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Obesity, mouse, mice

Navneet Matharu, Sawitree Rattanasopha, Serena Tamura, Lenka Maliskova, Yi Wang, Adelaide Bernard, Aaron Hardin, Walter L Eckalbar, Christian Vaisse, Nadav Ahituv
A wide-range of human diseases result from haploinsufficiency, where the function of one of the two gene copies is lost. Here, we targeted the remaining functional copy of a haploinsufficient gene using CRISPR-mediated activation (CRISPRa) in Sim1 and Mc4r heterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting of the Sim1 promoter or its distant hypothalamic enhancer upregulated its expression from the endogenous functional allele in a tissue-specific manner, rescuing the obesity phenotype in Sim1 heterozygous mice...
December 13, 2018: Science
Stefan Z Lutz, Anita M Hennige, Andreas Peter, Marketa Kovarova, Charisis Totsikas, Jürgen Machann, Stefan M Kröber, Bianca Sperl, Erwin Schleicher, Fritz Schick, Martin Heni, Axel Ullrich, Hans-Ulrich Häring, Norbert Stefan
Context: The effect of a lifestyle intervention to reduce liver fat content in nonalcoholic fatty liver disease in humans is influenced by genetics. We hypothesized that the functionally active amino acid exchange in humans Gly388Arg (mouse homologue: Gly385Arg) in the fibroblast growth factor receptor 4 (FGFR4), which regulates bile acid, lipid and glucose metabolism, may determine the dynamics of hepatic lipid accumulation and insulin sensitivity in humans. Mechanisms of this substitution were studied in mice under normal chow and high-fat diet...
December 12, 2018: Journal of Clinical Endocrinology and Metabolism
Jan-Inge Bjune, Christine Haugen, Oddrun Gudbrandsen, Ole P Nordbø, Hans J Nielsen, Villy Våge, Pål R Njølstad, Jørn V Sagen, Simon N Dankel, Gunnar Mellgren
OBJECTIVE: A causal obesity risk variant in the FTO locus was recently shown to inhibit adipocyte thermogenesis via increased adipose expression of the homeobox transcription factors IRX3 and IRX5. However, causal effects of IRX5 on fat storage remain to be shown in vivo, and discovery of downstream mediators may open new therapeutic avenues. METHODS: 17 WT and 13 Irx5 knockout (KO) mice were fed low-fat control (Ctr) or high-fat (HF) diet for 10 weeks. Body weight, energy intake and fat mass were measured...
December 11, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Odunayo O Mugisho, Colin R Green, David M Squirrell, Sarah Bould, Helen V Danesh-Meyer, Jie Zhang, Monica L Acosta, Ilva D Rupenthal
Diabetic retinopathy (DR) is a vascular disease of the neuroretina characterised by hyperglycaemia and inflammation. Current DR therapies target late-stage vascular defects and there is evidence to suggest that they contribute to geographic atrophy and retinal ganglion cell death long term. Therefore, alternative treatments that target common upstream disease mechanisms are needed. Recent studies have shown that connexin43 hemichannel blockers can reduce inflammation and prevent vessel leak in brain and spinal cord lesions...
December 8, 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Sarah Appel, Jon Grothe, Sarah Storck, Ruth Janoschek, Inga Bae-Gartz, Maria Wohlfarth, Marion Handwerk, Eva Hucklenbruch-Rother, Alexandra Gellhaus, Jörg Dötsch
Obesity and an unhealthy nutrition are on the rise and affect also women in childbearing age and hence, during pregnancy. Despite normal or even high birth weight the offspring suffers from long term metabolic risks. We hypothesized that fetal growth is disturbed during different intrauterine phases. Underlying molecular events remain elusive. Female mice were fed either a control diet (SD) or a high fat diet (HFD) after weaning until mating and during pregnancy. Pregnant mice were sacrificed at gestational time points G15...
