Pharmaconutrition strategy to resolve SARS-CoV-2-induced inflammatory cytokine storm in non-alcoholic fatty liver disease: Omega-3 long-chain polyunsaturated fatty acids

Inflammation is one of the primary factors associated with the causation and/or progression of several lifestyle disorders, including obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of disorders, and starts with simple steatosis, progresses to non-alcoholic steatohepatitis, and then advances to fibrosis, cirrhosis and finally, hepatocellular carcinoma, due to perpetual cycles of insults caused by inflammation and other cellular stress. Emerging evidence has documented that patients with NAFLD have severe coronavirus disease 2019 (COVID-19), and patients with COVID-19 have a higher liver injury and mortality. Although the exact cause or mechanism is not known, inflammatory cytokine storm is a characteristic feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is known to be associated with higher mortality among COVID-19 patients. Therefore, the COVID-19 pandemic seems to be a major concern in NAFLD patients, who have contracted SARS-CoV-2 infection and develop COVID-19. This is evident in patients at any stage of the NAFLD spectrum, as the inflammatory cytokine storm may cause and/or aggravate the progression or severity of NAFLD. Thus, there is a need for resolution of the inflammatory cytokine storm in these patients. A large body of evidence has demonstrated the efficacy of omega-3 long-chain polyunsaturated fatty acids (ω-3 LCPUFA) in NAFLD conditions, due to their anti-inflammatory, immunomodulatory and anti-viral properties. Therefore, intervention with ω-3 LCPUFA, an effective pharmaconutrient along with the standard treatment for COVID-19 may be useful in the management of the NAFLD spectrum in COVID-19 patients with pre-existing NAFLD conditions by resolving the inflammatory cytokine storm and thereby attenuating its progression. Although there are challenges in implementation, optimistically they can be circumvented and the pharmaconutrition strategy may be potentially helpful in tackling both the pandemics; NAFLD and COVID-19 at least in this subset of patients

Dietary fatty acid composition alters 11β-hydroxysteroid dehydrogenase type 1 gene expression in rat retroperitoneal white adipose tissue

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid action by converting inactive glucocorticoids to their active forms in vivo. Adipose-specific overexpression of 11β-HSD1 induces metabolic syndrome in mice, whereas 11β-HSD1 null mice are resistant to it. Dietary trans and saturated fatty acids (TFAs and SFAs) are involved in the development of metabolic syndrome, whereas polyunsaturated fatty acids (PUFA) offer protection against this. Here, we report the effects of chronic feeding of different diets containing vanaspati (TFA rich), palm oil (SFA rich) and sunflower oil (PUFA rich) at 10%level on 11β-HSD1 gene expression in rat retroperitoneal adipose tissue. 11β-HSD1 gene expression was significantly higher in TFA rich diet-fed rats compared to SFA rich diet-fed rats, which in turn was significantly higher than PUFA rich diet-fed rats. Similar trend was observed in the expression of CCAAT-enhancer binding protein-α (C/EBP-α), the main transcription factor required for the expression of 11β-HSD1. We propose that TFAs and SFAs increase local amplification of glucocorticoid action in adipose tissue by upregulating 11β-HSD1 by altering C/EBP-α-gene expression. The increased levels of glucocorticoids in adipose tissue may lead to development of obesity and insulin resistance, thereby increasing the risk of developing metabolic syndrome

A novel genetically-obese rat model with elevated 11beta-hydroxysteroid dehydrogenase type 1 activity in subcutaneous adipose tissue

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoids to active glucocorticoids and plays an important role in the development of obesity and metabolic syndrome. 11β-HSD1 activity is lower in liver and higher in omental adipose tissue of obese rodent models like obese zucker rats, Ob/Ob and db/db mice. Here, we report the 11β-HSD1 activity in liver and adipose tissue of lean and obese rats of WNIN/Ob strain, a new genetic rat model of obesity. 11β-HSD1 activity in liver, omental and subcutaneous adipose tissues of 3 month-old male WNIN/Ob lean and obese rats was assayed. As observed in other rodent models, 11β-HSD1 activity was lower in liver and higher in omental adipose tissue. In contrast to other rodent obese models, WNIN/Ob obese rats had elevated 11β-HSD1 activity in subcutaneous adipose tissue, which is in line with the observation in human obesity. Here, we conclude that dysregulation of 11β-HSD1 in WNIN/Ob obese rat model is identical to human obesity, which makes it an excellent model for studying the effect of 11β-HSD1 inhibitors in ameliorating obesity and metabolic syndrome

