Fatty acid binding protein 4 promotes autoimmune diabetes by recruitment and activation of pancreatic islet macrophages

Abstract

Both innate and adaptive immune cells are critical players in autoimmune destruction of insulin-producing β-cells in type 1 diabetes. However, the early pathogenic events triggering the recruitment and activation of innate immune cells in islets remain obscure. Here we show that circulating fatty acid binding protein 4 (FABP4) level is significantly elevated in type1 diabetes patients and their first-degree relatives, and positively correlates with the titers of several islet autoantibodies. In non-obese diabetic (NOD) mice, increased FABP4 expression in islet macrophages starts from the neonatal period, well before the occurrence of overt diabetes. Furthermore, the spontaneous development of autoimmune diabetes in NOD mice is markedly reduced by pharmacological inhibition or genetic ablation of FABP4, or adoptive transfer of FABP4-deficient bone marrow cells. Mechanistically, FABP4 activates innate immune responses in islets by enhancing the infiltration and polarization of macrophages to pro-inflammatory M1 subtype, thus creating an inflammatory milieu required for activation of diabetogenic CD8 + T cells and shift of CD4 + helper T cells towards the Th1 subtypes. These findings demonstrate FABP4 as a possible early mediator for β-5 cell autoimmunity by facilitating crosstalk between innate and adaptive immune cells, suggesting that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for autoimmune diabetes.

Multi-Omics Comparison of the Spontaneous Diabetes Mellitus and Diet-Induced Prediabetic Macaque Models

“…Both transcriptomic and proteomic data supported upregulation of FABP4 in both HFHS and sDM groups and showed the highest level in the former ( Figures 4F , 5C , D ). FABP4 is one of the biomarkers that has been associated with both type 1 and 2 DM ( Rodríguez-Calvo et al, 2019 ; Xiao et al, 2021 ). The abundance of phosphotransferase (GCK) in the sDM livers was much lower than those in either the NC or HFHS groups ( Figures 5B,D ), evidencing the repression of hepatic glycolysis in DM.…”

“…FABP4 regulates hepatic production of glucose ( Cao et al, 2013 ), and the mice with FABP4 deficiency have a lower risk for obesity-induced insulin resistance and type 2 DM ( Tuncman et al, 2006 ). Elevated levels of circulating FABP4 have been proposed as a marker of DM-related syndrome ( Rodríguez-Calvo et al, 2019 ), with a pro-diabetic impact in the process of diabetes in the pancreas ( Xiao et al, 2021 ). The upregulation of FABP4 expression in the liver might also have a role in the development of DM.…”

The Low-Expression Variant of FABP4 Is Associated With Cardiovascular Disease in Type 1 Diabetes

“…Since the first description of FABP4 as a circulating protein (37), studies regarding serum FABP4 have emerged (38). Although serum FABP4 studies in type 1 diabetes have been scarce, higher FABP4 serum levels have been associated with elevated preeclampsia risk (39,40), higher BMI (41), and worse glycemic control (42) and have been suggested to be involved in autoimmune destruction of b-cells in type 1 diabetes (43). In this study, we did not find any association between the FABP4 low-expression G allele and BMI, but in participants with normal AER, the low-expression G allele was associated with higher HbA 1c (Fig.…”

Adipose-Derived Lipid-Binding Proteins: The Good, the Bad and the Metabolic Diseases

“…In humans, serum levels of FABP4 are higher in obese, type 1 diabetic, type 2 diabetic and gestational diabetic individuals compared to non-obese, non-diabetic subjects [ 34 , 35 , 36 , 37 ]. Gastric bypass surgery reduces circulating FABP4 by 42% in obese patients with type 2 diabetes, whereas behavioral and nutritional intervention alone does not reduce the serum levels of FABP4 [ 35 ].…”

“…Gastric bypass surgery reduces circulating FABP4 by 42% in obese patients with type 2 diabetes, whereas behavioral and nutritional intervention alone does not reduce the serum levels of FABP4 [ 35 ]. Cohort studies including obese or diabetic patients with their family revealed that FABP4 levels were high with first-degree relatives of type 1 diabetic patients [ 37 ] and in children of obese parents, even if they were not obese themselves [ 38 ]. FABP4 plasma levels are positively associated with BMI, waist circumference and metabolic syndrome, but also with inflammatory markers like CRP or IL-6 in type 2 diabetic subjects [ 39 ].…”