{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:54Z","timestamp":1787028474495,"version":"build-2736575974"},"reference-count":64,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T00:00:00Z","timestamp":1650672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biomedical Research Networking Center on Neurodegenerative Diseases","award":["PIE14\/00061"],"award-info":[{"award-number":["PIE14\/00061"]}]},{"name":"Ministerio de ciencia e innovaci\u00f3n. Agencia estatal de investigaci\u00f3n","award":["PID2019-104376RB-I00"],"award-info":[{"award-number":["PID2019-104376RB-I00"]}]},{"DOI":"10.13039\/501100006541","name":"Comunidad de Madrid","doi-asserted-by":"publisher","award":["B2017\/BMD-3700"],"award-info":[{"award-number":["B2017\/BMD-3700"]}],"id":[{"id":"10.13039\/501100006541","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Uncoupling of metabolism and circadian activity is associated with an increased risk of a wide spectrum of pathologies. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain less defined. We recently showed that IGF-I targets orexin neurons in the lateral hypothalamus, and now we evaluated whether IGF-I modulates orexin neurons to align circadian rhythms with metabolism. Mice with disrupted IGF-IR activity in orexin neurons (Firoc mice) showed sexually dimorphic alterations in daily glucose rhythms and feeding activity patterns which preceded the appearance of metabolic disturbances. Thus, Firoc males developed hyperglycemia and glucose intolerance, while females developed obesity. Since IGF-I directly modulates orexin levels and hepatic expression of KLF genes involved in circadian and metabolic entrainment in an orexin-dependent manner, it seems that IGF-I entrains metabolism and circadian rhythms by modulating the activity of orexin neurons.<\/jats:p>","DOI":"10.3390\/ijms23094679","type":"journal-article","created":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T08:14:06Z","timestamp":1650701646000},"page":"4679","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Insulin-like Growth Factor I Couples Metabolism with Circadian Activity through Hypothalamic Orexin Neurons"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8431-2241","authenticated-orcid":false,"given":"Jaime","family":"Pignatelli","sequence":"first","affiliation":[{"name":"Cajal Institute-CSIC, 28002 Madrid, Spain"},{"name":"CIBERNED, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2693-1861","authenticated-orcid":false,"given":"M. Estrella Fernandez","family":"de Sevilla","sequence":"additional","affiliation":[{"name":"Cajal Institute-CSIC, 28002 Madrid, Spain"},{"name":"CIBERNED, 28029 Madrid, Spain"},{"name":"Medicine Faculty, Autonoma University, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6290-7300","authenticated-orcid":false,"given":"Jacob","family":"Sperber","sequence":"additional","affiliation":[{"name":"Cajal Institute-CSIC, 28002 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Horrillo","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences of Health, Area of Biochemistry and Molecular Biology, LAFEMEX Lab, University Rey Juan Carlos, 28933 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8169-681X","authenticated-orcid":false,"given":"Gema","family":"Medina-Gomez","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences of Health, Area of Biochemistry and Molecular Biology, LAFEMEX Lab, University Rey Juan Carlos, 28933 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8107-7947","authenticated-orcid":false,"given":"Ignacio Torres","family":"Aleman","sequence":"additional","affiliation":[{"name":"CIBERNED, 28029 Madrid, Spain"},{"name":"Achucarro Basque Neuroscience Center, 48940 Leioa, Spain"},{"name":"Ikerbasque Foundation for Science, 48009 Bilbao, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hegazi, S., Lowden, C., Garcia, J.R., Cheng, A.H., Obrietan, K., Levine, J.D., and Cheng, H.Y.M. (2019). A symphony of signals: Intercellular and intracellular signaling mechanisms underlying circadian timekeeping in mice and flies. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092363"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.molmet.2018.01.013","article-title":"Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-\u03b2 uptake in astrocytes","volume":"9","author":"Logan","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e04617","DOI":"10.7554\/eLife.04617","article-title":"Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant","volume":"3","author":"Izumo","year":"2014","journal-title":"eLife"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1016\/j.cell.2019.04.025","article-title":"Defining the independence of the liver circadian clock","volume":"177","author":"Koronowski","year":"2019","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/B978-0-444-59427-3.00001-0","article-title":"How rod, cone, and melanopsin photoreceptors come together to enlighten the mammalian circadian clock","volume":"Volume 