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
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
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Research Article Metabolism Therapeutics

Physiological mechanisms of sustained fumagillin-induced weight loss

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.

Authors

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

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Figure 7

Fumagillin treatment affects glycogen levels, but hepatic glycogen is not the mediator of fumagillin-induced changes in feeding behavior.

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Fumagillin treatment affects glycogen levels, but hepatic glycogen is no...
First 3 panels: rats were fed HF or SC diet for 12 weeks and then subjected to dietary intervention periods of 2 or 8 weeks, as described in Figure 1C. Liver and muscle samples were collected for measurement of glycogen levels or phospho-GSK3β levels at ZT6:00 (1 pm) at the 2-week or 8-week time points. Last 3 panels: rats were fed on HF diet for 12 weeks and then subjected to an intervention period of 4 weeks, during which rats were fed HF diet with fumagillin ad libitum (HF/FG) or an amount of HF food matched to the amount consumed by the HF/FG group (HF/PF), in the presence or absence of methionine restriction (MR). Liver samples were collected at ZT6:00 (1 pm), immediately prior to the normal once-daily provision of food. (A) Hepatic glycogen levels. Data are mean ± SD for n = 6 for each group. *P < 0.05 when compared with other groups at each time point. (B) Glycogen levels in gastrocnemius muscle. Data are mean ± SD for n = 6 for each group. *P < 0.05 when compared with other groups at each time point. (C) Ratio of phosphorylated GSK3β compared with total GSK3β in liver. Data are mean ± SD for n = 6 for each group. *P < 0.05 when compared with other groups at each time point. (D) Immunoblot analysis of liver samples obtained from rats treated with adenoviruses expressing either a Flag-tagged C-terminal deleted version of the muscle isoform of glycogen-targeting subunit of protein phosphatase 1 (GmΔC-Flag) (21) or β-galactosidase (βGal) and continuously fed the indicated diets for 1 week. (E) Hepatic glycogen levels in rats treated with the indicated adenoviruses. Data are mean ± SD for n = 5–7 animals per group. *P < 0.02 when compared with the other groups. (F) Changes in RER in response to daily provision of food at ZT6:00 (1 pm) (downward arrow) in rats fed the indicated diets and treated with the indicated adenoviruses. All diets in this experiment contained normal methionine levels. n = 5–7 for each treatment group. For all panels, 2-tailed, unpaired t tests were performed. P < 0.05 with a Bonferroni correction was used to define statistical significance among groups.