The role of vitamin B12 deficiency on hepatic metabolism of lipids

Background: Obesity is currently a worldwide epidemic that increases the risk of developing metabolic disorders like diabetes, hypertension and cardiovascular diseases (CVDs) which causes great public health concern. A series of studies involving animal models and epidemiological investigations have demonstrated a relationship between the importance of vitamin B12 (B12) and various components of metabolic syndrome. High prevalence of B12 deficiency has been shown in Europeans (27%) and South Indians (32%) with type 2 diabetes mellitus (T2DM) as well as several T2DM patients on prolonged metformin treatment. Similarly, studies in human adipose tissues showed evidence of dysregulation in lipids by low B12, accounting for higher adiposity and adipocyte dysfunction. However, the liver is the principal storage organ for B12, and hepatic contribution to the lipogenesis of the entire body is also significantly higher compared to adipose tissue. Several clinical studies have shown that metformin, the first drug of choice for T2DM treatment and proposed to reduce lipid levels in patients, had no effect on intrahepatic triglyceride levels. Metformin treatment has also shown an association with low B12 levels. Some studies in the liver have also reported no expression of adiponectin in the liver, unlike its receptors (adipoR1 and adipoR2). Adiponectin is an adipose tissue-derived hormone that regulates glucose and lipid metabolism and is known to upregulate glycolysis and fatty acid oxidation (FAO) as well as reduces gluconeogenesis in liver. Therefore, we hypothesized that low B12 may dysregulate hepatic metabolism of lipids and reduce the lipid lowering effect of metformin in the liver that might be improved by adiponectin treatment. Methods: Hep G2 cell line was cultured using custom-made B12 deficient Eagle’s Minimal Essential Medium (EMEM) and seeded in different concentrations of B12 media including 500nM (control) and 25pM (low) B12. Oil Red O (ORO) staining, RT-qPCR, total intracellular triglyceride (TG), radioactive flux assay, fatty acid profiling using gas chromatography and extracellular seahorse XF24 flux assay were employed to examine the effect of B12 on lipid metabolism. Results: The intrahepatic uptake of B12 was increased in lower circulating B12 concentrations by increased expression of B12 receptors (CD320) and transporters (TCN2), whereas decreased expressions of CD320 and TCN2 accounted for reduced B12 uptake in higher circulating B12 levels. Low B12 increased de novo lipogenesis and levels of fatty acid (FA) groups associated with higher CVD risk. There was further decrease in FAO and mitochondrial functional efficiency, accounting for high hepatic lipid accumulation in low B12. Similarly, the lipid lowering effect of metformin was decreased by low B12, but improved via adiponectin, in the metformin-treated hepatocyte cell line. Conclusion: Our data, therefore, provides novel evidence that B12 deficiency dysregulates lipid metabolism leading to hepatic lipid accumulation

Does bariatric surgery improve adipose tissue function?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134250/1/obr12429_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134250/2/obr12429.pd

Role of obesity in modulating the immune system

INTRODUCTION: Diet induced obesity (DIO) is a major driving force responsible for low-grade inflammation mediated immune system decline. Impaired immune defenses lead to a number of chronic diseases and ultimately to an increased mortality. DISCUSSION: Over half a billion people worldwide are considered overweight or obese. It has been estimated that $190 billion dollars was spent in the US on obesity-related healthcare costs just in 2005. Lower productivity, lost wages, higher insurance costs, and an increased strain on the healthcare system as a whole, are the hallmarks of the obesity epidemic. Considerable body of epidemiologic evidence implicates DIO as the major cause of numerous pathologies. The obese population doesn't just suffer increased mortality from chronic conditions such as, cardiovascular disease, pulmonary diseases, Type 2 diabetes, various cancers, hyperlipidemia, hypertension, non-alcoholic fatty liver disease (NAFLD), renal failure, osteoarthritis and many other slow-onset diseases. Obese individuals also have increased mortality for more acute conditions such as N1H1 influenza virus, allergic diseases, and post-surgical complications while also lowering the efficacy for vaccinations and Helicobacter pylori eradication therapies. Today scientists recognize adipose tissue as the largest endocrine organ in the human body, releasing a myriad of paracrine and endocrine molecular factors. During DIO these adipocytokines induce a proinflammatory switch in the adipose tissue machinery, initiating chronic low-grade inflammation. Sensing an ongoing attack the immune system responds trying to maintain homeostasis. DIO however, initiates a positive feedback loop, which perpetuates inflammation and further decimates immune system's capacity to resist threats and to restore order. CONCLUSION: While the basic obesity-inflammation-disease road map has been outlined, many questions remain. Multiple areas of immunometabolism and meta inflammation require deeper understanding, but two key recommendations for future studies stand out. First, since it is easier to prevent obesity than to reverse it, attention should be focused on elucidating the endocrine role of foodstuff. Second, to find cures for chronic conditions of the ever growing obese population, scientists must elucidate the mechanism of obesity-induced inflammation's function in diminishing immune system's capacity

