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Dysregulation of lipolysis and lipid metabolism on the development of obesity in the TSOD mouse
S62
POSTER Abstracts
P15
P16
Anti-obesity effects of the combined administration of CB1 receptor antagonist rimonabant and melanin concentrating hormone antagonist SNAP94847 in diet induced obese mice
Dysregulation of lipolysis and lipid metabolism on the development of obesity in the TSOD mouse
A.N.A. Verty ∗ , B.J. Oldfield
Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan
Dept of Physiology, Monash University, Melbourne, Australia Obesity is proving difficult to treat with the currently available pharmacological therapies as they provide modest weight loss or are accompanied by adverse side effects. This is true of the cannabinoid 1 receptor (CB1) antagonist rimonabant that has been discontinued from clinical use due increased incidence of depression. Here we report a study employing combination therapies to enhance the anorexigenic properties of rimonabant while altering its mood related effects. Specifically, we administered rimonabant in combination with SNAP-94847, an antagonist to the melanin-concentrating hormone (MCH) 1 receptor, in diet induced obese (DIO) male C57BL/6 mice. A bolus dose of rimonabant and SNAP-94847 produced a dose-dependent reduction in food intake at the 2 and 24 h measurement intervals. Combining sub-threshold doses of these drugs produced a significantly greater loss of body weight in DIO mice compared to vehicle and monotherapies. In addition, the combination of these drugs leads to a shift in markers of thermogenesis in BAT and lipid metabolism in WAT in directions consistent with reduced energy expenditure and increased lipolysis. Furthermore, co-administration produced a transient reduction in food intake, significantly reduced the fat mass, and adipocyte cell size. Most importantly, the ability of rimonabant to affect depression was significantly attenuated by SNAP-94847 in the forced swim test, a model of preclinical depression. These results provide proof of principle that the combination of rimonabant and MCH1 receptor antagonist is highly effective in reducing body weight below that achieved by rimonabant and SNAP-94847 monotherapies while reversing the effects of rimonabant on mood. doi:10.1016/j.orcp.2011.08.022
Y. Kobayashi ∗ , N. Tagawa
Background of study: In 1999, a new genetic animal model of type 2 diabetes, the Tsumura Suzuki Obese Diabetes (TSOD) mouse, has been developed. The TSOD mouse develops a moderate degree of obesity and diabetes. Aim: To investigate the potential association of dysregulation of lipolysis and lipid metabolism on the development of obesity in TSOD mice. Methods: Three-month-old TSOD and the agematched control (TSNO: Tsumura Suzuki NonObesity) male mice were obtained from The Institute for Animal Reproduction (Ibaraki, Japan). Serum glucose, total cholesterol (T-Cho), triglycerides (TG) and insulin were measured. Adipose tissues were removed and extracted lipids by acetone. Extracted lipids were analyzed by TLC and LC—MS. The expressions of mRNA of adipose tissue glycerol lipase (ATGL), hormone sensitive lipase (HSL), adipose phospholipase A2 (AdLPA2) and perilipin in epididymal adipose tissue were also measured by real-time PCR. Results: Serum levels of glucose, TG and insulin were significantly elevated in TSOD mice than those of TSNO. Clear spot corresponding to diacylglycerol (DG) was observed in the sample from TSOD but not from TSNO by TLC. Ratio of total DG levels against total TG ones in TSOD mice were higher than those in TSNO by LC—MS. Expression of ATGL, HSL and perilipin was significantry lower in TSOD than that in TSNO. However, mRNA expression of AdPLA2 in TSOD was significantly higher than that in TSNO. Conclusions: Dysregulation of lipolysis and lipid metabolism in adipose tissue contribute in part to the development of obesity in TSOD mice. Conflict of interest: None. doi:10.1016/j.orcp.2011.08.023 P17 Effect of oestrogen on isoproterenol activated lipolysis in murine adipocytes N. Tagawa ∗ , Y. Kobayashi Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan Background of study: Stress stimulates sympatho-adrenomedullary activity and lipolysis in
