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 still not clearly understood. In the present study, we found APN knockout (APN-KO) mice fed on a normal diet exhibited decreased trabecular structure and mineralization and increased bone marrow adiposity compared to wild-type (WT) mice. APN intracerebroventricular (ICV) infusions decreased uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), epinephrine and norepinephrine serum levels, and osteoclast numbers, while increasing osteoblast osteogenic markers expression and trabecular bone mass 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 (CB)-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 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.