The central role of a-klotho in regulation of metabolism resubmission Grant uri icon

abstract

  • The long-term objective of this proposal is to establish the previously uncovered signaling pathway of a-klotho-FGFR1-PI3K in AgRP or POMC neurons, which contributing to neuronal activity associated with obesity. Hypothalamic neurons, particularly the arcuate neurons located in the medial basal part of the hypothalamus, are capable of sensing nutrients and hormones such as glucose, leptin, insulin and lipid, to maintain energy homeostasis. We have preliminary evidence that a-klotho, a known anti-aging protein, is a novel humoral factor that target hypothalamus arcuate neurons, POMC and AgRP/NPY, which regulates energy and glucose metabolism. For example, central administration of a-klotho decreases food intake, fat mass, body weight, glucose level and increases energy expenditure in DIO mice. This and other findings lead us to the novel hypothesis that hypothalamic a-klotho signaling is required for the homeostatic regulation of energy metabolism. The proposed studies will focus on the effects of central a-klotho on metabolic function in varies mouse models of obesity and diabetes, and the neuronal mechanism underlying a-klotho's metabolic effects. These include a-klotho potential targeting POMC and AgRP/NPY neurons and signaling pathways that involve fibroblast growth factor receptor 1 (FGFR1) and the Phosphoinositide 3-kinase (P13 kinase).

date/time interval

  • September 2019 - June 2024

contributor