Altered gene expression of amyloid precursor protein in the adipose tissue and brain of obese mice fed with long-term high-fat diet and streptozotocin-induced diabetic mice

Abstract Background/objectives Visceral adiposity is associated with increased diabetes risk, while expansion of subcutaneous adipose tissue may be protective. However, the visceral compartment contains different fat depots. Peripancreatic adipose tissue (PAT) is an understudied visceral fat depot. Here, we aimed to define PAT functionality in lean and high-fat-diet (HFD)-induced obese mice. Subjects/methods Four adipose tissue depots (inguinal, mesenteric, gonadal, and peripancreatic adipose tissue) from chow- and HFD-fed male mice were compared with respect to adipocyte size (n = 4–5/group), cellular composition (FACS analysis, n = 5–6/group), lipogenesis and lipolysis (n = 3/group), and gene expression (n = 6–10/group). Radioactive tracers were used to compare lipid and glucose metabolism between these four fat depots in vivo (n = 5–11/group). To determine the role of PAT in obesity-associated metabolic disturbances, PAT was surgically removed prior to challenging the mice with HFD. PAT-ectomized mice were compared to sham controls with respect to glucose tolerance, basal and glucose-stimulated insulin levels, hepatic and pancreatic steatosis, and gene expression (n = 8–10/group). Results We found that PAT is a tiny fat depot (~0.2% of the total fat mass) containing relatively small adipocytes and many “non-adipocytes” such as leukocytes and fibroblasts. PAT was distinguished from the other fat depots by increased glucose uptake and increased fatty acid oxidation in both lean and obese mice. Moreover, PAT was the only fat depot where the tissue weight correlated positively with liver weight in obese mice (R = 0.65; p = 0.009). Surgical removal of PAT followed by 16-week HFD feeding was associated with aggravated hepatic steatosis (p = 0.008) and higher basal (p < 0.05) and glucose-stimulated insulin levels (p < 0.01). PAT removal also led to enlarged pancreatic islets and increased pancreatic expression of markers of glucose-stimulated insulin secretion and islet development (p < 0.05). Conclusions PAT is a small metabolically highly active fat depot that plays a previously unrecognized role in the pathogenesis of hepatic steatosis and insulin resistance in advanced obesity.

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Maternal high-fat diet associated with altered gene expression, DNA methylation, and obesity risk in mouse offspring

PLoS ONE ◽

10.1371/journal.pone.0192606 ◽

2018 ◽

Vol 13 (2) ◽

pp. e0192606 ◽

Cited By ~ 40

Author(s):

Madeline Rose Keleher ◽

Rabab Zaidi ◽

Shyam Shah ◽

M. Elsa Oakley ◽

Cassondra Pavlatos ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

High Fat Diet ◽

Obesity Risk ◽

High Fat ◽

Altered Gene Expression ◽

Altered Gene

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Effect of a long-term high-protein diet on survival, obesity development, and gut microbiota in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00363.2015 ◽

2016 ◽

Vol 310 (11) ◽

pp. E886-E899 ◽

Cited By ~ 25

Author(s):

Pia Kiilerich ◽

Lene Secher Myrmel ◽

Even Fjære ◽

Qin Hao ◽

Floor Hugenholtz ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Gut Microbiota ◽

