title: Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet.
abstract: Uncarboxylated osteocalcin (GluOC), a bone-derived hormone, regulates energy metabolism by stimulating insulin secretion, pancreatic β-cell proliferation, and adiponectin expression in adipocytes. Previously, we showed that long-term intermittent or daily oral administration of GluOC reduced the fasting blood glucose level, improved glucose tolerance, and increased the fasting serum insulin concentration as well as pancreatic β-cell area in female mice fed a normal or high-fat, high-sucrose diet. We have now performed similar experiments with male mice and found that such GluOC administration induced glucose intolerance, insulin resistance, and adipocyte hypertrophy in those fed a high-fat, high-sucrose diet. In addition, GluOC increased the circulating concentration of testosterone and reduced that of adiponectin in such mice. These phenotypes were not observed in male mice fed a high-fat, high-sucrose diet after orchidectomy, but they were apparent in orchidectomized male mice or intact female mice that were fed such a diet and subjected to continuous testosterone supplementation. Our results thus reveal a sex difference in the effects of GluOC on glucose homeostasis. Given that oral administration of GluOC has been considered a potentially safe and convenient option for the treatment or prevention of metabolic disorders, this sex difference will need to be taken into account in further investigations.
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry.|Division of Orthodontics, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yasutake
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry.|OBT Research Center, and.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mizokami
authors.affiliation: Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; and.
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Kawakubo-Yasukochi
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry.
authors.forename: Sakura
authors.initials: S
authors.lastname: Chishaki
authors.affiliation: Division of Orthodontics, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takahashi
authors.affiliation: Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, hirata1@dent.kyushu-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Hirata
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000473:pathology; D052242:Adiponectin / Q000378:metabolism; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D059305:Diet, High-Fat; D019422:Dietary Sucrose / Q000494:pharmacology*; D005260:Female; D018149:Glucose Intolerance / Q000139:chemically induced / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D006984:Hypertrophy / Q000139:chemically induced; D015151:Immunoblotting; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009919:Orchiectomy; D015675:Osteocalcin / Q000494:pharmacology*; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D013549:Sweetening Agents / Q000494:pharmacology*; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology
chemical_list: D052242:Adiponectin; D000728:Androgens; D001786:Blood Glucose; D019422:Dietary Sucrose; D007328:Insulin; D013549:Sweetening Agents; D015675:Osteocalcin; D013739:Testosterone
keywords: adiponectin; insulin resistance; osteocalcin; sex difference; testosterone