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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 in WT or AgRP KO mice acutely switched to a very high-fat diet.(A–F) Mice were switched from breeder chow to a 60% fat diet and started treatment with TTP2515 (30 mg/kg) or water twice daily. (A–C) Cumulative food intake, cumulative weight gain and fat mass were all significantly lower in TTP2515 treated mice. (D) Total T4 levels were significantly higher in TTP2515 treated mice. (E) Leptin levels tended to be lower in TTP2515 treated mice (p = 0.12). (F) Insulin levels were similar between groups. (G–J) In a separate experiment, AgRP KO mice on a 10% fat chow diet were switched to a 60% fat diet and started treatment with TTP2515 (5, 15, or 30 mg/kg) or water twice daily. (G,I) Cumulative caloric intake and cumulative weight gain were dose-dependently lower in TTP2515 treated mice compared to the water group. (H) Fat mass was lower in TTP2515 treated mice at both the 15 and 30 mg/kg doses vs. water. The 5 mg/kg group tended (p = 0.05) to have lower fat mass than the water group. (J) After 5 days of treatment, total T4 levels were equivalent between groups, however fasting and continued treatment revealed an increase in total T4 levels. *p<0.05, **p<0.01 vs water; ap<0.05 vs water, bp<0.05 vs 5 mg/kg, cp<0.05 vs 15 mg/kg.
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pone-0065317-g007: Effects of TTP2515 in WT or AgRP KO mice acutely switched to a very high-fat diet.(A–F) Mice were switched from breeder chow to a 60% fat diet and started treatment with TTP2515 (30 mg/kg) or water twice daily. (A–C) Cumulative food intake, cumulative weight gain and fat mass were all significantly lower in TTP2515 treated mice. (D) Total T4 levels were significantly higher in TTP2515 treated mice. (E) Leptin levels tended to be lower in TTP2515 treated mice (p = 0.12). (F) Insulin levels were similar between groups. (G–J) In a separate experiment, AgRP KO mice on a 10% fat chow diet were switched to a 60% fat diet and started treatment with TTP2515 (5, 15, or 30 mg/kg) or water twice daily. (G,I) Cumulative caloric intake and cumulative weight gain were dose-dependently lower in TTP2515 treated mice compared to the water group. (H) Fat mass was lower in TTP2515 treated mice at both the 15 and 30 mg/kg doses vs. water. The 5 mg/kg group tended (p = 0.05) to have lower fat mass than the water group. (J) After 5 days of treatment, total T4 levels were equivalent between groups, however fasting and continued treatment revealed an increase in total T4 levels. *p<0.05, **p<0.01 vs water; ap<0.05 vs water, bp<0.05 vs 5 mg/kg, cp<0.05 vs 15 mg/kg.

Mentions: Lean, BL6 mice maintained on breeder chow were all switched to a 60% fat diet and simultaneously started treatment with either TTP2515 (30 mg/kg) or water. After switching to a HFD, water treated mice increased their caloric intake (p<0.0001, baseline vs. day 1) while the TTP2515 treated mice actually decreased their caloric intake (p<0.05, baseline vs. day 1). Furthermore, daily food was significantly lower in TTP2515 compared to water treated mice during days 1–2 (p<0.0001), however by day 3 daily food intake was similar between groups. Cumulative caloric intake was significantly lower in TTP2515 vs. water treated mice during the entire treatment period (p<0.0001, Fig. 7A). Water treated mice gained weight after switching to the higher fat diet; oppositely, TTP2515 treated mice lost weight (p<0.01, Fig. 7B). A body composition measurement on day 4 revealed that TTP2515 treated mice had significantly lower fat mass compared to water treated mice (p<0.0001, Fig. 7C), while lean mass was equivalent between groups (Water 19.6±0.5 vs. TTP2515 19.7±0.4 g). At sacrifice, leptin (p = 0.12) and insulin levels were not significantly different between groups, however total T4 levels were higher (p<0.0001) in TTP2515 treated mice (Fig. 7D–F). No significant difference in 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 in WT or AgRP KO mice acutely switched to a very high-fat diet.