Central adiponectin administration reveals new regulatory mechanisms of bone metabolism in mice.
Adiponectin (APN), the most abundant adipocyte-secreted adipokine, regulates energy homeostasis and exerts well-characterized insulin-sensitizing properties. The peripheral or central effects of APN regulating bone metabolism are beginning to be explored but are still not clearly understood. In the present study, we found that APN-knockout (APN-KO) mice fed a normal diet exhibited decreased trabecular structure and mineralization and increased bone marrow adiposity compared with wild-type (WT) mice. APN intracerebroventricular infusions decreased uncoupling protein 1 (UCP1) expression in brown adipose tissue, epinephrine and norepinephrine serum levels, and osteoclast numbers, whereas osteoblast osteogenic marker expression and trabecular bone mass increased in APN-KO and WT mice. In addition, centrally administered APN increased hypothalamic tryptophan hydroxylase 2 (TPH2), cocaine- and amphetamine-regulated transcript (CART), and 5-hydroxytryptamine (serotonin) receptor 2C (Htr2C) expressions but decreased hypothalamic cannabinoid receptor-1 expression. Treatment of immortalized mouse neurons with APN demonstrated that APN-mediated effects on TPH2, CART, and Htr2C expression levels were abolished by downregulating adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif (APPL)-1 expression. Pharmacological increase in sympathetic activity stimulated adipogenic differentiation of bone marrow stromal cells (BMSC) and reversed APN-induced expression of the lysine-specific demethylases involved in regulating their commitment to the osteoblastic lineage. In conclusion, we found that APN regulates bone metabolism via central and peripheral mechanisms to decrease sympathetic tone, inhibit osteoclastic differentiation, and promote osteoblastic commitment of BMSC.
Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts; National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, China; Second Dental Center, Peking University School and Hospital of Stomatology, Beijing, China;
Yuwei
Y
Wu
Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts;
Qisheng
Q
Tu
Department of Sciences, Wentworth Institute of Technology, Boston, Massachusetts;
Paloma
P
Valverde
Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts;
Jin
J
Zhang
Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts;
Dana
D
Murray
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas;
Lily Q
LQ
Dong
Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts;
Jessica
J
Cheng
Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts;
Hua
H
Jiang
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts;
Maribel
M
Rios
Departments of Mechanical Engineering, Biomedical Engineering, and Orthopedic Surgery, Boston University, Boston, Massachusetts; and.
Elise
E
Morgan
National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, China; Second Dental Center, Peking University School and Hospital of Stomatology, Beijing, China;
Zhihui
Z
Tang
Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts; Department of Anatomy and Cell Biology, Tufts University School of Medicine and Sackler Graduate School of Biomedical Sciences, Boston, Massachusetts jk.chen@tufts.edu.
Jake
J
Chen
D052242:Adiponectin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011487:Protein Conformation; D011859:Radiography; D011897:Random Allocation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D052242:Adiponectin; D050071:Bone Density Conservation Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins
adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif 1; adiponectin; bone marrow stromal cells; hypothalamus; tryptophan hydroxylase 2