Dietary Fat ◽

High Fat Diet ◽

High Fat ◽

Low Fat ◽

Low Fat Diet ◽

Low Protein

Female C57BL/6J mice were fed a regular low-fat diet or high-fat diets combined with either high or low protein-to-sucrose ratios during their entire lifespan to examine the long-term effects on obesity development, gut microbiota, and survival. Intake of a high-fat diet with a low protein/sucrose ratio precipitated obesity and reduced survival relative to mice fed a low-fat diet. By contrast, intake of a high-fat diet with a high protein/sucrose ratio attenuated lifelong weight gain and adipose tissue expansion, and survival was not significantly altered relative to low-fat-fed mice. Our findings support the notion that reduced survival in response to high-fat/high-sucrose feeding is linked to obesity development. Digital gene expression analyses, further validated by qPCR, demonstrated that the protein/sucrose ratio modulated global gene expression over time in liver and adipose tissue, affecting pathways related to metabolism and inflammation. Analysis of fecal bacterial DNA using the Mouse Intestinal Tract Chip revealed significant changes in the composition of the gut microbiota in relation to host age and dietary fat content, but not the protein/sucrose ratio. Accordingly, dietary fat rather than the protein/sucrose ratio or adiposity is a major driver shaping the gut microbiota, whereas the effect of a high-fat diet on survival is dependent on the protein/sucrose ratio.

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Low Carbohydrate/High-Fat Diet Attenuates Cardiac Hypertrophy, Remodeling, and Altered Gene Expression in Hypertension

Hypertension ◽

10.1161/01.hyp.0000248430.26229.0f ◽

2006 ◽

Vol 48 (6) ◽

pp. 1116-1123 ◽

Cited By ~ 74

Author(s):

Isidore C. Okere ◽

Martin E. Young ◽

Tracy A. McElfresh ◽

David J. Chess ◽

Victor G. Sharov ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Hypertrophy ◽

High Fat Diet ◽

High Fat ◽

Altered Gene Expression ◽

Low Carbohydrate ◽

Altered Gene

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The Effects of Poncirus fructus on Insulin Resistance and the Macrophage-Mediated Inflammatory Response in High Fat Diet-Induced Obese Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20122858 ◽

2019 ◽

Vol 20 (12) ◽

pp. 2858 ◽

Cited By ~ 3

Author(s):

Mia Kim ◽

Mi Hyeon Seol ◽

Byung-Cheol Lee

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Kupffer Cells ◽

High Fat Diet ◽

Inflammatory Responses ◽

Low Grade ◽

Obese Mice ◽

High Fat ◽

Epididymal Fat

Obesity is a chronic low-grade inflammatory condition in which hypertrophied adipocytes and adipose tissue immune cells, mainly macrophages, contribute to increased circulating levels of proinflammatory cytokines. Obesity-associated chronic low-grade systemic inflammation is considered a focal point and a therapeutic target in insulin resistance and metabolic diseases. We evaluate the effect of Poncirus fructus (PF) on insulin resistance and its mechanism based on inflammatory responses in high-fat diet (HFD)-induced obese mice. Mice were fed an HFD to induce obesity and then administered PF. Body weight, epididymal fat and liver weight, glucose, lipid, insulin, and histologic characteristics were evaluated to determine the effect of PF on insulin resistance by analyzing the proportion of macrophages in epididymal fat and liver and measured inflammatory gene expression. PF administration significantly decreased the fasting and postprandial glucose, fasting insulin, HOMA-IR, total-cholesterol, triglycerides, and low-density lipoprotein cholesterol levels. The epididymal fat tissue and liver showed a significant decrease of fat accumulation in histological analysis. PF significantly reduced the number of adipose tissue macrophages (ATMs), F4/80+ Kupffer cells, and CD68+ Kupffer cells, increased the proportion of M2 phenotype macrophages, and decreased the gene expression of inflammatory cytokines. These results suggest that PF could be used to improve insulin resistance through modulation of macrophage-mediated inflammation and enhance glucose and lipid metabolism.

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Adipose tissue energy metabolism: altered gene expression profile of mice subjected to long‐term caloric restriction

The FASEB Journal ◽

10.1096/fj.03-0678fje ◽

2003 ◽

Vol 18 (2) ◽

pp. 1-26 ◽

Cited By ~ 116

Author(s):

Yoshikazu Higami ◽

Thomas D. Pugh ◽

Grier P. Page ◽

David B. Allison ◽

Tomas A. Prolla ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Energy Metabolism ◽

Caloric Restriction ◽

Gene Expression Profile ◽

Expression Profile ◽

Altered Gene Expression ◽

Altered Gene

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Engineered human brown adipocyte microtissues improved glucose and insulin homeostasis in high fat diet-induced obese and diabetic mice

