A leptin-regulated circuit controls glucose mobilization during noxious stimuli
Jonathan N. Flak, … , Kamal Rahmouni, Martin G. Myers Jr.
Jonathan N. Flak, … , Kamal Rahmouni, Martin G. Myers Jr.
Published July 17, 2017
Citation Information: J Clin Invest. 2017;127(8):3103-3113. https://doi.org/10.1172/JCI90147.
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Research Article Endocrinology Neuroscience

A leptin-regulated circuit controls glucose mobilization during noxious stimuli

Abstract

Adipocytes secrete the hormone leptin to signal the sufficiency of energy stores. Reductions in circulating leptin concentrations reflect a negative energy balance, which augments sympathetic nervous system (SNS) activation in response to metabolically demanding emergencies. This process ensures adequate glucose mobilization despite low energy stores. We report that leptin receptor–expressing neurons (LepRb neurons) in the periaqueductal gray (PAG), the largest population of LepRb neurons in the brain stem, mediate this process. Application of noxious stimuli, which often signal the need to mobilize glucose to support an appropriate response, activated PAG LepRb neurons, which project to and activate parabrachial nucleus (PBN) neurons that control SNS activation and glucose mobilization. Furthermore, activating PAG LepRb neurons increased SNS activity and blood glucose concentrations, while ablating LepRb in PAG neurons augmented glucose mobilization in response to noxious stimuli. Thus, decreased leptin action on PAG LepRb neurons augments the autonomic response to noxious stimuli, ensuring sufficient glucose mobilization during periods of acute demand in the face of diminished energy stores.

Authors

Jonathan N. Flak, Deanna Arble, Warren Pan, Christa Patterson, Thomas Lanigan, Paulette B. Goforth, Jamie Sacksner, Maja Joosten, Donald A. Morgan, Margaret B. Allison, John Hayes, Eva Feldman, Randy J. Seeley, David P. Olson, Kamal Rahmouni, Martin G. Myers Jr.

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Figure 7

PAGLepRb neurons act via the PBN to increase blood glucose.

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PAGLepRb neurons act via the PBN to increase blood glucose. (A) LeprCre ...
(A) LeprCre mice were injected with AAV-hM3dq in the PAG and either a GFP-expressing control virus (n = 7) or AAV-TetTOX-GFP (n = 10) to constitutively express GFP or GFP plus TetTOX in the PBN, respectively. All mice were randomly assigned to receive vehicle control or CNO; mice received the other treatment the following week (B and C). Glycemic responses following vehicle injection were not different between groups and were thus combined into a single control group. (D) Our data demonstrate that PAGLepRb neurons act via the PBN to mobilize glucose and increase adrenal SNA when activated by noxious stimuli such as pain and hypercapnia. In the presence of sufficient energy stores, leptin inhibits these neurons to limit sympathetic activation and hyperglycemia to appropriate levels during the response to noxious stimuli. When energy stores are depleted, however, loss of leptin inhibition of PAGLepRb neurons augments sympathetic and glycemic responses to noxious stimuli to ensure a sufficient glucose mobilization in response to noxious stimuli, despite reduced overall sympathetic tone and the depletion of energy stores. Data are plotted as mean ± SEM; groups with different letters are significantly different. P < 0.05. Data in panel B were analyzed using 2-way repeated-measures ANOVA with Fisher’s LSD post hoc test. Data in panel C were analyzed using 1-way ANOVA with Fisher’s LSD post hoc test.