Inositols Depletion and Resistance: Principal Mechanisms and Therapeutic Strategies.

Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term "inositols" refers to five natural stereoisomers, among which myo-Inositol (myo-Ins) is the most abundant one. Several mechanisms contribute to regulate cellular and tissue homeostasis of myo-Ins levels, including its endogenous synthesis and catabolism, transmembrane transport, intestinal adsorption and renal excretion. Alterations in these mechanisms can lead to a reduction of inositols levels, exposing patient to several pathological conditions, such as Polycystic Ovary Syndrome (PCOS), hypothyroidism, hormonal and metabolic imbalances, like weight gain, hyperinsulinemia, dyslipidemia, and metabolic syndrome. Indeed, myo-Ins is involved in different physiological processes as a key player in signal pathways, including reproductive, hormonal, and metabolic modulation. Genetic mutations in genes codifying for proteins of myo-Ins synthesis and transport, competitive processes with structurally similar molecules, and the administration of specific drugs that cause a central depletion of myo-Ins as a therapeutic outcome, can lead to a reduction of inositols levels. A deeper knowledge of the main mechanisms involved in cellular inositols depletion may add new insights for developing tailored therapeutic approaches and shaping the dosages and the route of administration, with the aim to develop efficacious and safe approaches counteracting inositols depletion-induced pathological events.

Dietary myo-inositol deficiency decreased intestinal immune function related to NF-κB and TOR signaling in the intestine of young grass carp (Ctenopharyngodon idella).

In this study, we investigated the effects of dietary myo-inositol on the intestinal immune barrier function and related signaling pathway in young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (221.33 ±â€¯0.84 g) were fed six diets containing graded levels of myo-inositol (27.0, 137.9, 286.8, 438.6, 587.7 and 737.3 mg/kg) for 10 weeks. After the growth trial, fish were challenged with Aeromonas hydrophila. The results indicated that compared with the optimal dietary myo-inositol level, myo-inositol deficiency (27.0 mg/kg diet): (1) decreased lysozyme (LZ) and acid phosphatase (ACP) activities, as well as complement 3 (C3), C4 and immunoglobulin M (IgM) contents in the proximal intestine (PI), middle intestine (MI) and distal intestine (DI) of young grass carp (P < 0.05). (2) down-regulated the mRNA levels of anti-microbial substance: liver expressed antimicrobial peptide (LEAP) 2A, LEAP-2B, hepcidin, ß-defensin-1 and mucin2 in the PI, MI and DI of young grass carp (P < 0.05). (3) up-regulated pro-inflammatory cytokines [IL-1ß (not in DI), TNF-α and IL-8], nuclear factor kappa B P65 (not NF-κB P52), c-Rel, IκB kinaseα (IKKα), IKKß and IKKγ mRNA levels in the PI, MI and DI of young grass carp (P < 0.05); and down-regulated pro-inflammatory cytokines IL-15 (not in DI) and inhibitor of κBα (IκBα) mRNA levels (P < 0.05). (4) down-regulated the mRNA levels of anti-inflammatory cytokines [IL-10 (not in DI), IL-11, IL-4/13B (not IL-4/13A), TGF-ß1 and TGF-ß2], target of rapamycin (TOR), eIF4E-binding proteins 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6k1) in the PI, MI and DI of young grass carp (P < 0.05). All data indicated that myo-inositol deficiency could decrease fish intestine immunity and cause inflammation under infection of A. hydrophila. Finally, the optimal dietary myo-inositol levels for the ACP and LZ activities in the DI were estimated to be 415.1 and 296.9 mg/kg diet, respectively.

Dietary myo-inositol deficiency decreased the growth performances and impaired intestinal physical barrier function partly relating to nrf2, jnk, e2f4 and mlck signaling in young grass carp (Ctenopharyngodon idella).