Signals from adipose tissue in morbid obesity and effect on depot specific differences

Signals from adipose tissue, such as interleukin-6 (IL-6) and asymmetric dimethyl arginine (ADMA), an endogenous nitric oxide inhibitor, explain the link between obesity and metabolic diseases. Previously published human studies have used omental adipose tissue to study visceral depots, based on the assumption that all visceral adipose tissues are similar. This study, for the first time, assessed the release of five adipokines (adiponectin, leptin, IL-6, MCP-1 and RANTES) from the subcutaneous and two omental depots. Components of the cyclooxygenase (COX) and the nitric oxide (NO) pathways, that regulate cytokine release in other tissues, were also investigated for their putative role(s) in mediating adipokine release. RANTES release was greatest from the gastric fat pad. However, significantly higher circulating RANTES levels suggest that adipose tissue is unlikely to be the main source of RANTES release. Inhibition of the COX pathway, especially COX-2, reduced IL-6 release from subcutaneous adipose tissue. Prostacyclin synthase (PGI2S) activity was higher in the omental tissue and its protein expression was elevated in the stromavascular fraction from this depot. PGI2S activity appears to mainly reside in the non-adipocyte cells and is more coupled to IL-6 production in adipose tissue. Serum insulin and CRP levels, and systolic blood pressure, directly associated with subcutaneous tissue ADMA content, while BMI correlated with omental ADMA release. ADMA release was higher from the omental depot. However, while DDAH2 expression was higher compared to DDAH1 in adipose tissue, there was no depot specific difference in the expression of either isoform. In conclusion, this study showed adipose depot specific differences of RANTES release, a novel adipokine, from a hitherto poorly studied depot, the gastric fat pad. Characteristics of the omental adipose tissues differed depending on location and paracrine factors that may mediate the adipokine release. These regulatory pathways included components of the COX and NO pathways

Adipokines 2.0

Once viewed solely as fat storage cells, adipocytes and their adipokines have now been proven to be central for human health. Understanding that overweight and obesity may increase the risk for various diseases requires detailed characterization of adipokine function. Weight gain, weight regain, and fasting affect adipocyte health and accordingly their secretome. Different adipose tissue deposits exist and they vary in cellular composition and function. The evidence is strong of a role of adipokines in cancer, reproductive function, neurological diseases, cardiovascular diseases ,and rheumatoid arthritis. Adipokines are considered useful biomarkers for adipose tissue and metabolic health, and may be used as diagnostic tools in rheumatoid arthritis, cancer, or sepsis. This book contains 10 original articles and 9 review articles focusing on these bioactive peptides. Several articles deal with chemerin, an adipokine discovered more than 20 years ago. Data so far have resulted in promising insights related to its biological function. We are only beginning to understand the multiple roles of chemerin, the mechanisms regulating its activity, and the signaling pathways used by this chemokine. Adipokine receptor agonists and antagonists may result in the formulation of novel drugs and ultimately may lead to new therapeutic targets to be used in clinical practice

