High Fat
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2021 ◽  
Vol 4 (1) ◽  
Young-Sil Yoon ◽  
Weiyi Liu ◽  
Sam Van de Velde ◽  
Shigenobu Matsumura ◽  
Ezra Wiater ◽  

AbstractObesity is a major risk factor for the development of type II diabetes. Increases in adipose tissue mass trigger insulin resistance via the release of pro-inflammatory cytokines from adipocytes and macrophages. CREB and the CRTC coactivators have been found to promote insulin resistance in obesity, although the mechanism is unclear. Here we show that high fat diet feeding activates the CREB/CRTC pathway in adipocytes by decreasing the expression of SIK2, a Ser/Thr kinase that phosphorylates and inhibits CRTCs. SIK2 levels are regulated by the adipogenic factor C/EBPα, whose expression is reduced in obesity. Exposure to PPARγ agonist rescues C/EBPα expression and restores SIK2 levels. CRTC2/3 promote insulin resistance via induction of the chemokines CXCL1/2. Knockout of CRTC2/3 in adipocytes reduces CXCL1/2 expression and improves insulin sensitivity. As administration of CXCL1/2 reverses salutary effects of CRTC2/3 depletion, our results demonstrate the importance of the CREB/CRTC pathway in modulating adipose tissue function.

2021 ◽  
Dan Zhao ◽  
Xue-qin Zhang ◽  
Wen-jing Guo ◽  
Zhi-hui Cui ◽  
Yi-cheng Wang ◽  

Abstract Ovarian failure in postmenopausal female leads E2 to dramatic decrease which is an important reason of menopausal dyslipidemia. PCSK9 as a secretory lipid metabolic regulator plays a critical role in the cholesterol metabolism by negatively regulating LDLR in hepatocytes. Clinical data showed PCSK9 was elevated and positively correlated with LDL-C in the blood of postmenopausal women. However, the relationship between E2 and PCSK9 and the role of PCSK9 in postmenopausal dyslipidemia are still unclear. In this research, 10-week-old ovariectomized mice were fed for 4 weeks with normal diet or high-fat diet, then tested the lipid metabolism profiles and PCSK9 in the blood and the expression of LDLR and PCSK9 in the liver. On this basis, PCSK9-/- ovariectomized mice were used to further verify the effect of PCSK9 in dyslipidemia of ovariectomized mice. Finally, the ovariectomized mice with high-fat diet were subcutaneous injected respectively with E2 or PCSK9 inhibitor alone or both together for 2 weeks and were tested as previous experiment. The results showed PCSK9, TC and LDL-c all increased in the blood of in WT ovariectomized mice and their PCSK9 is positively correlated with LDL-c, while there were on obvious lipid metabolism disorder in the PCSK9−/− ovariectomized mice. PCSK9 inhibitor increased the LDLR on the liver and ameliorated the dyslipidemia in WT ovariectomized mice. It suggests that PCSK9 plays an important role in the dyslipidemia of ovariectomized mice, which provides a new strategy for clinical diagnosis and treatment of the dyslipidemia in post-menopause.

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2839
Asish K. Ghosh

Cardiovascular disease is the leading cause of accelerated as well as chronological aging-related human morbidity and mortality worldwide. Genetic, immunologic, unhealthy lifestyles including daily consumption of high-carb/high-fat fast food, lack of exercise, drug addiction, cigarette smoke, alcoholism, and exposure to environmental pollutants like particulate matter (PM)-induced stresses contribute profoundly to accelerated and chronological cardiovascular aging and associated life threatening diseases. All these stressors alter gene expression epigenetically either through activation or repression of gene transcription via alteration of chromatin remodeling enzymes and chromatin landscape by DNA methylation or histone methylation or histone acetylation. Acetyltransferase p300, a major epigenetic writer of acetylation on histones and transcription factors, contributes significantly to modifications of chromatin landscape of genes involved in cellular aging and cardiovascular diseases. In this review, the key findings those implicate acetyltransferase p300 as a major contributor to cellular senescence or aging related cardiovascular pathologies including vascular dysfunction, cardiac hypertrophy, myocardial infarction, cardiac fibrosis, systolic/diastolic dysfunction, and aortic valve calcification are discussed. The efficacy of natural or synthetic small molecule inhibitor targeting acetyltransferase p300 in amelioration of stress-induced dysregulated gene expression, cellular aging, and cardiovascular disease in preclinical study is also discussed.

