The neuropeptide secretin regulates blood glucose homeostasis via tanycyte-arcuate nucleus axis

Abstract

Blood glucose homeostasis is critical for animal survival. Impairment in long-term blood glucose or energy homeostasis will unavoidably lead to many metabolic diseases like diabetes and obesity. The homeostasis is mainly determined by two pathways, including the circulating hormone-induced endocrine functions, and the coordination between the central nerve system and peripheral glucose-regulatory organs. Insulin and glucagon are two antagonistic hormones to directly control blood glucose, and the gastrointestinal incretin factors including glucagon-like peptide-1 (GLP-1) and gastric inhibitory hormone (GIP) also play a modulatory role in this process. Apart from peripheral hormonal regulation of blood glucose, there is emerging evidence showing that the communication between central nervous system and the peripheral is also essential in metabolic processes, but our knowledge of this mechanism and the neural substrates involved are incomplete. In this study, we firstly find the robust expression of secretin receptor (SCTR) in a unique group of ependymal cells, tanycyte, around the third ventricle in brain. Using immunostaining, electron microscopy, 2-photon imaging, we show that this Tanycyte SCTR+ can be activated by secretin in CSF. More interestingly, via anterograde tracing tool, we find that Tanycyte SCTR+ has a structural connection with POMC-expressing neurons, and also selectively activates POMC neuron. Like other glial cells, tanycyte SCTR+ can release ATP as gliotransmitter to potentiate hypothalamic neurons. Surprisingly, the knockdown (KD) of SCTR expression in tanycyte leads to a series of metabolic problems like overweight, hyperglycemia and insulin deficiency. These observations are attributed to the autocrine deficiency and dysfunction of sympathetic innervation in pancreas. While manipulating tanycyte SCTR+ by chemogenetic and optogenetic tool directly control blood glucose level and insulin release. In summary, these observations not only reveal the function of secretin in blood glucose homeostasis, but show how gastrointestinal hormone shapes hypothalamic circuitry. This study will also shed light on novel strategies for future management of pathological conditions related to impairments of metabolic homeostatic controls.