A Synaptic Amplifier of Hunger for Regaining Body Weight in the Hypothalamus

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2023 Mar 25

PMID 36965483

Authors

Katarzyna Grzelka

Hannah Wilhelms

Stephan Dodt

Marie-Luise Dreisow

Joseph C Madara

Samuel J Walker

Chen Wu

Daqing Wang

Bradford B Lowell

Henning Fenselau

Affiliations

Soon will be listed here.

Abstract

Restricting caloric intake effectively reduces body weight, but most dieters fail long-term adherence to caloric deficit and eventually regain lost weight. Hypothalamic circuits that control hunger drive critically determine body weight; yet, how weight loss sculpts these circuits to motivate food consumption until lost weight is regained remains unclear. Here, we probe the contribution of synaptic plasticity in discrete excitatory afferents on hunger-promoting AgRP neurons. We reveal a crucial role for activity-dependent, remarkably long-lasting amplification of synaptic activity originating from paraventricular hypothalamus thyrotropin-releasing (PVH) neurons in long-term body weight control. Silencing PVH neurons inhibits the potentiation of excitatory input to AgRP neurons and diminishes concomitant regain of lost weight. Brief stimulation of the pathway is sufficient to enduringly potentiate this glutamatergic hunger synapse and triggers an NMDAR-dependent gaining of body weight that enduringly persists. Identification of this activity-dependent synaptic amplifier provides a previously unrecognized target to combat regain of lost weight.

Citing Articles

Long-term impact of obesity: Unraveling adipose epigenetic memory.

Hinte L, Castellano-Castillo D, von Meyenn F Clin Transl Med. 2025; 15(3):e70254.

PMID: 40035115 PMC: 11876844. DOI: 10.1002/ctm2.70254.

Heat acclimation in mice requires preoptic BDNF neurons and postsynaptic potentiation.

Chen B, Gao C, Liu C, Guo T, Hu J, Xue J Cell Res. 2024; 35(3):224-227.

PMID: 39725738 DOI: 10.1038/s41422-024-01064-6.

Parallel gut-to-brain pathways orchestrate feeding behaviors.

Wang H, Lou R, Wang Y, Hao L, Wang Q, Li R Nat Neurosci. 2024; 28(2):320-335.

PMID: 39627537 DOI: 10.1038/s41593-024-01828-8.

Paraventricular hypothalamic RUVBL2 neurons suppress appetite by enhancing excitatory synaptic transmission in distinct neurocircuits.

Xing M, Li Y, Zhang Y, Zhou J, Ma D, Zhang M Nat Commun. 2024; 15(1):8939.

PMID: 39414808 PMC: 11484884. DOI: 10.1038/s41467-024-53258-6.

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.

References

Liu T, Kong D, Shah B, Ye C, Koda S, Saunders A . Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron. 2012; 73(3):511-22. PMC: 3278709. DOI: 10.1016/j.neuron.2011.11.027. View

Cowley M, Smith R, Diano S, Tschop M, Pronchuk N, Grove K . The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 2003; 37(4):649-61. DOI: 10.1016/s0896-6273(03)00063-1. View

Sumithran P, Prendergast L, Delbridge E, Purcell K, Shulkes A, Kriketos A . Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011; 365(17):1597-604. DOI: 10.1056/NEJMoa1105816. View

Goldstein N, McKnight A, Carty J, Arnold M, Betley J, Alhadeff A . Hypothalamic detection of macronutrients via multiple gut-brain pathways. Cell Metab. 2021; 33(3):676-687.e5. PMC: 7933100. DOI: 10.1016/j.cmet.2020.12.018. View

Lledo P, Hjelmstad G, Mukherji S, Soderling T, Malenka R, Nicoll R . Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. Proc Natl Acad Sci U S A. 1995; 92(24):11175-9. PMC: 40594. DOI: 10.1073/pnas.92.24.11175. View

