A Leptin-regulated Circuit Controls Glucose Mobilization During Noxious Stimuli

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2017 Jul 18

PMID 28714862

Citations 19

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Functionally Separate Populations of Ventromedial Hypothalamic Neurons in Obesity and Diabetes: A Report on Research Supported by Pathway to Stop Diabetes.

Flak J Diabetes. 2024; 74(1):4-11.

PMID: 39418333 PMC: 11664020. DOI: 10.2337/dbi24-0011.

History and future of leptin: Discovery, regulation and signaling.

Munzberg H, Heymsfield S, Berthoud H, Morrison C Metabolism. 2024; 161:156026.

PMID: 39245434 PMC: 11570342. DOI: 10.1016/j.metabol.2024.156026.

Control of Physiologic Glucose Homeostasis via the Hypothalamic Modulation of Gluconeogenic Substrate Availability.

Hashsham A, Kodur N, Su J, Tomlinson A, Yacawych W, Flak J bioRxiv. 2024; .

PMID: 38826340 PMC: 11142065. DOI: 10.1101/2024.05.20.594873.

Ventromedial hypothalamic nucleus subset stimulates tissue thermogenesis via preoptic area outputs.

Basu R, Elmendorf A, Lorentz B, Mahler C, Lazzaro O, App B Mol Metab. 2024; 84:101951.

PMID: 38729241 PMC: 11112375. DOI: 10.1016/j.molmet.2024.101951.

Leptin signaling and leptin resistance.

Liu J, Lai F, Hou Y, Zheng R Med Rev (2021). 2023; 2(4):363-384.

PMID: 37724323 PMC: 10388810. DOI: 10.1515/mr-2022-0017.

References

Walker D, Cassella J, Lee Y, De Lima T, Davis M . Opposing roles of the amygdala and dorsolateral periaqueductal gray in fear-potentiated startle. Neurosci Biobehav Rev. 1998; 21(6):743-53. DOI: 10.1016/s0149-7634(96)00061-9. View

Behbehani M . Functional characteristics of the midbrain periaqueductal gray. Prog Neurobiol. 1995; 46(6):575-605. DOI: 10.1016/0301-0082(95)00009-k. View

Bachtell R, Weitemier A, Galvan-Rosas A, Tsivkovskaia N, Risinger F, Phillips T . The Edinger-Westphal-lateral septum urocortin pathway and its relationship to alcohol consumption. J Neurosci. 2003; 23(6):2477-87. PMC: 6742045. View

ODonnell C, Schaub C, HAINES A, Berkowitz D, Tankersley C, Schwartz A . Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med. 1999; 159(5 Pt 1):1477-84. DOI: 10.1164/ajrccm.159.5.9809025. View

Carrive P . The periaqueductal gray and defensive behavior: functional representation and neuronal organization. Behav Brain Res. 1993; 58(1-2):27-47. DOI: 10.1016/0166-4328(93)90088-8. View

Linnman C, Moulton E, Barmettler G, Becerra L, Borsook D . Neuroimaging of the periaqueductal gray: state of the field. Neuroimage. 2011; 60(1):505-22. PMC: 3288184. DOI: 10.1016/j.neuroimage.2011.11.095. View

OBrien P, Hur J, Hayes J, Backus C, Sakowski S, Feldman E . BTBR ob/ob mice as a novel diabetic neuropathy model: Neurological characterization and gene expression analyses. Neurobiol Dis. 2014; 73:348-55. PMC: 4416075. DOI: 10.1016/j.nbd.2014.10.015. View

Mason P . Deconstructing endogenous pain modulations. J Neurophysiol. 2005; 94(3):1659-63. DOI: 10.1152/jn.00249.2005. View

Schwartz M, Seeley R, Tschop M, Woods S, Morton G, Myers M . Cooperation between brain and islet in glucose homeostasis and diabetes. Nature. 2013; 503(7474):59-66. PMC: 3983910. DOI: 10.1038/nature12709. View

10.

Flak J, Patterson C, Garfield A, DAgostino G, Goforth P, K Sutton Hickey A . Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. Nat Neurosci. 2014; 17(12):1744-1750. PMC: 4255234. DOI: 10.1038/nn.3861. View

11.

Carter M, Soden M, Zweifel L, Palmiter R . Genetic identification of a neural circuit that suppresses appetite. Nature. 2013; 503(7474):111-4. PMC: 3878302. DOI: 10.1038/nature12596. View

12.

Leshan R, Greenwald-Yarnell M, Patterson C, Gonzalez I, Myers Jr M . Leptin action through hypothalamic nitric oxide synthase-1-expressing neurons controls energy balance. Nat Med. 2012; 18(5):820-3. PMC: 3531967. DOI: 10.1038/nm.2724. View

13.

Lovick T . Pro-nociceptive action of cholecystokinin in the periaqueductal grey: a role in neuropathic and anxiety-induced hyperalgesic states. Neurosci Biobehav Rev. 2008; 32(4):852-62. DOI: 10.1016/j.neubiorev.2008.01.003. View

14.

Bandler R, Keay K, Floyd N, Price J . Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res Bull. 2000; 53(1):95-104. DOI: 10.1016/s0361-9230(00)00313-0. View

15.

Patterson C, Leshan R, Jones J, Myers Jr M . Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells. Brain Res. 2011; 1378:18-28. PMC: 3042504. DOI: 10.1016/j.brainres.2011.01.010. View

16.

Wall N, Wickersham I, Cetin A, De La Parra M, Callaway E . Monosynaptic circuit tracing in vivo through Cre-dependent targeting and complementation of modified rabies virus. Proc Natl Acad Sci U S A. 2010; 107(50):21848-53. PMC: 3003023. DOI: 10.1073/pnas.1011756107. View

17.

Hinder L, Vincent A, Hayes J, McLean L, Feldman E . Apolipoprotein E knockout as the basis for mouse models of dyslipidemia-induced neuropathy. Exp Neurol. 2012; 239:102-10. PMC: 3534788. DOI: 10.1016/j.expneurol.2012.10.002. View

18.

Teppema L, Veening J, Kranenburg A, Dahan A, BERKENBOSCH A, Olievier C . Expression of c-fos in the rat brainstem after exposure to hypoxia and to normoxic and hyperoxic hypercapnia. J Comp Neurol. 1997; 388(2):169-90. DOI: 10.1002/(sici)1096-9861(19971117)388:2<169::aid-cne1>3.0.co;2-#. View

19.

Bittencourt J, Vaughan J, Arias C, Rissman R, Vale W, Sawchenko P . Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors. J Comp Neurol. 1999; 415(3):285-312. View

20.

Garfield A, Shah B, Madara J, Burke L, Patterson C, Flak J . A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia. Cell Metab. 2014; 20(6):1030-7. PMC: 4261079. DOI: 10.1016/j.cmet.2014.11.006. View