LBODP003 Effects Of 4-weeks’ Treatment With Intraperitoneal Colchicine On Metabolic And Inflammatory Outcomes In Mice Fed A High-fat Diet
Abstract Health-deteriorating effects of obesity include chronic inflammation and insulin resistance (IR). A recent pilot human trial reported reduced IR in colchicine-treated vs. placebo-treated adults with obesity. Thus, we examined anti-inflammatory and metabolic effects of two commonly employed...
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| Veröffentlicht in: | Journal of the Endocrine Society 2022-11, Vol.6 (Supplement_1), p.A2-A2 |
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| description | Abstract
Health-deteriorating effects of obesity include chronic inflammation and insulin resistance (IR). A recent pilot human trial reported reduced IR in colchicine-treated vs. placebo-treated adults with obesity. Thus, we examined anti-inflammatory and metabolic effects of two commonly employed dosing regimens of colchicine, 0.2 mg/kg and 0. 02mg/kg, in a high-fat diet (HFD; 45%) mouse obesity model. We placed male C57BL/6J mice on HFD from ages 8 through 16 weeks. At age 12 weeks, mice were randomized to: high-dose colchicine (CHD 0.2 mg/kg, n=28), low dose colchicine (CLD, 0. 02mg/kg, n=26) or vehicle (V, n=26), injected intraperitoneally (IP) for 4 weeks. Serum CRP was measured by ELISA. Dual-energy X-ray absorptiometry (DXA) scans and fasting IP glucose tolerance (GTT) and insulin-tolerance (ITT) tests were performed at baseline and following treatment. Hepatic tissue was processed for immunoblotting to determine expression of NLRP3 and caspase-1. Changes in pre- vs. post-treatment serum CRP were significantly different in the CHD group (Mean±SD: -0.57±3.1µg/mL) vs. V (+3.64±2.9µg/mL; p |
| doi_str_mv | 10.1210/jendso/bvac150.003 |
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Health-deteriorating effects of obesity include chronic inflammation and insulin resistance (IR). A recent pilot human trial reported reduced IR in colchicine-treated vs. placebo-treated adults with obesity. Thus, we examined anti-inflammatory and metabolic effects of two commonly employed dosing regimens of colchicine, 0.2 mg/kg and 0. 02mg/kg, in a high-fat diet (HFD; 45%) mouse obesity model. We placed male C57BL/6J mice on HFD from ages 8 through 16 weeks. At age 12 weeks, mice were randomized to: high-dose colchicine (CHD 0.2 mg/kg, n=28), low dose colchicine (CLD, 0. 02mg/kg, n=26) or vehicle (V, n=26), injected intraperitoneally (IP) for 4 weeks. Serum CRP was measured by ELISA. Dual-energy X-ray absorptiometry (DXA) scans and fasting IP glucose tolerance (GTT) and insulin-tolerance (ITT) tests were performed at baseline and following treatment. Hepatic tissue was processed for immunoblotting to determine expression of NLRP3 and caspase-1. Changes in pre- vs. post-treatment serum CRP were significantly different in the CHD group (Mean±SD: -0.57±3.1µg/mL) vs. V (+3.64±2.9µg/mL; p<0. 001) and CLD (+0.72±2.3µg/mL) compared to V (p=0. 03). Changes in CRP for CHD compared to CLD did not differ significantly (p=0.47). DXA-measured body composition changes pre-vs. post-treatment for fat mass were significantly reduced for CHD (-0.26±2. 0g) vs. V (+1.24±2.1g; p=0. 04) and CHD vs. CLD (+1.52±2.2g; p=0. 01). Lean body mass changes were not significant between treatments (p=0.69). GTT glucose concentrations were not significantly different between treatments across timepoints (Group x time interaction: p=0.24) and GTT areas under curves (AUC) were not significantly different between treatments (p=0.96). Analysis of ITT glucose measures revealed a significant group x time interaction (p=0. 03) and group effect for CHD vs. V (p=0. 009) as well as significant differences in ITT AUCs (p=0. 03) such that insulin tolerance was significantly worse for CHD: CHD AUC 19803±2662, CLD 18487±3703, V 17436±3138mg/dLx120min. Hepatic NLRP3 fold-change protein expression of treatment groups compared to V was not significant for CHD (p=0.75) or CLD (p=0.21). However, hepatic caspase-1 protein expression fold-change was significantly lower in the CHD (p=0. 008), but not the CLD group (p=0.19). We conclude that 4-weeks of IP colchicine at 0.2mg/kg (CHD) significantly suppressed serum CRP and hepatic caspase-1 protein expression compared to V, indicating CHD reduced inflammation, whereas 0. 02mg/kg colchicine (CLD) did not. However, our data suggest that 4 weeks of the CHD dose may potentially worsen whole-body insulin resistance, even though it induced a reduction in fat mass, suggesting a possible toxicity from chronic high-dose colchicine treatment. Further studies are warranted to elucidate metabolic effects of colchicine administration in murine diet-induced obesity models.
