Limits...
Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways.

Tedesco L, Valerio A, Dossena M, Cardile A, Ragni M, Pagano C, Pagotto U, Carruba MO, Vettor R, Nisoli E - Diabetes (2010)

Bottom Line: Cannabinoid type 1 (CB1) receptor is involved in whole-body and cellular energy metabolism.ACEA decreased mitochondrial biogenesis and eNOS expression, activated p38 MAPK, and reduced AMPK phosphorylation in white adipocytes.The ACEA effects on mitochondria were antagonized by nitric oxide donors and by p38 MAPK silencing.

View Article: PubMed Central - PubMed

Affiliation: Integrated Laboratories Network, Center for Study and Research on Obesity, and Department of Pharmacology, Chemotherapy and Medical Toxicology, School of Medicine, University of Milan, Milan, Italy.

ABSTRACT

Objective: Cannabinoid type 1 (CB1) receptor is involved in whole-body and cellular energy metabolism. We asked whether CB1 receptor stimulation was able to decrease mitochondrial biogenesis in different metabolically active tissues of obese high-fat diet (HFD)-fed mice.

Research design and methods: The effects of selective CB1 agonist arachidonyl-2-chloroethanolamide (ACEA) and endocannabinoids anandamide and 2-arachidonoylglycerol on endothelial nitric oxide synthase (eNOS) expression were examined, as were mitochondrial DNA amount and mitochondrial biogenesis parameters in cultured mouse and human white adipocytes. These parameters were also investigated in white adipose tissue (WAT), muscle, and liver of mice chronically treated with ACEA. Moreover, p38 mitogen-activated protein kinase (MAPK) phosphorylation was investigated in WAT and isolated mature adipocytes from eNOS(-/-) and wild-type mice. eNOS, p38 MAPK, adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial biogenesis were investigated in WAT, muscle, and liver of HFD mice chronically treated with ACEA.

Results: ACEA decreased mitochondrial biogenesis and eNOS expression, activated p38 MAPK, and reduced AMPK phosphorylation in white adipocytes. The ACEA effects on mitochondria were antagonized by nitric oxide donors and by p38 MAPK silencing. White adipocytes from eNOS(-/-) mice displayed higher p38 MAPK phosphorylation than wild-type animals under basal conditions, and ACEA was ineffective in cells lacking eNOS. Moreover, mitochondrial biogenesis was downregulated, while p38 MAPK phosphorylation was increased and AMPK phosphorylation was decreased in WAT, muscle, and liver of ACEA-treated mice on a HFD.

Conclusions: CB1 receptor stimulation decreases mitochondrial biogenesis in white adipocytes, through eNOS downregulation and p38 MAPK activation, and impairs mitochondrial function in metabolically active tissues of dietary obese mice.

Show MeSH

Related in: MedlinePlus

CB1 receptor stimulation increases body weight in obese mice. A: Body weight of ACEA- or vehicle-treated mice on a HFD compared with vehicle-treated mice on a chow regular diet (n = 10 animals per group; *P < 0.05 vs. vehicle-treated mice on a HFD). ○, chow plus vehicle; ●, chow plus ACEA; □, HFD plus vehicle; ■, HFD plus ACEA. B–D: Adiposity (expressed as percentage of weight of visceral and subcutaneous fat when value of vehicle (Veh)-treated mice on chow regular diet is 100), cumulative food intake, and feed efficiency (n = 8 animals per group; *P < 0.05 **P < 0.01 vs. vehicle-treated mice on a chow regular diet and †P < 0.05 vs. vehicle-treated mice on a HFD).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2963541&req=5

Figure 7: CB1 receptor stimulation increases body weight in obese mice. A: Body weight of ACEA- or vehicle-treated mice on a HFD compared with vehicle-treated mice on a chow regular diet (n = 10 animals per group; *P < 0.05 vs. vehicle-treated mice on a HFD). ○, chow plus vehicle; ●, chow plus ACEA; □, HFD plus vehicle; ■, HFD plus ACEA. B–D: Adiposity (expressed as percentage of weight of visceral and subcutaneous fat when value of vehicle (Veh)-treated mice on chow regular diet is 100), cumulative food intake, and feed efficiency (n = 8 animals per group; *P < 0.05 **P < 0.01 vs. vehicle-treated mice on a chow regular diet and †P < 0.05 vs. vehicle-treated mice on a HFD).

Mentions: Interestingly, unlike chow regular diet–fed mice, the mean body weight and adiposity of the ACEA-treated mice were higher compared with those of the vehicle-treated mice on the HFD (Fig. 7A and B). Cumulative food intake was comparable between the two groups (Fig. 7C), although ACEA-treated mice showed a greater feed efficiency than their vehicle-treated controls (Fig. 7D). These results suggest that a CB1 receptor stimulation may impair the oxidative metabolism in WAT, muscle, and liver and lead to further increase of body weight and adiposity in obese animals on a HFD.


Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways.

Tedesco L, Valerio A, Dossena M, Cardile A, Ragni M, Pagano C, Pagotto U, Carruba MO, Vettor R, Nisoli E - Diabetes (2010)

CB1 receptor stimulation increases body weight in obese mice. A: Body weight of ACEA- or vehicle-treated mice on a HFD compared with vehicle-treated mice on a chow regular diet (n = 10 animals per group; *P < 0.05 vs. vehicle-treated mice on a HFD). ○, chow plus vehicle; ●, chow plus ACEA; □, HFD plus vehicle; ■, HFD plus ACEA. B–D: Adiposity (expressed as percentage of weight of visceral and subcutaneous fat when value of vehicle (Veh)-treated mice on chow regular diet is 100), cumulative food intake, and feed efficiency (n = 8 animals per group; *P < 0.05 **P < 0.01 vs. vehicle-treated mice on a chow regular diet and †P < 0.05 vs. vehicle-treated mice on a HFD).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2963541&req=5

Figure 7: CB1 receptor stimulation increases body weight in obese mice. A: Body weight of ACEA- or vehicle-treated mice on a HFD compared with vehicle-treated mice on a chow regular diet (n = 10 animals per group; *P < 0.05 vs. vehicle-treated mice on a HFD). ○, chow plus vehicle; ●, chow plus ACEA; □, HFD plus vehicle; ■, HFD plus ACEA. B–D: Adiposity (expressed as percentage of weight of visceral and subcutaneous fat when value of vehicle (Veh)-treated mice on chow regular diet is 100), cumulative food intake, and feed efficiency (n = 8 animals per group; *P < 0.05 **P < 0.01 vs. vehicle-treated mice on a chow regular diet and †P < 0.05 vs. vehicle-treated mice on a HFD).
Mentions: Interestingly, unlike chow regular diet–fed mice, the mean body weight and adiposity of the ACEA-treated mice were higher compared with those of the vehicle-treated mice on the HFD (Fig. 7A and B). Cumulative food intake was comparable between the two groups (Fig. 7C), although ACEA-treated mice showed a greater feed efficiency than their vehicle-treated controls (Fig. 7D). These results suggest that a CB1 receptor stimulation may impair the oxidative metabolism in WAT, muscle, and liver and lead to further increase of body weight and adiposity in obese animals on a HFD.

Bottom Line: Cannabinoid type 1 (CB1) receptor is involved in whole-body and cellular energy metabolism.ACEA decreased mitochondrial biogenesis and eNOS expression, activated p38 MAPK, and reduced AMPK phosphorylation in white adipocytes.The ACEA effects on mitochondria were antagonized by nitric oxide donors and by p38 MAPK silencing.

View Article: PubMed Central - PubMed

Affiliation: Integrated Laboratories Network, Center for Study and Research on Obesity, and Department of Pharmacology, Chemotherapy and Medical Toxicology, School of Medicine, University of Milan, Milan, Italy.

ABSTRACT

Objective: Cannabinoid type 1 (CB1) receptor is involved in whole-body and cellular energy metabolism. We asked whether CB1 receptor stimulation was able to decrease mitochondrial biogenesis in different metabolically active tissues of obese high-fat diet (HFD)-fed mice.

Research design and methods: The effects of selective CB1 agonist arachidonyl-2-chloroethanolamide (ACEA) and endocannabinoids anandamide and 2-arachidonoylglycerol on endothelial nitric oxide synthase (eNOS) expression were examined, as were mitochondrial DNA amount and mitochondrial biogenesis parameters in cultured mouse and human white adipocytes. These parameters were also investigated in white adipose tissue (WAT), muscle, and liver of mice chronically treated with ACEA. Moreover, p38 mitogen-activated protein kinase (MAPK) phosphorylation was investigated in WAT and isolated mature adipocytes from eNOS(-/-) and wild-type mice. eNOS, p38 MAPK, adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial biogenesis were investigated in WAT, muscle, and liver of HFD mice chronically treated with ACEA.

Results: ACEA decreased mitochondrial biogenesis and eNOS expression, activated p38 MAPK, and reduced AMPK phosphorylation in white adipocytes. The ACEA effects on mitochondria were antagonized by nitric oxide donors and by p38 MAPK silencing. White adipocytes from eNOS(-/-) mice displayed higher p38 MAPK phosphorylation than wild-type animals under basal conditions, and ACEA was ineffective in cells lacking eNOS. Moreover, mitochondrial biogenesis was downregulated, while p38 MAPK phosphorylation was increased and AMPK phosphorylation was decreased in WAT, muscle, and liver of ACEA-treated mice on a HFD.

Conclusions: CB1 receptor stimulation decreases mitochondrial biogenesis in white adipocytes, through eNOS downregulation and p38 MAPK activation, and impairs mitochondrial function in metabolically active tissues of dietary obese mice.

Show MeSH
Related in: MedlinePlus