The Role of Melanin Concentrating Hormone in Central Chemoreception: a Knock‐down Study by siRNAs in the Lateral Hypothalamus

Abstract

Melanin concentrating hormone (MCH), a neuropeptide in the lateral hypothalamus (LHA), has been implicated in regulating food intake, energy balance, and cardiovascular control. Hypothalamic MCH neurons are known to have multisynaptic connections with diaphragm motoneurons, and to send projections to many central chemoreceptor sites although there are no physiological observations on whether MCH is involved in respiratory control. To test the hypothesis that MCH play a role in central chemoreception, we knocked down the expression of MCH by injecting a pool of siRNAs that target the MCH precursor gene (pMCH) into the LHA in rats and then measured changes in breathing, body weight, blood glucose, blood pressure, and heart rate. RT‐PCR data demonstrated a 60% reduction of pMCH mRNA expression in rats injected with pMCH siRNAs compared to rats received control scrambled siRNAs (n=5, P<0.001). Compared to pretreatment baseline, knock‐down of pMCH resulted in 1) a 20–30% increase in the VE/VO2 in response to 5 & 7% CO2 72hr after pMCH siRNA injection; 2) a 10% decrease in body weight and 30% reduction in blood glucose level; 3) an increase in both heart rate and blood pressure (n=4). There are no significant findings observed in the rats that received scrambled siRNAs. This study uses a siRNA approach to demonstrate the involvement of a hypothalamic peptide, MCH, in central chemoreception (HL 28066).