Central Administration of an Endoplasmic Reticulum Stress Inducer Inhibits the Anorexigenic Effects of Leptin and Insulin
Abstract
Leptin and insulin are important anorexigenic hormones acting on the hypothalamus. However, most obese humans and animals have reduced hypothalamic responses to leptin and insulin. Increased endoplasmic reticulum (ER) stress has been shown to cause insulin resistance in the livers of obese animals. In the present study, we investigated a role of ER stress in the development of central leptin and insulin resistance. Intracerebroventricular (ICV) administration of the ER stress inducer thapsigargin (TG) increased food intake and body weight. Furthermore, ICV or intra‐hypothalamic administration of TG inhibited the anorexigenic and weight‐reducing effects of leptin and insulin. ICV administration of TG by itself activated signal‐transduction‐activated‐transcript‐3 (STAT3) and Akt in the hypothalamus, but prevented a further activation of hypothalamic STAT3 and Akt by leptin and insulin. We also found that the expression of the ER stress markers such as phosphorylation of the inositol‐requiring kinase‐1 (IRE1), spliced form of X‐box‐binding protein‐1 (XBP‐1s), glucose‐regulated/binding immunoglobulin protein‐78, and C/EBP homology protein (CHOP) increased in the hypothalami of diet‐induced obese (DIO) mice. Furthermore, treatment of chemical chaperone 4‐phenyl butylic acid significantly improved central leptin resistance in DIO mice. These findings suggest that increased hypothalamic ER stress in obese animals may induce central leptin and insulin resistance.
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Induction of ER stress in the brain of mice and rats increases food intake and body weight and blocks the anorexic effects of insulin and leptin.
“induction of ER stress in the brain of mice and rats increases food intake and body weight and blocks the anorexic effects of insulin and leptin (140, 199).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [199]
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“homeostasis, underlying obesity and, importantly, leptin resistance [46,101,145,151].”
BackgroundInfluentialNew Pharmacological Perspectives for the Leptin Receptor in the Treatment of Obesity
Roujeau, C., Jockers, R., & Dam, J. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00167 · Cited by 70 · see citing works
“ER stress in the brain also contributes to central insulin-resistance along with leptin resistance (66).”
BackgroundInsights into amylin–leptin synergy
Trevaskis, J. L., Parkes, D. G., & Roth, J. D. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.03.006 · Cited by 68 · see citing works
Modulation of leptin resistance by food compounds
Aragonès, G., Ardid‐Ruiz, A., Ibars, M., Suárez, M., & Bladé, C. (2016) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201500964 · Cited by 66 · see citing works
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“Excess palmitate induces ER stress and apoptosis in the mHypoE-44 hypothalamic cell line [26], while CNS administration of an ER stress inducer inhibits the hypophagic effects of leptin and insulin [27].”
Backgroundp53 in AgRP neurons is required for protection against diet-induced obesity via JNK1
Quiñones, M., Al–Massadi, O., Folgueira, C., Bremser, S., Gallego, R., Torres‐Leal, F. L., Haddad-Tóvolli, R., García‐Cáceres, C., Hernández-Bautista, R., Lam, B., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05711-6 · Cited by 62 · see citing works
Mechanisms of insulin resistance in the amygdala: Influences on food intake
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Induced autophagy reduces virus output in dengue infected monocytic cells.
Panyasrivanit, M., Greenwood, M., Murphy, D., Isidoro, C., Auewarakul, P., & Smith, D. R. (2011) · Virology · doi:10.1016/j.virol.2011.07.010 · Cited by 61 · see citing works
“To determine if autophagy is induced in U937 cells in response to ER stress, cells were treatedwith various concentrations of the sarco/endoplasmic reticulum Ca ATPase inhibitor thapsigargin, a commonly used ER stress inducer (Bachar et al., 2009; Bertolotti et al., 2000; Won et al., 2009).”
