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 ␣2␦-1, a calcium channel subunit and thrombospondin receptor, in triggering overeating in mice with central BDNF depletion. We show reduced ␣2␦-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 ␣2␦-1 by gabapentin infusion into wild-type VMH significantly increases feeding and body weight gain. Importantly, viral-mediated ␣2␦-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 ␣2␦-1 on feeding and implicate ␣2␦-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 ␣2␦-1 in appetite control and suggest a mechanism underlying weight gain in humans treated with gabapentinoid drugs.

Alpha2delta-1 in SF1 + Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

“…This observation was surprising considering our previous finding that rescuing an α2δ-1 deficit broadly in the VMH of adult mice with central BDNF depletion mitigated their hyperphagic behavior and obesity (Cordeira et al, 2014). There are several potential explanations for this discrepancy.…”

“…Our previous investigations suggested a role of alpha2delta-1 (α2δ-1) in energy and glucose balance control acting downstream of brain-derived neurotrophic factor (BDNF) in the VMH (Cordeira et al, 2014). BDNF signals through the tyrosine kinase B (TrkB) receptor to support neuronal survival, differentiation, and synaptic plasticity (Reichardt, 2006).…”

Astrocytic Process Plasticity and IKKβ/NF-κB in Central Control of Blood Glucose, Blood Pressure, and Body Weight

“…While future investigation on these neurons is needed, we directed a research effort in this work to BDNF-expressing neurons, because previous reports have pointed out that administration of GABA receptor antagonist can increase BDNF in several brain regions (Enna et al, 2006; Heese et al, 2000), and besides, BDNF is expressed in the VMH and PVN of hypothalamus and masterly regulates feeding behavior and energy homeostasis (An et al, 2015; Cordeira et al, 2014), while our results in Figure 5 revealed that astrocytic IKKβ/NF-κB activation remarkably rendered many neurons in these two subregions to be more responsible to GABA. We questioned if BDNF neurons in these subregions might be partially responsible for feeding and body weight in the same line as the effect of GABA manipulation.…”

Common Medications Which Lead to Unintended Alterations in Weight Gain or Organ Lipotoxicity

“…Boulac reported a dose-dependent weight gain as well, over 6 months of treatment in large open-label study involving 610 patients [130]. Weight gain associated with gabapentin is related to overeating and increased appetite, possibly due to central mechanisms on hypothalamic pathways [131]. Even though there are no reports on the risk of gabapentin and fatty liver or visceral obesity, it is relevant that gabapentin is commonly prescribed for peripheral neuropathy occurring as a complication of diabetes.…”