December 10, 2018: Endocrinology
Lisa Lindheim, Maria Manti, Romina Fornes, Mina Bashir, Paulo Czarnewski, Oscar E Diaz, Maike Seifert, Lars Engstrand, Eduardo J Villablanca, Barbara Obermayer-Pietsch, Elisabet Stener-Victorin
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder of unclear etiology in women and is characterized by androgen excess, insulin resistance, and mood disorders. The gut microbiome is known to influence conditions closely related with PCOS, and several recent studies have observed changes in the stool microbiome of women with PCOS. The mechanism by which the gut microbiome interacts with PCOS is still unknown. We used a mouse model to investigate if diet-induced maternal obesity and maternal DHT exposure, mimicking the lean and obese PCOS women, cause lasting changes in the gut microbiome of offspring...
December 1, 2018: Journal of the Endocrine Society
Yong Liu, Lin Wang, Mao Luo, Ni Chen, Xin Deng, Jing He, Liping Zhang, Pei Luo, Jianbo Wu
Plasminogen activator inhibitor-1 (PAI-1) is increasingly recognized as a mediator in extracellular matrix (ECM) accumulation in diabetic nephropathy. Previous studies implicate PAI-1 in adipose tissue (AT) expansion while also contributing to insulin resistance. As inflammation is also known to occur in perirenal AT during obesity, we hypothesized that in a high-fat diet (HFD)-induced obese mouse model, PAI-1 contributes to macrophage-mediated inflammation and diabetic nephropathy. The HFD mice showed increased expression of PAI-1 in perirenal fat and also displayed increased fat weight and macrophage numbers...
December 11, 2018: American Journal of Physiology. Endocrinology and Metabolism
Linlin Zhang, Mengyao Bai, Hongju Tang, Feiye Zhou, Qin Zhu, Shushu Wang, Kecheng Zhu, Qianqian Liu, Yun Liu, Xiao Wang, Yabin Ma, Libin Zhou
AIMS: Enhanced hepatic gluconeogenesis an important cause of hyperglycemia in type 2 diabetes. However, the regulatory mechanisms underlying disordered hepatic gluconeogenesis remains largely unclear. In the present study, we investigated the potential role of hepatic neuregulin 4 (Nrg4) in the regulation of gluconeogenesis in mice. MAIN METHODS: Microarray analysis was performed in primary mouse hepatocytes treated with or without 8-Br-cAMP. Primary mouse hepatocytes transfected with Nrg4 overexpressing or shRNA adenovirus were used to detect the expressions of the key gluconeogenic genes and glucose output...
December 4, 2018: Life Sciences
Wei Guo, Dong Li, Yan You, Wanzhen Li, Bin Hu, Sulin Zhang, Lei Miao, Ming Xian, Yizhun Zhu, Xiaoyan Shen
Hepatic gluconeogenesis makes a significant contribution to the pathogenesis of obesity and its related insulin resistance. Cystathionine γ-lyase (CSE; also cystathionase), a principal hydrogen sulfide (H2 S)-synthesizing enzyme in the liver, is involved in glucose and lipid metabolism disorders. However, the roles and precise mechanisms of CSE/H2 S in obesity and its related insulin resistance remain obscure. Here we show that CSE knockout exacerbated high-fat diet-induced mouse obesity as well as its related insulin resistance...
December 10, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
M Russo, A Marquez, M C Abeijón-Mukdsi, A Santacruz, A López-Malo, P Gauffin-Cano, R Medina
The effect of oral administration of spray-dried microcapsules of feruloyl esterase (FE) producing Lactobacillus fermentum CRL1446 (Lf) and Lactobacillus johnsonii CRL1231 (Lj) on high fat diet-induced obese mice was investigated to evaluate whether these strains could be used as a biotherapeutic for obesity. Swiss albino mice were divided into a normal diet fed group receiving empty microcapsules (control), a high fat diet plus empty microcapsules (HFD group), HFD plus microcapsules with Lf (HFD-Lf group) and HDF plus microcapsules with Lj (HFD-Lj group)...
