{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:43:59Z","timestamp":1791297839813,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2012,5,4]],"date-time":"2012-05-04T00:00:00Z","timestamp":1336089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Peptide Science"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:p>The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Unfortunately, leptin monotherapy is insufficient in reversing obesity in rodents or humans. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. However, as the uniqueness of this combination therapy remains unclear, we assessed whether co\u2010administration of leptin with other weight loss\u2010inducing hormones equally restores leptin responsiveness in diet\u2010induced obese (DIO) mice. Accordingly, we report here the design and characterization of a series of site\u2010specifically enhanced leptin analogs of high potency and sustained action that, when administered in combination with exendin\u20104 or fibroblast growth factor 21 (FGF21), restores leptin responsiveness in DIO mice after an initial body weight loss of 30%. Using either combination, body weight loss was enhanced compared with either exendin\u20104 or FGF21 monotherapy, and leptin alone was sufficient to maintain the reduced body weight. In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. Accordingly, we find that a hypothalamic counter\u2010regulatory response to weight loss, assessed using changes in hypothalamic agouti related peptide (AgRP) levels, is triggered by caloric restriction, but blunted by treatment with exendin\u20104. We conclude that leptin re\u2010sensitization requires pharmacotherapy but does not appear to be restricted to a unique signaling pathway. Our findings provide preclinical evidence that high activity, long\u2010acting leptin analogs are additively efficacious when used in combination with other weight\u2010lowering agents. Copyright \u00a9 2012 European Peptide Society and John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/psc.2408","type":"journal-article","created":{"date-parts":[[2012,5,5]],"date-time":"2012-05-05T05:09:04Z","timestamp":1336194544000},"page":"383-393","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":146,"title":["Restoration of leptin responsiveness in diet\u2010induced obese mice using an optimized leptin analog in combination with exendin\u20104 or FGF21"],"prefix":"10.1002","volume":"18","author":[{"given":"Timo D.","family":"M\u00fcller","sequence":"first","affiliation":[{"name":"Metabolic Disease Institute, Division of Endocrinology, Diabetes &amp; Metabolism Department of Internal Medicine College of Medicine University of Cincinnati  Cincinnati OH 45230 USA"},{"name":"Institute of Diabetes and Obesity Helmholtz Center Munich, German Research Center for Environmental Health (GmbH)  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine M.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Ambrx, Inc.  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