{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:47:06Z","timestamp":1785422826142,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,29]]},"group-title":"Physiology","reference-count":91,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01HL128970"],"award-info":[{"award-number":["R01HL128970"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 HL174409"],"award-info":[{"award-number":["R01 HL174409"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["S10OD032420"],"award-info":[{"award-number":["S10OD032420"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Rationale<\/jats:title>\n                  <jats:p>There is no effective pharmacotherapy for obesity hypoventilation syndrome (OHS). Intranasal leptin augments the hypercapnic ventilatory response (HCVR), attenuates upper airway obstruction, and increases ventilation during sleep in diet-induced obese (DIO) mice. Respiratory effects of leptin can be attenuated by serotonergic antagonists.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To establish if serotonergic innervation of the hypoglossal motoneurons (XII MN) mediates effects of leptin on OHS.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We examined effects of intranasal leptin on the HCVR, sleep architecture, arousal latency, flow limited (obstructed) and non-flow limited breathing, genioglossus muscle (GG) activity and metabolic rate across sleep\/wake states in the presence and absence of serotonergic neurons innervating XII MN in DIO\n                    <jats:italic>Sert-flp<\/jats:italic>\n                    mice expressing\n                    <jats:italic>FlpO<\/jats:italic>\n                    recombinase in the serotonergic neurons. These mice were transfected into the XII MN with retrograde adeno-associated virus carrying either\n                    <jats:italic>FlpO<\/jats:italic>\n                    -dependent caspase or control yellow fluorescent protein (YFP).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Measurements and Main Results<\/jats:title>\n                  <jats:p>\n                    Control YFP virus was densely localized to the serotonergic neurons of the medullary raphe (MR), but not the dorsal raphe (DR), and these neurons were ablated by caspase. Leptin enhanced the HCVR, increased arousal latency in males, but not in females, and these effects were abolished by caspase. Neither leptin nor caspase affected sleep architecture or metabolic rate. Leptin increased GG activity awake and during NREM sleep, attenuated pharyngeal obstruction and increased minute ventilation in NREM and REM sleep. All effects of leptin were abolished by the\n                    <jats:italic>FlpO<\/jats:italic>\n                    -dependent caspase.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Leptin treats OHS by stimulating MR serotonergic neurons, which project to XII MN and stimulate pharyngeal muscles during sleep.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.23.734005","type":"posted-content","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:30:15Z","timestamp":1782750615000},"source":"Crossref","is-referenced-by-count":0,"title":["Leptin alleviates obesity hypoventilation\n                  <i>via<\/i>\n                  serotonergic pathways"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6983-1611","authenticated-orcid":false,"given":"Dashdulam","family":"Davaanyam","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Science"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie Alexis","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Science"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junia L","family":"de Deus","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Science"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Kyung","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Science"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cole R","family":"Winston","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Science"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Science"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateus R.","family":"Amorim","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Science"},{"name":"Department of Physiology, Medical School of Ribeir\u00e3o Preto, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Mendelowitz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Science"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vsevolod Y.","family":"Polotsky","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Science"},{"name":"Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Science"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070109051156000_2026.06.23.734005v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(66)90117-X"},{"key":"2026070109051156000_2026.06.23.734005v1.2","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.4187\/respcare.10551347","article-title":"Obesity hypoventilation syndrome: a state-of-the-art review","volume":"55","year":"2010","journal-title":"Respir Care"},{"key":"2026070109051156000_2026.06.23.734005v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2003.08.022"},{"key":"2026070109051156000_2026.06.23.734005v1.4","first-page":"165","article-title":"Ventilatory control and the obesity hypoventilation syndrome","volume":"119","year":"1979","journal-title":"Am. 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