Presentation: No date and time listed</description><identifier>ISSN: 2472-1972</identifier><identifier>EISSN: 2472-1972</identifier><identifier>DOI: 10.1210/jendso/bvac150.003</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Adipose Tissue, Appetite, & Obesity</subject><ispartof>Journal of the Endocrine Society, 2022-11, Vol.6 (Supplement_1), p.A2-A2</ispartof><rights>The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624528/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624528/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids></links><search><creatorcontrib>Arner, Brooke E</creatorcontrib><creatorcontrib>Levine, Jordan A</creatorcontrib><creatorcontrib>Miller, Emily K</creatorcontrib><creatorcontrib>Patel, Tushar P</creatorcontrib><creatorcontrib>Jain, Arad</creatorcontrib><creatorcontrib>Gupta, Suryaa</creatorcontrib><creatorcontrib>Roberson, Robin B</creatorcontrib><creatorcontrib>Demidowich, Andrew P</creatorcontrib><creatorcontrib>Yanovski, Jack A</creatorcontrib><title>LBODP003 Effects Of 4-weeks’ Treatment With Intraperitoneal Colchicine On Metabolic And Inflammatory Outcomes In Mice Fed A High-fat Diet</title><title>Journal of the Endocrine Society</title><description>Abstract
Health-deteriorating effects of obesity include chronic inflammation and insulin resistance (IR). A recent pilot human trial reported reduced IR in colchicine-treated vs. placebo-treated adults with obesity. Thus, we examined anti-inflammatory and metabolic effects of two commonly employed dosing regimens of colchicine, 0.2 mg/kg and 0. 02mg/kg, in a high-fat diet (HFD; 45%) mouse obesity model. We placed male C57BL/6J mice on HFD from ages 8 through 16 weeks. At age 12 weeks, mice were randomized to: high-dose colchicine (CHD 0.2 mg/kg, n=28), low dose colchicine (CLD, 0. 02mg/kg, n=26) or vehicle (V, n=26), injected intraperitoneally (IP) for 4 weeks. Serum CRP was measured by ELISA. Dual-energy X-ray absorptiometry (DXA) scans and fasting IP glucose tolerance (GTT) and insulin-tolerance (ITT) tests were performed at baseline and following treatment. Hepatic tissue was processed for immunoblotting to determine expression of NLRP3 and caspase-1. Changes in pre- vs. post-treatment serum CRP were significantly different in the CHD group (Mean±SD: -0.57±3.1µg/mL) vs. V (+3.64±2.9µg/mL; p<0. 001) and CLD (+0.72±2.3µg/mL) compared to V (p=0. 03). Changes in CRP for CHD compared to CLD did not differ significantly (p=0.47). DXA-measured body composition changes pre-vs. post-treatment for fat mass were significantly reduced for CHD (-0.26±2. 0g) vs. V (+1.24±2.1g; p=0. 04) and CHD vs. CLD (+1.52±2.2g; p=0. 01). Lean body mass changes were not significant between treatments (p=0.69). GTT glucose concentrations were not significantly different between treatments across timepoints (Group x time interaction: p=0.24) and GTT areas under curves (AUC) were not significantly different between treatments (p=0.96). Analysis of ITT glucose measures revealed a significant group x time interaction (p=0. 03) and group effect for CHD vs. V (p=0. 009) as well as significant differences in ITT AUCs (p=0. 03) such that insulin tolerance was significantly worse for CHD: CHD AUC 19803±2662, CLD 18487±3703, V 17436±3138mg/dLx120min. Hepatic NLRP3 fold-change protein expression of treatment groups compared to V was not significant for CHD (p=0.75) or CLD (p=0.21). However, hepatic caspase-1 protein expression fold-change was significantly lower in the CHD (p=0. 008), but not the CLD group (p=0.19). We conclude that 4-weeks of IP colchicine at 0.2mg/kg (CHD) significantly suppressed serum CRP and hepatic caspase-1 protein expression compared to V, indicating CHD reduced inflammation, whereas 0. 02mg/kg colchicine (CLD) did not. However, our data suggest that 4 weeks of the CHD dose may potentially worsen whole-body insulin resistance, even though it induced a reduction in fat mass, suggesting a possible toxicity from chronic high-dose colchicine treatment. Further studies are warranted to elucidate metabolic effects of colchicine administration in murine diet-induced obesity models.
