title: Generation of novel long-acting globular adiponectin molecules.
abstract: Adiponectin is an adipocyte-derived hormone that has been shown to play important roles in the regulation of glucose and energy homeostasis. It exists as homotrimers or complexes containing multiple homotrimer units in plasma. The recombinant adiponectin proteins have been difficult to produce, making it challenging for both research as well as potential therapeutic development. Here, we show a novel approach for the generation of globular adiponectin that involves linking three monomer sequences together in tandem to generate one continuous polypeptide, which we have termed single-chain globular adiponectin (sc-gAd). To improve the pharmacokinetic properties of sc-gAd further, we fused it to an Fc fragment. The combined effects of single-chain and Fc fusion improved the plasma half-life from less than 2 h to close to 2 weeks. Using adeno-associated virus as a delivery method, we demonstrate that Fc-sc-gAd improved both fasting glucose levels and the tolerance to a glucose challenge in ob/ob mice without changes in body weight. Therefore, our results demonstrated the feasibility of generating globular adiponectin trimers from a single polypeptide and a long-acting globular adiponectin that could serve as a starting point for adiponectin-based therapeutics. This novel approach could also be applied to other complement factor C1q family members; in particular, this opens the possibility to study the biological functions of precisely defined heterotrimers of various family members that had not been previously possible.
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Ge
authors.forename: Yumei
authors.initials: Y
authors.lastname: Xiong
authors.forename: Bryan
authors.initials: B
authors.lastname: Lemon
authors.forename: Ki Jeong
authors.initials: KJ
authors.lastname: Lee
authors.forename: Jay
authors.initials: J
authors.lastname: Tang
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.forename: Nessa
authors.initials: N
authors.lastname: Hawkins
authors.forename: John
authors.initials: J
authors.lastname: Laudemann
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Min
authors.forename: David
authors.initials: D
authors.lastname: Penny
authors.forename: Tom
authors.initials: T
authors.lastname: Wolfe
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Richard
authors.initials: R
authors.lastname: Zhang
authors.forename: Weh-Chen
authors.initials: WC
authors.lastname: Yeh
authors.forename: Wenyan
authors.initials: W
authors.lastname: Shen
authors.forename: Richard
authors.initials: R
authors.lastname: Lindberg
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Jackie
authors.initials: J
authors.lastname: Sheng
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D011994:Recombinant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; D011994:Recombinant Proteins