POSTER Abstracts
P15
P16
Anti-obesity effects of the combined administration of CB1 receptor antagonist rimonabant and melanin concentrating hormone antagonist SNAP94847 in diet induced obese mice
Dysregulation of lipolysis and lipid metabolism on the development of obesity in the TSOD mouse
A.N.A. Verty ∗ , B.J. Oldfield
Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan
Dept of Physiology, Monash University, Melbourne, Australia Obesity is proving difficult to treat with the currently available pharmacological therapies as they provide modest weight loss or are accompanied by adverse side effects. This is true of the cannabinoid 1 receptor (CB1) antagonist rimonabant that has been discontinued from clinical use due increased incidence of depression. Here we report a study employing combination therapies to enhance the anorexigenic properties of rimonabant while altering its mood related effects. Specifically, we administered rimonabant in combination with SNAP-94847, an antagonist to the melanin-concentrating hormone (MCH) 1 receptor, in diet induced obese (DIO) male C57BL/6 mice. A bolus dose of rimonabant and SNAP-94847 produced a dose-dependent reduction in food intake at the 2 and 24 h measurement intervals. Combining sub-threshold doses of these drugs produced a significantly greater loss of body weight in DIO mice compared to vehicle and monotherapies. In addition, the combination of these drugs leads to a shift in markers of thermogenesis in BAT and lipid metabolism in WAT in directions consistent with reduced energy expenditure and increased lipolysis. Furthermore, co-administration produced a transient reduction in food intake, significantly reduced the fat mass, and adipocyte cell size. Most importantly, the ability of rimonabant to affect depression was significantly attenuated by SNAP-94847 in the forced swim test, a model of preclinical depression. These results provide proof of principle that the combination of rimonabant and MCH1 receptor antagonist is highly effective in reducing body weight below that achieved by rimonabant and SNAP-94847 monotherapies while reversing the effects of rimonabant on mood. doi:10.1016/j.orcp.2011.08.022
Y. Kobayashi ∗ , N. Tagawa
Background of study: In 1999, a new genetic animal model of type 2 diabetes, the Tsumura Suzuki Obese Diabetes (TSOD) mouse, has been developed. The TSOD mouse develops a moderate degree of obesity and diabetes. Aim: To investigate the potential association of dysregulation of lipolysis and lipid metabolism on the development of obesity in TSOD mice. Methods: Three-month-old TSOD and the agematched control (TSNO: Tsumura Suzuki NonObesity) male mice were obtained from The Institute for Animal Reproduction (Ibaraki, Japan). Serum glucose, total cholesterol (T-Cho), triglycerides (TG) and insulin were measured. Adipose tissues were removed and extracted lipids by acetone. Extracted lipids were analyzed by TLC and LC—MS. The expressions of mRNA of adipose tissue glycerol lipase (ATGL), hormone sensitive lipase (HSL), adipose phospholipase A2 (AdLPA2) and perilipin in epididymal adipose tissue were also measured by real-time PCR. Results: Serum levels of glucose, TG and insulin were significantly elevated in TSOD mice than those of TSNO. Clear spot corresponding to diacylglycerol (DG) was observed in the sample from TSOD but not from TSNO by TLC. Ratio of total DG levels against total TG ones in TSOD mice were higher than those in TSNO by LC—MS. Expression of ATGL, HSL and perilipin was significantry lower in TSOD than that in TSNO. However, mRNA expression of AdPLA2 in TSOD was significantly higher than that in TSNO. Conclusions: Dysregulation of lipolysis and lipid metabolism in adipose tissue contribute in part to the development of obesity in TSOD mice. Conflict of interest: None. doi:10.1016/j.orcp.2011.08.023 P17 Effect of oestrogen on isoproterenol activated lipolysis in murine adipocytes N. Tagawa ∗ , Y. Kobayashi Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan Background of study: Stress stimulates sympatho-adrenomedullary activity and lipolysis in