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 August 1, 2017; First 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 1

Hyperglycemic and c-Fos responses to noxious stimuli.

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Hyperglycemic and c-Fos responses to noxious stimuli. (A) Ad libitum–fed...
(A) Ad libitum–fed (n = 10) and overnight-fasted (n = 8) C57BL/6 mice were injected with intra–hind paw formalin (5%, 20 μl), and blood glucose concentrations were measured over the subsequent 3 hours. Data are plotted as mean ± SEM. (B) LepRbeGFP-L10a mice were treated with (C, D, G, H) intra–hind paw formalin (n = 4, veh; n = 5, formalin) as in A or (E, F, I, J) 2DG (n = 5, veh; n = 4, 2DG) (500 mg/kg, i.p.) and perfused under anesthesia. Brains were collected and sectioned; sections were stained for c-Fos (DAB, purple) and GFP (green). Images (C, E, G, I) are representative of 4–5 similar animals for each treatment. Graphs show colocalized cells/total LepRb cells, plotted as percentage, mean ± SEM. *P < 0.05. Scale bars: 100 μm. Data in panel A were analyzed by 2-way repeated-measures ANOVA with Fisher’s LSD post hoc test, and data in panels D, F, H, and J were analyzed by 1-tailed t test.