Participation of adrenergic modulation in the effects of PDE4 inhibition on fatty liver in obese mice

• Grant number: 23/14038-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Effective date (Start): March 20, 2024
• Effective date (End): March 19, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Francisco José Albuquerque de Paula
• Grantee: Hellen Veida Paraguassu da Silva
• Supervisor: Ana Isabel Dias Neto Domingos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: University of Oxford, England
• Associated to the scholarship: 22/09687-8 - The effect of peripheral and central inhibition of phosphodiesterase 4 on diet-induced inflammation, BP.DD

Abstract

Non-alcoholic fatty liver disease is characterized by the pathological increase of lipid droplets and its decreased utilization in hepatocytes. In addition, this condition is associated with increased sympathetic nervous system imbalance, which is reversed by anti-inflammatory approaches. The inhibition of Phosphodiesterase 4 (PDE4) can strongly inhibit the release of TNF-alpha and reduce inflammation induced by LPS challenge. Additionally, it was shown that the PDE4 knockout mouse is resistant to diet-induced obesity. In our study, PDE4 inhibition reverses the increase in triglycerides in the liver and increased the noradrenaline content in obese animals. The aim of this study is to assess the effect of rolipram, a phosphodiesterase 4 inhibitor, in the sympathetic nervous system bundles in the liver of obese animals. To verify whether PDE4 inhibition changes the innervation density in the liver in obese animals, clearing of the tissue will be performed to label tyrosine hydroxylase fibers. In addition, obese animals treated with rolipram will undergo sympathetic denervation to assess whether the effects of PDE4 inhibition are dependent on sympathetic activity.