ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice
Abstract α/β-hydrolase domain 6 (ABHD6) is a lipase linked to physiological functions affecting energy metabolism. Brain ABHD6 degrades 2-arachidonoylglycerol and thereby modifies cannabinoid receptor signalling. However, its functional role within mesoaccumbens circuitry critical for motivated beha...
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54819-5 |
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| author | David Lau Stephanie Tobin Horia Pribiag Shingo Nakajima Alexandre Fisette Dominique Matthys Anna Kristyna Franco Flores Marie-Line Peyot S. R. Murthy Madiraju Marc Prentki David Stellwagen Thierry Alquier Stephanie Fulton |
| author_facet | David Lau Stephanie Tobin Horia Pribiag Shingo Nakajima Alexandre Fisette Dominique Matthys Anna Kristyna Franco Flores Marie-Line Peyot S. R. Murthy Madiraju Marc Prentki David Stellwagen Thierry Alquier Stephanie Fulton |
| author_sort | David Lau |
| collection | DOAJ |
| description | Abstract α/β-hydrolase domain 6 (ABHD6) is a lipase linked to physiological functions affecting energy metabolism. Brain ABHD6 degrades 2-arachidonoylglycerol and thereby modifies cannabinoid receptor signalling. However, its functional role within mesoaccumbens circuitry critical for motivated behaviour and considerably modulated by endocannabinoids was unknown. Using three viral approaches, we show that control of the nucleus accumbens by neuronal ABHD6 is a key determinant of body weight and reward-directed behaviour in male mice. Contrary to expected outcomes associated with increasing endocannabinoid tone, loss of ABHD6 in nucleus accumbens, but not ventral tegmental area, neurons completely prevents diet-induced obesity, reduces food- and drug-seeking and enhances physical activity without affecting anxiodepressive behaviour. These effects are explained by attenuated inhibitory synaptic transmission onto medium spiny neurons. ABHD6 deletion in nucleus accumbens neurons and dopamine ventral tegmental area neurons produces contrasting effects on effortful responding for food. Intraventricular infusions of an ABHD6 inhibitor also restrain appetite and promote weight loss. Together, these results reveal functional specificity of pre- and post-synaptic mesoaccumbens neuronal ABHD6 to differentially control energy balance and propose ABHD6 inhibition as a potential anti-obesity tool. |
| format | Article |
| id | doaj-art-c1f42cea3f784e97af2dfbcaa7e9053f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c1f42cea3f784e97af2dfbcaa7e9053f2024-12-22T12:36:00ZengNature PortfolioNature Communications2041-17232024-12-0115112210.1038/s41467-024-54819-5ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male miceDavid Lau0Stephanie Tobin1Horia Pribiag2Shingo Nakajima3Alexandre Fisette4Dominique Matthys5Anna Kristyna Franco Flores6Marie-Line Peyot7S. R. Murthy Madiraju8Marc Prentki9David Stellwagen10Thierry Alquier11Stephanie Fulton12Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, McGill University Health CenterCentre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, McGill University Health CenterCentre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)Abstract α/β-hydrolase domain 6 (ABHD6) is a lipase linked to physiological functions affecting energy metabolism. Brain ABHD6 degrades 2-arachidonoylglycerol and thereby modifies cannabinoid receptor signalling. However, its functional role within mesoaccumbens circuitry critical for motivated behaviour and considerably modulated by endocannabinoids was unknown. Using three viral approaches, we show that control of the nucleus accumbens by neuronal ABHD6 is a key determinant of body weight and reward-directed behaviour in male mice. Contrary to expected outcomes associated with increasing endocannabinoid tone, loss of ABHD6 in nucleus accumbens, but not ventral tegmental area, neurons completely prevents diet-induced obesity, reduces food- and drug-seeking and enhances physical activity without affecting anxiodepressive behaviour. These effects are explained by attenuated inhibitory synaptic transmission onto medium spiny neurons. ABHD6 deletion in nucleus accumbens neurons and dopamine ventral tegmental area neurons produces contrasting effects on effortful responding for food. Intraventricular infusions of an ABHD6 inhibitor also restrain appetite and promote weight loss. Together, these results reveal functional specificity of pre- and post-synaptic mesoaccumbens neuronal ABHD6 to differentially control energy balance and propose ABHD6 inhibition as a potential anti-obesity tool.https://doi.org/10.1038/s41467-024-54819-5 |
| spellingShingle | David Lau Stephanie Tobin Horia Pribiag Shingo Nakajima Alexandre Fisette Dominique Matthys Anna Kristyna Franco Flores Marie-Line Peyot S. R. Murthy Madiraju Marc Prentki David Stellwagen Thierry Alquier Stephanie Fulton ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice Nature Communications |
| title | ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice |
| title_full | ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice |
| title_fullStr | ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice |
| title_full_unstemmed | ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice |
| title_short | ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice |
| title_sort | abhd6 loss of function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet induced obesity in male mice |
| url | https://doi.org/10.1038/s41467-024-54819-5 |
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