Role of Inositols and Inositol Phosphates in Energy Metabolism

Recently, inositols, especially myo-inositol and inositol hexakisphosphate, also known as phytic acid or IP6, with their biological activities received much attention for their role in multiple health beneficial effects. Although their roles in cancer treatment and prevention have been extensively reported, interestingly, they may also have distinctive properties in energy metabolism and metabolic disorders. We review inositols and inositol phosphate metabolism in mammalian cells to establish their biological activities and highlight their potential roles in energy metabolism. These molecules are known to decrease insulin resistance, increase insulin sensitivity, and have diverse properties with importance from cell signaling to metabolism. Evidence showed that inositol phosphates might enhance the browning of white adipocytes and directly improve insulin sensitivity through adipocytes. In addition, inositol pyrophosphates containing high-energy phosphate bonds are considered in increasing cellular energetics. Despite all recent advances, many aspects of the bioactivity of inositol phosphates are still not clear, especially their effects on insulin resistance and alteration of metabolism, so more research is needed.

Download Full-text

Phosphate, inositol and polyphosphates

Biochemical Society Transactions ◽

10.1042/bst20150215 ◽

2016 ◽

Vol 44 (1) ◽

pp. 253-259 ◽

Cited By ~ 21

Author(s):

Thomas M. Livermore ◽

Cristina Azevedo ◽

Bernadett Kolozsvari ◽

Miranda S.C. Wilson ◽

Adolfo Saiardi

Keyword(s):

Inositol Phosphates ◽

Inositol Phosphate ◽

High Energy ◽

Inorganic Polyphosphate ◽

Covalent Bonds ◽

Polymeric Form ◽

Phosphodiester Bond ◽

Signalling Molecules ◽

Inositol Ring ◽

Phosphate Groups

Eukaryotic cells have ubiquitously utilized the myo-inositol backbone to generate a diverse array of signalling molecules. This is achieved by arranging phosphate groups around the six-carbon inositol ring. There is virtually no biological process that does not take advantage of the uniquely variable architecture of phosphorylated inositol. In inositol biology, phosphates are able to form three distinct covalent bonds: phosphoester, phosphodiester and phosphoanhydride bonds, with each providing different properties. The phosphoester bond links phosphate groups to the inositol ring, the variable arrangement of which forms the basis of the signalling capacity of the inositol phosphates. Phosphate groups can also form the structural bridge between myo-inositol and diacylglycerol through the phosphodiester bond. The resulting lipid-bound inositol phosphates, or phosphoinositides, further expand the signalling potential of this family of molecules. Finally, inositol is also notable for its ability to host more phosphates than it has carbons. These unusual organic molecules are commonly referred to as the inositol pyrophosphates (PP-IPs), due to the presence of high-energy phosphoanhydride bonds (pyro- or diphospho-). PP-IPs themselves constitute a varied family of molecules with one or more pyrophosphate moiety/ies located around the inositol. Considering the relationship between phosphate and inositol, it is no surprise that members of the inositol phosphate family also regulate cellular phosphate homoeostasis. Notably, the PP-IPs play a fundamental role in controlling the metabolism of the ancient polymeric form of phosphate, inorganic polyphosphate (polyP). Here we explore the intimate links between phosphate, inositol phosphates and polyP, speculating on the evolution of these relationships.

Download Full-text

Tributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat-fed mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00053.2012 ◽

2012 ◽

Vol 303 (2) ◽

pp. E272-E282 ◽

Cited By ~ 77

Author(s):

Marco Aurélio Ramirez Vinolo ◽

Hosana G. Rodrigues ◽

William T. Festuccia ◽

Amanda R. Crisma ◽

Vitor S. Alves ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Plasma Lipid ◽