Fatty acid desaturation index correlates with body mass and adiposity indices of obesity in Wistar NIN obese mutant rat strains WNIN/Ob and WNIN/GR-Ob

BACKGROUND: Microsomal stearoyl-CoA desaturase1 (SCD1) is the rate limiting enzyme involved in the biosynthesis of monounsaturated fatty acids (MUFAs); palmitoleic (16:1) and oleic (18:1) acid from their respective substrates palmitic (16:0) and stearic (18:0) acids. The ratio of 18:1 to 18:0 has been implicated in the regulation membrane fluidity and function. SCD1 is abundantly expressed in obese humans as well as rodent models. However, no studies have correlated the fatty acid desaturation index (16:1/16:0 and 18:1/18:0), an indicator of SCD1 activity with the markers of obesity in terms of body mass index (BMI) and adiposity index (AI). Therefore, here, we attempted to relate the fatty acid desaturation index with BMI and AI in Wistar NIN-obese mutant rat strains namely, WNIN/Ob and WNIN/GR-Ob (with impaired glucose tolerance). METHODS: For this purpose, 200 days old male 6 lean and 6 obese rats of both strains were taken. Fatty acid composition was analyzed in plasma, various tissues such as liver, white adipose tissues (retroperitoneal, epididymal, omental, and subcutaneous) and brown adipose tissue. RESULTS: Fatty acid composition data showed significant increase in palmitoleic (16:1) and oleic (18:1) acid levels, which were reflected in increased desaturation index (16:1/16:0 and 18:1/18:0) in plasma and all the tissues of obese rats of both strains, when compared with their respective age and sex-matched lean rats. Further, we found a strong positive correlation between desaturation index, BMI and AI in plasma and most of the tissues analyzed. CONCLUSION: So far, plasma Δ(9 )desaturation index has been well correlated with hypertriglyceridemia and we, by employing two models of obesity namely, WNIN/Ob and WNIN/GR-Ob, have shown Δ(9 )desaturation index of plasma correlated with physical markers of obesity such as BMI and AI. In conclusion, Δ(9 )desaturation index may serve as a potential sensitive biochemical marker to assess the degree of obesity and impact of therapeutic/nutritional interventions to combat obesity, along with other indicators

Vitamin A decreases pre-receptor amplification of glucocorticoids in obesity: study on the effect of vitamin A on 11beta-hydroxysteroid dehydrogenase type 1 activity in liver and visceral fat of WNIN/Ob obese rats

<p>Abstract</p> <p>Background</p> <p>11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoids to active glucocorticoids and its inhibition ameliorates obesity and metabolic syndrome. So far, no studies have reported the effect of dietary vitamin A on 11β-HSD1 activity in visceral fat and liver under normal and obese conditions. Here, we studied the effect of chronic feeding of vitamin A-enriched diet (129 mg/kg diet) on 11β-HSD1 activity in liver and visceral fat of WNIN/Ob lean and obese rats.</p> <p>Methods</p> <p>Male, 5-month-old, lean and obese rats of WNIN/Ob strain (n = 16 for each phenotype) were divided into two subgroups consisting of 8 rats of each phenotype. Control groups received stock diet containing 2.6 mg vitamin A/kg diet, where as experimental groups received diet containing 129 mg vitamin A/Kg diet for 20 weeks. Food and water were provided <it>ad libitum</it>. At the end of the experiment, tissues were collected and 11β-HSD1 activity was assayed in liver and visceral fat.</p> <p>Results</p> <p>Vitamin A supplementation significantly decreased body weight, visceral fat mass and 11β-HSD1 activity in visceral fat of WNIN/Ob obese rats. Hepatic 11β-HSD1 activity and gene expression were significantly reduced by vitamin A supplementation in both the phenotypes. CCAAT/enhancer binding protein α (C/EBPα), the main transcription factor essential for the expression of 11β-HSD1, decreased in liver of vitamin A fed-obese rats, but not in lean rats. Liver × receptor α (LXRα), a nuclear transcription factor which is known to downregulate 11β-HSD1 gene expression was significantly increased by vitamin A supplementation in both the phenotypes.</p> <p>Conclusions</p> <p>This study suggests that chronic consumption of vitamin A-enriched diet decreases 11β-HSD1 activity in liver and visceral fat of WNIN/Ob obese rats. Decreased 11β-HSD1 activity by vitamin A may result in decreased levels of active glucocorticoids in adipose tissue and possibly contribute to visceral fat loss in these obese rats. Studying the role of various nutrients on the regulation of 11β-HSD1 activity and expression will help in the evolving of dietary approaches to treat obesity and insulin resistance.</p

