ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
Hypothalamic dysfunction of the thrombospondin receptor α2δ-1 underlies the overeating and obesity triggered by brain-derived neurotrophic factor deficiency.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 29 citations in OpenAlex.
- The Role of BDNF and TrkB in the Central Control of Energy and Glucose Balance: An Update.Biomolecules · 2024Review
- Pharmacotherapy causing weight gain and metabolic alteration in those with obesity and obesity-related conditions: A review.Annals of the New York Academy of Sciences · 2024Review
- Regulation of Satiety byBiomolecules · 2023Article
- Role of High Voltage-Gated CaCells · 2021Review
- Essential and sex-specific effects of mGluR5 in ventromedial hypothalamus regulating estrogen signaling and glucose balance.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Emerging roles for α2δ subunits in calcium channel function and synaptic connectivity.Current opinion in neurobiology · 2020Review
- Sex-specific Effects of α2δ-1 in the Ventromedial Hypothalamus of Female Mice Controlling Glucose and Lipid Balance.Endocrinology · 2020Article
- Neuronal αPflugers Archiv : European journal of physiology · 2020Review
- Auxiliary α2δ1 and α2δ3 Subunits of Calcium Channels Drive Excitatory and Inhibitory Neuronal Network Development.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- α-Neurexins Together with α2δ-1 Auxiliary Subunits Regulate CaThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- High Levels of SIRT1 Expression as a Protective Mechanism Against Disease-Related Conditions.Frontiers in endocrinology · 2018Review
- Alpha2delta-1 in SF1Cell reports · 2017Article
- Astrocytic Process Plasticity and IKKβ/NF-κB in Central Control of Blood Glucose, Blood Pressure, and Body Weight.Cell metabolism · 2017Article
- Neurotrophic factor control of satiety and body weight.Nature reviews. Neuroscience · 2016Review
- Ventromedial hypothalamic expression of Bdnf is required to establish normal patterns of afferent GABAergic connectivity and responses to hypoglycemia.Molecular metabolism · 2016Article
- Common Medications Which Lead to Unintended Alterations in Weight Gain or Organ Lipotoxicity.Current gastroenterology reports · 2016Review
- Nerve injury-induced calcium channel alpha-2-delta-1 protein dysregulation leads to increased pre-synaptic excitatory input into deep dorsal horn neurons and neuropathic allodynia.European journal of pain (London, England) · 2015Article
- The role of brain-derived neurotrophic factor in comorbid depression: possible linkage with steroid hormones, cytokines, and nutrition.Frontiers in psychiatry · 2014Review
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8 authors at 2 institutions in 1 country.
Funding
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.
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