF group. Multiple indices of reduced energy expenditure are observed in HF/FG but not HF/PF rats. HF/FG rats also exhibit changes in gut hormones linked to food intake, increased energy harvest by gut microbiota, and caloric spilling in the urine. Studies in gnotobiotic mice reveal that effects of fumagillin on energy expenditure but not feeding behavior may be mediated by the gut microbiota. In sum, fumagillin engages weight loss-inducing behavioral and physiologic circuits distinct from those activated by simple caloric restriction.

[1]  J. Vath,et al.  MetAP2 inhibition reduces food intake and body weight in a ciliopathy mouse model of obesity , 2019, bioRxiv.

[2]  Dennis D. Kim,et al.  Effects of MetAP2 inhibition on hyperphagia and body weight in Prader–Willi syndrome: A randomized, double‐blind, placebo‐controlled trial , 2017, Diabetes, obesity & metabolism.

[3]  F. Bäckhed,et al.  Microbial regulation of GLP-1 and L-cell biology , 2016, Molecular metabolism.

[4]  O. Ilkayeva,et al.  Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export , 2016, Molecular metabolism.

[5]  G. Abdeen,et al.  Mechanism Underlying the Weight Loss and Complications of Roux-en-Y Gastric Bypass. Review , 2015, Obesity Surgery.

[6]  T. Hughes,et al.  Ascending dose‐controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women , 2013, Obesity.

[7]  Barbara M. Bakker,et al.  The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism , 2013, Journal of Lipid Research.

[8]  B. Bay,et al.  Ablation of Dihydroceramide Desaturase 1, a Therapeutic Target for the Treatment of Metabolic Diseases, Simultaneously Stimulates Anabolic and Catabolic Signaling , 2013, Molecular and Cellular Biology.

[9]  Nicholas A. Bokulich,et al.  Quality-filtering vastly improves diversity estimates from Illumina amplicon sequencing , 2012, Nature Methods.

[10]  C. Newgard,et al.  A VGF-derived peptide attenuates development of type 2 diabetes via enhancement of islet β-cell survival and function. , 2012, Cell metabolism.

[11]  A. Shulkes,et al.  Long-term persistence of hormonal adaptations to weight loss. , 2011, The New England journal of medicine.

[12]  A. Jeukendrup,et al.  The Relationship between Substrate Metabolism, Exercise and Appetite Control , 2011, Sports medicine.

[13]  H. Lijnen,et al.  Fumagillin Reduces Adipose Tissue Formation in Murine Models of Nutritionally Induced Obesity , 2010, Obesity.

[14]  P. Legendre,et al.  Associations between species and groups of sites: indices and statistical inference. , 2009, Ecology.

[15]  Svati H Shah,et al.  A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. , 2009, Cell metabolism.

[16]  W. Hoogerwerf,et al.  Clock gene expression in the murine gastrointestinal tract: endogenous rhythmicity and effects of a feeding regimen. , 2007, Gastroenterology.

[17]  J. Flier,et al.  Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. , 2007, Cell metabolism.

[18]  S. Kliewer,et al.  Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. , 2007, Cell metabolism.

[19]  Eoin L. Brodie,et al.  Greengenes, a Chimera-Checked 16S rRNA Gene Database and Workbench Compatible with ARB , 2006, Applied and Environmental Microbiology.

[20]  Sanjin Zvonic,et al.  Characterization of peripheral circadian clocks in adipose tissues. , 2006, Diabetes.

[21]  R. Balusu,et al.  Treatment of cells with the angiogenic inhibitor fumagillin results in increased stability of eukaryotic initiation factor 2-associated glycoprotein, p67, and reduced phosphorylation of extracellular signal-regulated kinases. , 2004, Biochemistry.

[22]  David Millington,et al.  Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance , 2004, Nature Medicine.

[23]  F. Stephan,et al.  The “Other” Circadian System: Food as a Zeitgeber , 2002, Journal of biological rhythms.

[24]  S. Chevret,et al.  Fumagillin treatment of intestinal microsporidiosis. , 2002, The New England journal of medicine.

[25]  C. Newgard,et al.  Glycogen-targeting Subunits and Glucokinase Differentially Affect Pathways of Glycogen Metabolism and Their Regulation in Hepatocytes* , 2002, The Journal of Biological Chemistry.

[26]  P. Legendre,et al.  SPECIES ASSEMBLAGES AND INDICATOR SPECIES:THE NEED FOR A FLEXIBLE ASYMMETRICAL APPROACH , 1997 .

[27]  W. Bornmann,et al.  The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  D. Ingber,et al.  Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth , 1990, Nature.

[29]  R. Wohlhueter,et al.  Effects of ingestion of disproportionate amounts of amino acids. , 1970, Physiological reviews.

[30]  S. Yanovski,et al.  Long-term drug treatment for obesity: a systematic and clinical review. , 2014, JAMA.

[31]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[32]  D. Katzka.  Clock Gene Expression in the Murine Gastrointestinal Tract: Endogenous Rhythmicity and Effects of a Feeding Regimen , 2008 .