{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T15:30:13Z","timestamp":1789659013190,"version":"4.0.1"},"reference-count":0,"publisher":"American Diabetes Association","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"Brazilian Federal Agency for Support and Evaluation of Graduate Education","id":[{"id":"https:\/\/ror.org\/00x0ma614","id-type":"ROR","asserted-by":"crossref"}]},{"name":"FAEPA-HCFMRP-USP"},{"name":"National Council for Scientific and Technological Development","id":[{"id":"https:\/\/ror.org\/03swz6y49","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001807","name":"Funda de Ampar Pesquisa d Estado de S Paul","doi-asserted-by":"publisher","award":["2018\/18071-5"],"award-info":[{"award-number":["2018\/18071-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda de Ampar Pesquisa d Estado de S Paul","doi-asserted-by":"publisher","award":["2022\/09687-8"],"award-info":[{"award-number":["2022\/09687-8"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Obesity is marked by chronic low-grade inflammation and impaired thermogenic function of brown adipose tissue (BAT), contributing to decreased energy expenditure. BAT dissipates energy through uncoupling protein 1 (UCP1)-mediated thermogenesis, a process suppressed in obesity. Phosphodiesterase 4 (PDE4) inhibition reduces inflammation by decreasing TNF-\u03b1 release, and it has been linked to protection against metabolic dysfunction. Here, we investigated the effects of rolipram, a selective PDE4 inhibitor, in a model of diet-induced obesity. Male C57Bl\/6 mice were fed a chow or high-fat diet (HFD; 60% fat) for 10 weeks and treated daily with rolipram (2 mg\/kg, subcutaneous) or vehicle from week 8 on. Rolipram reduced body weight and adiposity in HFD-fed mice. It also enhanced BAT function, increasing thermogenic gene expression, UCP1 protein, noradrenaline content, and BAT temperature. PDE4 inhibition increased energy expenditure and heat production without altering locomotor activity. Corroborating these data, rolipram elevated cFOS expression and increased membrane excitability in neurons of the hypothalamic paraventricular nucleus, suggesting activation of hypothalamic pathways involved in energy balance and thermoregulation. These findings show that PDE4 inhibition attenuates diet-induced obesity by stimulating BAT thermogenesis and energy expenditure at least partially through central mechanisms, supporting PDE4 as a promising target for obesity treatment.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>ARTICLE HIGHLIGHTS<\/jats:title>\n                    <jats:p>Metabolic alterations in obesity encompass impaired thermogenesis and sympathetic activity, underscoring the need for new metabolic targets to treat this disease. This study tested whether inhibition of PDE4 by rolipram enhances energy expenditure and brown adipose tissue activity. Rolipram reduced body weight and adiposity and increased brown adipose tissue temperature, UCP1 protein levels, noradrenaline levels, and enhanced excitability of hypothalamic paroventricular nucleus neurons. These findings suggest that central PDE4 inhibition promotes brown adipose tissue thermogenic activity and contributes to the metabolic effects of rolipram.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-1135","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T16:56:26Z","timestamp":1789491386000},"update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Phosphodiesterase 4 Inhibition Attenuates Diet-Induced Obesity and Activates BAT Thermogenic Pathways Through Central Mechanisms"],"prefix":"10.2337","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5685-9170","authenticated-orcid":false,"given":"Hellen","family":"Veida-Raposo","sequence":"first","affiliation":[{"name":"1Department of Internal Medicine, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"2Department of Physiology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Am\u00e9lia Montenegro","family":"de Andrade","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrik Saul Barbosa","family":"Zarpellon","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele de Souza","family":"Seixas","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiza Mendon\u00e7a","family":"Duarte","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa Elvira","family":"Alarc\u00f3n-Yemp\u00e9n","sequence":"additional","affiliation":[{"name":"3Department of Biomolecular Sciences, Faculty of Pharmaceutical Sciences of Ribeir\u00e3o, Preto University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"4Department of Biochemistry, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline Alves","family":"de Jesus","sequence":"additional","affiliation":[{"name":"2Department of Physiology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciane Carla","family":"Alberici","sequence":"additional","affiliation":[{"name":"3Department of Biomolecular Sciences, Faculty of Pharmaceutical Sciences of Ribeir\u00e3o, Preto University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Maur\u00edcio","family":"Le\u00e3o","sequence":"additional","affiliation":[{"name":"2Department of Physiology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Antunes-Rodrigues","sequence":"additional","affiliation":[{"name":"2Department of Physiology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1262-3486","authenticated-orcid":false,"given":"Francisco Jos\u00e9 Albuquerque","family":"de Paula","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6271-758X","authenticated-orcid":false,"given":"Lucila Leico K.","family":"Elias","sequence":"additional","affiliation":[{"name":"2Department of Physiology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,9,15]]},"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db25-1135\/895194\/db251135.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db25-1135\/895194\/db251135.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T16:56:27Z","timestamp":1789491387000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/doi\/10.2337\/db25-1135\/172541\/Phosphodiesterase-4-Inhibition-Attenuates-Diet"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":0,"URL":"https:\/\/doi.org\/10.2337\/db25-1135","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]},"article-number":"db251135"}}