title: Hypothalamic dysfunction of the thrombospondin receptor α2δ-1 underlies the overeating and obesity triggered by brain-derived neurotrophic factor deficiency.
abstract: Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are critical components of the neural circuitry controlling appetite and body weight. Diminished BDNF signaling in mice results in severe hyperphagia and obesity. In humans, BDNF haploinsufficiency and the functional Bdnf Val66Met polymorphism have been linked to elevated food intake and body weight. The mechanisms underlying this dysfunction are poorly defined. We demonstrate a chief role of α2δ-1, a calcium channel subunit and thrombospondin receptor, in triggering overeating in mice with central BDNF depletion. We show reduced α2δ-1 cell-surface expression in the BDNF mutant ventromedial hypothalamus (VMH), an energy balance-regulating center. This deficit contributes to the hyperphagia exhibited by BDNF mutant mice because selective inhibition of α2δ-1 by gabapentin infusion into wild-type VMH significantly increases feeding and body weight gain. Importantly, viral-mediated α2δ-1 rescue in BDNF mutant VMH significantly mitigates their hyperphagia, obesity, and liver steatosis and normalizes deficits in glucose homeostasis. Whole-cell recordings in BDNF mutant VMH neurons revealed normal calcium currents but reduced frequency of EPSCs. These results suggest calcium channel-independent effects of α2δ-1 on feeding and implicate α2δ-1-thrombospondin interactions known to facilitate excitatory synapse assembly. Our findings identify a central mechanism mediating the inhibitory effects of BDNF on feeding. They also demonstrate a novel and critical role for α2δ-1 in appetite control and suggest a mechanism underlying weight gain in humans treated with gabapentinoid drugs.
authors.affiliation: Department of Neuroscience and Graduate Program in Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111, Graduate Program in Biochemical and Molecular Nutrition, Gerald J. and Dorothy R. Friedman School of Nutrition and Science Policy, Tufts University, Boston, Massachusetts 02111, and Department of Neurology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Cordeira
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Felsted
authors.forename: Sarah
authors.initials: S
authors.lastname: Teillon
authors.forename: Shabrine
authors.initials: S
authors.lastname: Daftary
authors.forename: Micaella
authors.initials: M
authors.lastname: Panessiti
authors.forename: Jena
authors.initials: J
authors.lastname: Wirth
authors.forename: Miguel
authors.initials: M
authors.lastname: Sena-Esteves
authors.forename: Maribel
authors.initials: M
authors.lastname: Rios
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency*; D018955:CD36 Antigens / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D005247:Feeding Behavior / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C512066:CACNA2D1 protein, mouse; D018955:CD36 Antigens; D015220:Calcium Channels