Obesity afflicts one in three Americans and is a leading cause of death and disability worldwide. Current therapies do not address obesity as fundamentally deregulated energy balance and have largely failed to curtail the ongoing epidemic. Better understanding of hypothalamic control over energy balance should lead to improved therapy. While extensive work has shown that hypothalamic glucose-responsive neurons can stimulate or suppress feeding, less is known about specialized hypothalamic glial cells called tanycytes that modulate the energy balance circuit. Tanycytes line the ventral third ventricle wall and are uniquely positioned between the hypothalamus and cerebrospinal fluid. They project long processes into the hypothalamus that form extensive contacts with the diet-responsive neurons, modulate the activity of orexigenic neurons, and are neurogenic progenitors for new neurons added to this circuit postnatally. Experimentally enhancing or ablating tanycyte-derived hypothalamic neurogenesis in rodents affects weight gain. However, the precise identity of neurogenic tanycytes is unclear and endogenous signaling mechanisms that regulate tanycyte germinal activity are unknown. Using an imaging technique developed for en-face analysis of cells lining the cerebral ventricles, preliminary studies in mice and humans revealed two segregated subsets of tanycytes-bi-ciliated tanycytes with two long cilia and uni-ciliated tanycytes with a single short primary cilium. Intriguingly, glucose-sensing molecules expressed in pancreatic beta cells were found localized to tanycyte primary cilia, suggesting a possible feedback mechanism used by these cells to detect energy balance. Preliminary experiments showed that ablating tanycyte cilia resulted in a diabetic-like phenotype. Tanycyte subsets also displayed distinct molecular marker expression that permitted construction of two Cre-expressing adenoviruses to specifically target and lineage-trace the two populations.
In Aim 1, this study will employ stereotactic 3rd ventricular injections of the Cre adenoviruses into Cre reporter mice to determine the identity of neurogenic tanycytes.
In Aim 2, the same injections will be used to ablate cilia in conditional knockout mice with floxed alleles of Kif3a, required fo ciliogenesis. These mice will then be subject to a battery of metabolic tests including measurements of food intake and energy expenditure with or without additional metabolic challenges including diet-induced obesity and glucoprivic states. The proposed work will provide deeper understanding of tanycyte subtypes, tanycyte-derived hypothalamic neurogenesis, and the function of tanycyte cilia in glucose-sensing and energy balance. From a therapeutic perspective, these results may foster future pharmacological experiments targeting tanycyte cilia with intraventricular therapies to modulate states of energy imbalance.
Improving therapies for obesity requires a better understanding of how the brain controls energy balance, or the equilibrium between energy intake and energy expenditure. This research will explore the function of a highly specialized yet understudied cell in the brain with important implications for controlling energy balance. Results from this work may reveal therapeutic strategies manipulating these cells to modulate energy balance.
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