Peritoneal Macrophages ◽

High Fat ◽

Beneficial Effects ◽

Treatment And Prevention ◽

Inflammatory Status

The aim of this study was to investigate whether treatment with tributyrin (Tb; a butyrate prodrug) results in protection against diet-induced obesity and associated insulin resistance. C57BL/6 male mice fed a standard chow or high-fat diet were treated with Tb (2 g/kg body wt, 10 wk) and evaluated for glucose homeostasis, plasma lipid profile, and inflammatory status. Tb protected mice against obesity and obesity-associated insulin resistance and dyslipidemia without food consumption being affected. Tb attenuated the production of TNFα and IL-1β by peritoneal macrophages and their expression in adipose tissue. Furthermore, in the adipose tissue, Tb reduced the expression of MCP-1 and infiltration by leukocytes and restored the production of adiponectin. These effects were associated with a partial reversion of hepatic steatosis, reduction in liver and skeletal muscle content of phosphorylated JNK, and an improvement in muscle insulin-stimulated glucose uptake and Akt signaling. Although part of the beneficial effects of Tb are likely to be secondary to the reduction in body weight, we also found direct protective actions of butyrate reducing TNFα production after LPS injection and in vitro by LPS- or palmitic acid-stimulated macrophages and attenuating lipolysis in vitro and in vivo. The results, reported herein, suggest that Tb may be useful for the treatment and prevention of obesity-related metabolic disorders.

Download Full-text

Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals

Journal of Investigative Medicine ◽

10.1136/jim-2017-000681 ◽

2018 ◽

Vol 66 (6) ◽

pp. 1019-1022 ◽

Cited By ~ 19

Author(s):

Luis Rodrigo Cataldo ◽

Rodrigo Fernández-Verdejo ◽

José Luis Santos ◽

Jose Eduardo Galgani

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

High Energy ◽

12S Rrna ◽

Model Assessment ◽

Metabolic Homeostasis ◽

Reading Frame ◽

Homeostatic Model Assessment ◽

Matsuda Index ◽

Insight Into

Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is a mitochondrial-derived peptide that attenuates weight gain and hyperinsulinemia when administered to high fat-fed mice. MOTS-c is therefore a potential regulator of metabolic homeostasis under conditions of high-energy supply. However, the effect of insulin resistance and obesity on plasma MOTS-c concentration in humans is unknown. To gain insight into MOTS-c regulation, we measured plasma MOTS-c concentration and analyzed its relationship with insulin sensitivity surrogates, in lean and obese humans (n=10 per group). Obese individuals had impaired insulin sensitivity as indicated by low Matsuda and high Homeostatic Model Assessment (HOMA) indexes. Although plasma MOTS-c concentration was similar in lean and obese individuals (0.48±0.16 and 0.52±0.15 ng/mL; p=0.60), it was correlated with HOMA (r=0.53; p<0.05) and Matsuda index (r=−0.46; p<0.05). Notably, when the groups were analyzed separately, the associations remained only in lean individuals. We conclude that plasma MOTS-c concentration is unaltered in human obesity. However, MOTS-c associates positively with insulin resistance mostly in lean individuals, indicating that plasma MOTS-c concentration depends on the metabolic status in this population. Such dependence seems altered when obesity settles. The implications of plasma MOTS-c for human metabolic homeostasis deserve future examination.

Download Full-text

Phospholipid Derivatives of Cinnamic Acid Restore Insulin Sensitivity in Insulin Resistance in 3T3-L1 Adipocytes

Nutrients ◽

10.3390/nu13103619 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3619

Author(s):

Małgorzata Małodobra-Mazur ◽

Dominika Lewoń ◽

Aneta Cierzniak ◽

Marta Okulus ◽

Anna Gliszczyńska

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Cinnamic Acid ◽

Insulin Response ◽

Aromatic Acids ◽

Insulin Resistant ◽

Beneficial Effects ◽

First Choice ◽

Derivatives Of

Background: Insulin resistance (IR) is a condition in which the physiological amount of insulin is insufficient to evoke a proper response of the cell, that is, glucose utilization. Metformin is the first choice for therapy, thanks to its glycemic efficacy and general tolerability. In addition, various natural compounds from plant extracts, spices, and essential oils have been shown to provide health benefits regarding insulin sensitivity. In the present study, we analyzed the effect of phospholipid derivatives of selected natural aromatic acids on insulin action and their potential use to overcome insulin resistance. Methods: The 3T3-L1 fibroblasts were differentiated into mature adipocytes; next, insulin resistance was induced by palmitic acid (16:0). Cells were further cultured with phenophospholipids at appropriate concentrations. To assess insulin sensitivity, we measured the insulin-stimulated glucose uptake, using a glucose uptake test. Results: We showed that cinnamic acid (CA) and 3-methoxycinnamic acid (3-OMe-CA) restored the proper insulin response. However, 1,2-dicinnamoyl-sn-glycero-3-phosphocholine (1,2-diCA-PC) and 1-cinnamoyl-2-palmitoyl-sn-glycero-3-phosphocholine (1-CA-2-PA-PC) improved insulin sensitivity in insulin-resistant adipocytes even stronger, exhibiting more beneficial effects. Conclusions: The binding of aromatic acids to phosphatidylcholine increases their beneficial effect on insulin sensitivity in adipocytes and expands their potential practical application as nutraceutical health-promoting agents.

