TY - JOUR
T1 - SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control
AU - Montgomery, Magdalene K.
AU - Bayliss, Jacqueline
AU - Devereux, Camille
AU - Bezawork-Geleta, Ayenachew
AU - Roberts, David
AU - Huang, Cheng
AU - Schittenhelm, Ralf B.
AU - Ryan, Andrew
AU - Townley, Scott L.
AU - Selth, Luke A.
AU - Biden, Trevor J.
AU - Steinberg, Gregory R.
AU - Samocha-Bonet, Dorit
AU - Meex, Ruth C.R.
AU - Watt, Matthew J.
PY - 2020/9/2
Y1 - 2020/9/2
N2 - Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3',5'-cyclic monophosphate (cAMP)-cAMP-dependent protein kinase (PKA)-cAMP response element-binding protein (CREB) signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Overexpression of SMOC1 in the liver or once-weekly intraperitoneal injections of a stabilized SMOC1-FC fusion protein induced durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without adverse effects on adiposity, liver histopathology, or inflammation. Furthermore, circulating SMOC1 correlated with hepatic and systemic insulin sensitivity and was decreased in obese, insulin-resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.
AB - Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3',5'-cyclic monophosphate (cAMP)-cAMP-dependent protein kinase (PKA)-cAMP response element-binding protein (CREB) signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Overexpression of SMOC1 in the liver or once-weekly intraperitoneal injections of a stabilized SMOC1-FC fusion protein induced durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without adverse effects on adiposity, liver histopathology, or inflammation. Furthermore, circulating SMOC1 correlated with hepatic and systemic insulin sensitivity and was decreased in obese, insulin-resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.
KW - SMOC1
KW - hepatokine
KW - metabolic regulation
KW - type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85090261493&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aaz8048
DO - 10.1126/scitranslmed.aaz8048
M3 - Article
C2 - 32878981
AN - SCOPUS:85090261493
SN - 1946-6242
VL - 12
JO - Science translational medicine
JF - Science translational medicine
IS - 559
M1 - eaaz8048
ER -
