The role of adipose-derived inflammatory cytokines in type 1 diabetes.
Adipose tissue dysfunction correlates with the development of diabetes. Mice with an adipocyte-specific deletion of the SUMO-specific protease SENP1 develop symptoms of type-1 diabetes mellitus (T1DM). Peri-pancreatic adipocytes (PATs) exert both systemic and paracrine effects on pancreases function. Our recent studies report that PATs of SENP1-deficient mice have increased proinflammatory cytokine production compared with other adipose depots. Proinflammatory cytokines produced from PATs not only have direct cytotoxic effects on pancreatic islets, but also increase CCL5 expression in adjacent pancreatic islets, which induces persistent inflammation in pancreases by acquisition of Th1 and Th17 effector T cell subsets. Small ubiquitin-like modifier (SUMO) can post-translationally conjugate to cellular proteins (SUMOylation) and modulate their biological functions. Several components in SUMOylation associate with T1DM susceptibility. We find that SUMOylation of NF-κB essential molecule NEMO augments NF-κB activity, NF-κB-dependent cytokine production and pancreatic inflammation. NF-κB inhibitor should provide therapeutic approach to block PAT inflammation and ameliorate the T1DM phenotype. We further propose that adipocytes in PATs may play a primary role in establishing pancreatic immune regulation at onset of diabetes, providing new insights into the molecular pathogenesis of type 1 diabetes.
The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
Lan
L
Shao
The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou, China.
Boya
B
Feng
The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou, China.
Yuying
Y
Zhang
The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
Huanjiao
H
Zhou
The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou, China.
Weidong
W
Ji
The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
Wang
W
Min
NEMO; NF-κB; SENP1; SUMOylation; Type 1 diabetes; adipocyte; cytokine