Cited by 395Regulation of Appetite and ObesityHypothalamic control of reproductive hormonesAdipokines, Inflammation, and Metabolic Diseases

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Evidence That the Caudal Brainstem Is a Target for the Inhibitory Effect of Leptin on Food Intake

Grill, Harvey J., Schwartz, Michael W., Kaplan, Joel M., Foxhall, James S., Breininger, John, Baskin, Denis G.·2002·Endocrinology

DOI 10.1210/endo.143.1.8589

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Abstract

Three experiments were performed to investigate the hypothesis that leptin action within the caudal brain stem (CBS) contributes to its intake inhibitory effects. The first experiment evaluated the anatomical distribution of leptin receptor mRNA in rat CBS using a sensitive fluorescence in situ hybridization method with a riboprobe specific for the long form of the leptin receptor (Ob-Rb). An Ob-Rb mRNA hybridization signal was detected in neurons of several CBS nuclei involved in the control of food intake, including the dorsal vagal complex and parabrachial nucleus. A strong hybridization signal was also obtained from neuronal cell bodies of a number of other structures including the hypoglossal, trigeminal, lateral reticular, and cochlear nuclei; locus ceruleus; and inferior olive. The anatomical profile revealed by fluorescence in situ hybridization was in good agreement with immunocytochemical analysis with an antibody specific to Ob-Rb. In a second experiment, exploring the relevance of CBS Ob-Rb to feeding behavior, rats were given a fourth intracerebroventricular (i.c.v.) injection of leptin (0.1, 0.83, or 5.0μ g; n = 9–11/group) or vehicle 30 min before lights-out on three consecutive days The two higher doses reduced food intake significantly at 2, 4, and 24 h after injection and caused significant reductions of body weight. The dose-response profiles for fourth i.c.v. administration were indistinguishable from those obtained from separate groups of rats that received leptin via a lateral i.c.v. cannula. In the last experiment, a ventricle-subthreshold dose of leptin (0.1 μg) microinjected unilaterally into the dorsal vagal complex suppressed food intake at 2, 4, and 24 h. The results indicate that the CBS contains neurons that are potentially direct targets for the action of leptin in the control of energy homeostasis.