199","author":"Lucas","year":"2012","journal-title":"Progress in Brain Research"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.molmet.2014.03.002","article-title":"Circadian control of glucose metabolism","volume":"3","author":"Kalsbeek","year":"2014","journal-title":"Mol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/s41574-019-0210-x","article-title":"The circadian regulation of food intake","volume":"15","author":"Challet","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.tem.2009.12.011","article-title":"Interactions of the circadian CLOCK system and the HPA axis","volume":"21","author":"Nader","year":"2010","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"132","DOI":"10.3389\/fnut.2019.00132","article-title":"At the interface of lifestyle, behavior, and circadian rhythms: Metabolic implications","volume":"6","author":"Bae","year":"2019","journal-title":"Front. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12576-016-0450-7","article-title":"The mammalian circadian clock and its entrainment by stress and exercise","volume":"67","author":"Tahara","year":"2017","journal-title":"J. Physiol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/nature11704","article-title":"Circadian topology of metabolism","volume":"491","author":"Bass","year":"2012","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E5464","DOI":"10.1073\/pnas.1700983114","article-title":"Hypocretin (orexin) is critical in sustaining theta\/gamma-rich waking behaviors that drive sleep need","volume":"114","author":"Vassalli","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10529","DOI":"10.1523\/JNEUROSCI.0784-11.2011","article-title":"Acute optogenetic silencing of orexin\/hypocretin neurons induces slow-wave sleep in mice","volume":"31","author":"Tsunematsu","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/nature06310","article-title":"Neural substrates of awakening probed with optogenetic control of hypocretin neurons","volume":"450","author":"Adamantidis","year":"2007","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.1523\/JNEUROSCI.3388-13.2014","article-title":"Acute suppressive and long-term phase modulation actions of orexin on the mammalian circadian clock","volume":"34","author":"Belle","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.cell.2019.02.017","article-title":"Insulin\/IGF-1 drives PERIOD synthesis to entrain circadian rhythms with feeding time","volume":"177","author":"Crosby","year":"2019","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wan, X., Wang, S., Xu, J., Zhuang, L., Xing, K., Zhang, M., Zhu, X., Wang, L., Gao, P., and Xi, Q. (2017). Dietary protein-induced hepatic IGF-1 secretion mediated by PPAR\u00e3 activation. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173174"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"653017","DOI":"10.1155\/2014\/653017","article-title":"PPARs integrate the mammalian clock and energy metabolism","volume":"2014","author":"Chen","year":"2014","journal-title":"PPAR Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1111\/j.1532-5415.1999.tb07431.x","article-title":"Low plasma insulin-like growth factor-1 concentrations predict worsening of insulin-mediated glucose uptake in older people","volume":"47","author":"Paolisso","year":"1999","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.2337\/diabetes.50.5.1110","article-title":"Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity","volume":"50","author":"Yakar","year":"2001","journal-title":"Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4356","DOI":"10.1210\/jc.2002-020343","article-title":"IGF-I\/IGF-binding protein-3 combination improves insulin resistance by GH-dependent and independent mechanisms","volume":"87","author":"Clemmons","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/acel.12415","article-title":"Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline","volume":"15","author":"Huffman","year":"2016","journal-title":"Aging Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.2337\/db21-0028","article-title":"Modulation of glucose production by central insulin requires IGF-1 receptors in AgRP neurons","volume":"70","author":"Mao","year":"2021","journal-title":"Diabetes"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.neuron.2006.04.032","article-title":"Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose","volume":"50","author":"Burdakov","year":"2006","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.2337\/db09-0385","article-title":"A major role for perifornical orexin neurons in the control of glucose metabolism in rat","volume":"58","author":"Yi","year":"1998","journal-title":"Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.neuropharm.2014.06.015","article-title":"Concurrent and robust regulation of feeding behaviors and metabolism by orexin neurons","volume":"85","author":"Inutsuka","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00109-002-0322-x","article-title":"Orexins: From neuropeptides to energy homeostasis and sleep\/wake regulation","volume":"80","author":"Beuckmann","year":"2002","journal-title":"J. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S0896-6273(01)00293-8","article-title":"Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity","volume":"30","author":"Hara","year":"2001","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15975","DOI":"10.1096\/fj.202001281RR","article-title":"Insulin-like growth factor I modulates sleep through hypothalamic orexin neurons","volume":"34","author":"Pignatelli","year":"2020","journal-title":"FASEB J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s00125-008-0929-8","article-title":"Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice","volume":"51","author":"Tsuneki","year":"2008","journal-title":"Diabetologia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15172","DOI":"10.1073\/pnas.0806717105","article-title":"Physiological significance of a peripheral tissue circadian clock","volume":"105","author":"Lamia","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nature09253","article-title":"Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes","volume":"466","author":"Marcheva","year":"2010","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.npep.2013.02.002","article-title":"Hypothalamic orexin prevents hepatic insulin resistance induced by social defeat stress in mice","volume":"47","author":"Tsuneki","year":"2013","journal-title":"Neuropeptides"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"36035","DOI":"10.1038\/srep36035","article-title":"Orexin signaling regulates both the hippocampal clock and the circadian oscillation of Alzheimer\u2019s disease-risk genes","volume":"6","author":"Ma","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1016\/j.febslet.2011.03.021","article-title":"Circadian disruption and SCN control of energy metabolism","volume":"585","author":"Kalsbeek","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fendo.2013.00018","article-title":"The physiological role of orexin\/hypocretin neurons in the regulation of sleep\/wakefulness and neuroendocrine functions","volume":"4","author":"Inutsuka","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10493","DOI":"10.1523\/JNEUROSCI.3171-04.2004","article-title":"Orexin neurons function in an efferent pathway of a food-entrainable circadian oscillator in eliciting food-anticipatory activity and wakefulness","volume":"24","author":"Mieda","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3389\/fnins.2013.00185","article-title":"Circadian adaptations to meal timing: Neuroendocrine mechanisms","volume":"7","author":"Patton","year":"2013","journal-title":"Front. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1007\/s00125-006-0273-9","article-title":"Diurnal rhythm in endogenous glucose production is a major contributor to fasting hyperglycaemia in type 2 diabetes. Suprachiasmatic deficit or limit cycle behaviour?","volume":"49","year":"2006","journal-title":"Diabetologia"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Fernandez de Sevilla, M.E., Pignatelli, J., Mendez, P., Zegarra-Valdivia, J.A., Torres Aleman, I., de Sevilla, M.F., Pignatelli, J., Mendez, P., Zegarra-Valdivia, J.A., and Alem\u00e1n, I.T. (2022). Insulin-like growth factor i mitigates post-traumatic stress by inhibiting amp-kinase in orexin neurons. Mol. Psychiatry.","DOI":"10.1038\/s41380-022-01442-9"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3389\/fendo.2013.00057","article-title":"Differential roles of orexin receptors in the regulation of sleep\/wakefulness","volume":"4","author":"Mieda","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"eabd0384","DOI":"10.1126\/sciadv.abd0384","article-title":"The mammalian circadian pacemaker regulates wakefulness via CRF neurons in the paraventricular nucleus of the hypothalamus","volume":"6","author":"Ono","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/nature10700","article-title":"Cryptochromes mediate rhythmic repression of the glucocorticoid receptor","volume":"480","author":"Lamia","year":"2011","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"459","DOI":"10.2337\/db14-0695","article-title":"Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice","volume":"64","author":"Tsuneki","year":"2015","journal-title":"Diabetes"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kalsbeek, A., Foppen, E., Schalij, I., Van Heijningen, C., van der Vliet, J., Fliers, E., and Buijs, R.M. (2008). Circadian control of the daily plasma glucose rhythm: An interplay of GABA and glutamate. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003194"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7604","DOI":"10.1523\/JNEUROSCI.5328-03.2004","article-title":"Behavioral\/systems\/cognitive suprachiasmatic GABAergic inputs to the paraventricular nucleus control plasma glucose concentrations in the rat via sympathetic innervation of the liver","volume":"24","author":"Kalsbeek","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.biopsych.2016.10.013","article-title":"Orexins mediate sex differences in the stress response and incognitive flexibility","volume":"81","author":"Grafe","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"244","DOI":"10.3389\/fnbeh.2014.00244","article-title":"Exercise reverses the effects of early life stress on orexin cell reactivity in male but not female rats","volume":"8","author":"James","year":"2014","journal-title":"Front. Behav. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/S0896-6273(03)00331-3","article-title":"Hypothalamic orexin neurons regulate arousal according to energy balance in mice","volume":"38","author":"Yamanaka","year":"2003","journal-title":"Neuron"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Xie, X., Kukino, A., Calcagno, H.E., Berman, A.M., Garner, J.P., and Butler, M.P. (2020). Natural food intake patterns have little synchronizing effect on peripheral circadian clocks. BMC Biol., 18.","DOI":"10.1186\/s12915-020-00872-7"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0149-7634(88)80002-2","article-title":"Hypothalamic paraventricular nucleus: Interaction between \u03b12-noradrenergic system and circulating hormones and nutrients in relation to energy balance","volume":"12","author":"Leibowitz","year":"1988","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.brainres.2017.07.006","article-title":"Effects of feeding time on daily rhythms of neuropeptide and clock gene expression in the rat hypothalamus","volume":"1671","author":"Wang","year":"2017","journal-title":"Brain Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1111\/ejn.13563","article-title":"Feeding during the rest phase promotes circadian conflict in nuclei that control energy homeostasis and sleep\u2013wake cycle in rats","volume":"45","author":"Saderi","year":"2017","journal-title":"Eur. J. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Landry, G.J., Kent, B.A., Patton, D.F., Jaholkowski, M., Marchant, E.G., and Mistlberger, R.E. (2011). Evidence for time-of-day dependent effect of neurotoxic dorsomedial hypothalamic lesions on food anticipatory circadian rhythms in rats. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024187"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5813","DOI":"10.1073\/pnas.1015551108","article-title":"Interaction between hypothalamic dorsomedial nucleus and the suprachiasmatic nucleus determines intensity of food anticipatory behavior","volume":"108","author":"Yi","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6808","DOI":"10.1073\/pnas.0902063106","article-title":"Daily rhythms of food-anticipatory behavioral activity do not require the known circadian clock","volume":"106","author":"Storch","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3389\/fendo.2015.00061","article-title":"Sexual dimorphism in glucose and lipid metabolism during fasting, hypoglycemia, and exercise","volume":"6","author":"Hedrington","year":"2015","journal-title":"Front. Endocrinol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"44","DOI":"10.3389\/fendo.2017.00044","article-title":"High-fat feeding does not disrupt daily rhythms in female mice because of protection by ovarian hormones","volume":"8","author":"Palmisano","year":"2017","journal-title":"Front. Endocrinol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.yfrne.2013.11.003","article-title":"Sex differences in circadian timing systems: Implications for disease","volume":"35","author":"Bailey","year":"2014","journal-title":"Front. Neuroendocrinol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1210\/er.2018-00151","article-title":"The Kr\u00fcppel-like factors and control of energy homeostasis","volume":"40","author":"Hsieh","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1128\/MCB.01141-09","article-title":"Kruppel-like factor KLF10 is a link between the circadian clock and metabolism in liver","volume":"30","author":"Guillaumond","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/0306-4522(90)90332-X","article-title":"Trophic effects of insulin-like growth factor-I on fetal rat hypothalamic cells in culture","volume":"35","author":"Naftolin","year":"1990","journal-title":"Neuroscience"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1093\/cercor\/bhx106","article-title":"A coordinated action of blood-borne and brain insulin-like growth factor I in the response to traumatic brain injury","volume":"28","author":"Santi","year":"2018","journal-title":"Cereb. Cortex"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT\u2013PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4679\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:59:24Z","timestamp":1760137164000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,23]]},"references-count":64,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23094679"],"URL":"https:\/\/doi.org\/10.3390\/ijms23094679","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.02.07.429949","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,23]]}}}