Limits...
Effects of AgRP inhibition on energy balance and metabolism in rodent models.

Dutia R, Kim AJ, Modes M, Rothlein R, Shen JM, Tian YE, Ihbais J, Victory SF, Valcarce C, Wardlaw SL - PLoS ONE (2013)

Bottom Line: TTP2515 potently suppressed food intake and weight gain in lean mice immediately after initiation of a high fat diet (HFD) but had no effect on these parameters in lean chow-fed mice.This study shows that TTP2515 exerts many effects consistent with AgRP inhibition however experiments in AgRP KO mice indicate some off-target effects of this drug.TTP2515 was particularly effective during fasting and in mice with leptin deficiency, conditions in which AgRP is elevated, as well as during acute and chronic HFD feeding.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Columbia University College of Physicians & Surgeons, New York, New York, United States of America.

ABSTRACT
Activation of brain melanocortin-4 receptors (MC4-R) by α-melanocyte-stimulating hormone (MSH) or inhibition by agouti-related protein (AgRP) regulates food intake and energy expenditure and can modulate neuroendocrine responses to changes in energy balance. To examine the effects of AgRP inhibition on energy balance, a small molecule, non-peptide compound, TTP2515, developed by TransTech Pharma, Inc., was studied in vitro and in rodent models in vivo. TTP2515 prevented AgRP from antagonizing α-MSH-induced increases in cAMP in HEK 293 cells overexpressing the human MC4-R. When administered to rats by oral gavage TTP2515 blocked icv AgRP-induced increases in food intake, weight gain and adiposity and suppression of T4 levels. In both diet-induced obese (DIO) and leptin-deficient mice, TTP2515 decreased food intake, weight gain, adiposity and respiratory quotient. TTP2515 potently suppressed food intake and weight gain in lean mice immediately after initiation of a high fat diet (HFD) but had no effect on these parameters in lean chow-fed mice. However, when tested in AgRP KO mice, TTP2515 also suppressed food intake and weight gain during HFD feeding. In several studies TTP2515 increased T4 but not T3 levels, however this was also observed in AgRP KO mice. TTP2515 also attenuated refeeding and weight gain after fasting, an effect not evident in AgRP KO mice when administered at moderate doses. This study shows that TTP2515 exerts many effects consistent with AgRP inhibition however experiments in AgRP KO mice indicate some off-target effects of this drug. TTP2515 was particularly effective during fasting and in mice with leptin deficiency, conditions in which AgRP is elevated, as well as during acute and chronic HFD feeding. Thus the usefulness of this drug in treating obesity deserves further exploration, to define the AgRP dependent and independent mechanisms by which TTP2515 exerts its effects on energy balance.

Show MeSH

Related in: MedlinePlus

Effects of TTP2515 on metabolic and calorimetry parameters in DIO mice.(A–E) DIO mice (16 weeks on 45% fat diet) received TTP2515 (30 mg/kg) or water twice daily via oral gavage. (A,B) TTP2515 treatment significantly decreased food intake and body weight gain. (C) Percent fat mass was significantly lower in TTP2515 treated mice at the end of the study. (D) TTP2515 treated mice had elevated total T4 levels. (E) Total T3 levels were similar between groups. (F–H) In a separate experiment DIO mice (45% fat diet for 15 weeks) received TTP2515 (30 mg/kg) or water twice daily via oral gavage. (F,G) Mean oxygen consumption and total activity were significantly decreased during the dark cycle of day 2 in TTP2515 treated mice. (H) Mean respiratory quotient was significantly decreased during the first half of the light cycle of day 3 in TTP2515 treated mice. **p<0.0001, *p<0.05 vs. water.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3675096&req=5