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Background
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Background
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Background
Increased Leptin Expression in the Dorsal Vagal Complex Suppresses Adiposity without Affecting Energy Intake and Metabolic Hormones
Boghossian, S., Lecklin, A., Dube, M. G., Kalra, P. S., & Kalra, S. P. (2006) · Obesity · doi:10.1038/oby.2006.115 · Cited by 19
“complex (DVC) of the brain stem acutely inhibited feeding and body weight (BW) (1,2,8,9).”
Background
Hydrogen sulfide depolarizes neurons in the nucleus of the solitary tract of the rat
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“…distinct in terms of their connectivity (Kalia and Mesulam, 1980), chemically distinct utilizing different neurotransmitters (Baskin et al., 2010; Grill et al., 2002; Kishi et al., 2003), or functionally distinct in that they serve different physiological functions (Altschuler et al., 1989).”
Background
Food-intake dysregulation in type 2 diabetic Goto-Kakizaki rats: Hypothesized role of dysfunctional brainstem thyrotropin-releasing hormone and impaired vagal output
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“…barrier, and are central targets of peripheral hormonal/nutritional signals, including ghrelin, cholecystokinin, and leptin, all hormones regulating food intake (Gross et al., 1990; Date et al., 2002; Grill et al., 2002; Zhang et al., 2004; Hussain and Bloom, 2013; Kanoski et al., 2012).”
Dynamic and extensive metabolic state-dependent regulation of cytokine expression and circulating levels
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Background
Lessons from experimental disruption of estrous cycles and behaviors.
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Background
Disrupted Leptin Signaling in the Lateral Hypothalamus and Ventral Premammillary Nucleus Alters Insulin and Glucagon Secretion and Protects Against Diet-Induced Obesity
Denroche, H. C., Glavas, M. M., Tudurí, E., Karunakaran, S., Quong, W. L., Philippe, M., Britton, H. M., Clee, S. M., & Kieffer, T. J. (2016) · Endocrinology · doi:10.1210/en.2015-1998 · Cited by 19
Innervation of skeletal muscle by leptin receptor-containing neurons
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“Despite this rather small population, previous experiments demonstrate that local injection of leptin into this brain area is sufficient to decrease food intake (Grill et al., 2002; Grill and Hayes, 2009).”
Result
Regulation of leptin receptor-expressing neurons in the brainstem by TRPV1
Zsombok, A., Jiang, Y., Gao, H., Anwar, I. J., Rezai-Zadeh, K. P., Enix, C. L., Münzberg, H., & Derbenev, A. V. (2014) · Physiological Reports · doi:10.14814/phy2.12160 · Cited by 16
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BackgroundInfluential
Age-related changes in acute central leptin effects on energy balance are promoted by obesity
Rostás, I., Tenk, J., Mikó, A., Füredi, N., Soós, S., Solymár, M., Lengyel, Á., Székely, M., Gaszner, B., Feller, D., et al. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.10.006 · Cited by 16
FGF19 in the Hindbrain Lowers Blood Glucose and Alters Excitability of Vagal Motor Neurons in Hyperglycemic Mice
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“In particular, the modulation of neuronal activity in the nucleus tractus solitarius (NTS) and the area postrema (AP) by gut derived signals has been clarified to be important for the regulation of meal termination (Grill et al., 2002).”
Background
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Responsiveness of hypothalamo-pituitary-adrenal axis to leptin is impaired in diet-induced obese rats
Shin, A. C., MohanKumar, S. M. J., Balasubramanian, P., Sirivelu, M. P., Linning, K. D., Woolcock, A., James, M., & MohanKumar, P. S. (2019) · Nutrition and Diabetes · doi:10.1038/s41387-019-0076-y · Cited by 15
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Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus
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Background
Leptin receptor-expressing neurons in ventromedial nucleus of the hypothalamus contribute to weight loss caused by fourth ventricle leptin infusions
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Brain stem as a target site for the metabolic side effects of olanzapine
Anwar, I. J., Miyata, K., & Zsombok, A. (2016) · Journal of Neurophysiology · doi:10.1152/jn.00387.2015 · Cited by 13
“The DVC has a pivotal role in energy and glucose homeostasis by integrating information from direct neural projections and from signals relevant to food intake and metabolic status (Berthoud 2002; Grill et al. 2002; Williams et al. 2007).”
Background
Electroacupuncture Reduces Weight Gain Induced by Rosiglitazone through PPARγ and Leptin Receptor in CNS
Jing, X., Ou, C., Chen, H., Wang, T., Xu, B., Lu, S.-F., & Zhu, B. (2016) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2016/8098561 · Cited by 13
“In addition, microinjection of leptin into the arcuate nucleus [54], the ventromedial hypothalamus [54, 55], and the nucleus of the solitary tract [56] inhibited food intake.”
Background
Neurohormonal pathways regulating food intake and changes after Roux-en-Y gastric bypass
Orlando, F. A., Gonçalves, C. G., George, Z. M., Halverson, J. D., Cunningham, P. R., & Meguid, M. M. (2005) · Surgery for Obesity and Related Diseases · doi:10.1016/j.soard.2005.05.009 · Cited by 13
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Background
CCK-sensitive C fibers activate NTS leptin receptor-expressing neurons via NMDA receptors
Neyens, D. M., Brenner, L., Calkins, R. J., Winzenried, E. T., Ritter, R. C., & Appleyard, S. M. (2023) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00238.2022 · Cited by 13
From Mammals to Insects: Exploring the Genetic and Neural Basis of Eating Behavior
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Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions
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Background
Integrated Effects of Leptin in the Forebrain and Hindbrain of Male Rats
Desai, B. N., & Harris, R. B. S. (2013) · Endocrinology · doi:10.1210/en.2013-1099 · Cited by 11
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Background
Short-term physiological hyperleptinemia decreases arterial blood pressure
Knight, W. D., Seth, R., Boron, J., & Overton, J. M. (2009) · Regulatory Peptides · doi:10.1016/j.regpep.2009.02.001 · Cited by 10
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“In separate extracellular neurophysiological recording studies from NTS neurons in vivo, the degree to which direct meal size controls were integrated with adiposity signals at the level of the caudal brainstem was evaluated.”
Influential
Ghrelin acts on rat dorsal vagal complex to stimulate feeding via arcuate neuropeptide Y/agouti-related peptide neurons activation.
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Bartness, T. J., & Demas, G. E. (2006) · Kluwer Academic Publishers eBooks · doi:10.1007/0-306-48643-1_15 · Cited by 9
“, hypothalamic sites such as the arcuate nucleus [Elmquist, 2001] or brainstem sites such as the dorsal vagal complex [Grill et al., 2002]).”
Background
Pharmacological and physiological activation of TGR5 in the NTS lowers food intake by enhancing leptin-STAT3 signaling
Bruce, K., Zhang, S., Garrido, A. N., Wang, M. T., Bachor, T. P., Wang, P., Xu, A. W., Yang, Z., & Lam, T. K. T. (2025) · Nature Communications · doi:10.1038/s41467-025-60331-1 · Cited by 9
Leptin Activation of Dorsal Raphe Neurons Inhibits Feeding Behavior
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Parabrachial nucleus neuron circuits that control feeding behavior and energy balance
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“Microinjection of leptin into the dorsal vagal complex, which contains the DMNV, caused an inhibition of food intake in rats (13).”
Background
Low-dose infusions of leptin into the nucleus of the solitary tract increase sensitivity to third ventricle leptin
Harris, R. B. S. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00562.2018 · Cited by 7
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Background
Effects of leptin on proliferation of astrocyte- and tanycyte-like neural stem cells in the adult mouse medulla oblongata
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“Although considerable emphasis has been made on the role of leptin in the hypothalamus, a less well recognised site of action of this hormone, relevant to the control of food intake, is at the level of the caudal brainstem [56].”
Background
The Brainstem Is a Key Target for Neuroendocrine Research on Obesity
Takahashi, K. (2003) · Endocrinology · doi:10.1210/en.2003-0969 · Cited by 7
“The brainstem is also a target for the inhibitory effect of leptin on food intake (19, 20).”
Background

