Leptin and leptin receptor signalling in diabetic cardiomyopathy
PhD student: Anna Strano
Supervisor at TUD: Kaomei Guan
Supervisor at KCL: Cynthia Andoniadou
Start date: 01.02.2019
The hypothalamus-pituitary (HP) axis regulates critical physiological processes such as metabolism, reproduction and growth. In response to nutrient-related and hormonal signals, hypothalamic neurons change their endocrine signalling affecting metabolism, food intake and energy expenditure. Leptin is a hormone secreted by the white adipose tissue and its receptor (LEPR) is found in many tissues in several alternatively spliced forms. While it is known that the signalling isoform OB-Rb is highly expressed in the hypothalamus, only little is known about their expression in the human heart. Binding of leptin to its receptor in the hypothalamic neurons inhibits feeding and generates satiety signals. In animal models, homozygous mutations in genes encoding leptin or LEPR lead to obesity, diabetes, cardiomyopathy, dyslipidaemia and infertility. In humans, mutations in LEPR are associated with early-onset obesity. In mouse obesity-models, leptin resistance of the hypothalamus has been proven to be an important mechanism. Therefore, understanding the role of leptin in the regulation of hypothalamus-released hormones in humans is important to shed light on underlying mechanisms leading to obesity and diabetes. In addition, several studies in mouse obesity-models correlate high levels of circulating leptin with the development of diabetic cardiomyopathy. Thus, the aims of this project are to study the influence of leptin and LEPR signalling in the regulation of obesity and neuroendocrine dysfunction and to explore the leptin role in patients with diabetic cardiomyopathy. The project focuses on the generation of human induced pluripotent stem cells with mutations in LEPR gene by using the CRISPR/Cas9 technology and their differentiation into cardiomyocytes and hypothalamic neurons to investigate the role of leptin and LEPR pathway in the development of diabetic cardiomyopathy. This study will provide important insight into the role of leptin and LEPR signalling in hypothalamic hormone release in diabetic patients and reveal new strategies for the regulation of leptin and LEPR signalling during diabetic cardiomyopathy.
Publications:
IP3R-mediated compensatory mechanism for calcium handling in human induced pluripotent stem cell-derived cardiomyocytes with cardiac ryanodine receptor deficiency. X. Luo, W. Li, K. Künzel, S. Henze, L. Cyganek, A. Strano, M. Poetsch, M. Schubert, K. Guan. Front Cell Dev Biol. 2020;8:772.
Role of Leptin in Cardiovascular Diseases. M.S. Poetsch*, A. Strano*, K. Guan. Front Endocrinol (Lausanne). 2020;11:354.
VE-PTP inhibition elicits eNOS phosphorylation to blunt endothelial dysfunction and hypertension in diabetes. M. Siragusa, A.F.O. Justo, P.F. Malacarne, A. Strano, A. Buch, B. Withers, K.G. Peters, I. Fleming. Cardiovasc Res. 2020;cvaa213.