MethodNeural Underpinnings of Obesity: The Role of Oxidative Stress and Inflammation in the Brain
Mullins, C. A., Gannaban, R. B., Khan, M. S. H., Shah, H., Siddik, M. A. B., Hegde, V. K., Reddy, P. H., & Shin, A. C. (2020) · Antioxidants · doi:10.3390/antiox9101018 · Cited by 54 · see citing works
“Won and colleagues [78] have shown that a single ICV injection of thapsigargin, an ER stress inducer, in mice increases hypothalamic ER stress markers such as pIRE1 and CHOP as expected, and reduces leptin’s appetite-suppressing action.”
BackgroundUllah, R., Rauf, N., Nabi, G., Shen, Y., Yu-Dong, Z., & Fu, J. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112012 · Cited by 58 · see citing works
Hypothalamic endoplasmic reticulum stress as a key mediator of obesity‐induced leptin resistance
Ye, Z., Liu, G., Guo, J., & Su, Z. (2018) · Obesity Reviews · doi:10.1111/obr.12673 · Cited by 54 · see citing works
“Pharmacologically (tunicamycin, thapsigargin or brefeldin A) induced ER stress dramatically blocked leptin-induced phosphorylation of STAT3 in the hypothalamus and augmented appetite and body weight gain in mice; on the other hand, chemical chaperones alleviated ER stress-induced leptin resistance and subsequently met…”
BackgroundEndoplasmic reticulum stress in the pathogenesis of hypertension
Young, C. N. (2017) · Experimental Physiology · doi:10.1113/ep086274 · Cited by 51 · see citing works
“…in the mediobasal hypothalamus (Purkayastha et al. 2011a; Zhang et al. 2008), findings that have been confirmed by others (Ozcan et al. 2009; Won et al. 2009; Ropelle et al. 2010; Cakir et al. 2013; Schneeberger et al. 2013; Contreras et al. 2014) and recently extended to the SFO (Horwath…”
BackgroundNeuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions
Kaneko, K., Xu, P., Cordonier, E. L., Chen, S. S., Ng, A., Xu, Y., Morozov, A., & Fukuda, M. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.08.039 · Cited by 49 · see citing works
“…HFD-induced obese mice exhibited both increased CNS Rap1 activity (Figure 7A and Figure S2B) and ER stress (Ozcan et al., 2009; Won et al., 2009; Zhang et al., 2008b) (Figure 7B), we next investigated whether Rap1 is involved in cellular processes that mediate HFD-induced ER…”
BackgroundHosoi, T., Yamaguchi, R., Noji, K., Matsuo, S., Baba, S., Toyoda, K., Suezawa, T., Kayano, T., Tanaka, S., & Ozawa, K. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201303227 · Cited by 48 · see citing works
“ER stress is known to be involved in the development of leptin resistance (Hosoi et al , 2008; Zhang et al , 2008; Ozcan et al , 2009; Won et al , 2009).”
Kim, J., Yun, E., Park, S.-W., Goo, T., & Seo, M. (2016) · Nutrients · doi:10.3390/nu8020100 · Cited by 43 · see citing works
“In particular, hypothalamic ER stress has been suggested to cause feeding behavior disorder and glucose dysregulation for promotion of obesity and diabetes [14–16].”