Download Full-text

Food Offer, Chronic Diarrhea and Preparedness to Alimentary Diabetes from the Second Year of Life Onwards

Journal of Food Research ◽

10.5539/jfr.v5n1p18 ◽

2015 ◽

Vol 5 (1) ◽

pp. 18

Author(s):

Mario Ciampolini ◽

Lorenzo Borselli

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Insulin Sensitivity ◽

Energy Intake ◽

Chronic Diarrhea ◽

High Energy ◽

The Body ◽

Functional Disorders ◽

Second Year Of Life ◽

Second Year

Background: We have worked out an alimentary behaviour based on a meal- after -meal individual limit of energy intake (IHMP). We have then studied the energy intake, the pre-prandial blood glucose concentration (blood glucose, BG) and the body weight of a group of children with chronic not specific diarrhea. Finally we have added BG tolerance tests to clinically healthy adults in order to ascertain a possible association between IHMP and insulin sensitivity, should functional disorders or overweight problems arise.Objective: With the present study we want to verify if mothers are capable of maintaining the IHMP and low pre-prandial BG levels in the eight years following the initial training, also in absence of diarrhea relapses. In adults the IHMP is associated to a good insulin sensitivity and this fact should be taken into consideration in order to reduce the increase of non - trasmissible deseases in the Western World.Methods: We recruited children with not specific chronic diarrhea (bowel functional disorders) and selected randomly 53 mother-child pairs as the control group and 100 to be trained. Mothers were taught both how to recognise the correspondence between the individual manifestations of hunger and the BG concentration (Initial Hunger Meal Pattern, IHMP). The aim was to get low BG levels before each meal, and, thanks to the skill acquired, to stop the insulin resistance. The energy intake and the pre-prandial BG levels were reported in weekly diaries while the symptoms were recorded through structured interviews after 3 and 6 months and after 2,4,6,8 years.Results: Energy intake reductions were significantly larger in trained than in control subjects at all 6 surveys after recruitment (P < 0.04 to < 0.0001) although growth was similar, Diarrhea and vomiting significantly dropped both in the trained group and in the control one compared to the beginning of the research. Larger reductions from base values in days with diarrhea in trained children (compared with controls) were found for the three initial months and in drug administration at the surveys after 2 years and after 8 yearsConclusion: Chronic non-specific diarrhea of the second year of life is associated with high energy intake and high pre-prandial BG for incomplete exhaustion of previous energy intake. In adults, this habit is associated with fattening/insulin resistance.

Download Full-text

Knockdown of angiopoietin-like 2 mimics the benefits of intermittent fasting on insulin responsiveness and weight loss

Experimental Biology and Medicine ◽

10.1177/1535370217745505 ◽

2017 ◽

Vol 243 (1) ◽

pp. 45-49 ◽

Cited By ~ 1

Author(s):

Cécile Martel ◽

Anthony Pinçon ◽

Alexandre Maxime Bélanger ◽

Xiaoyan Luo ◽

Marc-Antoine Gillis ◽

...

Keyword(s):

