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In vivo and in vitro evidence that leptin stimulates the hexosamine biosynthetic pathway (640.9)
Author(s) -
Zimmerman Arthur,
Harris Ruth
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.640.9
Subject(s) - leptin , medicine , endocrinology , glutamine , in vivo , chemistry , fructose , sucrose , in vitro , biology , obesity , biochemistry , amino acid , microbiology and biotechnology
We previously reported that glucosamine administration, which activates the hexosamine biosynthetic pathway (HBP), causes leptin resistance in rats. Here we tested whether nutrient activation of the HBP results in leptin resistance. Male Sprague‐Dawley rats received intraperitoneal infusions of saline or leptin (40 μg/day) for 12 days and were fed chow or a choice diet of chow, 30% sucrose solution, and lard. The choice diet caused leptin resistance and increased hepatic glutamine fructose 6‐phosphate amidotransferase (GFAT), a rate limiting enzyme in the HBP, and O‐linked N‐acetylglucosamine (O‐GlcNAc) protein modification. Leptin infusion increased GFAT and O‐GlcNAcylation in chow‐fed rats, whereas it had no additive effect in choice rats. To test for direct effects of leptin and glucose, HepG2 cells were incubated with high concentrations of glucose (18.5 mM) or with 5.5 mM glucose and leptin (0, 5, 10, 50, 100 or 500 ng/mL). Both leptin and glucose stimulated cellular GFAT and protein O‐GlcNAcylation. Thus, leptin stimulates the HBP both in vivo and in vitro, and activation of the HBP due to increased nutrient flux is associated with leptin resistance. Grant Funding Source : Supported by NIH grant DK 53903