BackgroundEndoplasmic reticulum stress and the on site function of resident PTP1B
Popov, D. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.05.048 · Cited by 42 · see citing works
Stress Signaling Between Organs in Metazoa
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Drug targeting of leptin resistance
Santoro, A. N., Raso, G. M., & Meli, R. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.05.012 · Cited by 41 · see citing works
“Mens Sana In Corpore Sano”: Exercise and Hypothalamic ER Stress
de Morentin, P. B. M., & López, M. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000464 · Cited by 38 · see citing works
“In their study, Carvalheira and colleagues used thapsigargin as ER stress inducer [26,31]; alternative drugs, such as tunicamycin (which interferes with protein glycosylation) and brefeldin A (which impairs ER-Golgi vesicular transport) [23–25], or ideally genetic models will provide new cues about the effect of exerc…”
BackgroundPGC-1α functions as a co-suppressor of XBP1s to regulate glucose metabolism
Lee, J., Hernández, M. A. S., Auen, T., Mucka, P., Lee, J., & Özcan, U. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.10.010 · Cited by 34 · see citing works
The Mechanism of Leptin Resistance in Obesity and Therapeutic Perspective
Engin, A. (2024) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-63657-8_16 · Cited by 37 · see citing works
Congur, I., Mingrone, G., & Guan, K. (2024) · Metabolism · doi:10.1016/j.metabol.2024.156062 · Cited by 33 · see citing works
Chen, J., Haase, N., Haange, S., Sucher, R., Münzker, J., Jäger, E., Schischke, K., Seyfried, F., von Bergen�, M., Hankir, M. K., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101214 · Cited by 34 · see citing works
Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis
Schneeberger, M., Gómez-Valadés, A. G., Altirriba, J., Sebastián, D., Ramírez, S., García, A., Esteban, Y., Drougard, A., Ferrés‐Coy, A., Bortolozzi, A. A., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.06.041 · Cited by 33 · see citing works
“In particular, the hypothalamus has emerged as a key area of theCNS, causally linking ER stress, leptin resistance, and overweight (Cakir et al., 2013; Contreras et al., 2014; Hosoi et al., 2008; Ozcan et al., 2009; Won et al., 2009; Zhang et al., 2008).”
BackgroundBlocking iNOS and endoplasmic reticulum stress synergistically improves insulin resistance in mice
Zanotto, T. M., Quaresma, P. G. F., Guadagnini, D., Weissmann, L., Santos, A. C., Vecina, J. F., Calisto, K. L., Santos, A., Prada, P. O., & Saad, M. J. A. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.12.005 · Cited by 32 · see citing works
“…protection from HFD-induced insulin resistance and glucose intolerance To assess whether the iNOS enzyme can modify the characteristics and metabolic profile of mice fed a HFD, we used animals with en access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).”
MethodInfluentialOh, S., Son, M., Choi, J., Choi, C. H., Park, K. Y., Son, K. H., & Byun, K. (2019) · Marine Drugs · doi:10.3390/md17100570 · Cited by 31 · see citing works
“IRE1 and PERK phosphorylation, and XBP1 splicing increase in the hypothalamus of HFD-induced obese rodents [29,33,34].”
BackgroundMechanisms Mediating the Actions of Fatty Acids in the Hypothalamus
Dragano, N. R. V., Monfort‐Pires, M., & Velloso, L. A. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.10.012 · Cited by 30 · see citing works
UPRmt and coordinated UPRER in type 2 diabetes
Kang, Z., Chen, F., Wu, W., Liu, R. R., Chen, T., & Xu, F. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.974083 · Cited by 29 · see citing works
“Furthermore, PERK phosphorylation levels are significantly increased and the STAT3 phosphorylation induced by leptin was markedly blunted in such mice (Ozcan et al., 2004; Hosoi et al., 2008; Zhang et al., 2008; Ozcan et al., 2009;Won et al., 2009; Cakir et al., 2013; Schneeberger et al., 2013; Lee and Ozcan, 2014; Wi…”
BackgroundFeed Your Head: Neurodevelopmental Control of Feeding and Metabolism
Lee, D. A., & Blackshaw, S. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170347 · Cited by 29 · see citing works
“Interestingly, direct pharmacological activation of the ER stress response through icv administration of thapsigargin blocks the anorexigenic effects of both leptin and insulin; such a mechanism involving a change in the ER stress response may underlie leptin resistance associated with overnutrition (175).”
