GM-CSF driven myeloid cells in adipose tissue link weight gain and insulin resistance via formation of 2-aminoadipate

n-3 PUFA have shown potential anti-obesity and insulin-sensitising properties. However, the mechanisms involved are not clearly established. The aim of the present study was to assess the effects of EPA administration, one of the n-3 PUFA, on body-weight gain and adiposity in rats fed on a standard or a high-fat (cafeteria) diet. The actions on white adipose tissue lipolysis, apoptosis and on several genes related to obesity and insulin resistance were also studied. Control and cafeteria-induced overweight male Wistar rats were assigned into two subgroups, one of them daily received EPA ethyl ester (1 g/kg) for 5 weeks by oral administration. The high-fat diet induced a very significant increase in both body weight and fat mass. Rats fed with the cafeteria diet and orally treated with EPA showed a marginally lower body-weight gain (P = 0·09), a decrease in food intake (P < 0·01) and an increase in leptin production (P < 0·05). EPA administration reduced retroperitoneal adipose tissue weight (P < 0·05) which could be secondary to the inhibition of the adipogenic transcription factor PPARγ gene expression (P < 0·001), and also to the increase in apoptosis (P < 0·05) found in rats fed with a control diet. TNFα gene expression was significantly increased (P < 0·05) by the cafeteria diet, while EPA treatment was able to prevent (P < 0·01) the rise in this inflammatory cytokine. Adiposity-corrected adiponectin plasma levels were increased by EPA. These actions on both TNFα and adiponectin could explain the beneficial effects of EPA on insulin resistance induced by the cafeteria diet.

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Breast Cancer Endocrine Therapy Exhausts Adipocyte Progenitors Promoting Weight Gain and Glucose Intolerance

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.080 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A41-A41

Author(s):

Elizabeth A Wellberg ◽

Stevi Johnson-Murguia ◽

Paul S MacLean ◽

James D Johnson ◽

Jane E B Reusch ◽

...

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Weight Gain ◽

Endocrine Therapy ◽

Estrogen Deprivation ◽

Adipocyte Progenitors ◽

Adipocyte Hypertrophy

Abstract Breast cancer survivors treated with anti-estrogen therapies report weight gain and have an elevated risk of type 2 diabetes. Here, we show that current tamoxifen use did not influence body mass index but associated with larger breast adipocyte diameter only in women with obesity, suggesting adipose tissue may be targeted by breast cancer therapies. To understand the mechanisms behind these clinical findings, we investigated the impact of estrogen deprivation and tamoxifen in a relevant pre-clinical murine model of obesity. Specifically, mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in single-cell RNA sequencing of mesenchymal stem cells from mouse adipose tissue, endocrine therapies associated with adipose accumulation and preadipocyte expansion, but resulted in adipocyte progenitor depletion only in the context of HFHS. Consequently, 7-week endocrine therapy supported adipocyte hypertrophy and was associated with hepatic steatosis, hyperinsulinemia, insulin resistance, and glucose intolerance, particularly in HFHS fed females. We administered HFHS fed females either metformin or pioglitazone, glucose lowering drugs used to treat diabetes, or treadmill interval exercise during endocrine therapy with the goal of improving whole body metabolism. All interventions prevented the effects of tamoxifen but not estrogen deprivation on adipocyte size and insulin resistance in HFHS-fed mice. This translational study suggests that endocrine therapies may act via ER-alpha to directly disrupt adipocyte progenitors and support adipocyte hypertrophy, leading to ectopic lipid deposition that may promote hyperinsulinemia, insulin resistance and type 2 diabetes. Interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

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Deletion of the gene encoding G0/G1 switch protein 2 (G0s2) alleviates high-fat-diet-induced weight gain and insulin resistance, and promotes browning of white adipose tissue in mice

Diabetologia ◽

10.1007/s00125-014-3429-z ◽

2014 ◽

Vol 58 (1) ◽

pp. 149-157 ◽

Cited By ~ 22

Author(s):

Wissal El-Assaad ◽

Karim El-Kouhen ◽

Amro H. Mohammad ◽

Jieyi Yang ◽

Masahiro Morita ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Weight Gain ◽

White Adipose Tissue ◽

High Fat Diet ◽

High Fat ◽

Gene Encoding

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Nrf2 deficiency in myeloid cells is not sufficient to protect mice from high-fat diet-induced adipose tissue inflammation and insulin resistance

