Hypothalamic dysfunction of the thrombospondin receptor α2δ-1 underlies the overeating and obesity triggered by brain-derived neurotrophic factor deficiency.

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.

Diminished diet-induced hyperglycemia and dyslipidemia and enhanced expression of PPARalpha and FGF21 in mice with hepatic ablation of brain-derived neurotropic factor.

Brain-derived neurotropic factor (BDNF) mediates many aspects of neuronal function, and plays a chief role in the central regulation of energy balance. In the periphery, it is expressed in organs involved in energy, lipid, and glucose homeostasis, including the liver, but its role there remains unclear. Here, we describe studies examining the effect of selectively depleting hepatic BDNF. Liver-specific mutant mice exhibited normal food intake and body weights when fed standard chow or high-fat diets (HFDs). However, whereas HFD intake induced mild hyperglycemia and hyperinsulinemia in wild-types (WTs), liver-specific BDNF mutants were protected from these effects. Serum levels of cholesterol and triglycerides were also elevated in HFD-fed WTs, but they were normal or slightly increased in BDNF mutants. Furthermore, whereas WTs fed HFD exhibited elevated levels of circulating alanine aminotransferase and aspartate aminotransferase, BDNF mutant males fed a similar diet had a normal content of both enzymes. Molecular analysis indicated that the livers of BDNF mutants fed HFD contained elevated levels of peroxisome proliferator-activated receptor alpha (Pparalpha or Ppara as listed in the MGI Database) and fibroblast growth factor 21 (Fgf21) transcripts compared with WTs. This is a notable finding as this pathway has anti-diabetic and lipid clearance effects. Accordingly, genes involved in lipid and glucose handling and targets of PPARalpha and FGF21 were upregulated in the BDNF mutant livers. The collective data indicate that hepatic BDNF might facilitate the emergence of insulin resistance, dyslipidemia, and liver disease following HFD challenge by suppressing PPARalpha and FGF21.

Severe deficits in 5-HT2A -mediated neurotransmission in BDNF conditional mutant mice.

BDNF is thought to provide critical trophic support for serotonin neurons. In order to determine postnatal effects of BDNF on the serotonin system, we examined a line of conditional mutant mice that have normal brain content of BDNF during prenatal development but later depletion of this neurotrophin in the postnatal period. These mice show a behavioral phenotype that suggests serotonin dysregulation. However, as shown here, the presynaptic serotonin system in the adult conditional mutant mice appeared surprisingly normal from histological, biochemical, and electrophysiological perspectives. By contrast, a dramatic and unexpected postsynaptic 5-HT2A deficit in the mutant mice was found. Electrophysiologically, serotonin neurons appeared near normal except, most notably, for an almost complete absence of expected 5-HT2A -mediated glutamate and GABA postsynaptic potentials normally displayed by these neurons. Further analysis showed that BDNF mutants had much reduced 5-HT2A receptor protein in dorsal raphe nucleus and a similar deficit in prefrontal cortex, a region that normally shows a high level of 5-HT2A receptor expression. Recordings in prefrontal slice showed a marked deficit in 5-HT2A -mediated excitatory postsynaptic currents, similar to that seen in the dorsal raphe. These findings suggest that postnatal levels of BDNF play a relatively limited role in maintaining presynaptic aspects of the serotonin system and a much greater role in maintaining postsynaptic 5-HT2A and possibly other receptors than previously suspected.

Reelin is expressed in the accessory olfactory system, but is not a guidance cue for vomeronasal axons.

Reelin is an extracellular matrix protein that regulates neuronal migration in the developing cerebral cortex, and axon outgrowth in the hippocampus. In the developing vomeronasal system, Reelin mRNA is expressed in perineural cells near the vomeronasal nerve, as well as in the vomeronasal organ, olfactory epithelium and olfactory and accessory olfactory bulbs, suggesting that it might regulate axon guidance or fasiculation. We tested that hypothesis by crossing reeler mice with VN12-IRES-tau-lacZ mice to investigate the role of reelin. The vomeronasal nerves are indistinguishable in normal and reeler mutant mice, strongly suggesting that Reelin does not provide a guidance cue for vomeronasal axons.