Transcriptome profiling of visceral adipose tissue in a novel obese rat model, WNIN/Ob & its comparison with other animal models

Background & objectives: Adipose tissue dysfunction in obesity is linked to the development of type 2 diabetes and cardiovascular diseases. We studied the differential gene expression in retroperitoneal adipose tissue of a novel obese rat model, WNIN/Ob, to understand the possible underlying transcriptional changes involved in the development of obesity and associatedcomorbidities in this model. Methods: Four month old, male WNIN/Ob lean and obese rats were taken, blood was collected and tissues were dissected. Body composition analysis and adipose tissue histology were performed. Global gene expression in retroperitoneal adipose tissue of lean and obese rats was studied by microarray using Affymetrix GeneChips. Results: One thousand and seventeen probe sets were downregulated and 963 probe sets were upregulated (more than two-fold) in adipose tissue of WNIN/Ob obese rats when compared to that of lean rats. Small nucleolar RNA (SnoRNA) made most of the underexpressed probe sets, whereas immune system-related genes werethe most overexpressed in the adipose tissues of obese rats. Genes coding for cytoskeletal proteinswere downregulated, whereas genes related to lipid biosynthesis were elevated in the adipose tissue of obese rats. Interpretation & conclusions: Majority of the altered genes and pathways in adipose tissue of WNIN/Ob obese rats were similar to the observations in other obese animal models and human obesity. Based on these observations, it is proposed that WNIN/Ob obese rat model may be a good model to study the mechanisms involved in the development of obesity and its comorbidities. Downregulation of SnoRNA appears to be a novel feature in this obese rat model

Transgenic zero-erucic and high-oleic mustard oil improves glucose clearance rate, erythrocyte membrane docosahexaenoic acid content and reduces osmotic fragility of erythrocytes in male Syrian golden hamsters

Brassica juncea, the Indian mustard variety has high erucic acid (22:1 n-9) in its oil, which causes several deleterious effects. The Centre for Genetic Manipulation of Crop Plants (India) has developed a zero-erucic and high-oleic acid transgenic mustard variety having 67% oleic acid, which is almost equivalent to that of olive oil, i.e. 71%. Therefore, we assessed its impact on erythrocyte osmotic fragility, fluidity and activities of membrane-bound enzymes and insulin sensitivity. 40 male Syrian golden hamsters of 6–8 weeks age, were divided into five groups, consisting of 8 hamsters in each and fed diet containing any one of the oils, i.e. groundnut (GNO), conventional mustard (OCM), low-erucic mustard (OLM), zero-erucic high-oleic transgenic mustard (OTM) and olive (OLO) at 10% level for 16 weeks. At the end, compared to OLO group, OTM-fed hamsters resisted osmotic shock-induced erythrocyte-haemolysis, which corroborated with higher docosahexaenoic acid (DHA; 22:6 n-3) levels in their erythrocyte membranes. However, it did affect neither the fluidity nor the activities of membrane-bound enzymes. Although fasting plasma glucose, insulin and free fatty acid levels were comparable among the various groups; during glucose challenge, OTM diet-fed animals displayed higher disposal rate of circulatory glucose, without altering the insulin levels, when compared to the conventional mustard; OCM. In conclusion, the consumption of oil from zero-erucic high-oleic transgenic mustard improved the DHA content of erythrocyte membrane, which possibly resisted haemolysis and enhanced glucose clearance during glucose overload. However, it did not affect the activities of erythrocyte membrane-bound enzymes and fluidity compared to olive oil. Keywords: Dietary fat, Membrane lipids, Insulin resistance, PUF