Physiological mechanisms of sustained fumagillin-induced weight loss

JCI Insight. 2018 Mar 8;3(5):e99453. doi: 10.1172/jci.insight.99453.


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.

Keywords: Behavior; Intermediary metabolism; Metabolism; Obesity; Therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / antagonists & inhibitors
  • Animals
  • Bacteria / drug effects
  • Bacteria / isolation & purification*
  • Bacteria / metabolism
  • Behavior, Animal / drug effects
  • Body Weight / drug effects
  • Cyclohexanes / administration & dosage*
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Energy Metabolism / drug effects*
  • Fatty Acids, Unsaturated / administration & dosage*
  • Feces / microbiology
  • Feeding Behavior / drug effects
  • Gastrointestinal Microbiome / drug effects*
  • Gastrointestinal Microbiome / physiology
  • Germ-Free Life / drug effects
  • Germ-Free Life / physiology
  • Glycoproteins / antagonists & inhibitors
  • Humans
  • Male
  • Methionyl Aminopeptidases
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy*
  • Obesity / etiology
  • Obesity / metabolism
  • Rats
  • Rats, Wistar
  • Sesquiterpenes / administration & dosage
  • Treatment Outcome
  • Weight Loss / drug effects


  • Cyclohexanes
  • Fatty Acids, Unsaturated
  • Glycoproteins
  • Sesquiterpenes
  • fumagillin
  • Aminopeptidases
  • METAP2 protein, human
  • Methionyl Aminopeptidases