Authors: Grill, H. J., Schwartz, M. W., Kaplan, J. M., Foxhall, J. S., Breininger, J., & Baskin, D. G.
Affiliations: University of Pennsylvania (US)
University of Washington (US)
Corresponding author: Grill, Harvey J.
ORCID: Grill, Harvey J.
Schwartz, Michael W.
Baskin, Denis G.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2002-01-01
Volume: 143
Issue: 1
Pages: 239-246
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/endo.143.1.8589
OpenAlex: W1976978438
Cited by: 395
References: 51
Citations by year: 2026: 2 · 2025: 4 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 12 · 2019: 8 · 2018: 14 · 2017: 8 · 2016: 11 · 2015: 11 · 2014: 20 · 2013: 22 · 2012: 28
FWCI: 7.67
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Veterans Affairs
University of Pennsylvania
University of Washington (DK17047)
National Institutes of Health (2r01dk012829-36, DK21397)
National Institute of Diabetes and Digestive and Kidney Diseases (DK 12829, R01DK042284, R01DK052989, DK-42284, DK-52989, DK-17047, DK 21397, P30DK017047)
National Institute of Neurological Disorders and Stroke (NS-32272)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords: leptin, caudal brainstem, food intake regulation, dorsal vagal complex, parabrachial nucleus, energy homeostasis, weight loss, hypothalamic-pituitary-thyroid axis
MeSH terms: Animals, Brain Stem, Carrier Proteins, Eating, Injections, Intraventricular, Male, Receptors, Cell Surface, Tissue Distribution, Vagus Nerve, Rats, Wistar, Protein Isoforms, Fourth Ventricle, Lateral Ventricles, Leptin, Rats, Receptors, Leptin

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Evidence That the Caudal Brainstem Is a Target for the Inhibitory Effect of Leptin on Food Intake

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