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. 2008 Dec;57(12):3231-8.
doi: 10.2337/db07-1690. Epub 2008 Sep 5.

Fatty Acid Synthase Inhibitors Modulate Energy Balance via Mammalian Target of Rapamycin Complex 1 Signaling in the Central Nervous System

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Free PMC article

Fatty Acid Synthase Inhibitors Modulate Energy Balance via Mammalian Target of Rapamycin Complex 1 Signaling in the Central Nervous System

Karine Proulx et al. Diabetes. .
Free PMC article

Abstract

Objective: Evidence links the hypothalamic fatty acid synthase (FAS) pathway to the regulation of food intake and body weight. This includes pharmacological inhibitors that potently reduce feeding and body weight. The mammalian target of rapamycin (mTOR) is an intracellular fuel sensor whose activity in the hypothalamus is also linked to the regulation of energy balance. The purpose of these experiments was to determine whether hypothalamic mTOR complex 1 (mTORC1) signaling is involved in mediating the effects of FAS inhibitors.

Research design and methods: We measured the hypothalamic phosphorylation of two downstream targets of mTORC1, S6 kinase 1 (S6K1) and S6 ribosomal protein (S6), after administration of the FAS inhibitors C75 and cerulenin in rats. We evaluated food intake in response to FAS inhibitors in rats pretreated with the mTOR inhibitor rapamycin and in mice lacking functional S6K1 (S6K1(-/-)). Food intake and phosphorylation of S6K1 and S6 were also determined after C75 injection in rats maintained on a ketogenic diet.

Results: C75 and cerulenin increased phosphorylation of S6K1 and S6, and their anorexic action was reduced in rapamycin-treated rats and in S6K1(-/-) mice. Consistent with our previous findings, C75 was ineffective at reducing caloric intake in ketotic rats. Under ketosis, C75 was also less efficient at stimulating mTORC1 signaling.

Conclusions: These findings collectively indicate an important interaction between the FAS and mTORC1 pathways in the central nervous system for regulating energy balance, possibly via modulation of neuronal glucose utilization.

Figures

FIG. 1.
FIG. 1.
C75 increases hypothalamic mTORC1 signaling. Representative Western blots from RPMI-treated or C75-treated (30 μg in 2 μl RPMI icv) rats (A and C) and quantification by image analysis of hypothalamic phosphorylation of S6K1 (B) and S6 (D). *P < 0.05; **P < 0.01 vs. RPMI-treated rats. pS6K1: bands were quantified. Means ± SE of seven rats in each condition.
FIG. 2.
FIG. 2.
mTORC1 signaling contributes to the anorexic effect of C75. Rapamycin (RAPA; 25 μg in 1 μl DMSO icv) prevents the effects of C75 (50 μg in 3 μl RPMI icv) on food intake (A and B) and on body weight change (C). Data are the mean of two separate experiments. Means ± SE of 9–15 rats in each treatment group. **P < 0.01; ***P < 0.001 vs. DMSO/RPMI-treated rats; #P < 0.05 vs. RAPA/C75-treated rats. D and E: The anorexic effect of C75 (20 mg/kg, in 1 ml/100 g body wt RPMI ip) is significantly reduced in S6K1−/− mice. F: Body weight change over 24 h in mice injected with RPMI or C75. Means ± SE of six mice in each treatment group. Food intake is expressed as the noncumulative amount consumed during different time intervals (A and D) and the cumulative amount eaten during 24 h (B and E). *P < 0.05; **P < 0.01; ***P < 0.001 vs. wild-type (RPMI)-treated mice; #P < 0.05 vs. S6K1−/− (C75)-treated mice.
FIG. 3.
FIG. 3.
Cerulenin activates hypothalamic mTORC1 signaling, and this effect is required for its anorexic action. A and B: Representative Western blots from VEH-treated or CERU-treated (90 μg in 2 μl RPMI-DMSO icv) rats and quantification by image analysis of hypothalamic phosphorylation of S6K1 and S6. *P < 0.05; ***P < 0.001 vs. VEH-treated rats. pS6K1: bands were quantified. Mean ± SE of five to seven rats in each condition. C and D: The anorexic effect of CERU (160 mg/kg in 1 ml/100 g body wt ip) is significantly reduced in S6K1−/− mice. E: Body weight change over 24 h in mice injected with VEH or CERU. Mean ± SE of eight mice in each treatment group. Food intake is expressed as the noncumulative amount consumed during different time intervals (C) and the cumulative amount eaten during 24 h (D). *P < 0.05, **P < 0.01; ***P < 0.001 vs. VEH-treated mice of the corresponding genotype; ##P < 0.01 vs. S6K1−/− CERU-treated mice. WT, wildtype.
FIG. 4.
FIG. 4.
The actions of C75 on food intake and on hypothalamic mTORC1 signaling are blunted in ketotic rats. A: Rats maintained on a ketogenic diet for 4 weeks while receiving a drinking solution of saccharin have elevated blood β-hydroxybutyrate concentration compared with those that consumed a solution of sucrose in addition to the ketogenic diet. Means ± SE of 17–18 rats in each treatment group. ***P < 0.001 vs. rats from the sucrose group. E: Both groups had similar plasma leucine levels. Means ± SE of six to seven rats in each treatment group. B: C75 (30 μg in 2 μl RPMI icv) does not reduce caloric intake in rats given access to saccharin alongside with the ketogenic diet, but it does so with sucrose. *P < 0.05 vs. RPMI-treated rats from the same group. Means ± SE of five to eight rats in each treatment group. C75 (30 μg in 2 μl RPMI icv) increased pS6K1 only in sucrose rats (C) and was less efficient at increasing pS6 in saccharin rats vs. sucrose rats (D). Two independent Western blots representative of RPMI- or C75-treated rats either from the sucrose or the saccharin groups (C and D) and quantification by image analysis of hypothalamic phosphorylation of S6K1 (C) and S6 (D). *P < 0.05 and ***P < 0.001 vs. RPMI-treated rats from the same group and #P < 0.05 vs. C75-treated rats from the sucrose group. Means ± SE of five to nine brains examined in each condition.

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