{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:51:20Z","timestamp":1790707880904,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["209933838"],"award-info":[{"award-number":["209933838"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University Leipzig, Medical Faculty","award":["Nachwuchsf\u00f6rderprogramm"],"award-info":[{"award-number":["Nachwuchsf\u00f6rderprogramm"]}]},{"DOI":"10.13039\/501100010215","name":"Deutsche Diabetes Gesellschaft","doi-asserted-by":"publisher","award":["Projektpreis der AG Diabetes und Niere 2020"],"award-info":[{"award-number":["Projektpreis der AG Diabetes und Niere 2020"]}],"id":[{"id":"10.13039\/501100010215","id-type":"DOI","asserted-by":"publisher"}]},{"name":"HI-MAG","award":["Young Scientist"],"award-info":[{"award-number":["Young Scientist"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl\/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg\/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.<\/jats:p>","DOI":"10.3390\/nu13082499","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T22:35:31Z","timestamp":1626993331000},"page":"2499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Leptin Improves Parameters of Brown Adipose Tissue Thermogenesis in Lipodystrophic Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Annett","family":"Hoffmann","sequence":"first","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany"},{"name":"Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1683-9276","authenticated-orcid":false,"given":"Thomas","family":"Ebert","sequence":"additional","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany"},{"name":"Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 17177 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed K.","family":"Hankir","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gesine","family":"Flehmig","sequence":"additional","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7625-7254","authenticated-orcid":false,"given":"Nora","family":"Kl\u00f6ting","sequence":"additional","affiliation":[{"name":"Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum M\u00fcnchen at the University of Leipzig, 04109 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Jessnitzer","sequence":"additional","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"L\u00f6ssner","sequence":"additional","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Stumvoll","sequence":"additional","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0208-2065","authenticated-orcid":false,"given":"Matthias","family":"Bl\u00fcher","sequence":"additional","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany"},{"name":"Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum M\u00fcnchen at the University of Leipzig, 04109 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Fasshauer","sequence":"additional","affiliation":[{"name":"Institute of Nutritional Science, Justus-Liebig-University, 35390 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"T\u00f6njes","sequence":"additional","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstanze","family":"Miehle","sequence":"additional","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Kralisch","sequence":"additional","affiliation":[{"name":"Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04109 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Knebel, B., M\u00fcller-Wieland, D., and Kotzka, J. (2020). Lipodystrophies\u2014Disorders of the Fatty Tissue. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228778"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1210\/jcem.87.5.8624","article-title":"Serum Adiponectin and Leptin Levels in Patients with Lipodystrophies","volume":"87","author":"Haque","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.diabres.2016.07.017","article-title":"Progranulin is increased in human and murine lipodystrophy","volume":"120","author":"Miehle","year":"2016","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1111\/cen.12976","article-title":"Circulating serum chemerin levels are elevated in lipodystrophy","volume":"84","author":"Miehle","year":"2015","journal-title":"Clin. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1056\/NEJMoa012437","article-title":"Leptin-Replacement Therapy for Lipodystrophy","volume":"346","author":"Oral","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"922","DOI":"10.4158\/EP11229.OR","article-title":"Clinical Effects of Long-Term Metreleptin Treatment in Patients with Lipodystrophy","volume":"17","author":"Chan","year":"2011","journal-title":"Endocr. Pract."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/nbt0414-300b","article-title":"Leptin therapy gains FDA approval","volume":"32","author":"Sinha","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_8","unstructured":"EMA (2018). Metreleptin for Treatment of Familial Partial Lipodystrophy (Orphan Decision Number: EU\/3\/12\/1022), European Medicines Agency."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1016\/j.bbadis.2018.07.015","article-title":"Leptin restores markers of female fertility in lipodystrophy","volume":"1864","author":"Eifler","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5550","DOI":"10.1096\/fj.201701427R","article-title":"Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: Adipose tissue-kidney crosstalk","volume":"32","author":"Liu","year":"2018","journal-title":"FASEB J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1161\/HYPERTENSIONAHA.119.13398","article-title":"Leptin Restores Endothelial Function via Endothelial PPAR\u03b3-Nox1\u2013Mediated Mechanisms in a Mouse Model of Congenital Generalized Lipodystrophy","volume":"74","author":"Faulkner","year":"2019","journal-title":"Hypertension"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.cmet.2010.03.007","article-title":"The Changed Metabolic World with Human Brown Adipose Tissue: Therapeutic Visions","volume":"11","author":"Nedergaard","year":"2010","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1152\/physrev.00015.2003","article-title":"Brown Adipose Tissue: Function and Physiological Significance","volume":"84","author":"Cannon","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"571659","DOI":"10.3389\/fendo.2020.571659","article-title":"Substrate Utilization by Brown Adipose Tissue: What\u2019s Hot and What\u2019s Not?","volume":"11","author":"McNeill","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1113\/jphysiol.1984.sp015431","article-title":"Effects of denervating brown adipose tissue on the responses to cold, hyperphagia and noradrenaline treatment in the rat","volume":"355","author":"Rothwell","year":"1984","journal-title":"J. Physiol."