scholarly journals Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus

2021 ◽  
Author(s):  
Longmin Chen ◽  
Jing Zhang ◽  
Yuan Zou ◽  
Faxi Wang ◽  
Jingyi Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Macrophage Polarization ◽  
Fatty Acid Uptake ◽  
Chromatin Accessibility ◽  
Acid Uptake ◽  
High Fat ◽  
M2 Polarization ◽  
Adipose Tissue Macrophages ◽  
Cold Challenge

AbstractKdm2a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation, differentiation, and apoptosis. Herein we found that myeloid-specific knockout of Kdm2a (LysM-Cre-Kdm2af/f, Kdm2a−/−) promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis. Kdm2a−/− increased H3K36me2 levels at the Pparg locus along with augmented chromatin accessibility and Stat6 recruitment, which rendered macrophages with preferential M2 polarization. Therefore, the Kdm2a−/− mice were highly protected from high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis, and featured by the reduced accumulation of adipose tissue macrophages and repressed chronic inflammation following HFD challenge. Particularly, Kdm2a−/− macrophages provided a microenvironment in favor of thermogenesis. Upon HFD or cold challenge, the Kdm2a−/− mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure. Collectively, our findings demonstrate the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization, providing novel insight that targeting Kdm2a in macrophages could be a viable therapeutic approach against obesity and insulin resistance.

scholarly journals Berberine elevates cardiolipin in heart of offspring from mouse dams with high fat diet-induced gestational diabetes mellitus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Laura K. Cole ◽  
Genevieve C. Sparagna ◽  
Marilyne Vandel ◽  
Bo Xiang ◽  
Vernon W. Dolinsky ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Mitochondrial Function ◽  
High Fat Diet ◽  
Fatty Acid Uptake ◽  
Isoquinoline Alkaloid ◽  
Acid Uptake ◽  
High Fat ◽  
Low Fat

AbstractBerberine (BBR) is an isoquinoline alkaloid from plants known to improve cardiac mitochondrial function in gestational diabetes mellitus (GDM) offspring but the mechanism is poorly understood. We examined the role of the mitochondrial phospholipid cardiolipin (CL) in mediating this cardiac improvement. C57BL/6 female mice were fed either a Lean-inducing low-fat diet or a GDM-inducing high-fat diet for 6 weeks prior to breeding. Lean and GDM-exposed male offspring were randomly assigned a low-fat, high-fat, or high-fat diet containing BBR at weaning for 12 weeks. The content of CL was elevated in the heart of GDM offspring fed a high fat diet containing BBR. The increase in total cardiac CL was due to significant increases in the most abundant and functionally important CL species, tetralinoleoyl-CL and this correlated with an increase in the expression of the CL remodeling enzyme tafazzin. Additionally, BBR treatment increased expression of cardiac enzymes involved in fatty acid uptake and oxidation and electron transport chain subunits in high fat diet fed GDM offspring. Thus, dietary BBR protection from cardiac dysfunction in GDM exposed offspring involves improvement in mitochondrial function mediated through increased synthesis of CL.

scholarly journals Interactions between CD36 and global intestinal alkaline phosphatase in mouse small intestine and effects of high-fat diet

2011 ◽  
Vol 301 (6) ◽  
pp. R1738-R1747 ◽  
Author(s):  
Matthew Lynes ◽  
Sonoko Narisawa ◽  
José Luis Millán ◽  
Eric P. Widmaier
Keyword(s):  
Fatty Acid ◽  
High Fat Diet ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Dependent Manner ◽  
High Fat ◽  
Intestinal Alkaline Phosphatase ◽  
Mouse Small Intestine ◽  
Mouse Intestine ◽  
Plasma Leptin

