Role of hypothalamic cholinergic receptor alpha7 (alpha7nAChR) in control of energy homeostasis and association with leptin signaling in mice

Abstract

Cholinergic signaling is mediated by activation of muscarinic and nicotinic receptors and has been described in the literature as a classical and important signaling in the regulation of inflammatory response. However, literature shows that nicotine, a pharmacological agonist of these receptors, promotes a reduction in body weight and food intake. Hence, recent studies have investigated the role of acetylcholine, the physiological agonist of these receptors, in controlling central energy homeostasis. Studies show that animals that do not express acetylcholine in brain regions that control energy homeostasis display excessive body weight gain and hyperphagia. This is a new research field and little is known about the receptors involved in this response and the association between their signaling and the hormones that control energy homeostasis. Leptin and insulin are the major hormones responsible for regulating central energy homeostasis. The hypothalamus is the regulatory center of energy homeostasis and evidences show that the ±7 nicotinic receptor (±7nAChR) is highly expressed in this region. Our aim is to evaluate the role of hypothalamic ±7nAChR in the control of energy homeostasis and its association with leptin signaling. Methods: The expression of neuropeptides involved in homeostasis regulation will be assessed in vitro after treatment with the agonist and the antagonist of the ±7nAChR receptor and with leptin. The presence of ±7nAChR receptor in energy homeostasis regulatory cells (POMC and NPY) will be evaluated by immunofluorescence of brain slices of male swiss mice. Some of the animals will undergo intracerebroventricular injection of ±7nAChR receptor agonist, antagonist and siRNA and will also be treated with leptin. Metabolic parameters will be measured by a indirect calorimetry and the expression of hypothalamic neuropeptides will be analyzed using Real-Time PCR. Our previous results have shown that ±7nAChR receptor modulates food intake by enhancing the expression of anorexigenic neuropeptides and suppressing the expression of orexigenic neuropeptides. We have also demonstrated the presence of ±7nAChR receptor in energy homeostasis regulatory cells by immunofluorescence of hypothalamic brain slices. Moreover, by evaluating the association between neuropeptide expression response and the activation of ±7nAChR and leptin stimulation, we found a modulation in the expression of these neuropeptides, suggesting a possible cross-talk between these signaling pathways. (AU)