Myeloid-specific deletion of Zfp36 protects against insulin resistance and fatty liver in diet-induced obese mice

Abstract

Obesity is associated with adipose tissue inflammation that contributes to insulin resistance. Zinc finger protein 36 (Zfp36) is an mRNA-binding protein that reduces inflammation by binding to cytokine transcripts and promoting their degradation. We hypothesized that myeloid-specific deficiency of Zfp36 would lead to increased adipose tissue inflammation and reduced insulin sensitivity in diet-induced obese mice. As expected, wild-type (Control) mice became obese and diabetic on a high-fat diet, and obese mice with myeloid-specific loss of Zfp36 [knockout (KO)] demonstrated increased adipose tissue and liver cytokine mRNA expression compared with Control mice. Unexpectedly, in glucose tolerance testing and hyperinsulinemic-euglycemic clamp studies, myeloid Zfp36 KO mice demonstrated improved insulin sensitivity compared with Control mice. Obese KO and Control mice had similar macrophage infiltration of the adipose depots and similar peripheral cytokine levels, but lean and obese KO mice demonstrated increased Kupffer cell (KC; the hepatic macrophage)-expressed Mac2 compared with lean Control mice. Insulin resistance in obese Control mice was associated with enhanced Zfp36 expression in KCs. Compared with Control mice, KO mice demonstrated increased hepatic mRNA expression of a multitude of classical (M1) inflammatory cytokines/chemokines, and this M1-inflammatory hepatic milieu was associated with enhanced nuclear localization of IKKβ and the p65 subunit of NF-κB. Our data confirm the important role of innate immune cells in regulating hepatic insulin sensitivity and lipid metabolism, challenge-prevailing models in which M1 inflammatory responses predict insulin resistance, and indicate that myeloid-expressed Zfp36 modulates the response to insulin in mice.

Role of Tristetraprolin in the Resolution of Inflammation

“…Consequently, modulating TTP might provide a promising avenue for the development of inflammation regulatory therapies. Specifically, therapeutic approaches to increase the TTP activity can be expected to ameliorate the course of numerous chronic inflammatory diseases with a previously shown connection to TTP, such as rheumatoid arthritis [ 108 , 114 , 115 ], atherosclerosis [ 116 ], diabetes [ 117 ], inflammatory bowel disease [ 118 ], chronic obstructive pulmonary disease [ 119 ], and autoimmune diseases [ 108 , 120 ]. Since chronic inflammatory diseases are a major health care burden, such approaches appear extremely appealing.…”

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

“…Neutrophil degranulation [52], innate immune system [53], platelet degranulation [54], extracellular matrix organization [55], diseases of glycosylation [56], platelet activation, signaling and aggregation [57], hemostasis [58], secretion [59], secretory vesicle [60], transmembrane transporter activity [61], cell adhesion [62], localization of cell [63], extracellular matrix [55], intrinsic component of plasma membrane [64], structural molecule activity [65], signaling receptor binding [66], have been highly noted in T2DM. Reports indicate that HIF1A [67], HLA-DRB1 [68], CHI3L1 [69], ADORA2A [70], ADRB2 [71], CLU (clusterin) [72], AGT (angiotensinogen) [73], VCAM1 [74], PPARA (peroxisome proliferator activated receptor alpha) [75], APOL1 [76], ZFP36 [77], PPM1B [78], SOCS1 [79], SNCA (synuclein alpha) [80], CTSS (cathepsin S) [81], IL6R [82], CFB (complement factor B) [83], DEFB1 [84], VNN1 [85], RAB27A [86], DPP4 [87], RARRES2 [88], CASP1 [89], LCN2 [90], REG3A [91], CD74 [92], PCSK2 [93], CHGB (chromogranin B) [94], TTR (transthyretin) [95], LRG1 [96], ALB (albumin) [97], DPP7 [98], APOH (apolipoprotein H) [99], CTSD (cathepsin D) [100], GCG (glucagon) [101], KCNQ1 [102], NR4A1 [103], PLIN5 [104], ALDH2 [105], ANG (angiogenin) [106], CLDN7 [107], PRLR (prolactin receptor) [108], SOD2 [109], MLXIPL (MLX interacting protein like) [110], CTSD (cathepsin D) [111], PECAM1 [112], ADA (adenosine deaminase) [113], MFGE8 [114], COL1A1 [115], COL3A1 [116], NID2 [117], ARG1 [118], CD93 [119], IGF2 […”

Insights into Molecular Mechanisms Underlying NAFLD by Protein-Protein Interaction Network Analysis of the Differentially Expressed Genes in NASH Patients.

“…Another study found that insulin resistance in obese mice was associated with enhanced Zfp36 expression in the hepatic macrophage (m1). The study of Caracciolo, V. et al, revealed that the myeloid-speci c deletion of Zfp36 protects against insulin resistance and fatty liver in mice whose obesity is diet-induced (27). Moreover, a signi cant correlation has been reported between TTP and hepatocarcinogenesis (28).…”