10.1101/2021.10.11.463939 ◽

2021 ◽

Author(s):

Ou Wang ◽

Li Han ◽

Haishuang Lin ◽

Mingmei Tian ◽

Shuyang Zhang ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

High Fat Diet ◽

Diabetic Mice ◽

High Fat ◽

Brown Adipose ◽

Insulin Homeostasis ◽

Human And Mouse

AbstractA large population of people is affected by obesity (OB) and its associated type 2 diabetes mellitus(T2DM). There are currently no safe and long-lasting anti-OB/T2DM therapies. Clinical data and preclinical transplantation studies show that transplanting metabolically active brown adipose tissue (BAT) is a promising approach to prevent and treat OB and its associated metabolic and cardiovascular diseases. However, most transplantation studies used mouse BAT, and it is uncertain whether the therapeutic effect would be applied to human BAT since human and mouse BATs have distinct differences. Here, we report the fabrication of three-dimensional (3D) human brown adipose microtissues, their survival and safety, and their capability to improve glucose and insulin homeostasis and manage body weight gain in high-fat diet (HFD)-induced OB and diabetic mice.Methods3D BA microtissues were fabricated and transplanted into the kidney capsule of Rag1-/- mice. HFD was initiated to induce OB 18 days after transplantation. A low dose of streptozotocin (STZ) was administrated after three month’s HFD to induce diabetes. The body weight, fat and lean mass, plasma glucose level, glucose tolerance and insulin sensitivity were recorded regularly. In addition, the levels of human and mouse adipokines in the serum were measured, and various tissues were harvested for histological and immunostaining analyses.ResultsWe showed that 3D culture promoted BA differentiation and uncoupling protein-1 (UCP-1) protein expression, and the microtissue size significantly influenced the differentiation efficiency and UCP-1 protein level. The optimal microtissue diameter was about 100 µm. Engineered 3D BA microtissues survived for the long term with angiogenesis and innervation, alleviated body weight and fat gain, and significantly improved glucose tolerance and insulin sensitivity. They protected the endogenous BAT from whitening and reduced mouse white adipose tissue (WAT) hypertrophy and liver steatosis. In addition, the microtissues secreted soluble factors and modulated the expression of mouse adipokines. We also showed that scaling up the microtissue production could be achieved using the 3D suspension culture or a 3D thermoreversible hydrogel matrix. Further, these microtissues can be preserved at room temperature for 24 hours or be cryopreserved for the long term without significantly sacrificing cell viability.ConclusionOur study showed that 3D BA microtissues could be fabricated at large scales, cryopreserved for the long term, and delivered via injection. BAs in the microtissues had higher purity, and higher UCP-1 protein expression than BAs prepared via 2D culture. In addition, 3D BA microtissues had good in vivo survival and tissue integration, and had no uncontrolled tissue overgrowth. Furthermore, they showed good efficacy in preventing OB and T2DM with a very low dosage compared to literature studies. Thus, our results show engineered 3D BA microtissues are promising anti-OB/T2DM therapeutics. They have considerable advantages over dissociated BAs or BAPs for future clinical applications in terms of product scalability, storage, purity, quality, and in vivo safety, dosage, survival, integration, and efficacy.

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Integrated Multiomic Analysis Reveals the High-Fat Diet Induced Activation of the MAPK Signaling and Inflammation Associated Metabolic Cascades via Histone Modification in Adipose Tissues

Frontiers in Genetics ◽

10.3389/fgene.2021.650863 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhe Wang ◽

Ming Zhu ◽

Meng Wang ◽

Yihui Gao ◽

Cong Zhang ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Energy Metabolism ◽

