Baris Akinci1,2, Angela Subauste1,3, Nevin Ajluni1, Nazanene H Esfandiari1, Rasimcan Meral1, Adam H Neidert1, Akin Eraslan1, Rita Hench1, Diana Rus1, Barbara McKenna4, Hero K Hussain5, Thomas L Chenevert5, Marwan K Tayeh6, Amit R Rupani6, Jeffrey W Innis6,7, Christos S Mantzoros8, Hari S Conjeevaram9, Charles L Burant1, Elif A Oral1,10. 1. Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. 2. Division of Endocrinology and Metabolism, Department of Internal Medicine, Dokuz Eylul University, Izmir, Turkey. 3. Division of Endocrinology and Diabetes, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA. 4. Department of Pathology, University of Michigan, Ann Arbor, MI, USA. 5. Department of Radiology, University of Michigan, Ann Arbor, MI, USA. 6. Departments of Pediatrics, University of Michigan, Ann Arbor, MI, USA. 7. Departments of Human Genetics, University of Michigan, Ann Arbor, MI, USA. 8. Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 9. Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. 10. Lead contact.
Abstract
BACKGROUND: Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve nonalcoholic steatohepatitis in more common forms of this heterogeneous condition. METHODS: Nine male patients with relative leptin deficiency (level < 25th percentile of body mass index- and gender-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for two distinctive open-label trials. Participants received leptin therapy in the form of metreleptin for 12 months. The primary endpoints were the global nonalcoholic steatohepatitis scores from paired liver biopsies scored blindly. FINDINGS: Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12-months of therapy. Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range: from 1 to 6, P = 0.004). In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment, and 18 completed a second liver biopsy. Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range: from -2 to 4, P = 0.008). In both studies, the predominant changes were in steatosis and hepatic injury scores. CONCLUSION: Our findings show that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy have reductions in hepatic steatosis and injury in response to exogenous leptin therapy. Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver.TRIAL REGISTRATION. ClinicalTrials.gov NCT00596934 and NCT01679197.
BACKGROUND: Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve nonalcoholic steatohepatitis in more common forms of this heterogeneous condition. METHODS: Nine male patients with relative leptin deficiency (level < 25th percentile of body mass index- and gender-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for two distinctive open-label trials. Participants received leptin therapy in the form of metreleptin for 12 months. The primary endpoints were the global nonalcoholic steatohepatitis scores from paired liver biopsies scored blindly. FINDINGS: Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12-months of therapy. Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range: from 1 to 6, P = 0.004). In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment, and 18 completed a second liver biopsy. Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range: from -2 to 4, P = 0.008). In both studies, the predominant changes were in steatosis and hepatic injury scores. CONCLUSION: Our findings show that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy have reductions in hepatic steatosis and injury in response to exogenous leptin therapy. Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver.TRIAL REGISTRATION. ClinicalTrials.gov NCT00596934 and NCT01679197.
Authors: Lidia S Szczepaniak; Pamela Nurenberg; David Leonard; Jeffrey D Browning; Jason S Reingold; Scott Grundy; Helen H Hobbs; Robert L Dobbins Journal: Am J Physiol Endocrinol Metab Date: 2004-08-31 Impact factor: 4.310
Authors: Rasimcan Meral; Benjamin J Ryan; Noemi Malandrino; Abdelwahab Jalal; Adam H Neidert; Ranganath Muniyappa; Barış Akıncı; Jeffrey F Horowitz; Rebecca J Brown; Elif A Oral Journal: Diabetes Care Date: 2018-10 Impact factor: 19.112
Authors: Stuart McPherson; Tim Hardy; Elsbeth Henderson; Alastair D Burt; Christopher P Day; Quentin M Anstee Journal: J Hepatol Date: 2014-12-01 Impact factor: 25.083
Authors: Yan Gao; Zhonggang Li; J Scott Gabrielsen; Judith A Simcox; Soh-hyun Lee; Deborah Jones; Bob Cooksey; Gregory Stoddard; William T Cefalu; Donald A McClain Journal: J Clin Invest Date: 2015-08-24 Impact factor: 14.808
Authors: Stephanie Brandt; Julia von Schnurbein; Christian Denzer; Wolfgang Kratzer; Martin Wabitsch Journal: Front Endocrinol (Lausanne) Date: 2022-05-23 Impact factor: 6.055
Authors: Vera Francisco; Maria Jesus Sanz; José T Real; Patrice Marques; Maurizio Capuozzo; Djedjiga Ait Eldjoudi; Oreste Gualillo Journal: Biology (Basel) Date: 2022-08-19