| First Author | Cordeira JW | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 2 | Pages | 554-65 |
| PubMed ID | 24403154 | Mgi Jnum | J:205578 |
| Mgi Id | MGI:5545841 | Doi | 10.1523/JNEUROSCI.1572-13.2014 |
| Citation | Cordeira JW, et al. (2014) Hypothalamic dysfunction of the thrombospondin receptor alpha2delta-1 underlies the overeating and obesity triggered by brain-derived neurotrophic factor deficiency. J Neurosci 34(2):554-65 |
| abstractText | 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 alpha2delta-1, a calcium channel subunit and thrombospondin receptor, in triggering overeating in mice with central BDNF depletion. We show reduced alpha2delta-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 alpha2delta-1 by gabapentin infusion into wild-type VMH significantly increases feeding and body weight gain. Importantly, viral-mediated alpha2delta-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 alpha2delta-1 on feeding and implicate alpha2delta-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 alpha2delta-1 in appetite control and suggest a mechanism underlying weight gain in humans treated with gabapentinoid drugs. |
