Dataset Information

Macrophage CD40 plays a minor role in obesity-induced metabolic dysfunction.

ABSTRACT: Obesity is a low-grade inflammatory disease that increases the risk for metabolic disorders. CD40-CD40L signaling plays a central role in obesity-induced inflammation. Genetic deficiency of CD40L in diet-induced obesity (DIO) ameliorates adipose tissue inflammation, hepatic steatosis and increases insulin sensitivity. Unexpectedly, absence of CD40 worsened insulin resistance and caused excessive adipose tissue inflammation and hepatosteatosis. To investigate whether deficiency of macrophage CD40 is responsible for the phenotype observed in the CD40-/- mice, we generated CD40flflLysMcre and fed them a standard (SFD) and 54% high fat obesogenic diet (HFD) for 13 weeks. No differences in body weight, adipose tissue weight, adipocyte size, plasma cholesterol or triglyceride levels could be observed between CD40flflLysMcre and wild type (WT) mice. CD40flflLysMcre displayed no changes in glucose tolerance or insulin resistance, but had higher plasma adiponectin levels when fed a SFD. Liver weights, liver cholesterol and triglyceride levels, as well as the degree of hepatosteatosis were not affected by absence of macrophage CD40. CD40flflLysMcre mice displayed a minor increase in adipose tissue leukocyte infiltration on SFD and HFD, which did not result in differences in adipose tissue cytokine levels. We here show that loss of macrophage CD40 signaling does not affect obesity induced metabolic dysregulation and indicates that CD40-deficiency on other cell-types than the macrophage is responsible for the metabolic dysregulation, adipose tissue inflammation and hepatosteatosis that are observed in CD40-/- mice.

SUBMITTER: Aarts SABM

PROVIDER: S-EPMC6086432 | biostudies-other | 2018

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Macrophage CD40 plays a minor role in obesity-induced metabolic dysfunction.

Aarts Suzanne A B M SABM Reiche Myrthe E ME den Toom Myrthe M Beckers Linda L Gijbels Marion J J MJJ Gerdes Norbert N de Winther Menno P J MPJ Lutgens Esther E

PloS one 20180810 8

Obesity is a low-grade inflammatory disease that increases the risk for metabolic disorders. CD40-CD40L signaling plays a central role in obesity-induced inflammation. Genetic deficiency of CD40L in diet-induced obesity (DIO) ameliorates adipose tissue inflammation, hepatic steatosis and increases insulin sensitivity. Unexpectedly, absence of CD40 worsened insulin resistance and caused excessive adipose tissue inflammation and hepatosteatosis. To investigate whether deficiency of macrophage CD40 ...[more]

PMID: 30096208

Similar Datasets

Project description:AimsIn cardiomyocytes, there is microRNA (miR) in the mitochondria that originates from the nuclear genome and matures in the cytoplasm before translocating into the mitochondria. Overexpression of one such miR, miR-181c, can lead to heart failure by stimulating reactive oxygen species (ROS) production and increasing mitochondrial calcium level ([Ca2+]m). Mitochondrial calcium uptake 1 protein (MICU1), a regulatory protein in the mitochondrial calcium uniporter complex, plays an important role in regulating [Ca2+]m. Obesity results in miR-181c overexpression and a decrease in MICU1. We hypothesize that lowering miR-181c would protect against obesity-induced cardiac dysfunction.Methods and resultsWe used an in vivo mouse model of high-fat diet (HFD) for 18 weeks and induced high lipid load in H9c2 cells with oleate-conjugated bovine serum albumin in vitro. We tested the cardioprotective role of lowering miR-181c by using miR-181c/d-/- mice (in vivo) and AntagomiR against miR-181c (in vitro). HFD significantly upregulated heart levels of miR-181c and led to cardiac hypertrophy in wild-type mice, but not in miR-181c/d-/- mice. HFD also increased ROS production and pyruvate dehydrogenase activity (a surrogate for [Ca2+]m), but the increases were alleviated in miR-181c/d-/- mice. Moreover, miR-181c/d-/- mice fed a HFD had higher levels of MICU1 than did wild-type mice fed a HFD, attenuating the rise in [Ca2+]m. Overexpression of miR-181c in neonatal ventricular cardiomyocytes (NMVM) caused increased ROS production, which oxidized transcription factor Sp1 and led to a loss of Sp1, thereby slowing MICU1 transcription. Hence, miR-181c increases [Ca2+]m through Sp1 oxidation and downregulation of MICU1, suggesting that the cardioprotective effect of miR-181c/d-/- results from inhibition of Sp1 oxidation.ConclusionThis study has identified a unique nuclear-mitochondrial communication mechanism in the heart orchestrated by miR-181c. Obesity-induced overexpression of miR-181c increases [Ca2+]m via downregulation of MICU1 and leads to cardiac injury. A strategy to inhibit miR-181c in cardiomyocytes can preserve cardiac function during obesity by improving mitochondrial function. Altering miR-181c expression may provide a pharmacologic approach to improve cardiomyopathy in individuals with obesity/type 2 diabetes.

Dataset Information

Macrophage CD40 plays a minor role in obesity-induced metabolic dysfunction.

Publications

Macrophage CD40 plays a minor role in obesity-induced metabolic dysfunction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets