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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.

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Effects of TTP2515 on metabolic and calorimetry parameters in leptin-deficient mice.Leptin-deficient mice received either TTP2515 at increasing doses (5–50 mg/kg) or water twice daily via oral gavage. (A) Food intake tended to be lower in TTP2515 treated mice during the 15 mg/kg treatment period and was significantly lower during the 30 and 50 mg/kg treatment periods. (B) Fat mass was significantly decreased after 24 days of TTP2515 treatment, while lean mass was not different between groups. (C) Body weight was significantly lower in TTP2515-treated mice on the 50 mg/kg dose. (D) Immediately upon starting the 50 mg/kg dose, mean respiratory quotient was significantly decreased in TTP2515 treated mice during the light cycle. (E) Total T4 levels at sacrifice were unchanged between groups. +p = 0.06, *p<0.05, **p<0.01 vs water.
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pone-0065317-g004: Effects of TTP2515 on metabolic and calorimetry parameters in leptin-deficient mice.Leptin-deficient mice received either TTP2515 at increasing doses (5–50 mg/kg) or water twice daily via oral gavage. (A) Food intake tended to be lower in TTP2515 treated mice during the 15 mg/kg treatment period and was significantly lower during the 30 and 50 mg/kg treatment periods. (B) Fat mass was significantly decreased after 24 days of TTP2515 treatment, while lean mass was not different between groups. (C) Body weight was significantly lower in TTP2515-treated mice on the 50 mg/kg dose. (D) Immediately upon starting the 50 mg/kg dose, mean respiratory quotient was significantly decreased in TTP2515 treated mice during the light cycle. (E) Total T4 levels at sacrifice were unchanged between groups. +p = 0.06, *p<0.05, **p<0.01 vs water.

Mentions: Leptin-deficient ob/ob mice maintained on a normal chow diet received either TTP2515 at increasing doses (5–50 mg/kg) or water treatment for 25 days. During days 1–13, mice were placed in the calorimetry system. In ob/ob mice, average daily food intake was decreased with 15 mg (p = 0.06), 30 mg/kg (p<0.05) and 50 mg/kg (p<0.01) TTP2515 treatment (Fig. 4A); significant reductions in body weight were observed at the 50 mg/kg dose (p<0.05, Fig. 4C). No effects on VO2, EE or activity were observed during any of the dosing periods except transiently at the 15 mg/kg dose, where mean VO2 and mean EE (p<0.05) were decreased during the dark cycle of day 6, with a trend for decreased activity (p = 0.10, Table 3). However, this decrease in VO2 and EE was not evident if adjusted for activity. Mean RQ was significantly lower in 50 mg/kg TTP2515 treated mice, however this was not noted at lower doses. The decrease in RQ was observed during the light cycle immediately upon starting the 50 mg/kg treatment on day 11 and was again noted on day 12 (Fig. 4D).


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 leptin-deficient mice.Leptin-deficient mice received either TTP2515 at increasing doses (5–50 mg/kg) or water twice daily via oral gavage. (A) Food intake tended to be lower in TTP2515 treated mice during the 15 mg/kg treatment period and was significantly lower during the 30 and 50 mg/kg treatment periods. (B) Fat mass was significantly decreased after 24 days of TTP2515 treatment, while lean mass was not different between groups. (C) Body weight was significantly lower in TTP2515-treated mice on the 50 mg/kg dose. (D) Immediately upon starting the 50 mg/kg dose, mean respiratory quotient was significantly decreased in TTP2515 treated mice during the light cycle. (E) Total T4 levels at sacrifice were unchanged between groups. +p = 0.06, *p<0.05, **p<0.01 vs water.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0065317-g004: Effects of TTP2515 on metabolic and calorimetry parameters in leptin-deficient mice.Leptin-deficient mice received either TTP2515 at increasing doses (5–50 mg/kg) or water twice daily via oral gavage. (A) Food intake tended to be lower in TTP2515 treated mice during the 15 mg/kg treatment period and was significantly lower during the 30 and 50 mg/kg treatment periods. (B) Fat mass was significantly decreased after 24 days of TTP2515 treatment, while lean mass was not different between groups. (C) Body weight was significantly lower in TTP2515-treated mice on the 50 mg/kg dose. (D) Immediately upon starting the 50 mg/kg dose, mean respiratory quotient was significantly decreased in TTP2515 treated mice during the light cycle. (E) Total T4 levels at sacrifice were unchanged between groups. +p = 0.06, *p<0.05, **p<0.01 vs water.
Mentions: Leptin-deficient ob/ob mice maintained on a normal chow diet received either TTP2515 at increasing doses (5–50 mg/kg) or water treatment for 25 days. During days 1–13, mice were placed in the calorimetry system. In ob/ob mice, average daily food intake was decreased with 15 mg (p = 0.06), 30 mg/kg (p<0.05) and 50 mg/kg (p<0.01) TTP2515 treatment (Fig. 4A); significant reductions in body weight were observed at the 50 mg/kg dose (p<0.05, Fig. 4C). No effects on VO2, EE or activity were observed during any of the dosing periods except transiently at the 15 mg/kg dose, where mean VO2 and mean EE (p<0.05) were decreased during the dark cycle of day 6, with a trend for decreased activity (p = 0.10, Table 3). However, this decrease in VO2 and EE was not evident if adjusted for activity. Mean RQ was significantly lower in 50 mg/kg TTP2515 treated mice, however this was not noted at lower doses. The decrease in RQ was observed during the light cycle immediately upon starting the 50 mg/kg treatment on day 11 and was again noted on day 12 (Fig. 4D).

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