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

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.

The Activity of Adiponectin in Bone

“…Similar to the previously described study, centrally administered adiponectin decreased sympathetic tone and produced increase in fractional volume of trabecular bone in both WT and APN-KO mice. Adiponectin infusion increased the expression of osteoblast markers and decreased the number of osteoclasts [44]. In contrast to the previous study [46], this study suggested that while the local effect of adiponectin on osteoblasts may oppose its central effect, adiponectin's effects on osteoclasts and bone resorption are similar regardless of the site of action.…”

“…Osteoblasts cultured from the APN-KO mice expressed lower levels of RANKL and higher levels of osteoprotegerin (OPG) than WT mice, a change that might explain the lower numbers of osteoclasts and the lower levels of circulating bone resorption markers found in the APN-KO mice. Intracerebroventricular infusion of adiponectin in APN-KO and WT mice was also used to differentiate between the local effect of adiponectin on bone and its centrally mediated activity, as in this model system only negligible amounts of the infused adiponectin reach the circulation [44]. Similar to the previously described study, centrally administered adiponectin decreased sympathetic tone and produced increase in fractional volume of trabecular bone in both WT and APN-KO mice.…”

“…Mild negative effects of adiponectin deficiency have been identified by a number of groups. In one such study, APN-KO mice had decreased fractional volume of trabecular bone, lower mineralization and increased bone marrow adiposity compared to the control mice [44]. In a recent study, microCT analysis of mice of different ages between 8 and 37 weeks identified reduced cortical area fraction and average cortical thickness in female APN-KO mice in comparison with age-matched controls in all the age groups, and reduced trabecular bone volume fraction only in young APN-KO mice [45].…”

“…In contrast to the previous study [46], this study suggested that while the local effect of adiponectin on osteoblasts may oppose its central effect, adiponectin's effects on osteoclasts and bone resorption are similar regardless of the site of action. Central adiponectin decreased osteoclasts and bone resorption through inhibition of RANKL expression, while peripheral adiponectin directly inhibited osteoclast differentiation using a mechanism that involved binding of the receptors expressed on osteoclast precursors [44]. One of the challenges of knockout animal studies is the adaption and compensation mechanisms that can sometimes mask the initial effect of the deficiency and lead to mistaken conclusions about the physiological role of the absent protein.…”

Chronic stress and body composition disorders: implications for health and disease

“…When there is a combination of impaired bone, muscle, and adipose tissue functions, a new clinical phenotypic entity arises, termed osteosarcopenic obesity, comprising the interrelation and consequent dyshomeostasis between the three tissues [84,85]. Currently, there is a lack of consensus regarding this clinical entity.…”