The novel role of alpha2delta-1 in hypothalamic control of energy and glucose homeostasis.
Understanding how the brain regulates energy and glucose homeostasis, in coordination
with peripheral tissues, is vital for developing effective treatments for obesity and
diabetes. Brain-derived neurotrophic factor (BDNF), a protein that supports neuronal
survival and synaptic plasticity, is an important player in this neural circuitry.
Genetic polymorphisms that impede BDNF function ... read morepose risk factors for obesity in humans.
Similarly, reduced BDNF signaling in rodents induces overeating, excessive weight gain,
and metabolic dysfunction. Neurons in the ventromedial hypothalamus (VMH) facilitate
energy and glucose homeostasis, in part through modulation of the sympathetic nervous
system, and are a critical substrate of BDNF action. In this dissertation, we focus on
elucidating the molecular and cellular mechanisms underlying BDNF action in the VMH. Our
investigations identified alpha2delta-1 (α2δ-1), a calcium channel subunit
and synaptogenic thrombospondin receptor, as a novel effector acting downstream of BDNF
in the VMH. We show that obese mice lacking BDNF in the brain have reduced cell surface
α2δ-1 expression in VMH cells. Furthermore, pharmacological inhibition of
α2δ-1 in the VMH of wild type mice elicited feeding and weight gain.
Notably, rescuing the α2δ-1 deficit in VMH cells of BDNF mutants, using
viral-mediated gene delivery, mitigated their overeating and body weight gain and
normalized defects in glucose homeostasis. These findings identify a previously
unrecognized role for α2δ-1 in feeding and glycemic control. Next, we
investigated whether α2δ-1 is a requisite factor in the VMH for energy and
glucose homeostasis. Considering their established role in these physiological
processes, we hypothesized that steroidogenic factor-1 (SF1) neurons in this region are
a critical substrate for α2δ-1. To test this, we generated mice with
selective deletion of α2δ-1 in this cell population. α2δ-1
mutant mice exhibit glucose intolerance and robust alterations in lipid storage, despite
normal energy balance. Additionally, α2δ-1 mutants have reduced
norepinephrine content in serum and white adipose tissue relative to controls,
indicative of blunted sympathetic output. Electrophysiological recordings revealed that
reduced activity of SF1 neurons, which send dense projections to sympathetic brain
centers, underlies the metabolic alterations observed in α2δ-1 mutants.
These results demonstrate a critical role of α2δ-1 in VMH SF1 neurons and
support the hypothesis that α2δ-1 exerts robust body weight-independent
effects on glucose control and lipid homeostasis. In summary, the work presented in this
dissertation provides novel mechanistic insights underlying BDNF and α2δ-1
action in energy balance and glycemic control in the hypothalamus, offering innovative
avenues for potential obesity and diabetic
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Maribel Rios.
Committee: Andrew Greenberg, Edward Saltzman, and Michele Jacob.
Keywords: Neurosciences, and Nutrition.read less