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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

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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 2

Fumagillin reduces white adipose tissue weights and improves insulin sensitivity in obese rats.

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Fumagillin reduces white adipose tissue weights and improves insulin sen...
Diet-induced obesity was induced in Wistar rats by feeding a high-fat (HF) diet for 12 weeks. A control group was fed a standard chow (SC) diet for the same time period. After the feeding period, rats were then subjected to dietary intervention periods of 2 or 8 weeks as described in Figure 1C. (A) Epididymal white adipose tissue (EWAT) weights for the groups described in Figure 1C, fed the indicated diets for 2 or 8 weeks (2W, 8W, respectively). +P < 0.05 compared with HF group after 2 weeks of diet intervention. @P < 0.05 when compared with HF and HF/FG groups after 2 weeks of diet intervention. #P < 0.05 when compared with the other 3 groups after 8 weeks of diet intervention. (B) Liver weights for the groups described in Figure 1C, fed the indicated diets for 2 or 8 weeks (2W, 8W, respectively). +P < 0.05 when compared with HF group after 2 weeks of diet intervention. *P < 0.05 when compared with HF group after 8 weeks of diet intervention. In A and B, tissue weights were normalized to body weight. n = 6 for each group. Data are presented as mean ± SD. (C) Glucose infusion rate during hyperinsulinemic-euglycemic clamps. A cohort of animals treated as described in Figure 1C were used. Data are presented as mean ± SD for n = 5–7 rats per group. +P < 0.05 when compared with other groups after 2 weeks of diet intervention. *P < 0.05 when compared with other groups after 8 weeks of diet interventions. For A–C, 2-tailed, unpaired t tests were performed. P < 0.05 with a Bonferroni correction was used to define statistical significance among groups.

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