The mechanisms of the saturable component of long-chain fatty acid (LCFA) transport across the small intestinal epithelium and its regulation by a high-fat diet (HFD) are uncertain. It is hypothesized here that the putative fatty acid translocase/CD36 and intestinal alkaline phosphatases (IAPs) function together to optimize LCFA transport. Phosphorylated CD36 (pCD36) was expressed in mouse enterocytes and dephosphorylated by calf IAP (CIAP). Uptake of fluorescently tagged LCFA into isolated enteroctyes was increased when cells were treated with CIAP; this was blocked with a specific CD36 inhibitor. pCD36 colocalized in enterocytes with the global IAP (gIAP) isozyme and, specifically, coimmunoprecipitated with gIAP, but not the duodenal-specific isozyme (dIAP). Purified recombinant gIAP dephosphorylated immunoprecipitated pCD36, and antiserum to gIAP decreased initial LCFA uptake in enterocytes. Body weight, adiposity, and plasma leptin and triglycerides were significantly increased in HFD mice compared with controls fed a normal-fat diet. HFD significantly increased immunoreactive CD36 and gIAP, but not dIAP, in jejunum, but not duodenum. Uptake of LCFA was increased in a CD36-dependent manner in enterocytes from HFD mice. It is concluded that CD36 exists in its phosphorylated and dephosphorylated states in mouse enterocytes, that pCD36 is a substrate of gIAP, and that dephosphorylation by IAPs results in increased LCFA transport capability. HFD upregulates CD36 and gIAP in parallel and enhances CD36-dependent fatty acid uptake. The interactions between these proteins may be important for efficient fat transport in mouse intestine, but whether the changes in gIAP and CD36 in enterocytes contribute to HFD-induced obesity remains to be determined.

MiR-495 regulates macrophage M1/M2 polarization and insulin resistance in high-fat diet-fed mice via targeting FTO

2019 ◽  
Vol 471 (11-12) ◽  
pp. 1529-1537 ◽  
Author(s):  
Fang Hu ◽  
Jingkai Tong ◽  
Bangli Deng ◽  
Jia Zheng ◽  
Chengzhi Lu
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
High Fat ◽  
M2 Polarization

Kupffer cell activation is a causal factor for hepatic insulin resistance

2010 ◽  
Vol 298 (1) ◽  
pp. G107-G116 ◽  
Author(s):  
Nicolas Lanthier ◽  
Olivier Molendi-Coste ◽  
Yves Horsmans ◽  
Nico van Rooijen ◽  
Patrice D. Cani ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Kupffer Cell ◽  
High Fat Diet ◽  
Cell Activation ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Short Term ◽  
Adipose Tissue Macrophages ◽  
Diet Model

Recruited adipose tissue macrophages contribute to chronic and low-grade inflammation causing insulin resistance in obesity. Similarly, we hypothesized here that Kupffer cells, the hepatic resident macrophages, play a pathogenic role in hepatic insulin resistance induced by a high-fat diet. Mice were fed a normal diet or high-fat diet for 3 days. Kupffer cell activation was evaluated by immunohistochemistry and quantitative RT-PCR. Insulin sensitivity was assessed in vivo by hyperinsulinemic-euglycemic clamp and insulin-activated signaling was investigated by Western blot. Liposome-encapsulated clodronate was injected intravenously to deplete macrophages prior to a short-term exposure to high-fat diet. Here, we characterized a short-term high-fat diet model in mice and demonstrated early hepatic insulin resistance and steatosis concurrent with Kupffer cell activation. We demonstrated that selective Kupffer cell depletion obtained by intravenous clodronate, without affecting adipose tissue macrophages, was sufficient to enhance insulin-dependent insulin signaling and significantly improve hepatic insulin sensitivity in vivo in this short-term high-fat diet model. Our study clearly shows that hepatic macrophage response participates to the onset of high-fat diet-induced hepatic insulin resistance and may therefore represent an attractive target for prevention and treatment of diet- and obesity-induced insulin resistance.

