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Publication
Myeloid-Specific Deletion of Zfp36 Protects Against Insulin Resistance and Fatty
Liver in Diet-Induced Obese Mice.
Authors Caracciolo V, Young J, Gonzales D, Ni Y, Flowers SJ, Summer R, Waldman SA, Kim
JK, Jung DY, Noh HL, Kim T, Blackshear PJ, O'Connell D, Bauer RC, Kallen CB
Submitted By Submitted Externally on 5/25/2018
Status Published
Journal American journal of physiology. Endocrinology and metabolism
Year 2018
Date Published 3/1/2018
Volume : Pages Not Specified : Not Specified
PubMed Reference 29509432
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
(KO) demonstrated increased adipose tissue and liver cytokine mRNA expression
compared to 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 to 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 M1
cytokines/chemokines and this M1-inflammatory hepatic milieu was associated with
enhanced nuclear localization of I?B kinase-ß (IKKß) and the p65 subunit of
nuclear factor-?B (NF?B). 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.




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