Physiological mechanisms of sustained fumagillin-induced weight loss

Jie An, Liping Wang, Michael L. Patnode, Vanessa K. Ridaura, Jonathan M. Haldeman, Robert D. Stevens, Olga Ilkayeva, James R. Bain, Michael J. Muehlbauer, Erin L. Glynn, Steven Thomas, Deborah Muoio, Scott A. Summers, James E. Vath, Thomas E. Hughes, Jeffrey I. Gordon, Christopher B. Newgard

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish
JournalJCI Insight
Volume3
Issue number5
DOIs
StatePublished - Mar 8 2018

Keywords

  • Behavior
  • Intermediary metabolism
  • Metabolism
  • Obesity
  • Therapeutics

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