| Brain-derived neurotrophic factor (BDNF) is a critical component of neural circuits that regulate energy homeostasis. BDNF and its receptor, TrkB, are expressed in a variety of key weight-regulating centers in the brain and disruptions of this signaling pathway have been implicated in obesity. In addition, BDNF is expressed in peripheral organs involved in energy and glucose homeostasis, including the liver, but its role there is poorly understood. The mechanisms mediating the central and peripheral actions of BDNF in relation to energy and glucose homeostasis remain to be elucidated.;The work presented in the first half of this dissertation investigates a central mechanism mediating the satiety effects of BDNF. It is known that BDNF synthesized in the ventromedial hypothalamus (VMH) acts as a satiety factor in the adult animal, however the molecular mechanisms mediating this effect are unclear. To address this, I conducted a genome-wide analysis of the VMH using two lines of BDNF mutant mice, one with a central depletion and one with adult-onset VMH/DMH depletion of BDNF. I identified cacna2d1 and its product, the voltage-gated calcium channel subunit, alpha 2delta-1, as a molecule acting downstream of BDNF in the VMH to mediate appetite control. Accordingly, alpha2delta-1 transcript levels in the VMH of wild type mice were modulated by energy status and inhibition of alpha2delta-1 activity there resulted in hyperphagia. These findings demonstrate a novel role for alpha2delta-1 in appetite control that likely facilitates the satiety effects of BDNF in the VMH.;In addition to examining the central effects of BDNF influencing energy balance, I investigated the role of hepatic BDNF in energy and glucose homeostasis. For this, I generated mice with selective depletion of this neurotrophin in the liver. These mice maintained normal energy homeostasis when fed normal chow or a high-fat diet (HFD). However, when fed a HFD, mutants exhibited improved glucose, insulin, and lipid profiles, relative to wild type mice fed the same diet. Furthermore, relative to wild types, the livers of BDNF mutants fed a HFD contained elevated levels of molecules with known anti-diabetic and lipid clearance effects, including PPARalpha and FGF21. These findings indicate a previously unrecognized role for BDNF in the liver, facilitating the deleterious effects of a HFD. In summary, this work demonstrates the contrasting role of BDNF in the brain versus the liver influencing energy and glucose homeostasis. |
