Chronic inflammation exacerbates glucose metabolism disorders in C57BL/6J mice fed with high-fat diet

Wu, Yuzhang; Wu, Tingting; Wu, Jun; Zhao, Lei; Li, Qing; Varghese, Zac; Moorhead, John F.; Powis, Stephen H.; Chen, Yaxi; Ruan, Xiong Z.

doi:10.1530/joe-13-0160

Cited by 50 publications

(30 citation statements)

References 32 publications

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“…Increase in islets mass, which begins early in HFD exposure, coincident with the onset of hyperglycemia and glucose intolerance, but before the onset of insulin resistance has been reported (Stamateris et al, ). Therefore, the higher increase in insulin secretion in response to glucose load in HFD mice may be correlate with increased pancreatic beta cell mass, consistent with previous study (Collins et al, ; Fraulob et al, ; Li et al, ; Wu et al, ).…”

Section: Discussionsupporting

confidence: 90%

GLP‐2 as Beneficial Factor in the Glucose Homeostasis in Mice Fed a High Fat Diet

Baldassano

Rappa

Amato

et al. 2015

Journal Cellular Physiology

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Glucagon like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to dietary nutrients, which acts through a specific receptor, the GLP-2 receptor (GLP-2R). The physiological effects of GLP-2 are multiple, involving also the intestinal adaptation to high fat diet (HFD). In consideration of the well-known relationship between chronic HFD and impaired glucose metabolism, in the present study we examined if the blocking of the GLP-2 signaling by chronic treatment with the GLP-2R antagonist, GLP-2 (3-33), leads to functional consequences in the regulation of glucose metabolism in HFD-fed mice. Compared with animals fed standard diet (STD), mice at the 10th week of HFD showed hyperglycaemia, glucose intolerance, high plasma insulin level after glucose load, increased pancreas weight and b cell expansion, but not insulin resistance. In HFD fed mice, GLP-2 (3-33) treatment for 4 weeks (from the 6th to the 10th week of diet) did not affect fasting glycaemia, but it significantly increased the glucose intolerance, both fasting and glucose-induced insulin levels, and reduced the sensitivity to insulin leading to insulin-resistance. In GLP-2 (3-33)-treated HFD mice pancreas was significantly heavier and displayed a significant increase in b-cell mass in comparison with vehicle-treated HFD mice. In STD mice, the GLP-2 (3-33) treatment did not affect fasted or glucose-stimulated glycemia, insulin, insulin sensitivity, pancreas weight and beta cell mass. The present study suggests that endogenous GLP-2 may act as a protective factor against the dysregulation of the glucose metabolism that occurs in HFD mice, because GLP-2 (3-33) worsens glucose metabolism disorders.J. Cell. Physiol. 230: 3029-3036, 2015. © 2015 Wiley Periodicals, Inc.Glucagon-like peptide-2 (GLP-2) is a 33-amino acid proglucagon-derived peptide, related in sequence to glucagon-like peptide-1 (GLP-1) and co-secreted in response to nutrients, and specifically fat and carbohydrates, from intestinal endocrine L cells (for review see Marathe et al., 2013;Baldassano and Amato, 2014;Drucker and Yusta, 2014). While GLP-1 is one of the most potent insulinotropic substances known, GLP-2 mainly acts to maintain intestinal homeostasis and to enhance barrier function (Holst, 2004;Janssen et al., 2013). GLP-2 also promotes the rapid stimulation of hexose transport (Cheeseman et al., 1997), reduces short-term food intake (Tang-Christensen et al., 2000;Baldassano et al., 2012) and can modulate the gastrointestinal functions, such as gastric emptying, intestinal motility, and intestinal enteric secretion GLP-2 has been reported to play a beneficial role in obesity condition (Cani et al., 2009). In general, obesity may be due to an high fat diet (HFD), nutritional condition that may lead to metabolic syndrome which is defined as a cluster of obesity, glucose intolerance, insulin resistance, hypertension, and dyslipidemia (Buettner et al., 2007;Shin et al., 2013). GLP-2, in genetically obese mice, lowers endotoxemia, reduces gut permeability, and decreases syst...

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Section: Discussionsupporting

confidence: 90%

GLP‐2 as Beneficial Factor in the Glucose Homeostasis in Mice Fed a High Fat Diet

Baldassano

Rappa

Amato

et al. 2015

Journal Cellular Physiology

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“…Obesity-induced chronic inflammation is triggered by metabolic signals such as excess nutrients, and involves inflammatory responses originated within metabolic cells such as adipocytes, hepatocytes or myocytes, resulting in damage to metabolic homeostasis with insulin resistance1617183642535455. In agreement with these studies, we have previously found activated NFkB pathway and increased expression of pro-inflammatory genes in insulin resistant myotubes derived from diabetic-obese subjects, but not in insulin sensitive myotubes derived from non-diabetic-lean subjects56.…”

Section: Discussionsupporting

confidence: 81%

Mitochondrial fat oxidation is essential for lipid-induced inflammation in skeletal muscle in mice

