Abstract
Cardiovascular disease is a common cause of morbidity and mortality in obese people with type 2 diabetes, which is often associated with increased levels of leptin. While many studies hint at the existence of important roles for both hyperleptinemia and leptin resistance in obesity and diabetes-associated cardiovascular disease, others support that leptin has cardioprotective effects. Leptin action comprises direct effects on cardiac tissue and indirect effects mediated via the sympathetic nervous system. Since the molecular underpinnings of leptin-regulated pathways in cardiac tissue in normoleptinemic animals remain less well defined, we addressed the effects of central leptin infusion on cardiac function and remodeling analyzing FOXO1/3 and mTORC1 pathways, paying special attention to PPARβ/δ as a key leptin signal regulator. We found that central leptin regulated dynamically the network between PPARβ/δ, FOXOs, and mTORC1 in cardiac tissue, through antioxidant, thermogenic and autophagy programs. Intracerebroventricular (ICV) leptin infusion (0.2µg/day) for 7 days in male 3-months-old Wistar rats induced protection from hypertrophy without increasing TBARS and protein carbonylation nor ROS/RSN cardiac levels. These effects were further supported by both increased of Sod2 and Ucp1 expression and reduced Tnf-α. Atrophy-related ubiquitin ligase Atrogin-1, accompanied by Beclin-1 and LC3II, gene products of the autophagic pathway response, were all upregulated by central leptin. In addition, mTORC1 activity and OXPHOS protein levels were decreased without affecting cellular function. Moreover, the content of carbonylated proteins did not increase upon the central leptin treatment, suggesting a key role of leptin in preventing cardiac oxidative stress. Finally, the pharmacological inhibition of PPARβ/δ, via in vivo administration of the selective antagonist GSK0660, blunted the induction of FOXO1/3 and Atrogin-1 in the heart mediated by icv leptin infusion. Together these data support that PPARβ/δ may act as a mediator of central leptin effects on cardiac cellular reprogramming through the activation of FOXO1/3 and the inactivation of mTORC1 pathways, and the upregulation of Atrogin-1 and the genes involved in energy uncoupling.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.