title: Increased hepatic insulin sensitivity in mice lacking inhibitory leptin receptor signals.
abstract: Leptin regulates food intake and energy expenditure by activating the long form of the leptin receptor (LepRb). Leptin also regulates glucose homeostasis by improving whole-body insulin sensitivity, but the mechanism remains undefined. Leptin action is mediated by phosphorylation of several tyrosine residues on LepRb. LepRb-Tyr985 plays an important role in the attenuation of LepRb signaling. We determined the contribution of LepRb-Tyr985-mediated signals to leptin action on insulin sensitivity using LepRb-Tyr985 mutant mice (l/l mice). Glucose tolerance and whole-body insulin-mediated glucose utilization were determined in wild-type (+/+) and l/l mice. Glucose tolerance was unaltered between female +/+ and l/l mice but enhanced in the male l/l mice. Serum insulin concentration was decreased at baseline and 15 min after a glucose injection in female l/l vs. +/+ mice (P < 0.05) but unaltered in the male l/l mice. However, basal and insulin-stimulated glucose transport in isolated soleus and extensor digitorum longus muscle was similar between +/+ and l/l mice, indicating skeletal muscle insulin sensitivity in vitro was not enhanced. Moreover, euglycemic-hyperinsulinemic clamps reveal hepatic, rather than peripheral, insulin sensitivity is enhanced in female l/l mice, whereas male l/l mice display both improved hepatic and peripheral insulin sensitivity. In conclusion, signals emanating from leptin receptor Tyr985 control hepatic insulin sensitivity in both female and male l/l mice. Lack of LepRb-Tyr985 signaling enhances whole-body insulin sensitivity partly through increased insulin action on the suppression of hepatic glucose production.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, von Eulers väg 4a, IV, SE-171 77, Stockholm, Sweden.
authors.forename: Robby Zachariah
authors.initials: RZ
authors.lastname: Tom
authors.forename: Rasmus J O
authors.initials: RJ
authors.lastname: Sjögren
authors.forename: Elaine
authors.initials: E
authors.lastname: Vieira
authors.forename: Stephan
authors.initials: S
authors.lastname: Glund
authors.forename: Eduardo
authors.initials: E
authors.lastname: Iglesias-Gutiérrez
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Garcia-Roves
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.forename: Marie
authors.initials: M
authors.lastname: Björnholm
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D005260:Female; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D054411:Receptors, Leptin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D005947:Glucose