Warfel

Bermudez

Mendoza

et al. 2016

Sci Rep

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Inflammation, lipotoxicity and mitochondrial dysfunction have been implicated in the pathogenesis of obesity-induced insulin resistance and type 2 diabetes. However, how these factors are intertwined in the development of obesity/insulin resistance remains unclear. Here, we examine the role of mitochondrial fat oxidation on lipid-induced inflammation in skeletal muscle. We used skeletal muscle-specific Cpt1b knockout mouse model where the inhibition of mitochondrial fatty acid oxidation results in accumulation of lipid metabolites in muscle and elevated circulating free fatty acids. Gene expression of pro-inflammatory cytokines, chemokines, and cytokine- and members of TLR-signalling pathways were decreased in Cpt1bm−/− muscle. Inflammatory signalling pathways were not activated when evaluated by multiplex and immunoblot analysis. In addition, the inflammatory response to fatty acids was reduced in primary muscle cells derived from Cpt1bm−/− mice. Gene expression of Cd11c, the M1 macrophage marker, was decreased; while Cd206, the M2 macrophage marker, was increased in skeletal muscle of Cpt1bm−/− mice. Finally, expression of pro-inflammatory markers was decreased in white adipose tissue of Cpt1bm−/− mice. We show that the inflammatory response elicited by elevated intracellular lipids in skeletal muscle is repressed in Cpt1bm−/− mice, strongly supporting the hypothesis that mitochondrial processing of fatty acids is essential for the lipid-induction of inflammation in muscle.

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“…Previous studies using obese models have shown increased inflammation to be associated with changes in glucose metabolism (41,67). In this study, obesity was also associated with a downregulation of ovarian glucose transporter gene expression (GLUT4 and GLUT9) compared with lean controls.…”

Section: Discussionsupporting

confidence: 50%

Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1

Ruebel

Shankar

Gaddy

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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A. Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1. Am J Physiol Endocrinol Metab 311: E269 -E277, 2016. First published June 7, 2016 doi:10.1152/ajpendo.00524.2015.-Obesity impairs reproductive functions through multiple mechanisms, possibly through disruption of ovarian function. We hypothesized that increased adiposity will lead to a proinflammatory gene signature and upregulation of Egr-1 protein in ovaries from obese (OB; n ϭ 7) compared with lean (LN; n ϭ 10) female Sprague-Dawley rats during the peri-implantation period at 4.5 days postcoitus (dpc). Obesity was induced by overfeeding (40% excess calories for 28 days) via total enteral nutrition prior to mating. OB dams had higher body weight (P Ͻ 0.001), greater fat mass (P Ͻ 0.001), and reduced lean mass (P Ͻ 0.05) and developed metabolic dysfunction with elevated serum lipids, insulin, leptin, and CCL2 (P Ͻ 0.05) compared with LN dams. Microarray analyses identified 284 differentially expressed genes between ovaries from LN vs. OB dams (Ϯ1.3 fold, P Ͻ 0.05). RT-qPCR confirmed a decrease in expression of glucose transporters GLUT4 and GLUT9 and elevation of proinflammatory genes, including CCL2, CXCL10, CXCL11, CCR2, CXCR1, and TNF␣ in ovaries from OB compared with LN (P Ͻ 0.05). Protein levels of PI3K and phosphorylated Akt were significantly decreased (P Ͻ 0.05), whereas nuclear levels of Egr-1 (P Ͻ 0.05) were increased in OB compared with LN ovaries. Moreover, Egr-1 was localized to granulosa cells, with the highest expression in cumulus cells of preovulatory follicles. mRNA expression of VCAN, AURKB, and PLAT (P Ͻ 0.05) correlated with %visceral fat weight (r ϭ 0.51, Ϫ0.77, and Ϫ0.57, respectively, P Յ 0.05), suggesting alterations in ovarian function with obesity. In summary, maternal obesity led to an upregulation of inflammatory genes and Egr-1 expression in peri-implantation ovarian tissue and a concurrent downregulation of GLUTs and Akt and PI3K protein levels.early growth response factor 1; gene expression; inflammation; obesity; reproduction IN THE US, 60% OF WOMEN OF REPRODUCTIVE AGE are either overweight or obese, which predisposes them to higher risk of infertility and pregnancy complications (12,21,57,59,60) and potentially leads to adverse effects on offspring development. Higher adiposity leads to hormonal dysregulation, decreased primordial follicle numbers at the initiation of follicular development, lower ovulation rates, a reduced number of cleaved blastocysts developing to eight cell stage and reduced implantation rates, and ultimately impaired reproductive function (11,16,17,22,33,35,61). Similarly, in experimental models, obesity leads to decreased primordial and preovulatory follicle numbers, increased follicular atresia and changes in steroidogenesis via decreased steroidogenic acute regulatory protein, and increased Cyp11a1 protein content in ovarian tissue (7,16,23,37,38,53,61). Evidence of lipid accumulation, endoplasmic reticulum stress, and oxidative stress in ova...

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Chronic inflammation exacerbates glucose metabolism disorders in C57BL/6J mice fed with high-fat diet

Cited by 50 publications

References 32 publications

GLP‐2 as Beneficial Factor in the Glucose Homeostasis in Mice Fed a High Fat Diet

GLP‐2 as Beneficial Factor in the Glucose Homeostasis in Mice Fed a High Fat Diet

Mitochondrial fat oxidation is essential for lipid-induced inflammation in skeletal muscle in mice

Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1

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