Limits...
Single rapamycin administration induces prolonged downward shift in defended body weight in rats.

Hebert M, Licursi M, Jensen B, Baker A, Milway S, Malsbury C, Grant VL, Adamec R, Hirasawa M, Blundell J - PLoS ONE (2014)

Bottom Line: Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection.Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight.In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.

ABSTRACT
Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy.

Show MeSH

Related in: MedlinePlus

Spaced injections of rapamycin have additive effect on body weight gain.A–C: A, C and E: Body weight gain (A), daily food intake (C) and food efficiency (E) of rats given two i.p. injections (broken lines, Day 0 and 14) of RAP (10 mg/kg each) or VEH with a 2-week interval. # p<0.05, ## p<0.01, ### p<0.001, VEH vs. RAP (two-way Mixed-ANOVA). Horizontal bars indicate the days when significance was seen. B, D and F: Cumulative body weight gain, food intake and food efficiency during the first three days post-injection. ***p<0.001, VEH vs. RAP. There was no statistical difference between two injections within the group (VEH1 vs. VEH2, RAP1 vs. RAP2) (two-way Mixed-ANOVA). G: The weight of white adipose tissues (WAT), epididymal and retroperitoneal pads, in rats treated twice with VEH or RAP. H: WAT weight normalized to the body weight of individual rat. # p<0.05, ### p<0.001 (unpaired t-test).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4008417&req=5

pone-0093691-g002: Spaced injections of rapamycin have additive effect on body weight gain.A–C: A, C and E: Body weight gain (A), daily food intake (C) and food efficiency (E) of rats given two i.p. injections (broken lines, Day 0 and 14) of RAP (10 mg/kg each) or VEH with a 2-week interval. # p<0.05, ## p<0.01, ### p<0.001, VEH vs. RAP (two-way Mixed-ANOVA). Horizontal bars indicate the days when significance was seen. B, D and F: Cumulative body weight gain, food intake and food efficiency during the first three days post-injection. ***p<0.001, VEH vs. RAP. There was no statistical difference between two injections within the group (VEH1 vs. VEH2, RAP1 vs. RAP2) (two-way Mixed-ANOVA). G: The weight of white adipose tissues (WAT), epididymal and retroperitoneal pads, in rats treated twice with VEH or RAP. H: WAT weight normalized to the body weight of individual rat. # p<0.05, ### p<0.001 (unpaired t-test).

Mentions: There are reports of resistance to RAP in other experimental contexts [14]. Thus, we examined whether a RAP administration (10 mg/kg, i.p.) would affect responses to a subsequent RAP treatment. Rats received a pair of RAP or VEH i.p. injections (n = 10 each) with a 2-week interval between injections. We found that the two injections of RAP were equally effective in reducing FI, FE and weight gain (Fig.2A–F). The VEH group showed a tendency of lower weight gain and FE after the second injection compared to the first, which may be due to age-dependent slowing of the rate of weight gain (Fig.2B). In RAP treated animals (n = 6), the white adipose tissues were significantly smaller than those of VEH controls (n = 5) (Fig.2G, H), consistent with previous reports showing decreased adiposity following chronic RAP administration [6], [7]. These data suggest that the RAP effect does not desensitize with intermittent injections, at least when injections are separated by 2 weeks, and it effectively reduces adiposity.


Single rapamycin administration induces prolonged downward shift in defended body weight in rats.

Hebert M, Licursi M, Jensen B, Baker A, Milway S, Malsbury C, Grant VL, Adamec R, Hirasawa M, Blundell J - PLoS ONE (2014)

Spaced injections of rapamycin have additive effect on body weight gain.A–C: A, C and E: Body weight gain (A), daily food intake (C) and food efficiency (E) of rats given two i.p. injections (broken lines, Day 0 and 14) of RAP (10 mg/kg each) or VEH with a 2-week interval. # p<0.05, ## p<0.01, ### p<0.001, VEH vs. RAP (two-way Mixed-ANOVA). Horizontal bars indicate the days when significance was seen. B, D and F: Cumulative body weight gain, food intake and food efficiency during the first three days post-injection. ***p<0.001, VEH vs. RAP. There was no statistical difference between two injections within the group (VEH1 vs. VEH2, RAP1 vs. RAP2) (two-way Mixed-ANOVA). G: The weight of white adipose tissues (WAT), epididymal and retroperitoneal pads, in rats treated twice with VEH or RAP. H: WAT weight normalized to the body weight of individual rat. # p<0.05, ### p<0.001 (unpaired t-test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4008417&req=5

pone-0093691-g002: Spaced injections of rapamycin have additive effect on body weight gain.A–C: A, C and E: Body weight gain (A), daily food intake (C) and food efficiency (E) of rats given two i.p. injections (broken lines, Day 0 and 14) of RAP (10 mg/kg each) or VEH with a 2-week interval. # p<0.05, ## p<0.01, ### p<0.001, VEH vs. RAP (two-way Mixed-ANOVA). Horizontal bars indicate the days when significance was seen. B, D and F: Cumulative body weight gain, food intake and food efficiency during the first three days post-injection. ***p<0.001, VEH vs. RAP. There was no statistical difference between two injections within the group (VEH1 vs. VEH2, RAP1 vs. RAP2) (two-way Mixed-ANOVA). G: The weight of white adipose tissues (WAT), epididymal and retroperitoneal pads, in rats treated twice with VEH or RAP. H: WAT weight normalized to the body weight of individual rat. # p<0.05, ### p<0.001 (unpaired t-test).
Mentions: There are reports of resistance to RAP in other experimental contexts [14]. Thus, we examined whether a RAP administration (10 mg/kg, i.p.) would affect responses to a subsequent RAP treatment. Rats received a pair of RAP or VEH i.p. injections (n = 10 each) with a 2-week interval between injections. We found that the two injections of RAP were equally effective in reducing FI, FE and weight gain (Fig.2A–F). The VEH group showed a tendency of lower weight gain and FE after the second injection compared to the first, which may be due to age-dependent slowing of the rate of weight gain (Fig.2B). In RAP treated animals (n = 6), the white adipose tissues were significantly smaller than those of VEH controls (n = 5) (Fig.2G, H), consistent with previous reports showing decreased adiposity following chronic RAP administration [6], [7]. These data suggest that the RAP effect does not desensitize with intermittent injections, at least when injections are separated by 2 weeks, and it effectively reduces adiposity.

Bottom Line: Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection.Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight.In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.

ABSTRACT
Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy.

Show MeSH
Related in: MedlinePlus