Effects of leptin on RTN chemoreceptor activity

• Grant number: 12/04813-3
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: July 12, 2012
• End date: October 11, 2012
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Eduardo Colombari
• Grantee: Mirian Bassi Solcia
• Supervisor: Daniel Kent Mulkey
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: University of Connecticut (UCONN), United States

Abstract

Leptin deficiency is a major factor for the development of obesity and respiratory disorders. Transgenic leptin-deficient mice (ob/ob) are obese and have attenuated ventilatory response to CO2 (hypercapnia). It is unclear whether the impaired ventilatory response caused by leptin deficiency (e.g. in ob/ob mice) results from a loss of excitatory leptin drive to respiratory chemoreceptors or from the morbid obesity that develops secondary to hyperphagia and reduced energy expenditure. Our previous evidence indicates that injections of leptin into the RTN of ob/ob mice increased VE-CO2 independently of obesity, thus suggesting that central leptin deficiency, rather than obesity per se, is the main cause of impaired ventilatory drive in these animals. These results also suggest that leptin effects respiratory drive at the level of the RVLM/RTN, possibly by activating RTN chemoreceptors. However the cellular and molecular mechanisms underlying the effects of leptin on breathing are yet to be determined. We hypothesize that leptin contributes to chemoreception by providing an excitatory drive to CO2/H+-sensitive RTN neurons. We propose that loss of excitatory leptin drive to chemosensitive RTN neurons during obesity-induced leptin deficiency will decrease chemoreceptor activity in vitro and blunt the whole animal ventilatory response to CO2. The purpose of our study is to characterize the effects of leptin on RTN neurons in wild-type and ob/ob mice. Thus, will be analyzed the acute effect of leptin on RTN chemosensitive neurons by the electrophysiology that is performed routinely in the laboratory of Dr. Mulkey (collaborator). It will be also assessed the participation of glial cells (astrocytes) on leptin acting ventilatory response. The expression of leptin receptors in neurons and astrocytes of RTN will be analyzed by immunohistochemistry. Alternatively, if leptin has no acute effect on RTN neuronal activity, there will be 3 days of leptin treatment in mice with guide cannula into the RTN. In this protocol will be measured the ventilatory response to CO2 by plethysmography (as preliminary data) followed by analysis of RTN neuronal activity by electrophysiology. (AU)