(A–F) Mice were switched from breeder chow to a 60% fat diet and started treatment with TTP2515 (30 mg/kg) or water twice daily. (A–C) Cumulative food intake, cumulative weight gain and fat mass were all significantly lower in TTP2515 treated mice. (D) Total T4 levels were significantly higher in TTP2515 treated mice. (E) Leptin levels tended to be lower in TTP2515 treated mice (p = 0.12). (F) Insulin levels were similar between groups. (G–J) In a separate experiment, AgRP KO mice on a 10% fat chow diet were switched to a 60% fat diet and started treatment with TTP2515 (5, 15, or 30 mg/kg) or water twice daily. (G,I) Cumulative caloric intake and cumulative weight gain were dose-dependently lower in TTP2515 treated mice compared to the water group. (H) Fat mass was lower in TTP2515 treated mice at both the 15 and 30 mg/kg doses vs. water. The 5 mg/kg group tended (p = 0.05) to have lower fat mass than the water group. (J) After 5 days of treatment, total T4 levels were equivalent between groups, however fasting and continued treatment revealed an increase in total T4 levels. *p<0.05, **p<0.01 vs water; ap<0.05 vs water, bp<0.05 vs 5 mg/kg, cp<0.05 vs 15 mg/kg.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3675096&req=5

pone-0065317-g007: Effects of TTP2515 in WT or AgRP KO mice acutely switched to a very high-fat diet.(A–F) Mice were switched from breeder chow to a 60% fat diet and started treatment with TTP2515 (30 mg/kg) or water twice daily. (A–C) Cumulative food intake, cumulative weight gain and fat mass were all significantly lower in TTP2515 treated mice. (D) Total T4 levels were significantly higher in TTP2515 treated mice. (E) Leptin levels tended to be lower in TTP2515 treated mice (p = 0.12). (F) Insulin levels were similar between groups. (G–J) In a separate experiment, AgRP KO mice on a 10% fat chow diet were switched to a 60% fat diet and started treatment with TTP2515 (5, 15, or 30 mg/kg) or water twice daily. (G,I) Cumulative caloric intake and cumulative weight gain were dose-dependently lower in TTP2515 treated mice compared to the water group. (H) Fat mass was lower in TTP2515 treated mice at both the 15 and 30 mg/kg doses vs. water. The 5 mg/kg group tended (p = 0.05) to have lower fat mass than the water group. (J) After 5 days of treatment, total T4 levels were equivalent between groups, however fasting and continued treatment revealed an increase in total T4 levels. *p<0.05, **p<0.01 vs water; ap<0.05 vs water, bp<0.05 vs 5 mg/kg, cp<0.05 vs 15 mg/kg.
Mentions: Lean, BL6 mice maintained on breeder chow were all switched to a 60% fat diet and simultaneously started treatment with either TTP2515 (30 mg/kg) or water. After switching to a HFD, water treated mice increased their caloric intake (p<0.0001, baseline vs. day 1) while the TTP2515 treated mice actually decreased their caloric intake (p<0.05, baseline vs. day 1). Furthermore, daily food was significantly lower in TTP2515 compared to water treated mice during days 1–2 (p<0.0001), however by day 3 daily food intake was similar between groups. Cumulative caloric intake was significantly lower in TTP2515 vs. water treated mice during the entire treatment period (p<0.0001, Fig. 7A). Water treated mice gained weight after switching to the higher fat diet; oppositely, TTP2515 treated mice lost weight (p<0.01, Fig. 7B). A body composition measurement on day 4 revealed that TTP2515 treated mice had significantly lower fat mass compared to water treated mice (p<0.0001, Fig. 7C), while lean mass was equivalent between groups (Water 19.6±0.5 vs. TTP2515 19.7±0.4 g). At sacrifice, leptin (p = 0.12) and insulin levels were not significantly different between groups, however total T4 levels were higher (p<0.0001) in TTP2515 treated mice (Fig. 7D–F). No significant difference in 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