},{"key":"ref_16","first-page":"839","article-title":"A leptin\u2013BDNF pathway regulating sympathetic innervation of adipose tissue","volume":"583","author":"Wang","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3182","DOI":"10.1101\/gad.12.20.3182","article-title":"Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: Model for congenital generalized lipodystrophy","volume":"12","author":"Shimomura","year":"1998","journal-title":"Genes Dev."},{"key":"ref_18","first-page":"73","article-title":"Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy","volume":"401","author":"Shimomura","year":"1999","journal-title":"Nat. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.cmet.2016.12.008","article-title":"Adipocyte Dynamics and Reversible Metabolic Syndrome in Mice with an Inducible Adipocyte-Specific Deletion of the Insulin Receptor","volume":"25","author":"Sakaguchi","year":"2017","journal-title":"Cell Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1194\/jlr.M045799","article-title":"Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 lipodystrophic mice independent of hepatocyte leptin receptors","volume":"55","author":"Cautivo","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1007\/s00125-016-4004-6","article-title":"Treatment of diet-induced lipodystrophic C57BL\/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation","volume":"59","author":"Bolze","year":"2016","journal-title":"Diabetologia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.2337\/db16-0212","article-title":"Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function","volume":"65","author":"Boucher","year":"2016","journal-title":"Diabetes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"40441","DOI":"10.1074\/jbc.M112.384545","article-title":"Leptin Activates Hepatic 5\u2032-AMP-activated Protein Kinase through Sympathetic Nervous System and \u03b11-Adrenergic Receptor: A potential mechanism for improvement of fatty liver in lipodystrophy by leptin","volume":"287","author":"Miyamoto","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1476-511X-7-8","article-title":"Effect of leptin infusion on insulin sensitivity and lipid metabolism in diet-induced lipodystrophy model mice","volume":"7","author":"Nagao","year":"2008","journal-title":"Lipids Health Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14623","DOI":"10.1073\/pnas.96.25.14623","article-title":"Torpor in mice is induced by both leptin-dependent and -independent mechanisms","volume":"96","author":"Gavrilova","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.bbadis.2015.10.022","article-title":"Leptin dose-dependently decreases atherosclerosis by attenuation of hypercholesterolemia and induction of adiponectin","volume":"1862","author":"Hoffmann","year":"2016","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"38124","DOI":"10.1038\/srep38124","article-title":"Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice","volume":"6","author":"Weiner","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1016\/j.celrep.2016.01.041","article-title":"Leptin Raises Defended Body Temperature without Activating Thermogenesis","volume":"14","author":"Fischer","year":"2016","journal-title":"Cell Rep."},{"key":"ref_29","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-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-07453-x","article-title":"Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue","volume":"9","author":"Pellegrinelli","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.mce.2017.01.011","article-title":"Thyroid hormones and browning of adipose tissue","volume":"458","author":"Weiner","year":"2017","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"E552","DOI":"10.1152\/ajpendo.00462.2017","article-title":"Leptin regulation of core body temperature involves mechanisms independent of the thyroid axis","volume":"315","author":"Deem","year":"2018","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Grover, A., Quaye, E., Brychta, R.J., Christensen, J., Startzell, M.S., Meehan, C.A., Valencia, A., Marshall, B., Chen, K.Y., and Brown, R.J. (2021). Leptin Decreases Energy Expenditure Despite Increased Thyroid Hormone in Patients with Lipodystrophy. J. Clin. Endocrinol. Metab.","DOI":"10.1210\/clinem\/dgab269"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"799","DOI":"10.2967\/jnumed.116.180992","article-title":"Sympathetic Innervation of Cold-Activated Brown and White Fat in Lean Young Adults","volume":"58","author":"Muzik","year":"2017","journal-title":"J. Nucl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4089","DOI":"10.2337\/db14-0746","article-title":"Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans","volume":"63","author":"Chondronikola","year":"2014","journal-title":"Diabetes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1016\/j.cmet.2016.04.029","article-title":"Brown Adipose Tissue Activation Is Linked to Distinct Systemic Effects on Lipid Metabolism in Humans","volume":"23","author":"Chondronikola","year":"2016","journal-title":"Cell Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6356","DOI":"10.1038\/ncomms7356","article-title":"Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development","volume":"6","author":"Boon","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nm.2297","article-title":"Brown adipose tissue activity controls triglyceride clearance","volume":"17","author":"Bartelt","year":"2011","journal-title":"Nat. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"E952","DOI":"10.1152\/ajpendo.00333.2019","article-title":"No insulating effect of obesity, neither in mice nor in humans","volume":"317","author":"Fischer","year":"2019","journal-title":"Am. J. Physiol.-Endocrinol. Metab."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/8\/2499\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:33:23Z","timestamp":1760164403000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/8\/2499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,22]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["nu13082499"],"URL":"https:\/\/doi.org\/10.3390\/nu13082499","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,22]]}}}