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Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet.

Hosick PA, AlAmodi AA, Storm MV, Gousset MU, Pruett BE, Gray W, Stout J, Stec DE - Int J Obes (Lond) (2013)

Bottom Line: Body weights were measured weekly and fasted blood glucose, insulin as well as body composition were measured every 6 weeks.Chronic CORM-A1 treatment in mice fed a high-fat diet resulted in significant decreases in fasted blood glucose, insulin and body fat and increased O2 consumption and heat production as compared with mice treated with iCORM-A1.Chronic CORM-A1 treatment also resulted in a significant decrease in adipocyte size and an increase in adipocyte number and in NRF-1, PGC-1α and UCP1 protein levels in epidydmal fat.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, MS, USA.

ABSTRACT

Objective: Induction of heme oxygenase-1 (HO-1) has been demonstrated to result in chronic weight loss in several rodent models of obesity. However, the specific contribution of the HO metabolite, carbon monoxide (CO) to this response remains unknown. In this study, we determined the effect of chronic low level administration of a specific CO donor on the progression of obesity and its effects on metabolism and adipocyte biology in mice fed a high-fat diet.

Design: Experiments were performed on C57BL/6J mice fed a high-fat diet (60%) from 4 weeks until 30 weeks of age. Mice were administered either the CO donor, carbon monoxide releasing molecules (CORM)-A1 (5 mg kg(-1), intraperitoneally every other day) or the inactive form of the drug (iCORM-A1). Body weights were measured weekly and fasted blood glucose, insulin as well as body composition were measured every 6 weeks. Food intake, O2 consumption, CO2 production, activity and body heat production were measured at 28 weeks after start of the experimental protocol.

Results: Chronic CORM-A1 attenuated the development of high fat induced obesity from 18 weeks until the end of the study. Chronic CORM-A1 treatment in mice fed a high-fat diet resulted in significant decreases in fasted blood glucose, insulin and body fat and increased O2 consumption and heat production as compared with mice treated with iCORM-A1. Chronic CORM-A1 treatment also resulted in a significant decrease in adipocyte size and an increase in adipocyte number and in NRF-1, PGC-1α and UCP1 protein levels in epidydmal fat.

Conclusion: Our results demonstrate that chronic CO treatment prevents the development of high-fat diet induced obesity via stimulation of metabolism and remodeling of adipocytes.

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A) fasted blood glucose measurements in control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. B) Plasma insulin measurements control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. C) Glucose tolerance test area under the curve (GTT-AUC) in control (n=4), high fat (HF) + CORM-A1 (n=6), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=6) treated mice. Glucose tolerance tests were performed in fasted mice at week 27 of the experimental protocol. D) Plasma adiponectin E) Plasma leptin measurements at week 30 of the experimental protocol control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. *= significant from HF treated mice, P<0.05. #= significant from iCORM-A1 treated mice, P<0.05. † = significant from control and CORM-A1 treated mice, P<0.05.
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Figure 3: A) fasted blood glucose measurements in control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. B) Plasma insulin measurements control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. C) Glucose tolerance test area under the curve (GTT-AUC) in control (n=4), high fat (HF) + CORM-A1 (n=6), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=6) treated mice. Glucose tolerance tests were performed in fasted mice at week 27 of the experimental protocol. D) Plasma adiponectin E) Plasma leptin measurements at week 30 of the experimental protocol control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. *= significant from HF treated mice, P<0.05. #= significant from iCORM-A1 treated mice, P<0.05. † = significant from control and CORM-A1 treated mice, P<0.05.

Mentions: Fasted blood glucose levels in both groups of mice fed a high fat diet were increased at both 24 and 30 weeks of treatment as compared to control mice (Figure 3A). However, fasted blood glucose levels were significantly lower in CORM-A1 treated as compared to iCORM-A1 treated mice at both time frames (Figure 3A). Plasma insulin levels were increased at both 24 and 30 weeks in both groups of mice fed a high fat diet as compared to control mice (Figure 3B). CORM-A1 treatment resulted in 30% decrease in plasma insulin levels as compared to iCORM-A1 treated mice at both 24 and 30 weeks (Figure 3B). In order to access in vivo insulin function, we performed a glucose tolerance test at 30 weeks of age. iCORM-A1 treated mice exhibited a significantly increased delay in the clearance of glucose as indicate by the greater area under the curve as compared to CORM-A1 and control mice (Figure 3C). No difference in glucose clearance was detected between control and high fat fed CORM-A1 treated mice. Plasma adiponectin levels measured at week 30 were decreased in both groups of mice fed a high fat diet as compared to control mice (Figure 3D). Plasma leptin levels were increased in both groups of mice fed a high fat diet as compared to control mice (Figure 3E); however, plasma leptin levels were reduced by 70% in CORM-A1 treated mice as compared to iCORM-A1 treated mice (Figure 3E).


Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet.