pone-0065317-g003: Effects of TTP2515 on metabolic and calorimetry parameters in DIO mice.(A–E) DIO mice (16 weeks on 45% fat diet) received TTP2515 (30 mg/kg) or water twice daily via oral gavage. (A,B) TTP2515 treatment significantly decreased food intake and body weight gain. (C) Percent fat mass was significantly lower in TTP2515 treated mice at the end of the study. (D) TTP2515 treated mice had elevated total T4 levels. (E) Total T3 levels were similar between groups. (F–H) In a separate experiment DIO mice (45% fat diet for 15 weeks) received TTP2515 (30 mg/kg) or water twice daily via oral gavage. (F,G) Mean oxygen consumption and total activity were significantly decreased during the dark cycle of day 2 in TTP2515 treated mice. (H) Mean respiratory quotient was significantly decreased during the first half of the light cycle of day 3 in TTP2515 treated mice. **p<0.0001, *p<0.05 vs. water.

Mentions: DIO mice were gavaged with TTP2515 (30 mg/kg) or water twice daily for 21 days. Cumulative food intake and body weight gain were significantly decreased compared to water-treated mice (Fig. 3A,B). On day 20, the TTP2515-treated mice had significantly reduced percent fat mass compared to water treated mice (p<0.05, Fig. 3C), lost a greater amount of fat during treatment vs. the water group (−2.6±0.4 g vs −0.5±0.2 g, p<0.001), and tended to have lower absolute fat grams after treatment (12.0±0.9 g vs 9.8±0.8 g, p = 0.08). No difference in lean mass was observed between groups after treatment (Table 2). Mice received their last dose of TTP2515 or water at 800 h on day 21 and were sacrificed 6 h later. Insulin levels tended to be lower in TTP2515 treated mice after a 6 h fast on day 15 of the study (p = 0.14) and both insulin (p = 0.13) and leptin levels (p = 0.13) at sacrifice tended to be lower in TTP2515 treated mice (Table 2). At sacrifice, total T4, but not T3, levels were significantly elevated by TTP2515 treatment (p<.0001, Fig. 3D,E). No significant difference in Pomc or Agrp mRNA in the mediobasal hypothalamus was detected.


Effects of AgRP inhibition on energy balance and metabolism in rodent models.

Dutia R, Kim AJ, Modes M, Rothlein R, Shen JM, Tian YE, Ihbais J, Victory SF, Valcarce C, Wardlaw SL - PLoS ONE (2013)

Effects of TTP2515 on metabolic and calorimetry parameters in DIO mice.(A–E) DIO mice (16 weeks on 45% fat diet) received TTP2515 (30 mg/kg) or water twice daily via oral gavage. (A,B) TTP2515 treatment significantly decreased food intake and body weight gain. (C) Percent fat mass was significantly lower in TTP2515 treated mice at the end of the study. (D) TTP2515 treated mice had elevated total T4 levels. (E) Total T3 levels were similar between groups. (F–H) In a separate experiment DIO mice (45% fat diet for 15 weeks) received TTP2515 (30 mg/kg) or water twice daily via oral gavage. (F,G) Mean oxygen consumption and total activity were significantly decreased during the dark cycle of day 2 in TTP2515 treated mice. (H) Mean respiratory quotient was significantly decreased during the first half of the light cycle of day 3 in TTP2515 treated mice. **p<0.0001, *p<0.05 vs. water.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675096&req=5