Histone Modification ◽

High Fat Diet ◽

Whole Genome ◽

Rna Seq ◽

High Fat ◽

Adipose Tissues

BackgroundThe number of diet induced obese population is increasing every year, and the incidence of type 2 diabetes is also on the rise. Histone methylation and acetylation have been shown to be associated with lipogenesis and obesity by manipulating gene expression via the formation of repression or activation domains on chromosomes.ObjectiveIn this study, we aimed to explore gene activation or repression and related biological processes by histone modification across the whole genome on a high-fat diet (HFD) condition. We also aimed to elucidate the correlation of these genes that modulated by histone modification with energy metabolism and inflammation under both short-term and long-term HFD conditions.MethodWe performed ChIP-seq analysis of H3K9me2 and H3K9me3 in brown and white adipose tissues (WATs; subcutaneous adipose tissue) from mice fed with a standard chow diet (SCD) or HFD and a composite analysis of the histone modification of H3K9me2, H3K9me3, H3K4me1 and H3K27ac throughout the whole genome. We also employed and integrated two bulk RNA-seq and a single-nuclei RNA sequencing dataset and performed western blotting (WB) to confirm the gene expression levels in adipose tissue of the SCD and HFD groups.ResultsThe ChIP-seq and transcriptome analysis of mouse adipose tissues demonstrated that a series of genes were activated by the histone modification of H3K9me2, H3K9me3, H3K4me1, and H3K27ac in response to HFD condition. These genes were enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in lipogenesis, energy metabolism and inflammation. Several genes in the activated mitogen-activated protein kinase (MAPK) pathway might be related to both inflammation and energy metabolism in mice, rats and humans fed with HFD for a short or long term, as showed by bulk RNA-seq and single nuclei RNA-seq datasets. Western blot analyses further confirmed the increased expression of MET, VEGFA and the enhanced phosphorylation ratio of p44/42 MAPK upon HFD treatment.ConclusionThis study expanded our understanding of the influence of eating behavior on obesity and could assist the identification of putative therapeutic targets for the prevention and treatment of metabolic disorders in the future.

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Allium hookeri Root Extract Inhibits Adipogenesis by Promoting Lipolysis in High Fat Diet-Induced Obese Mice

Nutrients ◽

10.3390/nu11102262 ◽

2019 ◽

Vol 11 (10) ◽

pp. 2262 ◽

Cited By ~ 2

Author(s):

Kim ◽

Jang ◽

Lee

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Fatty Acid ◽

White Adipose Tissue ◽

High Fat Diet ◽

Obese Mice ◽

High Fat ◽

Tissue Weight ◽

Adipose Tissue Weight ◽

Allium Hookeri

: Allium hookeri (AH) is widely consumed as a herbal medicine. It possesses biological activity against metabolic diseases. The objective of this study was to investigate effects of AH root water extract (AHR) on adipogenesis in 3T3-L1 cells and in high-fat diet (HFD)-induced obese mice. AHR inhibited lipid accumulation during adipocyte differentiation by downregulation of gene expression, such as hormone sensitive lipase (HSL), lipoprotein lipase (LPL) and an adipogenic gene, CCAAT/enhancer binding protein-α in 3T3-L1 preadipocytes. Oral administration of AHR significantly suppressed body weight gain, adipose tissue weight, serum leptin levels, and adipocyte cell size in HFD-induced obese mice. Moreover, AHR significantly decreased hepatic mRNA expression levels of cholesterol synthesis genes, such as 3-hydroxy-3-methylglutaryl CoA reductase, sterol regulatory element-binding transcription factor (SREBP)-2, and low-density lipoprotein receptor, as well as fatty acid synthesis genes, such as SREBP-1c and fatty acid synthase. Serum triglyceride levels were also lowered by AHR, likely as a result of the upregulating gene involved in fatty acid β-oxidation, carnitine palmitoyltransferase 1a, in the liver. AHR treatment activated gene expression of peroxisome proliferator-activated receptor-γ, which might have promoted HSL and LPL-medicated lipolysis, thereby reducing white adipose tissue weight. In conclusion, AHR treatment can improve metabolic alterations induced by HFD in mice by modifying expression levels of genes involved in adipogenesis, lipogenesis, and lipolysis in the white adipose tissue and liver.

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