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Identification and characterization of CTRP9, a novel secreted glycoprotein, from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin

G. William Wong^*,1,2, Sarah A. Krawczyk^*, Claire Kitidis-Mitrokostas^*, Guangtao Ge^*, Eric Spooner^*, Christopher Hug^*,, Ruth Gimeno and Harvey F. Lodish^*,,2

^* Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA;

Cardiovascular and Metabolic Diseases, Wyeth Research, Cambridge, Massachusetts, USA;

Division of Respiratory Disease, The Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA; and

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

² Correspondence: H.F.L., Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. E-mail: lodish{at}wi.mit.edu; G.W.W., Department of Physiology and Center for Metabolism and Obesity Research, 855 N. Wolfe St., Baltimore, MD 21205, USA. E-mail: gwwong{at}jhmi.edu

Adiponectin is a major insulin-sensitizing, multimeric hormone derived from adipose tissue that acts on muscle and liver to regulate whole-body glucose and lipid metabolism. Here, we describe a novel and highly conserved paralog of adiponectin designated as C1q/TNF-related protein (CTRP) 9. Of all the CTRP paralogs, CTRP9 shows the highest degree of amino acid identity to adiponectin in its globular C1q domain. CTRP9 is expressed predominantly in adipose tissue and females expresses higher levels of the transcript than males. Moreover, its expression levels in ob/ob mice changed in an age-dependent manner, with significant up-regulation in younger mice. CTRP9 is a secreted glycoprotein with multiple post-translational modifications in its collagen domain that include hydroxylated prolines and hydroxylated and glycosylated lysines. It is secreted as multimers (predominantly trimers) from transfected cells and circulates in the mouse serum with levels varying according to sex and metabolic state of mice. Furthermore, CTRP9 and adiponectin can be secreted as heterooligomers when cotransfected into mammalian cells, and in vivo, adiponectin/CTRP9 complexes can be reciprocally coimmunoprecipitated from the serum of adiponectin and CTRP9 transgenic mice. Biochemical analysis demonstrates that adiponectin and CTRP9 associate via their globular C1q domain, and this interaction does not require their conserved N-terminal cysteines or their collagen domains. Furthermore, we show that adiponectin and CTRP9 form heterotrimers. In cultured myotubes, CTRP9 specifically activates AMPK, Akt, and p44/42 MAPK signaling pathways. Adenovirus-mediated overexpression of CTRP9 in obese (ob/ob) mice significantly lowered serum glucose levels. Collectively, these results suggest that CTRP9 is a novel adipokine, and further study of CTRP9 will yield novel mechanistic insights into its physiological and metabolic function.—Wong, G. W., Krawczyk, S. A., Kitidis-Mitrokostas, C., Ge, G., Spooner, E., Hug, C., Gimeno, R., Lodish, H. F. Identification and characterization of CTRP9, a novel secreted glycoprotein from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin.

Key Words: C1q/TNF family • adipokine • diabetes • obesity