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Evidence That the Caudal Brainstem Is a Target for the Inhibitory Effect of Leptin on Food Intake
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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“functional leptin receptors are expressed in the hippocampus, hindbrain (including the nucleus of the solitary tract (NTS)), pyriform cortex and other olfactory processing areas, and in mesolimbic areas involved in reward including the ventral tegmental area (VTA) and substantia nigra (SN) (61, 72).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [72]
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“areas as well as extrahypothalamic sites (29, 41, 42), and”
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“leptin action in other brain areas in the control of energy homeostasis can be inferred (41, 42).”
BackgroundSelf-citationPrior, L. J., Eikelis, N., Armitage, J. A., Davern, P. J., Burke, S. L., Montani, J.-P., Barzel, B., & Head, G. A. (2010) · Hypertension · doi:10.1161/hypertensionaha.109.141119 · Cited by 157
Early life programming of obesity and metabolic disease
Cottrell, E. C., & Ozanne, S. E. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.11.017 · Cited by 158
Neuronal control of energy homeostasis
Gao, Q., & Horváth, T. L. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.11.063 · Cited by 160
Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells
Patterson, C. M., Leshan, R. L., Jones, J. C., & Myers, M. G. (2011) · Brain Research · doi:10.1016/j.brainres.2011.01.010 · Cited by 149
“…LepRb neurons, including elsewhere in the hypothalamus, including the lateral hypothalamic area (LHA), as well as in the midbrain and brainstem (Grill et al., 2002; Hayes et al., 2010; Hommel et al., 2006; Leinninger et al., 2009; Leinninger and Myers, 2008; Leshan et al., 2009; Leshan et al.,…”
BackgroundDistribution of leptin‐sensitive cells in the postnatal and adult mouse brain
Caron, É., Sachot, C., Prévot, V., & Bouret, S. G. (2009) · The Journal of Comparative Neurology · doi:10.1002/cne.22219 · Cited by 162
“Single-label in situ hybridization was performed as previously reported by our laboratories (Gu et al., 1999; Bouret et al., 2004a).”
MethodBrainstem Nutrient Sensing in the Nucleus of the Solitary Tract Inhibits Feeding
Blouet, C., & Schwartz, G. J. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.10.003 · Cited by 154
“…establishing the role of direct NTS leptin, GLP-1 and ghrelin sensing in the homeostatic regulation of food intake (Faulconbridge et al., 2003; Grill et al., 2002; Hayes et al., 2009; Hayes et al., 2011b), these data support a role for the cmNTS as an important metabolicsensing niche in the…”
BackgroundInfluentialCentral Nervous System Regulation of Food Intake
Schwartz, M. W. (2006) · Obesity · doi:10.1038/oby.2006.275 · Cited by 150
“The response to input from satiety-related signals is, therefore, hypothesized to be regulated by input from adiposity-related signals, but whether this effect involves hypothalamic input from adiposity signals or a direct action of leptin in the hindbrain (62) awaits further study.”
BackgroundSelf-citationDevelopment of Leptin‐Sensitive Circuits
Bouret, S. G., & Simerly, R. B. (2007) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2007.01563.x · Cited by 143
THE CRITICAL ROLE OF THE MELANOCORTIN SYSTEM IN THE CONTROL OF ENERGY BALANCE
Seeley, R. J., Drazen, D. L., & Clegg, D. J. (2004) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.24.012003.132428 · Cited by 145
Huo, L., Maeng, L. Y., Bjørbæk, C., & Grill, H. J. (2007) · Endocrinology · doi:10.1210/en.2006-1572 · Cited by 147
“The icv administration or microinjection of leptin directly into the NTS (at the level of the AP) is sufficient to reduce short-term food intake and body weight gain (29).”
BackgroundSelf-citationModulation of vagal afferent excitation and reduction of food intake by leptin and cholecystokinin
Peters, J. H., Simasko, S. M., & Ritter, R. C. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.06.017 · Cited by 144
Leptin Signaling in the Nucleus Tractus Solitarii Increases Sympathetic Nerve Activity to the Kidney
Mark, A. L., Agassandian, K., Morgan, D. A., Liu, X., Cassell, M. D., & Rahmouni, K. (2009) · Hypertension · doi:10.1161/hypertensionaha.108.124255 · Cited by 139
“Discussion The major new findings from this study are as follows: (1) leptin receptor signaling in the NTS increases SNA to kidney but not to BAT; (2) sympathoactivation to microinjection of leptin into the NTS was associated with an increase in arterial pressure; and (3) the renal sympathetic nerve responses to NTS l…”
BackgroundLeptin and the systems neuroscience of meal size control
Grill, H. J. (2009) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.10.005 · Cited by 138
Self-citationCharacterization of Leptin-Responsive Neurons in the Caudal Brainstem
Ellacott, K. L. J., Halatchev, I. G., & Cone, R. D. (2006) · Endocrinology · doi:10.1210/en.2005-0877 · Cited by 132
“Leptin receptors are found in the caudal brainstem of rodents (22, 23), and administration of leptin into the fourth ventricle causes a reduction in nocturnal food intake comparable with lateral ventricular administration (23).”