BackgroundMarcos, J. L., Olivares-Barraza, R., Ceballo, K., Wastavino, M., Ortiz, V., Riquelme, J., Martínez-Pinto, J., Muñoz, P., Cruz, G., & Sotomayor‐Zárate, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021468 · Cited by 29 · see citing works
“Moreover, under a positive energy balance, the secretion of hormones such as leptin (produced by white adipose tissue) or insulin (produced by β-pancreatic cells [14]) stimulates the glutamatergic neurons of the VMH that stimulate the anorexigenic neurons that produce the pro-opiomelanocortin (POMC) and cocaine–amphet…”
BackgroundInfluentialMilbank, E., Martínez, M. C., & Andriantsitohaina, R. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.11.002 · Cited by 29 · see citing works
“On the other hand, obesity induces ER stress within the hypothalamus leading to the development of insulin and leptin resistance and weight gain (Won et al., 2009; Zhang et al., 2008).”
BackgroundAcute Exercise Decreases Tribbles Homolog 3 Protein Levels in the Hypothalamus of Obese Rats
Rodrigues, B. D. A., Pauli, L. S. S., de Souza, C. T., da Silva, A. S. R., Cintra, D. E., Marinho, R., de Moura, L. P., Ropelle, E. C. C., Botezelli, J. D., Ropelle, E. R., et al. (2014) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000000585 · Cited by 28 · see citing works
AMPK in the Ventromedial Nucleus of the Hypothalamus: A Key Regulator for Thermogenesis
Liu, H., Xu, Y., & Hu, F. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.578830 · Cited by 28 · see citing works
“Central injection of ER stress inducers, such as tunicamycin or thapsigargin, accelerates the development of obesity (52, 143).”
BackgroundHypothalamic Lipids: Key Regulators of Whole Body Energy Balance
González‐García, I., Fernø, J., Diéguez, C., Nogueiras, R., & López, M. (2016) · Neuroendocrinology · doi:10.1159/000448432 · Cited by 28 · see citing works
Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth
Park, S., Sethi, S., & Bouret, S. G. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00876 · Cited by 26 · see citing works
“Hypothalamic ER stress has recently emerged as a casual factor in the development of central leptin resistance (18, 30, 31).”
BackgroundTherapeutic use of recombinant methionyl human leptin
Vatier, C., Gautier, J., & Vigouroux, C. (2012) · Biochimie · doi:10.1016/j.biochi.2012.03.013 · Cited by 28 · see citing works
“reticulum (ER) capacity: ER stress blocks leptin action and generates leptin resistance in mice, suggesting that ER stress provides a potential mechanism for the development of leptin resistance [64].”
Microbiota determines insulin sensitivity in TLR2-KO mice
Guadagnini, D., Rocha, G. Z., Santos, A., Assalin, H. B., Hirabara, S. M., Curi, R., Oliveira, A. G., Prada, P. O., & Saad, M. J. A. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116793 · Cited by 27 · see citing works
Fluvoxamine Attenuated Endoplasmic Reticulum Stress-Induced Leptin Resistance
Hosoi, T., Miyahara, T., Kayano, T., Yokoyama, S., & Ozawa, K. (2012) · Frontiers in Endocrinology · doi:10.3389/fendo.2012.00012 · Cited by 24 · see citing works
“We and others have recently proposed endoplasmic reticulum stress (ER stress) to be involved in the development of leptin resistance (Hosoi et al., 2008; Zhang et al., 2008; Hosoi and Ozawa, 2009, 2010; Milanski et al., 2009; Özcan et al., 2009; Won et al., 2009).”
BackgroundKim, J., Yun, E., Quan, F., Park, S.-W., & Goo, T. (2017) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2017/3607089 · Cited by 24 · see citing works
“Indeed, hypothalamic ER stress and leptin resistance are associated with increased energy intake and body weight [10, 11].”
BackgroundZhou, R., He, M. X., Fan, J., Li, R., Zuo, Y.-F., Li, B., Gao, G., & Sun, T. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.947295 · Cited by 23 · see citing works
“Mice with diet-induced obesity (DIO) have increased expression of hypothalamic ER stress markers, including phospho-PERK (p-PERK), phosphoeukaryotic initiation factor-2α (p-eIF2α), and phospho-IRE1 (p-IRE1) (Won et al., 2009; Cakir et al., 2013).”
