Gliopeptidic regulation of the hypothalamic melanocortin system and energy balance by endozepines
Lieu : Centre Broca Nouvelle-Aquitaine
Associate Professor, Department of Medicine, Université de Montréal
Head, Cardiometabolic research theme at CRCHUM
Co-director, Montreal Diabetes Research Center
Director, CRCHUM Metabolic Phenotyping Core Facility
Thierry Alquier est en sabbatique à NutriNeuro en juillet-août 2019
The hypothalamus plays a key role in the regulation of appetite and body weight. This control relies on neuronal populations that sense circulating metabolic signals including lipids and activate neuroendocrine and behavioral responses to maintain body weight.
Long time though to be the “glue” that holds the brain together, glial cells are now recognized for their key roles in brain energetics, neuronal activity and plasticity. Astrocytes, the most abundant glial cells, are implicated in complex and fundamental behaviours such as breathing and sleeping, and have recently emerged as key players in energy homeostasis.
However, the mechanisms by which hypothalamic astrocytes affect energy balance neurocircuitry remain largely unknown. We identified Acyl-CoA Binding Protein (ACBP) as a protein strongly expressed in hypothalamic astrocytes where it regulates the intracellular metabolism of unsaturated fatty acids. ACBP is also secreted and cleaved to generate endozepines including the octadecaneuropeptide which modulate GABAA receptor signaling. We demonstrated that targeted ACBP loss-of-function in astrocytes promoted diet-induced hyperphagia and obesity in both male and female mice, an effect prevented by genetic rescue of ACBP in arcuate astrocytes. Interestingly, mice with astroglial ACBP deficiency were unresponsive to the anorectic effect of oleic acid. The ACBP-derived octadecaneuropeptide selectively activated anorectic pro-opiomelanocortin neurons in the arcuate nucleus via a GABAA-independent mechanism and supressed feeding while increasing carbohydrate utilization via the melanocortin system, and induced weight loss in obese mice. These findings uncovered ACBP as a hypothalamic gliopeptide playing a key role in energy balance and exerting strong anorectic effects via the central melanocortin system.
The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system.
Bouyakdan K, Martin H, Liénard F, Budry L, Taib B, Rodaros D, Chrétien C, Biron É, Husson Z, Cota D, Pénicaud L, Fulton S, Fioramonti X, Alquier T.
J Clin Invest. 2019;130:2417-2430.
Oleic Acid in the Ventral Tegmental Area Inhibits Feeding, Food Reward, and Dopamine Tone.
Hryhorczuk C, Sheng Z, Décarie-Spain L, Giguère N, Ducrot C, Trudeau LÉ, Routh VH, Alquier T, Fulton S.
Saturated high-fat feeding independent of obesity alters hypothalamus-pituitary-adrenal axis function but not anxiety-like behaviour.
Hryhorczuk C, Décarie-Spain L, Sharma S, Daneault C, Rosiers CD, Alquier T, Fulton S.
α/β-Hydrolase Domain 6 in the Ventromedial Hypothalamus Controls Energy Metabolism Flexibility.
Fisette A, Tobin S, Décarie-Spain L, Bouyakdan K, Peyot ML, Madiraju SRM, Prentki M, Fulton S, Alquier T.
Cell Rep. 2016;17(5):1217-1226.
DBI/ACBP loss-of-function does not affect anxiety-like behaviour but reduces anxiolytic responses to diazepam in mice.
Budry L, Bouyakdan K, Tobin S, Rodaros D, Marcher AB, Mandrup S, Fulton S, Alquier T.
Behav Brain Res. 2016;313:201-207.
A novel role for central ACBP/DBI as a regulator of long-chain fatty acid metabolism in astrocytes.
Bouyakdan K, Taïb B, Budry L, Zhao S, Rodaros D, Neess D, Mandrup S, Faergeman NJ, Alquier T.
J Neurochem. 2015;133(2):253-65.