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1753
Maria Chiara Valerii ◽  
Silvia Turroni ◽  
Carla Ferreri ◽  
Michela Zaro ◽  
Anna Sansone ◽  

Several studies showed that D-Limonene can improve metabolic parameters of obese mice via various mechanisms, including intestinal microbiota modulation. Nevertheless, its effective doses often overcome the acceptable daily intake, rising concerns about toxicity. In this study we administered to C57BL/6 mice for 84 days a food supplement based on D-Limonene, adsorbed on dietary fibers (FLS), not able to reach the bloodstream, to counteract the metabolic effects of a high-fat diet (HFD). Results showed that daily administration of D-Limonene (30 and 60 mg/kg body weight) for 84 days decreased the weight gain of HFD mice. After 84 days we observed a statistically significant difference in weight gain in the group of mice receiving the higher dose of FLS compared to HFD mice (35.24 ± 4.56 g vs. 40.79 ± 3.28 g, p < 0.05). Moreover, FLS at both doses tested was capable of lowering triglyceridemia and also fasting glycemia at the higher dose. Some insights on the relevant fatty acid changes in hepatic tissues were obtained, highlighting the increased polyunsaturated fatty acid (PUFA) levels even at the lowest dose. FLS was also able to positively modulate the gut microbiota and prevent HFD-associated liver steatosis in a dose-dependent manner. These results demonstrate that FLS at these doses can be considered non-toxic and could be an effective tool to counteract diet-induced obesity and ameliorate metabolic profile in mice.

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3703
Latha Ramalingam ◽  
Kalhara R. Menikdiwela ◽  
Stephani Spainhour ◽  
Tochi Eboh ◽  
Naima Moustaid-Moussa

Pre-pregnancy obesity is a contributing factor for impairments in offspring metabolic health. Interventional strategies during pregnancy are a potential approach to alleviate and/or prevent obesity and obesity related metabolic alterations in the offspring. Fish oil (FO), rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) exerts metabolic health benefits. However, the role of FO in early life remains still unknown. Hence, this study objective was to determine the effect of FO supplementation in mice from pre-pregnancy through lactation, and to study the post-natal metabolic health effects in gonadal fat and liver of offspring fed high fat (HF) diet with or without FO. Female C57BL6J mice aged 4–5 weeks were fed a HF (45% fat) diet supplemented with or without FO (30 g/kg of diet) and low fat (LF; 10% fat) pre-pregnancy through lactation. After weaning, offspring (male and female) from HF or FO dams either continued the same diet (HF-HF and FO-FO) or switched to the other diet (HF-FO and FO-HF) for 13 weeks, creating four groups of treatment, and LF-LF was used as a control group. Serum, gonadal fat and liver tissue were collected at termination for metabolic analyses. Offspring of both sexes fed HF with or without fish oil gained (p < 0.05) more weight post weaning, compared to LF-LF-fed mice. All the female offspring groups supplemented with FO had reduced body weight compared to the respective male groups. Further, FO-FO supplementation in both sexes (p < 0.05) improved glucose clearance and insulin sensitivity compared to HF-HF. All FO-FO fed mice had significantly reduced adipocyte size compared to HF-HF group in both male and females. Inflammation, measured by mRNA levels of monocyte chemoattractant protein 1 (Mcp1), was reduced (p < 0.05) with FO supplementation in both sexes in gonadal fat and in the liver. Markers of fatty acid synthesis, fatty acid synthase (Fasn) showed no sex specific differences in gonadal fat and liver of mice supplemented with HF. Female mice had lower liver triglycerides than male counterparts. Supplementation of FO in mice improved metabolic health of offspring by lowering markers of lipid synthesis and inflammation.

