[R01] Mechanisms for Hypothalamic Control of Glucose Mobilization
Ente: National Institute of Diabetes and Digestive and Kidney Diseases
Scadenza: 2031-06-30
Importo max: 672.600 EUR
Paese: US
Descrizione
While the appropriate control of glucose production enables animals to adapt to a variety of
environmental and physiological challenges, inappropriate glucose mobilization can promote metabolic
diseases. For example, unrestrained hepatic glucose production is an early development in type 2 diabetes
and excessive glucose mobilization during critical illness causes “stress hyperglycemia”, increasing the risk of
mortality. Current medical therapies (e.g., insulin) focus on normalizing blood glucose rather than correcting the
underlying pathology that leads to glycemic dysregulation. To devise treatments for disorders that arise from
dysregulated glucose production we must understand the systems that control glucose mobilization.
The dorsomedial compartment of the ventromedial nucleus of the hypothalamus (dmVMN) controls
hypothalamic-pituitary-adrenal ( HPA) axis activation, adrenal catecholamine secretion, and SNS outflow to
metabolic tissues to mediate the context-specific coordination of glucose mobilization . While previously studied
as a single population, recent work from our laboratory demonstrates that multiple distinct populations of
glucose-mobilizing VMN neurons must exist. The overarching goal of this project is to understand the distinct
dmVMN neural circuits that tailor the activity of each glucose-mobilizing mechanism appropriately for specific
contexts.
Our single-nucleus RNA-sequencing analysis defined 3 classes of dmVMN neurons (Classes 1–3).
Class 1 neurons, which represent over 50% of all dmVMN neurons, contain two distinct neural subtypes
(defined by the expression of Lepr or Glipr1, respectively). While VMNLepr neurons promote energy
expenditure and glucose disposal (rather than glucose production) our preliminary data suggest that VMNGlipr1
neurons activate the HPA axis to mobilize glucose during psychologic stress. In contrast, Class 3 neurons
(marked by Vglut3; VMNVglut3 neurons) do not modulate the HPA axis, although they promote glucose
production during fasting in addition to psychological stress. While we predict that Class 2 VMNNpffr2 neurons
also contribute to glucose mobilization, the lack of preliminary data regarding the function of these neurons
compels us to focus on VMNGlipr1 and VMNVglut3 neurons in this proposal. We hypothesize that VMNGlipr1
neurons respond to psychological stressors to engage the HPA axis while VMNVglut3 neurons respond to both
psychological stressors and nutrient cues to promote adrenal catecholamine release and SNS activation.
Using our validated, genetically modified mouse models we will define the regulation, physiologic and
pathophysiologic functions, and mechanisms of action for these glucose-mobilizing dmVMN populations. In
addition to elucidating mechanisms that contribute to glucose homeostasis, the results of these studies could
potentially enable the rational design of targeted treatments for disorders that result from dysregulated glucose
mobilization.
Istituzione: UNIVERSITY OF MICHIGAN AT ANN ARBOR
PI: Alison Holley Affinati
Progetto: 1R01DK143970-01A1
Settori: National Institute of Diabetes and Digestive and Kidney Diseases
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