A Parabrachial-Hypothalamic Cholecystokinin Neurocircuit Controls Counterregulatory Responses to Hypoglycemia

Abstract

SummaryHypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCKLPBN) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1VMH) are the specific target of CCKLPBN glucoregulatory neurons. This discrete CCKLPBN→SF1VMH neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCKLPBN neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia.

Functional identification of a neurocircuit regulating blood glucose

“…These LPBN neurons express both leptin receptor and CCK, and, like photoactivation of VMN SF1 neurons, pharmacogenetic activation of LPBN LepRb CCK neurons raises blood glucose levels in association with increased secretion of glucagon and corticosterone. Conversely, inhibition of LPBN LepRb CCK neurons blunts the glycemic response to glucoprivation (9,10), an effect resembling the consequences of optogenetic silencing of VMN SF1 neurons during insulin-induced hypoglycemia in the current studies. Because these LPBN LepRb CCK neurons project to the dmVMN and cVMN and because the induction of CRRs after activation of PBN LepRb CCK neurons is attenuated by pharmacogenetic inhibition of VMN SF1 neurons (10), we hypothesized that the former neurons provide ascending, stimulatory input to the subset of VMN SF1 neurons that project to the aBNST.…”

“…By comparison, few activated neurons were present in the ventrolateral (vl) portion of the VMN, an area associated with reproduction and aggressive behavior (32)(33)(34)(35). Together, these findings implicate subsets of SF1 neurons located in central and dorsomedial regions of the VMN in glycemic control (10).…”

“…In addition to the VMN, recent evidence suggests that the CRR to hypoglycemia involves a subset of neurons in the LPBN marked by coexpression of leptin receptor and CCK (9,10). Because these LPBN LepRb CCK neurons also project to the VMN, we sought to determine whether they are anatomically coupled to VMN SF1 neurons identified herein as having a physiological role in glucose counterregulation.…”

Distinct neural mechanisms for the control of thirst and salt appetite in the subfornical organ

“…Considering it together with the affinity of CCK receptors (600 pM for CCKAR; 300 pM for CCKBR) (Weiland et al, 2004), circulating CCK is unlikely to activate CCK receptors in the SFO. The CCK-expressing neurons were reportedly located in the parabrachial nucleus (Garfield et al, 2014) and nucleus tractus solitaries (D'Agostino et al, 2016), both of which were also known to be related to body fluid homeostasis (Johnson, 2007). Because neurons in these nuclei have projections to the SFO (McKinley et al, 2003), CCK originated from these neurons may contribute to the suppression of water neurons.…”

The role of leptin in diabetes: metabolic effects

“…Future studies are further warranted to better characterise and understand the neurons and neurocircuits that mediate the glucose-lowering and other neuroendocrine effects of leptin in uDM. To facilitate this, new advancements in neuroscience technologies, such as optogenetics and designer receptors exclusively activated by designer drugs (DREADDs), hold promise in the functional mapping and manipulation of discrete populations of cells involved in glycaemic control [54,55], similar to that which has been applied to increase our knowledge of feeding behaviour [56][57][58].…”