Hosick PA, AlAmodi AA, Storm MV, Gousset MU, Pruett BE, Gray W, Stout J, Stec DE - Int J Obes (Lond) (2013)

A) fasted blood glucose measurements in control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. B) Plasma insulin measurements control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. C) Glucose tolerance test area under the curve (GTT-AUC) in control (n=4), high fat (HF) + CORM-A1 (n=6), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=6) treated mice. Glucose tolerance tests were performed in fasted mice at week 27 of the experimental protocol. D) Plasma adiponectin E) Plasma leptin measurements at week 30 of the experimental protocol control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. *= significant from HF treated mice, P<0.05. #= significant from iCORM-A1 treated mice, P<0.05. † = significant from control and CORM-A1 treated mice, P<0.05.
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Figure 3: A) fasted blood glucose measurements in control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. B) Plasma insulin measurements control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. C) Glucose tolerance test area under the curve (GTT-AUC) in control (n=4), high fat (HF) + CORM-A1 (n=6), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=6) treated mice. Glucose tolerance tests were performed in fasted mice at week 27 of the experimental protocol. D) Plasma adiponectin E) Plasma leptin measurements at week 30 of the experimental protocol control (n=4), high fat (HF) + CORM-A1 (n=9), and high fat (HF) + inactive CORM-A1 (iCORM-A1, n=9) treated mice. *= significant from HF treated mice, P<0.05. #= significant from iCORM-A1 treated mice, P<0.05. † = significant from control and CORM-A1 treated mice, P<0.05.
Mentions: Fasted blood glucose levels in both groups of mice fed a high fat diet were increased at both 24 and 30 weeks of treatment as compared to control mice (Figure 3A). However, fasted blood glucose levels were significantly lower in CORM-A1 treated as compared to iCORM-A1 treated mice at both time frames (Figure 3A). Plasma insulin levels were increased at both 24 and 30 weeks in both groups of mice fed a high fat diet as compared to control mice (Figure 3B). CORM-A1 treatment resulted in 30% decrease in plasma insulin levels as compared to iCORM-A1 treated mice at both 24 and 30 weeks (Figure 3B). In order to access in vivo insulin function, we performed a glucose tolerance test at 30 weeks of age. iCORM-A1 treated mice exhibited a significantly increased delay in the clearance of glucose as indicate by the greater area under the curve as compared to CORM-A1 and control mice (Figure 3C). No difference in glucose clearance was detected between control and high fat fed CORM-A1 treated mice. Plasma adiponectin levels measured at week 30 were decreased in both groups of mice fed a high fat diet as compared to control mice (Figure 3D). Plasma leptin levels were increased in both groups of mice fed a high fat diet as compared to control mice (Figure 3E); however, plasma leptin levels were reduced by 70% in CORM-A1 treated mice as compared to iCORM-A1 treated mice (Figure 3E).

Bottom Line: Body weights were measured weekly and fasted blood glucose, insulin as well as body composition were measured every 6 weeks.Chronic CORM-A1 treatment in mice fed a high-fat diet resulted in significant decreases in fasted blood glucose, insulin and body fat and increased O2 consumption and heat production as compared with mice treated with iCORM-A1.Chronic CORM-A1 treatment also resulted in a significant decrease in adipocyte size and an increase in adipocyte number and in NRF-1, PGC-1α and UCP1 protein levels in epidydmal fat.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, MS, USA.

ABSTRACT

Objective: Induction of heme oxygenase-1 (HO-1) has been demonstrated to result in chronic weight loss in several rodent models of obesity. However, the specific contribution of the HO metabolite, carbon monoxide (CO) to this response remains unknown. In this study, we determined the effect of chronic low level administration of a specific CO donor on the progression of obesity and its effects on metabolism and adipocyte biology in mice fed a high-fat diet.

Design: Experiments were performed on C57BL/6J mice fed a high-fat diet (60%) from 4 weeks until 30 weeks of age. Mice were administered either the CO donor, carbon monoxide releasing molecules (CORM)-A1 (5 mg kg(-1), intraperitoneally every other day) or the inactive form of the drug (iCORM-A1). Body weights were measured weekly and fasted blood glucose, insulin as well as body composition were measured every 6 weeks. Food intake, O2 consumption, CO2 production, activity and body heat production were measured at 28 weeks after start of the experimental protocol.

Results: Chronic CORM-A1 attenuated the development of high fat induced obesity from 18 weeks until the end of the study. Chronic CORM-A1 treatment in mice fed a high-fat diet resulted in significant decreases in fasted blood glucose, insulin and body fat and increased O2 consumption and heat production as compared with mice treated with iCORM-A1. Chronic CORM-A1 treatment also resulted in a significant decrease in adipocyte size and an increase in adipocyte number and in NRF-1, PGC-1α and UCP1 protein levels in epidydmal fat.

Conclusion: Our results demonstrate that chronic CO treatment prevents the development of high-fat diet induced obesity via stimulation of metabolism and remodeling of adipocytes.

Show MeSH
Related in: MedlinePlus