title: Hexosamines regulate leptin production in human subcutaneous adipocytes.
abstract: The hexosamine biosynthetic pathway has recently been proposed as a mechanism through which cells "sense" nutrient flux to regulate leptin release. This study was undertaken to examine the regulation of leptin production by hexosamines in human adipocytes. Adipose tissue UDP-N-acetylglucosamine, an end product of hexosamine biosynthesis, was elevated 3.2-fold, and ob messenger ribonucleic acid was elevated 2-fold in the sc adipose tissue of 17 obese [body mass index (BMI), 41.3+/-12.0 kg/m2; age, 31+/-5 yr] subjects compared to 14 lean (BMI, 23.4+/-1.6 kg/m2; age, 33+/-11 yr) subjects. Serum leptin was increased 2.7-fold in the obese subjects. A significant positive relationship was found between adipose tissue UDP-N-acetylglucosamine and BMI (Spearman correlation = 0.576; P = 0.0007) and between UDP-N-acetylglucosamine and serum leptin (Spearman correlation = 0.4650; P = 0.0145). Treatment of isolated sc adipocytes with 1 mmol/L glucosamine, an intermediate product in UDP-N-acetylglucosamine biosynthesis, increased leptin release 21.4+/-17.6% (mean +/- SD) over control (P = 0.0365) and 74.5+/-82.8% over control (P = 0.0271) in adipocytes from lean (BMI, 23.2+/-1.6 kg/m2; n = 6) and obese (BMI, 55.4+/-13.0 kg/m2,; n = 9) subjects, respectively, by 48 h of culture. Inhibition of UDP-N-acetylglucosamine biosynthesis with 6-diazo-5-oxo-norleucine reduced glucose-stimulated leptin release from cultured adipocytes 21.8+/-32.4% (P = 0.0395; n = 12) and ob gene expression 19.9+/-18.9% (P = 0.0208; n = 8) by 48 h of treatment. These findings suggest that hexosamine biosynthesis regulates leptin production in human adipose tissue.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USA. rconsidi@iupui.edu
authors.forename: R V
authors.initials: RV
authors.lastname: Considine
authors.forename: R C
authors.initials: RC
authors.lastname: Cooksey
authors.forename: L B
authors.initials: LB
authors.lastname: Williams
authors.forename: R L
authors.initials: RL
authors.lastname: Fawcett
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.forename: W T
authors.initials: WT
authors.lastname: Ambrosius
authors.forename: R M
authors.initials: RM
authors.lastname: Whitfield
authors.forename: R
authors.initials: R
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Inman
authors.forename: J
authors.initials: J
authors.lastname: Huse
authors.forename: D A
authors.initials: DA
authors.lastname: McClain
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D015992:Body Mass Index; D002478:Cells, Cultured; D003980:Diazooxonorleucine / Q000494:pharmacology; D005944:Glucosamine / Q000494:pharmacology; D006595:Hexosamines / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D020738:Leptin / Q000096:biosynthesis* / Q000097:blood; D009765:Obesity / Q000378:metabolism; D013268:Stimulation, Chemical; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism
chemical_list: D006595:Hexosamines; D020738:Leptin; D003980:Diazooxonorleucine; D014537:Uridine Diphosphate N-Acetylglucosamine; D005944:Glucosamine