Insulin Resistance ◽

Weight Gain ◽

Insulin Sensitivity ◽

Energy Intake ◽

Intermittent Fasting ◽

Wild Type ◽

Beneficial Effects ◽

Obesity And Diabetes ◽

Ad Libitum ◽

Insulin Responsiveness

Angiopoietin-like 2 (ANGPTL2) is an inflammatory adipokine linking obesity to insulin resistance. Intermittent fasting, on the other hand, is a lifestyle intervention able to prevent obesity and diabetes but difficult to implement and maintain. Our objectives were to characterize a link between ANGPTL2 and intermittent fasting and to investigate whether the knockdown of ANGPTL2 reproduces the benefits of intermittent fasting on weight gain and insulin responsiveness in knockdown and wild-type littermates mice. Intermittent fasting, access to food ad libitum once every other day, was initiated at the age of three months and maintained for four months. Intermittent fasting decreased by 63% (p < 0.05) gene expression of angptl2 in adipose tissue of wild-type mice. As expected, intermittent fasting improved insulin sensitivity (p < 0.05) and limited weight gain (p < 0.05) in wild-type mice. Knockdown mice fed ad libitum, however, were comparable to wild-type mice following the intermittent fasting regimen: insulin sensitivity and weight gain were identical, while intermittent fasting had no additional impact on these parameters in knockdown mice. Energy intake was similar between both wild-type fed intermittent fasting and ANGPTL2 knockdown mice fed ad libitum, suggesting that intermittent fasting and knockdown of ANGPTL2 equally lower feeding efficiency. These results suggest that the reduction of ANGPTL2 could be a useful and promising strategy to prevent obesity and insulin resistance, although further investigation of the mechanisms linking ANGPTL2 and intermittent fasting is warranted. Impact statement Intermittent fasting is an efficient diet pattern to prevent weight gain and improve insulin sensitivity. It is, however, a difficult regimen to follow and compliance is expected to be very low. In this work, we demonstrate that knockdown of ANGPTL2 in mice fed ad libitum mimics the beneficial effects of intermittent fasting on weight gain and insulin sensitivity in wild-type mice. ANGPTL2 is a cytokine positively associated with fat mass in humans, which inactivation in mice improves resistance to a high-fat metabolic challenge. This study provides a novel pathway by which IF acts to limit obesity despite equivalent energy intake. The development of a pharmacological ANGPTL2 antagonist could provide an efficient tool to reduce the burden of obesity.

Download Full-text

Swim Training Attenuates Inflammation and Improves Insulin Sensitivity in Mice Fed with a High-Fat Diet

International Journal of Endocrinology ◽

10.1155/2017/5940732 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Guangzeng Zhang ◽

Pengfei Yu ◽

Xiaomeng Liu

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

High Fat Diet ◽

Metabolic Disorders ◽

Inflammatory Mediator ◽

Resting Energy Expenditure ◽

High Fat ◽

Beneficial Effects ◽

Sedentary Group ◽

Tnf Α

Exercise could afford multiple beneficial effects on obesity-related metabolic disorders. To address this issue, C57BL/6J mice were used to investigate the effects of 13 weeks of swim training on HFD-induced obesity and related insulin resistance and inflammation. Our results show that swim training can significantly prevent HFD-induced weight gain and increase resting energy expenditure without affecting food intake. The insulin sensitivity was enhanced in the HFD + swim group than in the HFD + sedentary group. Moreover, swim training considerably decreased serum LPS content and downregulates epididymis white adipose tissue (eWAT) expression of the inflammatory mediatorTnf-α,Il-6, andMcp-1. In summary, 13 weeks of swim training could reverse HFD-induced metabolic disorders including insulin resistance and inflammation.

Download Full-text

Insulin resistance and cancer: the role of insulin and IGFs

Endocrine Related Cancer ◽

10.1530/erc-12-0324 ◽

2012 ◽

Vol 20 (1) ◽

pp. R1-R17 ◽

Cited By ~ 132

Author(s):

Sefirin Djiogue ◽

Armel Hervé Nwabo Kamdje ◽

Lorella Vecchio ◽

Maulilio John Kipanyula ◽

Mohammed Farahna ◽

...

Keyword(s):