December 10, 2018: Beneficial Microbes
Xinting Wang, Lingbiao Xin, Zhongchao Duan, Zhiyu Zuo, Yuan Wang, Yuanyuan Ren, Wei Zhang, Xiaoming Sun, Xin Liu, Lin Ge, Xi Yang, Zhi Yao, Jie Yang
In the current study, we explored the impact of Tudor-staphylococcal nuclease (SN) on obesity induced by a high-fat diet (HFD) in mice, because the functional involvement of Tudor-SN in lipid metabolism in vivo is unknown. HFD-transgenic (Tg) mice exhibited reductions in hepatic steatosis and systemic insulin resistance. There was no difference in hepatic lipid accumulation between chow-fed wild-type (WT) and chow-fed Tg mice; consistently, no difference in activation of the lipogenic pathway was detected. Overactivation of hepatic nuclear sterol regulatory element-binding protein (nSrebp2)-2, the central regulator of cholesterol metabolic proteins, was observed in HFD-Tg livers along with improved cholesterol homeostasis, but no such changes were observed in HFD-WT livers...
December 6, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Fabio Ciccarone, Serena Castelli, Laura Ioannilli, Maria Rosa Ciriolo
SCOPE: Epigenetic aberrations caused by environmental factors and lifestyle choices have been associated with the development of a number of pathologies including cardiovascular disorders. However, whether obesity-related heart dysfunction can occur via epigenetic mechanisms is largely undisclosed. The manifested role of DNA hydroxymethylation in heart pathophysiology prompted us to investigate its levels/machinery in heart of mice fed with high fat diet (HFD) and its possible relation with genes linked to obesity-associated cardiac remodelling...
December 4, 2018: Molecular Nutrition & Food Research
Asha Recino, Shu Uin Gan, Kian Chuan Sia, Yvonne Sawyer, Jenny Trendell, Richard Kay, Fiona M Gribble, Frank Reimann, Rob Foale, Maria Notaridou, Nick Holmes, Andrew Lever, Kok Onn Lee, Amit Nathwani, Anne Cooke, Roy Calne, Maja Wallberg
We report the restoration of euglycaemia in chemically induced diabetic C57BL/6 mice and spontaneously diabetic Non Obese Diabetic (NOD) mice by intravenous systemic administration of a single-stranded adeno-associated virus (ssAAV2/8) codon optimised (co) vector encoding furin cleavable human proinsulin under a liver-specific promoter. There were no immunological barriers to efficacy of insulin gene therapy in chemically induced C57BL/6 mice, which enjoyed long-lasting correction of hyperglycaemia after therapy, up to 250 days...
December 4, 2018: Gene Therapy
Simona Terzo, Gaetano Felice Caldara, Vincenzo Ferrantelli, Roberto Puleio, Giovanni Cassata, Flavia Mulè, Antonella Amato
Pistachios contain beneficial substances such as unsaturated fatty acids, phytosterols, and polyphenols. In the present study, we investigated if pistachio consumption is able to prevent or to revert hyperglycemia, dyslipidemia, hepatic steatosis, and adipose tissue morphological alterations caused by high fat diet (HFD) in the mouse. Moreover, the impact of pistachio intake on the mRNA expression of peroxisome proliferator-activated receptor γ ( PPAR-γ ), fatty acid transport proteins ( FAT-P ), fatty acid synthase ( FAS ), stearoyl-CoA desaturase ( SCD1 ), and sterol regulatory element-binding transcription factor-1c ( SREBP-1c ) in liver and adipose tissue was also analyzed...
December 1, 2018: Nutrients
Simon T Bond, Sarah C Moody, Yingying Liu, Mete Civelek, Claudio J Villanueva, Paul Gregorevic, Bronwyn A Kingwell, Andrea L Hevener, Aldons J Lusis, Darren C Henstridge, Anna C Calkin, Brian G Drew
Mitochondrial dynamics refers to the constant remodelling of mitochondrial populations by multiple cellular pathways which help maintain mitochondrial health and function. Disruptions to mitochondrial dynamics often leads to mitochondrial dysfunction, which is frequently associated with disease in rodents and humans. Consistent with this, obesity is associated with reduced mitochondrial function in white adipose tissue, partly via alterations in mitochondrial dynamics. Several proteins are known to regulate mitochondrial dynamics including the E3 ubiquitin ligase MARCH5; however, the role of these proteins in adipocytes has been poorly studied...