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2012.02.022 ◽

2012 ◽

Vol 52 (9) ◽

pp. 1708-1715 ◽

Cited By ~ 31

Author(s):

Akshaya K. Meher ◽

Poonam R. Sharma ◽

Vitor A. Lira ◽

Masayuki Yamamoto ◽

Thomas W. Kensler ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

High Fat Diet ◽

Myeloid Cells ◽

Adipose Tissue Inflammation ◽

High Fat ◽

Tissue Inflammation

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Loss of Pdk1-Foxo1 Signaling in Myeloid Cells Predisposes to Adipose Tissue Inflammation and Insulin Resistance

Diabetes ◽

10.2337/db11-0770 ◽

2012 ◽

Vol 61 (8) ◽

pp. 1935-1948 ◽

Cited By ~ 40

Author(s):

Y. Kawano ◽

J. Nakae ◽

N. Watanabe ◽

S. Fujisaka ◽

K. Iskandar ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Myeloid Cells ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation

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PAFR in adipose tissue macrophages is associated with anti-inflammatory phenotype and metabolic homoeostasis

Clinical Science ◽

10.1042/cs20150538 ◽

2016 ◽

Vol 130 (8) ◽

pp. 601-612 ◽

Cited By ~ 7

Author(s):

Luciano Ribeiro Filgueiras ◽

Marianna Mainardi Koga ◽

Paula G. Quaresma ◽

Edson Kiyotaka Ishizuka ◽

Marlise B.A. Montes ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Weight Gain ◽

Essential Role ◽

Hepatic Insulin Resistance ◽

Tissue Weight ◽

Adipose Tissue Weight ◽

Adipose Tissue Macrophages ◽

Inflammatory Phenotype ◽

Inflammatory Macrophages

We found an essential role for PAFR in adipose tissue macrophages. PAFR deficiency leads to infiltration of pro-inflammatory macrophages in the adipose tissue, weight gain, reduced glucose tolerance and hepatic insulin resistance, followed by hepatic steatosis.

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Inhibition of Mitochondrial Fission and iNOS in the Dorsal Vagal Complex Protects from Overeating and Weight Gain

10.1101/2020.06.26.173641 ◽

2020 ◽

Author(s):

Bianca Patel ◽

Lauryn New ◽

Joanne C. Griffiths ◽

Jim Deuchars ◽

Beatrice M. Filippi

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Adipose Tissue ◽

Weight Gain ◽

Food Intake ◽

Feeding Behaviour ◽

Body Weight Gain ◽

Mitochondrial Fission ◽

Dorsal Vagal Complex ◽

Cumulative Food Intake

AbstractThe dorsal vagal complex (DVC) senses changes in insulin levels and controls glucose homeostasis, feeding behaviour and body weight. Three days of high-fat diet (HFD) in rats is sufficient to induce insulin resistance in the DVC and impair its ability to regulate feeding behaviour. HFD-feeding is associated with increased mitochondrial fission in the DVC and fission is regulated by dynamin-related protein 1 (Drp1). Higher Drp1 activity can inhibit insulin signalling, although the exact mechanisms controlling body weight remain elusive. Here we show that Drp1 activation in DVC leads to higher body weight in rats and Drp1 inhibition in HFD-fed rats reduced body weight gain, cumulative food intake and adipose tissue, and prevented insulin resistance. Rats expressing active Drp1 in the DVC had higher levels of inducible nitric oxide synthase (iNOS) and knockdown of iNOS in the DVC of HFD-fed rats led to a reduction in body weight gain, cumulative food intake and adipose tissue, and prevented insulin resistance. In obese insulin-resistant animals, inhibition of mitochondrial fission or DVC iNOS knockdown restored insulin sensitivity and decreased food intake, body weight and fat deposition. Finally, we show that inhibiting mitochondrial fission in DVC astrocytes is sufficient to protect rats from developing HFD-dependent insulin resistance, hyperphagia, body weight gain and fat deposition. Our study uncovers new molecular and cellular targets for brain regulation of whole-body metabolism, which could inform new strategies to combat obesity and diabetes.