Insulin Resistance ◽

Cell Proliferation ◽

Energy Metabolism ◽

Cell Fate ◽

Molecular Mechanisms ◽

Tumor Development ◽

Epidemiological Studies ◽

High Energy

Insulin, IGF1, and IGF2 are the most studied insulin-like peptides (ILPs). These are evolutionary conserved factors well known as key regulators of energy metabolism and growth, with crucial roles in insulin resistance-related metabolic disorders such as obesity, diseases like type 2 diabetes mellitus, as well as associated immune deregulations. A growing body of evidence suggests that insulin and IGF1 receptors mediate their effects on regulating cell proliferation, differentiation, apoptosis, glucose transport, and energy metabolism by signaling downstream through insulin receptor substrate molecules and thus play a pivotal role in cell fate determination. Despite the emerging evidence from epidemiological studies on the possible relationship between insulin resistance and cancer, our understanding on the cellular and molecular mechanisms that might account for this relationship remains incompletely understood. The involvement of IGFs in carcinogenesis is attributed to their role in linking high energy intake, increased cell proliferation, and suppression of apoptosis to cancer risks, which has been proposed as the key mechanism bridging insulin resistance and cancer. The present review summarizes and discusses evidence highlighting recent advances in our understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity, as well as those areas where there remains a paucity of data. It is anticipated that issues discussed in this paper will also recover new therapeutic targets that can assist in diagnostic screening and novel approaches to controlling tumor development.

Download Full-text

The quantitative spectrum of inositol phosphate metabolites in avian erythrocytes, analysed by proton n.m.r. and h.p.l.c. with direct isomer detection

Biochemical Journal ◽

10.1042/bj2640323 ◽

1989 ◽

Vol 264 (2) ◽

pp. 323-333 ◽

Cited By ~ 25

Author(s):

T Radenberg ◽

P Scholz ◽

G Bergmann ◽

G W Mayr

Keyword(s):

Mammalian Cells ◽

Inositol Phosphates ◽

Inositol Phosphate ◽

Detection System ◽

Anion Exchange Chromatography ◽

Exchange Chromatography ◽

Phosphate Metabolism ◽

Qualitative And Quantitative ◽

Inositol Phosphate Metabolism ◽

Avian Erythrocytes

The spectrum of inositol phosphate isomers present in avian erythrocytes was investigated in qualitative and quantitative terms. Inositol phosphates were isolated in micromolar quantities from turkey blood by anion-exchange chromatography on Q-Sepharose and subjected to proton n.m.r. and h.p.l.c. analysis. We employed a h.p.l.c. technique with a novel, recently described complexometric post-column detection system, called ‘metal-dye detection’ [Mayr (1988) Biochem. J. 254, 585-591], which enabled us to identify non-radioactively labelled inositol phosphate isomers and to determine their masses. The results indicate that avian erythrocytes contain the same inositol phosphate isomers as mammalian cells. Denoted by the ‘lowest-locant rule’ [NC-IUB Recommendations (1988) Biochem. J. 258, 1-2] irrespective of true enantiomerism, these are Ins(1,4)P2, Ins(1,6)P2, Ins(1,3,4)P3, Ins(1,4,5)P3, Ins(1,3,4,5)P4, Ins(1,3,4,6)P4, Ins(1,4,5,6)P4, Ins(1,3,4,5,6)P5, and InsP6. Furthermore, we identified two inositol trisphosphate isomers hitherto not described for mammalian cells, namely Ins(1,5,6)P3 and Ins(2,4,5)P3. The possible position of these two isomers in inositol phosphate metabolism and implications resulting from absolute abundances of inositol phosphates are discussed.

Download Full-text

Beneficial Oxidative Stress-Related trans-Resveratrol Effects in the Treatment and Prevention of Breast Cancer

Applied Sciences ◽

10.3390/app112211041 ◽

2021 ◽

Vol 11 (22) ◽

pp. 11041

Author(s):

Alessandra Quarta ◽

Antonio Gaballo ◽

Biswajita Pradhan ◽

Srimanta Patra ◽

Mrutyunjay Jena ◽

...

Keyword(s):

Breast Cancer ◽

Oxidative Stress ◽

Biological Activities ◽

Tumor Development ◽

Primary Sources ◽

Beneficial Effects ◽

Chemotherapy Drugs ◽

Treatment And Prevention ◽

The Impact ◽

Prevention Of Breast Cancer

Resveratrol is one of the most investigated polyphenols for its multiple biological activities and many beneficial effects. These are mainly related to its ability to scavenge free radicals and reduce oxidative stress. Resveratrol has also been shown to have the ability to stimulate the production of antioxidant enzymes, which interact with numerous signaling pathways involved in tumor development, and to possess side effects associated with the use of chemotherapy drugs. In this review article we summarized the main discoveries about the impact resveratrol can have in helping to prevent, as well as adjuvant treating, breast cancer. A brief overview of the primary sources of resveratrol as well as some approaches for improving its bioavailability have been also discussed.

Download Full-text