pone-0065317-g003: Effects of TTP2515 on metabolic and calorimetry parameters in DIO mice.(A–E) DIO mice (16 weeks on 45% fat diet) received TTP2515 (30 mg/kg) or water twice daily via oral gavage. (A,B) TTP2515 treatment significantly decreased food intake and body weight gain. (C) Percent fat mass was significantly lower in TTP2515 treated mice at the end of the study. (D) TTP2515 treated mice had elevated total T4 levels. (E) Total T3 levels were similar between groups. (F–H) In a separate experiment DIO mice (45% fat diet for 15 weeks) received TTP2515 (30 mg/kg) or water twice daily via oral gavage. (F,G) Mean oxygen consumption and total activity were significantly decreased during the dark cycle of day 2 in TTP2515 treated mice. (H) Mean respiratory quotient was significantly decreased during the first half of the light cycle of day 3 in TTP2515 treated mice. **p<0.0001, *p<0.05 vs. water.
Mentions: DIO mice were gavaged with TTP2515 (30 mg/kg) or water twice daily for 21 days. Cumulative food intake and body weight gain were significantly decreased compared to water-treated mice (Fig. 3A,B). On day 20, the TTP2515-treated mice had significantly reduced percent fat mass compared to water treated mice (p<0.05, Fig. 3C), lost a greater amount of fat during treatment vs. the water group (−2.6±0.4 g vs −0.5±0.2 g, p<0.001), and tended to have lower absolute fat grams after treatment (12.0±0.9 g vs 9.8±0.8 g, p = 0.08). No difference in lean mass was observed between groups after treatment (Table 2). Mice received their last dose of TTP2515 or water at 800 h on day 21 and were sacrificed 6 h later. Insulin levels tended to be lower in TTP2515 treated mice after a 6 h fast on day 15 of the study (p = 0.14) and both insulin (p = 0.13) and leptin levels (p = 0.13) at sacrifice tended to be lower in TTP2515 treated mice (Table 2). At sacrifice, total T4, but not T3, levels were significantly elevated by TTP2515 treatment (p<.0001, Fig. 3D,E). No significant difference in Pomc or Agrp mRNA in the mediobasal hypothalamus was detected.

Bottom Line: TTP2515 potently suppressed food intake and weight gain in lean mice immediately after initiation of a high fat diet (HFD) but had no effect on these parameters in lean chow-fed mice.This study shows that TTP2515 exerts many effects consistent with AgRP inhibition however experiments in AgRP KO mice indicate some off-target effects of this drug.TTP2515 was particularly effective during fasting and in mice with leptin deficiency, conditions in which AgRP is elevated, as well as during acute and chronic HFD feeding.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Columbia University College of Physicians & Surgeons, New York, New York, United States of America.

ABSTRACT
Activation of brain melanocortin-4 receptors (MC4-R) by α-melanocyte-stimulating hormone (MSH) or inhibition by agouti-related protein (AgRP) regulates food intake and energy expenditure and can modulate neuroendocrine responses to changes in energy balance. To examine the effects of AgRP inhibition on energy balance, a small molecule, non-peptide compound, TTP2515, developed by TransTech Pharma, Inc., was studied in vitro and in rodent models in vivo. TTP2515 prevented AgRP from antagonizing α-MSH-induced increases in cAMP in HEK 293 cells overexpressing the human MC4-R. When administered to rats by oral gavage TTP2515 blocked icv AgRP-induced increases in food intake, weight gain and adiposity and suppression of T4 levels. In both diet-induced obese (DIO) and leptin-deficient mice, TTP2515 decreased food intake, weight gain, adiposity and respiratory quotient. TTP2515 potently suppressed food intake and weight gain in lean mice immediately after initiation of a high fat diet (HFD) but had no effect on these parameters in lean chow-fed mice. However, when tested in AgRP KO mice, TTP2515 also suppressed food intake and weight gain during HFD feeding. In several studies TTP2515 increased T4 but not T3 levels, however this was also observed in AgRP KO mice. TTP2515 also attenuated refeeding and weight gain after fasting, an effect not evident in AgRP KO mice when administered at moderate doses. This study shows that TTP2515 exerts many effects consistent with AgRP inhibition however experiments in AgRP KO mice indicate some off-target effects of this drug. TTP2515 was particularly effective during fasting and in mice with leptin deficiency, conditions in which AgRP is elevated, as well as during acute and chronic HFD feeding. Thus the usefulness of this drug in treating obesity deserves further exploration, to define the AgRP dependent and independent mechanisms by which TTP2515 exerts its effects on energy balance.

Show MeSH
Related in: MedlinePlus