Suyama S, Ralevski A, Liu Z, Dietrich M, Yada T, Simonds S . Plasticity of calcium-permeable AMPA glutamate receptors in Pro-opiomelanocortin neurons. Elife. 2017; 6. PMC: 5538821. DOI: 10.7554/eLife.25755. View

Nakajima K, Cui Z, Li C, Meister J, Cui Y, Fu O . Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake. Nat Commun. 2016; 7:10268. PMC: 4729878. DOI: 10.1038/ncomms10268. View

Lerchner W, Xiao C, Nashmi R, Slimko E, van Trigt L, Lester H . Reversible silencing of neuronal excitability in behaving mice by a genetically targeted, ivermectin-gated Cl- channel. Neuron. 2007; 54(1):35-49. DOI: 10.1016/j.neuron.2007.02.030. View

Rau A, Hentges S . GABAergic Inputs to POMC Neurons Originating from the Dorsomedial Hypothalamus Are Regulated by Energy State. J Neurosci. 2019; 39(33):6449-6459. PMC: 6697391. DOI: 10.1523/JNEUROSCI.3193-18.2019. View

10.

Su Z, Alhadeff A, Betley J . Nutritive, Post-ingestive Signals Are the Primary Regulators of AgRP Neuron Activity. Cell Rep. 2017; 21(10):2724-2736. PMC: 5724395. DOI: 10.1016/j.celrep.2017.11.036. View

11.

Zhu C, Jiang Z, Xu Y, Cai Z, Jiang Q, Xu Y . Profound and redundant functions of arcuate neurons in obesity development. Nat Metab. 2020; 2(8):763-774. PMC: 7687864. DOI: 10.1038/s42255-020-0229-2. View

12.

Jais A, Bruning J . Arcuate Nucleus-Dependent Regulation of Metabolism-Pathways to Obesity and Diabetes Mellitus. Endocr Rev. 2021; 43(2):314-328. PMC: 8905335. DOI: 10.1210/endrev/bnab025. View

13.

Nakajima K, Cui Z, Li C, Meister J, Cui Y, Fu O . Corrigendum: Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake. Nat Commun. 2016; 7:11019. PMC: 4782055. DOI: 10.1038/ncomms11019. View

14.

Gyengesi E, Liu Z, DAgostino G, Gan G, Horvath T, Gao X . Corticosterone regulates synaptic input organization of POMC and NPY/AgRP neurons in adult mice. Endocrinology. 2010; 151(11):5395-402. PMC: 2954711. DOI: 10.1210/en.2010-0681. View

15.

Aklan I, Atasoy N, Yavuz Y, Ates T, Coban I, Koksalar F . NTS Catecholamine Neurons Mediate Hypoglycemic Hunger via Medial Hypothalamic Feeding Pathways. Cell Metab. 2019; 31(2):313-326.e5. PMC: 9017597. DOI: 10.1016/j.cmet.2019.11.016. View

16.

Vella K, Ramadoss P, Lam F, Harris J, Ye F, Same P . NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways. Cell Metab. 2011; 14(6):780-90. PMC: 3261758. DOI: 10.1016/j.cmet.2011.10.009. View

17.

Hrabovszky E, Wittmann G, Turi G, Liposits Z, Fekete C . Hypophysiotropic thyrotropin-releasing hormone and corticotropin-releasing hormone neurons of the rat contain vesicular glutamate transporter-2. Endocrinology. 2004; 146(1):341-7. DOI: 10.1210/en.2004-0856. View

18.

Krashes M, Shah B, Koda S, Lowell B . Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab. 2013; 18(4):588-95. PMC: 3822903. DOI: 10.1016/j.cmet.2013.09.009. View

19.

Tong Q, Ye C, Jones J, Elmquist J, Lowell B . Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci. 2009; 11(9):998-1000. PMC: 2662585. DOI: 10.1038/nn.2167. View

20.

Luquet S, Perez F, Hnasko T, Palmiter R . NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science. 2005; 310(5748):683-5. DOI: 10.1126/science.1115524. View