BackgroundHuo, L., Grill, H. J., & Bjørbæk, C. (2006) · Diabetes · doi:10.2337/diabetes.55.03.06.db05-1143 · Cited by 127
“We have previously shown the presence of leptin receptor mRNA and leptin-inducible STAT3 tyrosine phosphorylation in the NTS of rats (12,21).”
Self-citationLeptin: a diverse regulator of neuronal function
Harvey, J. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04205.x · Cited by 127
Padilla, S. L., Reef, D. K., & Zeltser, L. M. (2011) · Endocrinology · doi:10.1210/en.2011-1665 · Cited by 120
Schwartz, G. J., & Moran, T. H. (2002) · Endocrinology · doi:10.1210/en.2002-220352 · Cited by 119
“The NTS contains leptin receptors (17, 31), and fourth ventricular or direct NTS leptin administration has been demonstrated to inhibit food intake (31).”
BackgroundLeptin reverses declines in satiation in weight-reduced obese humans
Kissileff, H. R., Thornton, J. C., Torres, M., Pavlovich, K. H., Mayer, L. S., Kalari, V., Leibel, R. L., & ROSENBAUM, M. S. (2012) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.111.012385 · Cited by 121
“In addition to being hypometabolic (16, 19–23), leptindeficient humans and rodents are also hyperphagic and demonstrate reduced satiation and, to a lesser degree, increased hunger, thereby creating the optimal biological conditions that promote weight gain in leptin-deficient states (24).”
BackgroundQuan, W., Kim, H.-K., Moon, E., Kim, S. S., Choi, C. S., Komatsu, M., Jeong, Y. T., Lee, M., Kim, K.-W., Kim, M.-S., et al. (2012) · Endocrinology · doi:10.1210/en.2011-1882 · Cited by 118
Role of leptin in the regulation of gonadotropin secretion in farm animals
Barb, C. R., & Kraeling, R. R. (2004) · Animal Reproduction Science · doi:10.1016/j.anireprosci.2004.04.032 · Cited by 113
“Furthermore, evidence now exists that the brain stem is a direct target for leptin in the regulation of food intake and neuroendocrine function (Grill et al., 2002; Hosoi et al., 2002).”
BackgroundEnergy regulatory signals and food reward
Figlewicz, D. P., & Sipols, A. J. (2010) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2010.03.002 · Cited by 116
“Other CNS sites and neural systems are targets for insulin and leptin action (Figlewicz et al., 1990; Figlewicz, 2003; Grill et al., 2002; Harvey, 2007; McNay, 2007).”
BackgroundDioxins, the aryl hydrocarbon receptor and the central regulation of energy balance
Lindén, J., Lensu, S., Tuomisto, J., & Pohjanvirta, R. (2010) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2010.07.002 · Cited by 108
“Intracerebroventricular administration of exogenous leptin or insulin induces marked reductions in food intake and body weight [153,163,223,396].”
The blood-brain barrier: connecting the gut and the brain
Banks, W. A. (2008) · Regulatory Peptides · doi:10.1016/j.regpep.2007.08.027 · Cited by 104
Williams, D. L., Bowers, R. R., Bartness, T. J., Kaplan, J. M., & Grill, H. J. (2003) · Endocrinology · doi:10.1210/en.2003-0440 · Cited by 102
Self-citationFrom observation to experimentation: leptin action in the mediobasal hypothalamus
Williams, K. W., Scott, M. M., & Elmquist, J. K. (2009) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26788d · Cited by 104
“In addition, fourth ventricle administration of leptin reduces food ingestion and weight gain within 24 h, and these effects are mimicked by microinjection of the peptide into either the fourth ventricle or the NTS (58).”
BackgroundInfluentialExpression of leptin receptor gene in developing and adult zebrafish
Liu, Q., Chen, Y., Copeland, D. L., Ball, H. C., Duff, R. J., Rockich, B. E., & Londraville, R. L. (2009) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2009.11.015 · Cited by 102
“…especially the dorsal vagal complex, contains leptin receptor mRNA and protein (Elmquist et al., 1998; Mercer et al., 1998; Buyse et al., 2001; Grill et al., 2002), and is thought to play crucial roles in integration of leptin signals and meal-related satiety signals (Grill and Kaplan, 2002;…”
BackgroundPsychological and Neurobiological Correlates of Food Addiction
Kalon, E., Hong, J., Tobin, C. T., & Schulte, T. (2016) · International review of neurobiology · doi:10.1016/bs.irn.2016.06.003 · Cited by 117
Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis
Pardini, A. W., Hồng, N. T., Figlewicz, D. P., Baskin, D. G., Williams, D. L., Kim, F., & Schwartz, M. W. (2006) · Brain Research · doi:10.1016/j.brainres.2006.06.109 · Cited by 101
Self-citationLeptin-induced satiation mediated by abdominal vagal afferents
Peters, J. H., McKay, B. M., Simasko, S. M., & Ritter, R. C. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00716.2004 · Cited by 100
“It is well established that systemic administration of milligram doses of leptin (8) or injection of microgram amounts of leptin into the forebrain (15, 22) or hindbrain (7) ventricles reduces 24-h food intake and decreases meal size.”
Background
Metadata
- 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.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2002-01-01
- Volume
- 143
- Issue
- 1
- Pages
- 239-246
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- 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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