Central adiponectin administration reveals new regulatory mechanisms of bone metabolism in mice

Am J Physiol Endocrinol Metab. 2014 Jun 15;306(12):E1418-30. doi: 10.1152/ajpendo.00048.2014. Epub 2014 Apr 29.

Abstract

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.

Keywords: adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif 1; adiponectin; bone marrow stromal cells; hypothalamus; tryptophan hydroxylase 2.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / antagonists & inhibitors
  • Adiponectin / chemistry
  • Adiponectin / genetics
  • Adiponectin / pharmacology*
  • Adiposity / drug effects
  • Animals
  • Bone Density Conservation Agents / administration & dosage
  • Bone Density Conservation Agents / antagonists & inhibitors
  • Bone Density Conservation Agents / chemistry
  • Bone Density Conservation Agents / pharmacology*
  • Bone Marrow / drug effects*
  • Bone Marrow / metabolism
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / drug effects*
  • Bone and Bones / metabolism
  • Cell Line
  • Gene Expression Regulation / drug effects
  • Gene Silencing
  • Humans
  • Hypothalamus / cytology
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Infusions, Intraventricular
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Osteogenesis / drug effects*
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / pharmacology*
  • Protein Conformation
  • Radiography
  • Random Allocation
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / pharmacology*

Substances

  • Adiponectin
  • Bone Density Conservation Agents
  • Peptide Fragments
  • Recombinant Proteins