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CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin.

Cardinal P, André C, Quarta C, Bellocchio L, Clark S, Elie M, Leste-Lasserre T, Maitre M, Gonzales D, Cannich A, Pagotto U, Marsicano G, Cota D - Mol Metab (2014)

Bottom Line: Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown.Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin.Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.

View Article: PubMed Central - PubMed

Affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.

ABSTRACT
Metabolic flexibility allows rapid adaptation to dietary change, however, little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.

No MeSH data available.


Related in: MedlinePlus

CB1 receptors in SF1-positive neurons regulate SNS activity, lipid oxidation and WAT lipolysis. (A) In-cage locomotor activity, (B) VO2 consumption and (C) respiratory quotient (RQ) during the dark and light phases determined in 15-weeks old chow-fed male SF1-CB1-WT and SF1-CB1-KO mice at 22 °C ambient temperature (n = 5–6). (d) RQ during the dark and light phases assessed in 15-weeks old chow-fed male SF1-CB1-WT and SF1-CB1-KO mice at 15 °C ambient temperature (n = 6). (E) Representative sagittal (main figure) and transverse (smaller insets) PET images showing 18F-FDG accumulation expressed as standard absorption values (SUV) in the BAT of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice. Red lines indicate the image sections reported in the transverse views; images were from the study with the β3R agonist CL 316,243. SUV quantification after (F) 4 h exposure to 6 °C or (G) treatment with β3R agonist of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice expressed as % of basal non-stimulated condition in the same animals (n = 6). (H) Representative western blot scans and (I) quantification of β3R, phospho-HSL ser 660, phospho-HSL ser 563, HSL and ATGL protein expression in the WAT of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice maintained at 22 °C (n = 6–11; β-actin: loading control). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; #P < 0.05 and ##P < 0.01 genotype effect.
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fig3: CB1 receptors in SF1-positive neurons regulate SNS activity, lipid oxidation and WAT lipolysis. (A) In-cage locomotor activity, (B) VO2 consumption and (C) respiratory quotient (RQ) during the dark and light phases determined in 15-weeks old chow-fed male SF1-CB1-WT and SF1-CB1-KO mice at 22 °C ambient temperature (n = 5–6). (d) RQ during the dark and light phases assessed in 15-weeks old chow-fed male SF1-CB1-WT and SF1-CB1-KO mice at 15 °C ambient temperature (n = 6). (E) Representative sagittal (main figure) and transverse (smaller insets) PET images showing 18F-FDG accumulation expressed as standard absorption values (SUV) in the BAT of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice. Red lines indicate the image sections reported in the transverse views; images were from the study with the β3R agonist CL 316,243. SUV quantification after (F) 4 h exposure to 6 °C or (G) treatment with β3R agonist of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice expressed as % of basal non-stimulated condition in the same animals (n = 6). (H) Representative western blot scans and (I) quantification of β3R, phospho-HSL ser 660, phospho-HSL ser 563, HSL and ATGL protein expression in the WAT of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice maintained at 22 °C (n = 6–11; β-actin: loading control). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; #P < 0.05 and ##P < 0.01 genotype effect.

Mentions: Since there were no obvious alterations in food intake that could explain the decreased adiposity of SF1-CB1-KO mice, we assessed whether this phenomenon could be due to changes in locomotor activity or in the use of energy substrates. Chow-fed SF1-CB1-KO and WT littermates had similar activity (Figure 3A) and VO2 consumption (Figure 3B) at 22 °C ambient temperature, but SF1-CB1-KO mice showed decreased respiratory quotient (RQ, Figure 3C), suggesting a higher consumption rate of lipids as energy source.


CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin.

Cardinal P, André C, Quarta C, Bellocchio L, Clark S, Elie M, Leste-Lasserre T, Maitre M, Gonzales D, Cannich A, Pagotto U, Marsicano G, Cota D - Mol Metab (2014)

CB1 receptors in SF1-positive neurons regulate SNS activity, lipid oxidation and WAT lipolysis. (A) In-cage locomotor activity, (B) VO2 consumption and (C) respiratory quotient (RQ) during the dark and light phases determined in 15-weeks old chow-fed male SF1-CB1-WT and SF1-CB1-KO mice at 22 °C ambient temperature (n = 5–6). (d) RQ during the dark and light phases assessed in 15-weeks old chow-fed male SF1-CB1-WT and SF1-CB1-KO mice at 15 °C ambient temperature (n = 6). (E) Representative sagittal (main figure) and transverse (smaller insets) PET images showing 18F-FDG accumulation expressed as standard absorption values (SUV) in the BAT of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice. Red lines indicate the image sections reported in the transverse views; images were from the study with the β3R agonist CL 316,243. SUV quantification after (F) 4 h exposure to 6 °C or (G) treatment with β3R agonist of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice expressed as % of basal non-stimulated condition in the same animals (n = 6). (H) Representative western blot scans and (I) quantification of β3R, phospho-HSL ser 660, phospho-HSL ser 563, HSL and ATGL protein expression in the WAT of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice maintained at 22 °C (n = 6–11; β-actin: loading control). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; #P < 0.05 and ##P < 0.01 genotype effect.
© Copyright Policy - CC BY-NC-SA
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4209357&req=5

fig3: CB1 receptors in SF1-positive neurons regulate SNS activity, lipid oxidation and WAT lipolysis. (A) In-cage locomotor activity, (B) VO2 consumption and (C) respiratory quotient (RQ) during the dark and light phases determined in 15-weeks old chow-fed male SF1-CB1-WT and SF1-CB1-KO mice at 22 °C ambient temperature (n = 5–6). (d) RQ during the dark and light phases assessed in 15-weeks old chow-fed male SF1-CB1-WT and SF1-CB1-KO mice at 15 °C ambient temperature (n = 6). (E) Representative sagittal (main figure) and transverse (smaller insets) PET images showing 18F-FDG accumulation expressed as standard absorption values (SUV) in the BAT of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice. Red lines indicate the image sections reported in the transverse views; images were from the study with the β3R agonist CL 316,243. SUV quantification after (F) 4 h exposure to 6 °C or (G) treatment with β3R agonist of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice expressed as % of basal non-stimulated condition in the same animals (n = 6). (H) Representative western blot scans and (I) quantification of β3R, phospho-HSL ser 660, phospho-HSL ser 563, HSL and ATGL protein expression in the WAT of chow-fed male SF1-CB1-WT and SF1-CB1-KO mice maintained at 22 °C (n = 6–11; β-actin: loading control). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; #P < 0.05 and ##P < 0.01 genotype effect.
Mentions: Since there were no obvious alterations in food intake that could explain the decreased adiposity of SF1-CB1-KO mice, we assessed whether this phenomenon could be due to changes in locomotor activity or in the use of energy substrates. Chow-fed SF1-CB1-KO and WT littermates had similar activity (Figure 3A) and VO2 consumption (Figure 3B) at 22 °C ambient temperature, but SF1-CB1-KO mice showed decreased respiratory quotient (RQ, Figure 3C), suggesting a higher consumption rate of lipids as energy source.

Bottom Line: Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown.Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin.Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.

View Article: PubMed Central - PubMed

Affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.

ABSTRACT
Metabolic flexibility allows rapid adaptation to dietary change, however, little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.

No MeSH data available.


Related in: MedlinePlus