Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation.
Recombinant leptin offers a viable treatment for lipodystrophy (LD) syndromes. However, due to its short plasma half-life, leptin replacement therapy requires at least daily subcutaneous (s.c.) injections. Here, we optimised this treatment strategy in LD mice by using a novel leptin version with extended plasma half-life using PASylation technology.



A long-acting leptin version was prepared by genetic fusion with a 600 residue polypeptide made of Pro, Ala and Ser (PASylation), which enlarges the hydrodynamic volume and, thus, retards renal filtration, allowing less frequent injection. LD was induced in C57BL/6J mice by feeding a diet supplemented with conjugated linoleic acid (CLA). Chronic and acute effects of leptin treatment were assessed by evaluating plasma insulin levels, insulin tolerance, histological liver sections, energy expenditure, energy intake and body composition.



In a cohort of female mice, 4 nmol PAS-leptin (applied via four s.c. injections every 3 days) successfully alleviated the CLA-induced LD phenotype, which was characterised by hyperinsulinaemia, insulin intolerance and hepatosteatosis. The same injection regimen had no measurable effect when unmodified recombinant leptin was administered at an equivalent dose. In a cohort of LD males, a single s.c. injection of PAS-leptin did not affect energy expenditure but inhibited food intake and promoted a shift in fuel selection towards preferential fat oxidation, which mechanistically substantiates the metabolic improvements.



The excellent pharmacological properties render PASylated leptin an agent of choice for refining both animal studies and therapeutic strategies in the context of LD syndromes and beyond.
Lehrstuhl für Molekulare Ernährungsmedizin and Else Kröner-Fresenius Center, Technische Universität München, Gregor-Mendel-Str. 2, 85354, Freising (Weihenstephan), Germany.|Research Center for Nutrition and Food Science (ZIEL), Technische Universität München, Freising (Weihenstephan), Germany.
Florian
F
Bolze
Lehrstuhl für Molekulare Ernährungsmedizin and Else Kröner-Fresenius Center, Technische Universität München, Gregor-Mendel-Str. 2, 85354, Freising (Weihenstephan), Germany.|Research Center for Nutrition and Food Science (ZIEL), Technische Universität München, Freising (Weihenstephan), Germany.
Andrea
A
Bast
Lehrstuhl für Molekulare Ernährungsmedizin and Else Kröner-Fresenius Center, Technische Universität München, Gregor-Mendel-Str. 2, 85354, Freising (Weihenstephan), Germany.|Research Center for Nutrition and Food Science (ZIEL), Technische Universität München, Freising (Weihenstephan), Germany.
Sabine
S
Mocek
Munich Center for Integrated Protein Science (CIPS-M) and Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354, Freising (Weihenstephan), Germany.
Volker
V
Morath
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Detian
D
Yuan
Lehrstuhl für Molekulare Ernährungsmedizin and Else Kröner-Fresenius Center, Technische Universität München, Gregor-Mendel-Str. 2, 85354, Freising (Weihenstephan), Germany.|Research Center for Nutrition and Food Science (ZIEL), Technische Universität München, Freising (Weihenstephan), Germany.
Nadine
N
Rink
Munich Center for Integrated Protein Science (CIPS-M) and Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354, Freising (Weihenstephan), Germany.
Martin
M
Schlapschy
Lehrstuhl für Molekulare Ernährungsmedizin and Else Kröner-Fresenius Center, Technische Universität München, Gregor-Mendel-Str. 2, 85354, Freising (Weihenstephan), Germany.|Research Center for Nutrition and Food Science (ZIEL), Technische Universität München, Freising (Weihenstephan), Germany.
Anika
A
Zimmermann
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Mathias
M
Heikenwalder
Munich Center for Integrated Protein Science (CIPS-M) and Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354, Freising (Weihenstephan), Germany. skerra@tum.de.|XL-protein GmbH, Freising, Germany. skerra@tum.de.
Arne
A
Skerra
Lehrstuhl für Molekulare Ernährungsmedizin and Else Kröner-Fresenius Center, Technische Universität München, Gregor-Mendel-Str. 2, 85354, Freising (Weihenstephan), Germany. mk@tum.de.|Research Center for Nutrition and Food Science (ZIEL), Technische Universität München, Freising (Weihenstephan), Germany. mk@tum.de.
Martin
M
Klingenspor
D000818:Animals; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D020738:Leptin / Q000737:chemistry / Q000627:therapeutic use*; D044243:Linoleic Acids, Conjugated / Q000633:toxicity; D050356:Lipid Metabolism / Q000187:drug effects; D008060:Lipodystrophy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL
D007328:Insulin; D020738:Leptin; D044243:Linoleic Acids, Conjugated
Conjugated linoleic acid; Fuel selection; Leptin; Lipodystrophy; Metabolic rate; PASylation; Therapeutic protein