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
View: Text | PDF
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

×

Figure 5

Fumagillin feeding affects feeding rhythm and expression of circadian genes.

Options: View larger image (or click on image) Download as PowerPoint
Fumagillin feeding affects feeding rhythm and expression of circadian ge...
Wistar rats were fed a HF diet for 12 weeks and then subjected to an intervention period of 4 weeks, during which they consumed HF diet ad libitum (HF), HF diet with fumagillin (HF/FG), or an amount of HF food matched to the amount consumed by the HF/FG group (HF/PF). (A–C) Average food intake measured in these 3 groups of rats daily over 4 time periods after daily food provision at ZT6:00 (1:00 pm). The periods sampled were ZT6:00–10:00, ZT10:00–14:00, ZT14:00–2:00, and ZT2:00–6:00, equating to 1–5 pm, 5–9 pm, 9 pm–9 am, and 9 am–1 pm. n = 3, 5, and 4 for HF, HF/FG, and HF/PF groups, respectively. HF group compared with HF/FG or HF/PF groups for total food intake; P < 0.000009. HF group compared with HF/FG group for food intake during ZT6:00–2:00 (1 pm–9 am); P < 0.04. HF group compared with HF/PF group for food intake during all time periods except for ZT10:00–14:00 (5–9 pm); P < 0.04. HF/FG group compared with HF/PF group for food intake during all time periods except for ZT2:00–6:00 (9 am–1 pm); P < 0.002. (D) Expression levels of Bmal1 (upper panel), Clock (middle panel), and Per1 (lower panel) transcripts in liver, stomach, duodenum, jejunum, ileum, colon, cecum, epididymal white adipose tissue (EWAT), and mesenteric white adipose tissue (MWAT). Samples were collected after 10 days of diet intervention. Data represent means ± SD for n = 3, 5, and 4 for HF, HF/FG, and HF/PF groups, respectively. *P < 0.05 when compared with the other 2 groups. #P < 0.05 when compared with the HF group. +P < 0.05 when compared with HF/FG 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.