Berry polyphenol absorption and the effect of northern berries on metabolism, ectopic fat accumulation, and associated diseases

The prevalence of obesity and type 2 diabetes has increased at an alarming rate in developed countries. It seems in the light of current knowledge that metabolic syndrome may not develop at all without NAFLD, and NAFLD is estimated to be as common as metabolic syndrome in western population (23 % occurrence). Fat in the liver is called ectopic fat, which is triacylglycerols within the cells of non-adipose tissue. Serum alanine aminotransferase (ALT) values correlate positively with liver fat proportions, and increased activity of ALT predicts type 2 diabetes independently from obesity. Berries, high in natural bioactive compounds, have indicated the potential to reduce the risk of obesity-related diseases. Ectopic fat induces common endocrine excretion of adipose tissue resulting in the overproduction of inflammatory markers, which further induce insulin resistance by multiple mechanisms. Insulin resistance inducing hyperinsulinemia and lipolysis in adipocytes increases the concentration of free fatty acids and consequently causes further fat accumulation in hepatocytes. Polyphenolic fractions of berries have been shown to reverse inflammatory reaction cascades in in vitro and animal studies, and moreover to decrease ectopic fat accumulation. The aim of this thesis was to explore the role of northern berries in obesity-related diseases. The absorption and metabolism of selected berry polyphenols, flavonol glycosides and anthocyanins, was investigated in humans, and metabolites of the studied compounds were identified in plasma and urine samples (I, II). Further, the effects of berries on the risk factors of metabolic syndrome were studied in clinical intervention trials (III, IV), and the different fractions of sea buckthorn berry were tested for their ability to reduce postprandial glycemia and insulinemia after high-glucose meal in a postprandial study with humans (V). The marked impact of mixed berries on plasma ALT values (III), as well as indications of the positive effects of sea buckthorn, its fractions and bilberry on omental adiposity and adhesion molecules (IV) were observed. In study V, sea buckthorn and its polyphenol fractions had a promising effect on potprandial metabolism after high-glucose meal. In the literature review, the possible mechanisms behind the observed effects have been discussed with a special emphasis on ectopic fat accumulation. The literature review indicated that especially tannins and flavonoids have shown potential in suppressing diverse reaction cascades related to systemic inflammation, ectopic fat accumulation and insulin resistance development.Siirretty Doriast

Trpc1-Mediated Ca2+ Entry Regulates Metabolism By Modulating Adipose Differentiation, Autophagy, And Adiponectin Secretion