December 4, 2018: American Journal of Physiology. Endocrinology and Metabolism
Guoqing Wu, Yanan Wang, Yuhui Yang, Yonghui Shi, Jin Sun, Yunchong Xu, Tingyu Luo, Guowei Le
SCOPE: Dietary methionine restriction (MR) promotes multi-faceted health benefits. Moreover, lower rate of protein synthesis by dietary MR is associated with life span extension. The goal of this work is to explore how dietary MR would affect protein metabolism in a mouse model of high-fat diet-induced obesity (DIO). METHODS AND RESULTS: DIO mice (male C57BL/6) were subjected to dietary MR for 22 weeks. High-throughput sequencing technology, qRT-PCR analysis, and the dual luciferase reporter assay were performed to verify that MiR-328-3p directly targets cystathionine γ-lyase (CSE) to modulate endogenous H2 S production...
December 4, 2018: Molecular Nutrition & Food Research
Amy Christensen, Christian J Pike
Development of Alzheimer's disease (AD) is regulated by interactive effects of genetic and environmental risk factors. The most significant genetic risk factor for AD is the ε4 allele of apolipoprotein E ( APOE4), which has been shown to exert greater AD risk in women. An important modifiable AD risk factor is obesity and its associated metabolic dysfunctions. Whether APOE genotype might interact with obesity in females to regulate AD pathogenesis is unclear. To investigate this issue, we studied the effects of Western diet (WD) on female EFAD mice, a transgenic mouse model of AD that includes human APOE alleles ε3 (E3FAD) and ε4 (E4FAD)...
December 3, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Célia Fourrier, Clémentine Bosch-Bouju, Raphaël Boursereau, Julie Sauvant, Agnès Aubert, Lucile Capuron, Guillaume Ferreira, Sophie Layé, Nathalie Castanon
Although the high prevalence of anxiety in obesity increasingly emerges as significant risk factor for related severe health complications, the underlying pathophysiological mechanisms remain poorly understood. Considering that chronic inflammation is a key component of obesity and is well known to impact brain function and emotional behavior, we hypothesized that it may similarly contribute to the development of obesity-related anxiety. This hypothesis was experimentally tested by measuring whether chronic food restriction, a procedure known to reduce inflammation, or chronic anti-inflammatory treatment with ibuprofen improved anxiety-like behavior and concomitantly decreased peripheral and/or hippocampal inflammation characterizing a model of severe obesity, the db/db mice...
November 30, 2018: Brain, Behavior, and Immunity
Jie Liu, Grzegorz Godlewski, Tony Jourdan, Ziyi Liu, Resat Cinar, Keming Xiong, George Kunos
Endocannabinoids promote energy conservation in obesity, whereas cannabinoid-1 receptor (CB1 R) blockade reverses body weight gain and insulin resistance and increases energy expenditure. Here we investigated the molecular mechanisms of the catabolic effects of CB1 R blockade in the liver. Exposure of primary mouse hepatocytes and HepG2 cells to the CB1 R agonist ACEA inhibited the expression of Sirt1 and Rictor, a component of mTORC2, and suppressed insulin-induced Akt phosphorylation at ser473. These effects were reversed by peripheral CB1 R antagonist JD5037 in control hepatocytes but not in hepatocytes deficient in Sirt1 and/or Rictor, indicating that these two proteins are required for the CB1 R-mediated inhibition of insulin signaling...
December 1, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Wai San Cheang, Wing Tak Wong, Li Wang, Chak Kwong Cheng, Chi Wai Lau, Ronald Chin Wan Ma, Aimin Xu, Nanping Wang, Yu Huang, Xiao Yu Tian
Sirtuin 1 (SIRT1) activation reduces oxidative stress, inhibits inflammatory responses, and retards cellular senescence in endothelial cells in mouse models of diabetes. However, whether SIRT1 also plays a protective role in vascular dysfunction of diabetic and obese mice is not fully characterized. Previous work showed that peroxisome proliferator-activated receptor δ (PPARδ) is beneficial in diabetic vascular dysfunction. Whether PPARδ is involved in the beneficial effect of SIRT1 on vascular endothelial function is unknown...
November 29, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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