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An extract of chokeberry attenuates weight gain and modulates insulin, adipogenic and inflammatory signalling pathways in epididymal adipose tissue of rats fed a fructose-rich diet

British Journal Of Nutrition ◽

10.1017/s000711451100599x ◽

2011 ◽

Vol 108 (4) ◽

pp. 581-587 ◽

Cited By ~ 76

Author(s):

Bolin Qin ◽

Richard A. Anderson

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Weight Gain ◽

Zinc Finger Protein ◽

Insulin Signalling ◽

Epididymal Adipose Tissue ◽

Control Group ◽

Mrna Levels ◽

The Metabolic Syndrome

Chokeberries are a rich source of anthocyanins, which may contribute to the prevention of obesity and the metabolic syndrome. The aim of the present study was to determine if an extract from chokeberries would reduce weight gain in rats fed a fructose-rich diet (FRD) and to explore the potential mechanisms related to insulin signalling, adipogenesis and inflammatory-related pathways. Wistar rats were fed a FRD for 6 weeks to induce insulin resistance, with or without chokeberry extract (CBE) added to the drinking-water (100 and 200 mg/kg body weight, daily: CBE100 and CBE200). Both doses of CBE consumption lowered epididymal fat, blood glucose, TAG, cholesterol and LDL-cholesterol. CBE consumption also elevated plasma adiponectin levels and inhibited plasma TNF-α and IL6, compared with the control group. There were increases in the mRNA expression for Irs1, Irs2, Pi3k, Glut1, Glut4 and Gys1, and decreases in mRNA levels of Gsk3β. The protein and gene expression of adiponectin and Pparγ mRNA levels were up-regulated and Fabp4, Fas and Lpl mRNA levels were inhibited. The levels of gene expression of inflammatory cytokines, such as Il1β, Il6 and Tnfα were lowered, and protein and gene expression of ZFP36 (zinc finger protein) were enhanced in the epididymal adipose tissue of the rats that consumed the CBE200 extract. In summary, these results suggest that the CBE decreased risk factors related to insulin resistance by modulating multiple pathways associated with insulin signalling, adipogenesis and inflammation.

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Lycopene supplementation attenuates western diet-induced body weight gain through increasing the expressions of thermogenic/mitochondrial functional genes and improving insulin resistance in the adipose tissue of obese mice

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2019.03.008 ◽

2019 ◽

Vol 69 ◽

pp. 63-72 ◽

Cited By ~ 12

Author(s):

Jia Wang ◽

Yao Suo ◽

Jinlei Zhang ◽

Qianhui Zou ◽

Xintong Tan ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Adipose Tissue ◽

Weight Gain ◽

Body Weight Gain ◽

Western Diet ◽

Functional Genes ◽

Obese Mice

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The role of GM-CSF in adipose tissue inflammation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00061.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. E1038-E1046 ◽

Cited By ~ 60

Author(s):

Dong-Hoon Kim ◽

Darleen Sandoval ◽

Jacquelyn A. Reed ◽

Emily K. Matter ◽

Emeline G. Tolod ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Knockout Mice ◽

Wild Type ◽

Tissue Macrophage ◽

Gm Csf ◽

Adipose Tissue Macrophage ◽

Mesenteric Fat

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine that has a central action to reduce food intake and body weight. Consistent with this, GM-CSF knockout mice are more obese and hyperphagic than wild-type mice. However, in lung, GM-CSF is an important determinant of macrophage infiltration. Consequently, we sought to determine if GM-CSF might contribute to adipose tissue macrophage accumulation, insulin resistance, and low-grade inflammation that occurs when animals gain weight on a high-fat diet (HFD). We therefore determined how targeted genetic disruption of GM-CSF can affect adipose tissue macrophage and cytokine gene expression as well as glucose homeostasis by performing hyperinsulinemic-euglycemic clamps. The number of macrophages and CCR2 gene expression in adipose tissue of GM-CSF knockout mice was decreased relative to those in wild-type mice, and the adipocyte size of mesenteric fat was increased in GM-CSF knockout mice on a HFD compared with wild-type mice. The level of mRNA of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α, and macrophage inflammatory protein-1α was significantly lower in mesenteric fat of GM-CSF knockout mice on the HFD than in wild-type mice. Using the hyperinsulinemic-euglycemic clamp technique, GM-CSF knockout mice had greater overall insulin sensitivity. This increase was due to enhanced peripheral uptake and utilization of glucose rather than to increased hepatic insulin sensitivity. Collectively, the data suggest that the GM-CSF knockout mutation ameliorates peripheral insulin resistance in spite of increased adiposity by reducing inflammation in adipose tissue in response to a HFD.

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