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Health-deteriorating effects of obesity include chronic inflammation and insulin resistance (IR). A recent pilot human trial reported reduced IR in colchicine-treated vs. placebo-treated adults with obesity. Thus, we examined anti-inflammatory and metabolic effects of two commonly employed dosing regimens of colchicine, 0.2 mg/kg and 0. 02mg/kg, in a high-fat diet (HFD; 45%) mouse obesity model. We placed male C57BL/6J mice on HFD from ages 8 through 16 weeks. At age 12 weeks, mice were randomized to: high-dose colchicine (CHD 0.2 mg/kg, n=28), low dose colchicine (CLD, 0. 02mg/kg, n=26) or vehicle (V, n=26), injected intraperitoneally (IP) for 4 weeks. Serum CRP was measured by ELISA. Dual-energy X-ray absorptiometry (DXA) scans and fasting IP glucose tolerance (GTT) and insulin-tolerance (ITT) tests were performed at baseline and following treatment. Hepatic tissue was processed for immunoblotting to determine expression of NLRP3 and caspase-1. Changes in pre- vs. post-treatment serum CRP were significantly different in the CHD group (Mean±SD: -0.57±3.1µg/mL) vs. V (+3.64±2.9µg/mL; p<0. 001) and CLD (+0.72±2.3µg/mL) compared to V (p=0. 03). Changes in CRP for CHD compared to CLD did not differ significantly (p=0.47). DXA-measured body composition changes pre-vs. post-treatment for fat mass were significantly reduced for CHD (-0.26±2. 0g) vs. V (+1.24±2.1g; p=0. 04) and CHD vs. CLD (+1.52±2.2g; p=0. 01). Lean body mass changes were not significant between treatments (p=0.69). GTT glucose concentrations were not significantly different between treatments across timepoints (Group x time interaction: p=0.24) and GTT areas under curves (AUC) were not significantly different between treatments (p=0.96). Analysis of ITT glucose measures revealed a significant group x time interaction (p=0. 03) and group effect for CHD vs. V (p=0. 009) as well as significant differences in ITT AUCs (p=0. 03) such that insulin tolerance was significantly worse for CHD: CHD AUC 19803±2662, CLD 18487±3703, V 17436±3138mg/dLx120min. Hepatic NLRP3 fold-change protein expression of treatment groups compared to V was not significant for CHD (p=0.75) or CLD (p=0.21). However, hepatic caspase-1 protein expression fold-change was significantly lower in the CHD (p=0. 008), but not the CLD group (p=0.19). We conclude that 4-weeks of IP colchicine at 0.2mg/kg (CHD) significantly suppressed serum CRP and hepatic caspase-1 protein expression compared to V, indicating CHD reduced inflammation, whereas 0. 02mg/kg colchicine (CLD) did not. However, our data suggest that 4 weeks of the CHD dose may potentially worsen whole-body insulin resistance, even though it induced a reduction in fat mass, suggesting a possible toxicity from chronic high-dose colchicine treatment. Further studies are warranted to elucidate metabolic effects of colchicine administration in murine diet-induced obesity models.
Presentation: No date and time listed</abstract><cop>US</cop><pub>Oxford University Press</pub><doi>10.1210/jendso/bvac150.003</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adipose Tissue, Appetite, & Obesity |
| title | LBODP003 Effects Of 4-weeks’ Treatment With Intraperitoneal Colchicine On Metabolic And Inflammatory Outcomes In Mice Fed A High-fat Diet |
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