A multitude of organs play a critical role in managing metabolism including the liver, pancreas, gut, brain, muscle, and adipose tissue. Abnormal function in any one of these can offset the metabolic balance and negatively affect whole body function thereby contributing to the development of metabolic complications and obesity. Although no single metabolic abnormality is responsible for obesity, understanding how normal cellular processes are regulated provides us with knowledge to reverse them during times of dysfunction. The main focus of this dissertation is on the regulation of adipose tissue due to its dual role of storing excess lipids and endocrine organ capabilities. Adipocytes, along with a majority of other cell types, are highly dependent on calcium (Ca2+), thus the role of Ca2+ and the involvement of the Ca2+ channel Transient Receptor Potential Canonical 1 (TRPC1) were studied. The evidence provided in this dissertation shows that Ca2+ entry in adipocytes, especially upon store-depletion, plays an important role in adipocyte differentiation, autophagy, and adipokine secretion and subsequently metabolic regulation. The endogenous Ca2+ entry channel in both subcutaneous and visceral adipocytes was found to be dependent on TRPC1-STIM1 complexes and altering or blocking TRPC1 resulted in dysfunctional adipocytes. Adipocyte differentiation, the process of pre-adipocytes converting to adipocytes, is a tightly regulated process with Ca2+ dependency. Blockage of TRPC1-mediated Ca2+ entry with SKF-96365 inhibited differentiation which was indicated by decreased lipid accumulation and expression of PPAR, FAPB4, and perilipin in both subcutaneous adipose tissue (Subc AT) and visceral adipose tissue (VAT). Loss of TRPC1 in either adipose tissue type resulted in a reduced ability to differentiate which occurred prior to PPAR expression indicating TRPC1-mediated Ca2+ entry is necessary for the initial stages of differentiation. Diets high in fat induce unhealthy expansion of adipose tissue, while exercise reduces adipocyte size and lipid content. Mice deficient of TRPC1 function and challenged with both a high-fat diet and exercise had lower fat mass and fasting glucose concentrations along with decreased adipocyte numbers. Further investigation indicated a decrease in autophagy with a concurrent increase in apoptosis. Together, this data shows that TRPC1 inhibits the positive effects of exercise under a high-fat diet-induced obesity environment. Adipose tissue is an important endocrine organ responsible for secreting a number of cytokines, including adiponectin and leptin, which have a functional role in modulating metabolism. Secretion of adiponectin from adipose tissue has been found to be Ca2+ dependent, but the identity of the responsible Ca2+ channel is unknown. This study provides evidence that TRPC1 deficient mice have reduced serum adiponectin concentration which is believed to be due to an inability of adipose tissue to properly secrete adiponectin. Further, it was shown that loss of TRPC1-mediated Ca2+ influx is involved in SNARE complex formation necessary for proper exocytosis of adiponectin loaded vesicles. Serum adiponectin concentrations have been shown to be correlated to adiponectin receptor expression, thus it was investigated whether reduces in serum adiponectin concentrations observed in TRPC1 deficient mice was due to dysfunctional adiponectin signaling in muscle. Within this study, it was observed that skeletal muscle of TRPC1 deficient mice have reduced adiponectin targets including PGC1α, lipid metabolism, and mitochondrial biogenesis mRNA expression. Though data suggests AdipoRon initiated adiponectin signaling in muscle is Ca2+ and SOCE dependent, TRPC1 is not a contributing member as loss of TRPC1 did not inhibit Ca2+ influx or PGC1α expression indicating decreased adiponectin targets is likely due to reduce serum adiponectin concentrations. Overall, evidence from the combined studies suggests TRPC1-mediated Ca2+ influx is an important regulator of adipocyte processes necessary for maintaining a healthy body

The metabolic regulation of cellular ageing

The incidence of obesity and type 2 diabetes (T2D) are increasing in the UK and there is evidencethat these disorders influence the ageing process. The mechanisms by which obesity/diabetesmight regulate ageing are poorly understood. This study aimed to investigate the links betweenbody composition, metabolic disease and ageing, as well as the role of cellular senescence onnutrient homeostasis. Study participants had biochemical and anthropometric measurements taken. DNA analysis was used to measure telomere length (TL) using real-time PCR and plasmawas used to quantify circulating factors using ELISA. Human dermal fibroblasts were madesenescent and conditioned media was collected and used to treat AML-12, C2C12 and 3T3-L1cell lines. Following treatment glucose content of cell media was measured. TL exhibited a significant negative association amongst individuals retaining excess visceral fat(p <0.001) and plasma irisin levels positively correlate and predict TL (p = 0.01) in the controlcohort. There was no significant association between irisin and TL in the T2D cohort (p = 0.333),and a 3-fold higher concentration of irisin was observed in individuals with T2D in comparisonto controls (p < 0.0001). Irisin was a statistically significant predictor of soluble E-selectin (p =0.003) in type 2 diabetics. 40% Conditioned media from senescent HDF reduced the ability ofC2C12 to utilise glucose after 24 and 48 hours and AML-12 hepatocytes after 48 hours (p<0.0001, p <0.01) quantification of circulating glycerol in 3T3-L1 adipocytes following treatmentwith 20% and 40% conditioned media suggests lipotoxic tendencies (p <0.05 and p <0.001). In conclusion this study highlights the importance of maintaining adequate body fat in preservingTL, provides novel data regarding the role of irisin in healthy and obese/type 2 diabeticindividuals and insights into the relation between ageing and insulin resistance