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Nuclear Receptor Signaling Atlas
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PPARγ in vagal sensory neurons and the untoward effects of thiazolidinediones
Joel Elmquist
UT Southwestern
Thiazolidinediones (TZDs) are anti-diabetic agents that are potent activators of peroxisome proliferatoractivated receptor-γ (PPARγ). Despite their robust insulin-sensitizing effect, chronic use of TZDs can cause untoward side effects including excessive weight gain, fluid retention, edema, and heart failure. These issues have significantly limited the clinical use of this class of anti-diabetic drugs. Emerging evidence suggests that these untoward side effects may involve actions of PPARγ agonists on the nervous system. However, the mechanisms underlying putative neuron-specific PPARγ activation and side effects remains poorly understood. Insights into this relationship may provide opportunities to develop novel PPARγ agonists with fewer adverse effects.

The vagus nerve (including both the parasympathetic motor and sensory input) innervates the heart and is a critical modulator of cardiovascular function. Recently, we systematically profiled the expression patterns of all known murine nuclear receptors (NRs) in laser-captured vagal sensory neurons (VSNs). We found that several NRs, including PPARγ, were expressed at moderate to high levels in VSNs. Notably, these include neurons that innervate the carotid body and aortic arch and convey information regarding blood oxygen and arterial pressure to the brain for the regulation of the baroreceptor reflex. Furthermore, we found that PPARγ expression in VSNs is nutritionally regulated and regulates diet-induced thermogenesis by modulating parasympathetic (vagal) activities.

Activation of vagal afferents affects both sympathetic and parasympathetic output to key target organs. However, the role of NRs in vagal sensory neurons (including PPARγ activation) on cardiovascular function following chronic TZD treatment has not been studied. We hypothesize that chronic PPARγ activation in vagal neurons contributes to the adverse body weight and cardiovascular effects associated with TZD treatment. We will directly test this with the following Specific Aims:

Specific Aim 1. To determine whether PPARγ activation in vagal neurons contributes to excessive weight gain following chronic TZD treatment.

We have recently found that the loss of PPARγ in Phox2b neurons leads to a decrease in body weight due to due to an increase in diet-induced thermogenesis that involves an active reprograming of the body’s white adipocytes towards a thermogenic, brown adipocyte cell fate. We hypothesize that PPARγ activation in Phox2b neurons by chronic TZD treatment (rosiglitazone or pioglitazone) contributes to excessive weight gain, and that this increase in weight will be blunted in the mice that lack PPARγ in Phox2b neurons.

Specific Aim 2. To determine whether PPARγ activation in vagal neurons contributes to the adverse cardiovascular effects of Rosiglitazone.

We have found that the loss of PPARγ in Phox2b neurons alters vagal-mediated behaviors. Given the important role for the parasympathetic vagus nerve in the regulation of cardiovascular function, we hypothesize that chronic activation of PPARγ in VSNs will affect cardiac physiology. To this end, we will investigate parameters known to be clinically associated with heart failure in wildtype mice and in mice that lack PPARγ in Phox2b neurons following chronic TZD treatment.