FP24-4 Adiponectin Exerts, Through FoxO1, Two Opposite Influences On Bone Mass Accrual in Animals Fed a Normal Diet

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP24-New Mechanisms in Bone Biology: From Cells to Genetics, & Mice to Men
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:00 AM
Room 121 (Moscone Center)

Poster Board SUN-202
Daisuke Kajimura*, Ha On Lee, Kyle J Riley and Gerard Karsenty
Columbia University Medical Center, New York, NY
Adiponectin is an adipokine or adipocyte-derived hormone with ill-defined functions in animals fed a normal diet. The observation that adiponectin synthesis is increased by the osteoblast-derived hormone osteocalcin suggests that adiponectin could be regulating some functions of the osteoblasts in vivo. To test this hypothesis we used cell-based assays and studied Adiponectin-deficient mice fed a normal diet at various ages. Analysis of these mutant mice before 3 months of age showed that, as anticipated, adiponectin signals in osteoblasts where its main functions are to increase Rankl expression and osteoclast differentiation, to hamper proliferation and to favor apoptosis of osteoblasts. As a result of these various functions adiponectin decreases bone mass and circulating osteocalcin levels in young mice. We further showed through the generation and characterization of mice lacking each of its known receptors in an osteoblast-specific manner that adiponectin fulfills these functions independently of these receptors, of AMPK phosphorylation or ceramide production. Instead, adiponectin regulation of osteoblasts proliferation and apoptosis occurs in a FoxO1-dependent manner. Unexpectedly, analysis of adiponectin functions in older mice revealed that this hormone affects bone mass through a second and different mechanism. Indeed, adiponectin signals in neurons of the locus coeruleus where it decreases the activity of the sympathetic nervous system; as a result it increases bone mass, and decreases energy expenditure, blood pressure and heart rate in mice beyond 3 months of age.  Cell-specific gene deletion experiments show that the regulation of the sympathetic tone by adiponectin also occurs in a FoxO1-dependent manner. This study identifies target cells, functions and at least one signaling molecule for adiponectin in animals fed a normal diet. It also reveals that adiponectin is a peculiar hormone since it regulates a particular function, bone mass accrual, in two opposite manners depending on which cells it acts. Likewise, this study reveals an unusual aspect of the adipocyte as an endocrine cell in the sense that it secretes two hormones, adiponectin and leptin that exert opposite influences on the sympathetic nervous system and the physiological functions it influences in animals fed a normal diet.

Nothing to Disclose: DK, HOL, KJR, GK

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