Generation of novel long-acting globular adiponectin molecules.
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.
Ge
Hongfei
H
Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA.
Xiong
Yumei
Y
Lemon
Bryan
B
Lee
Ki Jeong
KJ
Tang
Jay
J
Wang
Ping
P
Weiszmann
Jennifer
J
Hawkins
Nessa
N
Laudemann
John
J
Min
Xiaoshan
X
Penny
David
D
Wolfe
Tom
T
Liu
Qiang
Q
Zhang
Richard
R
Yeh
Weh-Chen
WC
Shen
Wenyan
W
Lindberg
Richard
R
Wang
Zhulun
Z
Sheng
Jackie
J
Li
Yang
Y
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
D052242:Adiponectin; D011994:Recombinant Proteins