BackgroundGenetic Targeting of GRP78 in the VMH Improves Obesity Independently of Food Intake
Liñares‐Pose, L., Rial‐Pensado, E., Estévez‐Salguero, Á., Milbank, E., González‐García, I., Rodríguez, C., Seoane‐Collazo, P., Martínez‐Sánchez, N., Nogueiras, R., Prieto, D., et al. (2018) · Genes · doi:10.3390/genes9070357 · Cited by 18 · see citing works
“In the same line of findings, it has been exposed that obesity and overnutrition-induced inflammation could promote hypothalamic ER stress, leading to insulin and l ptin resistance and, ultimately to weight gain [15,16,20,21,23,39,40].”
BackgroundHypothalamic neuronal cellular and subcellular abnormalities in experimental obesity
Razolli, D. S., Moura‐Assis, A., Bombassaro, B., & Velloso, L. A. (2019) · International Journal of Obesity · doi:10.1038/s41366-019-0451-8 · Cited by 18 · see citing works
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Glucose-regulated protein 78 binds to and regulates the melanocortin-4 receptor
Yoon, Y. R., Lee, T., Choi, M.-H., Shin, S. W., Ko, Y., Rhyu, I. J., Kim, D. H., Seong, J. K., & Baik, J. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0144-8 · Cited by 17 · see citing works
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Recent progress on action and regulation of anorexigenic adipokine leptin
Nakagawa, T., & Hosoi, T. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1172060 · Cited by 17 · see citing works
“The negative effects of ER stress on leptin signaling in the LepR-expressing neurons in mouse brains were also reported by other research groups (56, 57), reinforcing the notion that mitigating ER”
BackgroundBeall, C., Hanna, L., & Ellacott, K. L. J. (2017) · Comprehensive physiology · doi:10.1002/cphy.c160045 · Cited by 16 · see citing works
Sai, K., Morioka, S., Takaesu, G., Muthusamy, N., Ghashghaei, H. T., Hanafusa, H., Matsumoto, K., & Ninomiya‐Tsuji, J. (2016) · Journal of Cell Science · doi:10.1242/jcs.180505 · Cited by 15 · see citing works
- Authors
- Won, J. C., Jang, P., Namkoong, C., Koh, E. H., Kim, S. K., Park, J., Lee, K., & Kim, M.
- Affiliations
- Inje University (KR)
- University of Ulsan (KR)
- Konkuk University (KR)
- Corresponding author
- Kim, Min‐Seon
- Venue
- Obesity
- Publisher
- Wiley
- Published
- 2009-10
- Volume
- 17
- Issue
- 10
- Pages
- 1861-1865
- ISSN
- 1930-7381 (ISSN-L)
- 1930-739X
- OpenAlex
- W2037010692
- Cited by
- 153
- References
- 30
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 9 · 2020: 6 · 2019: 13 · 2018: 11 · 2017: 16 · 2016: 15 · 2015: 12 · 2014: 8 · 2013: 16 · 2012: 12
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Obesity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- endoplasmic reticulum stress, leptin resistance, insulin resistance, hypothalamus, thapsigargin, anorectic effect, dietary intake, body weight, STAT3, Akt, IRE1, XBP1, CHOP, 4-phenylbutyric acid, chemical chaperones, diet-induced obesity
- MeSH terms
- Regulatory Factor X Transcription Factors, X-Box Binding Protein 1, Animals, DNA-Binding Proteins, Endoplasmic Reticulum, Enzyme Inhibitors, Hypothalamus, Insulin, Male, Mice, Inbred C57BL, Obesity, RNA, Transcription Factors, Blotting, Western, Thapsigargin, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, Leptin, STAT3 Transcription Factor, Mice, Transcription Factor CHOP
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