Kehinde S. Olaniyi ◽  
Christopher O. Akintayo ◽  
Adesola A. Oniyide ◽  
Adams O. Omoaghe ◽  
Mosunmola B. Oyeleke ◽  

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3693
Riitta Ryyti ◽  
Antti Pemmari ◽  
Rainer Peltola ◽  
Mari Hämäläinen ◽  
Eeva Moilanen

The prevalence of nonalcoholic fatty liver disease (NAFLD) is growing worldwide in association with Western-style diet and increasing obesity. Lingonberry (Vaccinium vitis-idaea L.) is rich in polyphenols and has been shown to attenuate adverse metabolic changes in obese liver. This paper investigated the effects of lingonberry supplementation on hepatic gene expression in high-fat diet induced obesity in a mouse model. C57BL/6N male mice were fed for six weeks with either a high-fat (HF) or low-fat (LF) diet (46% and 10% energy from fat, respectively) or HF diet supplemented with air-dried lingonberry powder (HF + LGB). HF diet induced a major phenotypic change in the liver, predominantly affecting genes involved in inflammation and in glucose and lipid metabolism. Lingonberry supplementation prevented the effect of HF diet on an array of genes (in total on 263 genes) associated particularly with lipid or glucose metabolic process (such as Mogat1, Plin4, Igfbp2), inflammatory/immune response or cell migration (such as Lcn2, Saa1, Saa2, Cxcl14, Gcp1, S100a10) and cell cycle regulation (such as Cdkn1a, Tubb2a, Tubb6). The present results suggest that lingonberry supplementation prevents HF diet-induced adverse changes in the liver that are known to predispose the development of NAFLD and its comorbidities. The findings encourage carrying out human intervention trials to confirm the results, with the aim of recommending the use of lingonberries as a part of healthy diet against obesity and its hepatic and metabolic comorbidities.

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258942
Chenyu Zhu ◽  
Rui Xu ◽  
Yuxin Li ◽  
Michael Andrade ◽  
Deng Ping Yin

Obese subjects have increase probabilities of developing type 2 diabetes (T2D). In this study, we sought to determine whether gastric bypass prevents the progression of prediabetes to overt diabetes in genetically modified mice and chemically induced diabetic mice. Roux-en-Y gastric bypass (RYGB) was performed in C57BL/KsJ-db/db null (BKS-db/db,) mice, high-fat diet (HFD)-fed NONcNZO10/LtJ (NZO) mice, C57BL/6 db/db null (B6-db/db) mice and streptozotocin (STZ)-induced diabetic mice. Food consumption, body weight, fat mass, fast blood glucose level, circulating insulin and adiponectin and glucose tolerance test were analyzed. The liver and pancreatic tissues were subjected to H&E and immunohistochemistry staining and islet cells to flow cytometry for apoptotic analysis. RYGB resulted in sustained normoglycemia and improved glucose tolerance in young prediabetic BKS-db/db mice (at the age of 6 weeks with hyperglycemia and normal insulinemia) and HFD-fed NZO and B6-db/db mice. Remarkably, RYGB improved liver steatosis, preserved the pancreatic β-cells and reduced β-cell apoptosis with increases in circulating insulin and adiponectin in young prediabetic BKS-db/db mice. However, RYGB neither reversed hyperglycemia in adult diabetic BKS-db/db mice (12 weeks old) nor attenuated hyperglycemia in STZ-induced diabetic mice. These results demonstrate that gastric bypass improves hyperglycemia in genetically modified prediabetic mice; however, it should be performed prior to β-cells exhaustion.

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