scholarly journals Myeloid Sirtuin 6 Deficiency Causes Insulin Resistance in High-Fat Diet–Fed Mice by Eliciting Macrophage Polarization Toward an M1 Phenotype

Diabetes ◽  
2017 ◽  
Vol 66 (10) ◽  
pp. 2659-2668 ◽  
Author(s):  
Youngyi Lee ◽  
Sun-O Ka ◽  
Hye-Na Cha ◽  
Yu-Na Chae ◽  
Mi-Kyung Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Macrophage Polarization ◽  
High Fat ◽  
M1 Phenotype

scholarly journals Influence of high fat diet and resveratrol supplementation on placental fatty acid uptake in the Japanese macaque

Placenta ◽  
2015 ◽  
Vol 36 (8) ◽  
pp. 903-910 ◽  
Author(s):  
P. O'Tierney-Ginn ◽  
V. Roberts ◽  
M. Gillingham ◽  
J. Walker ◽  
P.A. Glazebrook ◽  
...  
Keyword(s):  
Fatty Acid ◽  
High Fat Diet ◽  
Japanese Macaque ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
High Fat

scholarly journals TLR4/AP-1-Targeted Anti-Inflammatory Intervention Attenuates Insulin Sensitivity and Liver Steatosis

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Xiang Hu ◽  
Jing Zhou ◽  
Sha-sha Song ◽  
Wen Kong ◽  
Yan-Chuan Shi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Signaling Pathway ◽  
High Fat Diet ◽  
Macrophage Polarization ◽  
Liver Steatosis ◽  
Lipid Deposition ◽  
Sirna Transfection ◽  
High Fat ◽  
Metabolic Inflammation

Insulin resistance has been shown to be the common pathogenesis of many metabolic diseases. Metainflammation is one of the important characteristics of insulin resistance. Macrophage polarization mediates the production and development of metainflammation. Toll-like receptor 4 (TLR4) mediates macrophage activity and is probably the intersection of immunity and metabolism, but the detailed mechanism is probably not fully understood. Activated protein 1 (AP1) signaling pathway is very important in macrophage activation-mediated inflammation. However, it is unclear whether AP1 signaling pathway mediates metabolic inflammation in the liver. We aimed to investigate the effects of macrophage TLR4-AP1 signaling pathway on hepatocyte metabolic inflammation, insulin sensitivity, and lipid deposition, as well as to explore the potential of TLR4-AP1 as new intervention targets of insulin resistance and liver steatosis. TLR4 and AP1 were silenced in the RAW264.7 cells by lentiviral siRNA transfection. In vivo transduction of lentivirus was administered in mice fed with high-fat diet. Insulin sensitivity and inflammation were evaluated in the treated cells or animals. Our results indicated that TLR4/AP-1 siRNA transfection alleviated high-fat diet-induced systemic and hepatic inflammation, obesity, and insulin resistance in mice. Additionally, TLR4/AP-1 siRNA transfection mitigated palmitic acid- (PA-) induced inflammation in RAW264.7 cells and metabolic abnormalities in cocultured AML hepatocytes. Herein, we propose that TLR4-AP1 signaling pathway activation plays a crucial role in high fat- or PA-induced metabolic inflammation and insulin resistance in hepatocytes. Intervention of the TLR4 expression regulates macrophage polarization and metabolic inflammation and further alleviates insulin resistance and lipid deposition in hepatocytes.

scholarly journals Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

2016 ◽  
Vol 36 (21) ◽  
pp. 2715-2727 ◽  
Author(s):  
Wojciech G. Garbacz ◽  
Peipei Lu ◽  
Tricia M. Miller ◽  
Samuel M. Poloyac ◽  
Nicholas S. Eyre ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Glycogen Synthesis ◽  
Metabolic Stress ◽  
Density Lipoprotein ◽  
Fatty Acid Uptake ◽  
Arachidonic Acid Metabolite ◽  
Acid Uptake ◽  
High Fat

The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome.

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