In this study, we investigated the effects of dietary myo-inositol on the growth and intestinal physical barrier functions of young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (221.83 ± 0.84 g) were fed six diets containing graded levels of myo-inositol (27.0, 137.9, 286.8, 438.6, 587.7 and 737.3 mg/kg) for 10 weeks. After the growth trial, fish were challenged with Aeromonas hydrophila for 14 days. The results indicated that compared with optimal myo-inositol levels, myo-inositol deficiency (27.0 mg/kg diet): (1) decreased glutathione (GSH) contents and antioxidant enzymes activities, and down-regulated the mRNA levels of antioxidant enzymes [not glutathione-S-transferase (gst) p1 and gstp2] and NF-E2-related factor 2 (nrf2), whereas up-regulated the reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl (PC) contents, and the mRNA levels of Kelch-like-ECH-associated protein 1 (keap1) in three intestinal segments of young grass carp (P < 0.05). (2) Up-regulated cysteinyl aspartic acid-protease (caspase)-2, -3, -7, -8, -9, apoptotic protease activating factor-1 (apaf-1), Bcl2-associated X protein (bax), fas ligand (fasl), gen-activated protein kinase (p38mapk) and c-Jun N-terminal protein kinase (jnk) mRNA levels, whereas down-regulated B-cell lymphoma-2 (bcl-2), inhibitor of apoptosis proteins (iap) and myeloid cell leukemia-1 (mcl-1) mRNA levels in three intestinal segments of young grass carp (P < 0.05). (3) Down-regulated mRNA levels of cell cycle proteins cyclin b, cyclin d, cyclin e and E2F transcription factor 4 (e2f4) in three intestinal segments of young grass carp (P < 0.05). (4) Down-regulated the mRNA levels of zonula occludens (zo) 1, zo-2, occludin, claudin-b, -c, -f, -3c, -7a, -7b as well as -11, and up-regulated the mRNA levels of claudin-12, -15a (not -15b) and myosin light chain kinase (mlck) in three intestinal segments of young grass carp (P < 0.05). All above data indicated that dietary myo-inositol deficiency could damage physical barrier function in three intestinal segments of fish. Finally, the myo-inositol requirements based on the percent weight gain (PWG), reactive oxygen species (ROS) contents in the proximal intestine (PI), relative mRNA levels of caspase-2 (PI), cyclin b (MI) as well as claudin-b (PI) were estimated to be 276.7, 304.1, 327.9, 416.7 and 313.2 mg/kg diet, respectively.

Nutritional and Acquired Deficiencies in Inositol Bioavailability. Correlations with Metabolic Disorders.

Communities eating a western-like diet, rich in fat, sugar and significantly deprived of fibers, share a relevant increased risk of both metabolic and cancerous diseases. Even more remarkable is that a low-fiber diet lacks some key components-as phytates and inositols-for which a mechanistic link has been clearly established in the pathogenesis of both cancer and metabolic illness. Reduced bioavailability of inositol in living organisms could arise from reduced food supply or from metabolism deregulation. Inositol deregulation has been found in a number of conditions mechanistically and epidemiologically associated to high-glucose diets or altered glucose metabolism. Indeed, high glucose levels hinder inositol availability by increasing its degradation and by inhibiting both myo-Ins biosynthesis and absorption. These underappreciated mechanisms may likely account for acquired, metabolic deficiency in inositol bioavailability.

Perturbation of the Vacuolar ATPase: A NOVEL CONSEQUENCE OF INOSITOL DEPLETION.

Depletion of inositol has profound effects on cell function and has been implicated in the therapeutic effects of drugs used to treat epilepsy and bipolar disorder. We have previously shown that the anticonvulsant drug valproate (VPA) depletes inositol by inhibiting myo-inositol-3-phosphate synthase, the enzyme that catalyzes the first and rate-limiting step of inositol biosynthesis. To elucidate the cellular consequences of inositol depletion, we screened the yeast deletion collection for VPA-sensitive mutants and identified mutants in vacuolar sorting and the vacuolar ATPase (V-ATPase). Inositol depletion caused by starvation of ino1Δ cells perturbed the vacuolar structure and decreased V-ATPase activity and proton pumping in isolated vacuolar vesicles. VPA compromised the dynamics of phosphatidylinositol 3,5-bisphosphate (PI3,5P2) and greatly reduced V-ATPase proton transport in inositol-deprived wild-type cells. Osmotic stress, known to increase PI3,5P2 levels, did not restore PI3,5P2 homeostasis nor did it induce vacuolar fragmentation in VPA-treated cells, suggesting that perturbation of the V-ATPase is a consequence of altered PI3,5P2 homeostasis under inositol-limiting conditions. This study is the first to demonstrate that inositol depletion caused by starvation of an inositol synthesis mutant or by the inositol-depleting drug VPA leads to perturbation of the V-ATPase.

Inositol and human reproduction. From cellular metabolism to clinical use.

Inositol is an organic compound of high biological importance that is widely distributed in nature. It belongs to the sugar family and is mainly represented by its two dominant stereoisomers: myo-inositol and D-chiro-inositol that are found in the organism in the physiological serum ratio 40:1. Inositol and its derivatives are important components of the structural phospholipids of the cell membranes and are precursors of the second messengers of many metabolic pathways. A high concentration of myoinositol is found in the follicular fluid and in semen. Inositol deficiency and the impairment of the inositol-dependent pathways may play an important role in the pathogenesis of insulin resistance and hypothyroidism. The results of the research also point out the potential beneficial role of inositol supplementation in polycystic ovarian syndrome and in the context of assisted reproduction technologies and in vitro fertilization. The main aim of the article is to overview the major inositol-dependent metabolic pathways and to discuss its importance for reproduction.

Renal depletion of myo-inositol is associated with its increased degradation in animal models of metabolic disease.

Renal depletion of myo-inositol (MI) is associated with the pathogenesis of diabetic nephropathy in animal models, but the underlying mechanisms involved are unclear. We hypothesized that MI depletion was due to changes in inositol metabolism and therefore examined the expression of genes regulating de novo biosynthesis, reabsorption, and catabolism of MI. We also extended the analyses from diabetes mellitus to animal models of dietary-induced obesity and hypertension. We found that renal MI depletion was pervasive across these three distinct disease states in the relative order: hypertension (-51%)>diabetes mellitus (-35%)>dietary-induced obesity (-19%). In 4-wk diabetic kidneys and in kidneys derived from insulin-resistant and hypertensive rats, MI depletion was correlated with activity of the MI-degrading enzyme myo-inositol oxygenase (MIOX). By contrast, there was decreased MIOX expression in 8-wk diabetic kidneys. Immunohistochemistry localized the MI-degrading pathway comprising MIOX and the glucuronate-xylulose (GX) pathway to the proximal tubules within the renal cortex. These findings indicate that MI depletion could reflect increased catabolism through MIOX and the GX pathway and implicate a common pathological mechanism contributing to renal oxidative stress in metabolic disease.

Inositol-deficient food augments a behavioral effect of long-term lithium treatment mediated by inositol monophosphatase inhibition: an animal model with relevance for bipolar disorder.

Lithium treatment in rodents markedly enhances cholinergic agonists such as pilocarpine. This effect can be reversed in a stereospecific manner by administration of inositol, suggesting that the effect of lithium is caused by inositol monophosphatase inhibition and consequent inositol depletion. If so, inositol-deficient food would be expected to enhance lithium effects. Inositol-deficient food was prepared from inositol-free ingredients. Mice with a homozygote knockout of the inositol monophosphatase 1 gene unable to synthesize inositol endogenously and mimicking lithium-treated animals were fed this diet or a control diet. Lithium-treated wild-type animals were also treated with the inositol-deficient diet or control diet. Pilocarpine was administered after 1 week of treatment, and behavior including seizures was assessed using rating scale. Inositol-deficient food-treated animals, both lithium treated and with inositol monophosphatase 1 knockout, had significantly elevated cholinergic behavior rating and significantly increased or earlier seizures compared with the controls. The effect of inositol-deficient food supports the role of inositol depletion in the effects of lithium on pilocarpine-induced behavior. However, the relevance of this behavior to other more mood-related effects of lithium is not clear.

Abnormalities in myo-inositol metabolism associated with type 2 diabetes in mice fed a high-fat diet: benefits of a dietary myo-inositol supplementation.

We previously reported that a chronic supplementation with myo-inositol (MI) improved insulin sensitivity and reduced fat accretion in mice. We then tested the potency of such dietary intervention in the prevention of insulin resistance in C57BL/6 male mouse fed a high-fat diet (HFD). In addition, some abnormalities in inositol metabolism were reported to be associated with insulin resistance in several animal and human studies. We then investigated the presence of such anomalies (i.e. inosituria and an inositol intra-tissue depletion) in this diet-induced obesity (DIO) mouse model, as well as the potential benefit of a MI supplementation for inositol intra-tissue deficiency correction. HFD (60 % energy from fat) feeding was associated with inosituria and inositol intra-tissue depletion in the liver and kidneys. MI supplementation (0·58 mg/g per d) restored inositol pools in kidneys (partially) and liver (fully). HFD feeding for 4 months induced ectopic lipid redistribution to liver and muscles, fasting hyperglycaemia and hyperinsulinaemia, insulin resistance and obesity that were not prevented by MI supplementation, despite a significant improvement in insulin sensitivity parameter K insulin tolerance test and a reduction in white adipose tissue (WAT) mass ( - 17 %, P< 0·05). MI supplementation significantly reduced fatty acid synthase activity in epididymal WAT, which might explain its beneficial, but modest, effect on WAT accretion in HFD-fed mice. Finally, we found some abnormalities in inositol metabolism in association with a diabetic phenotype (i.e. insulin resistance and fasting hyperglycaemia) in a DIO mouse model. Dietary MI supplementation was efficient in the prevention of inositol intra-tissue depletion, but did not prevent insulin resistance or obesity efficiently in this mouse model.

BiP-bound and nonclustered mode of Ire1 evokes a weak but sustained unfolded protein response.

In eukaryotic cells under nonstressed conditions, the endoplasmic reticulum (ER)-located molecular chaperone BiP is associated with an ER-membrane protein Ire1 to inhibit its self-association. While ER stress leads Ire1 to form transiently BiP-unbound clusters, which strongly evoke the unfolded protein response (UPR), here we propose an alternative activation status of Ire1. When yeast cells are physiologically ER-stressed by inositol depletion for a prolonged time, the UPR is weakly activated in a sustained manner after a transient peak of activation. During persistent stress, Ire1 foci disappear, while Ire1 continues to be self-associated. Under these conditions, Ire1 may be activated as a homo-dimer, as it shows considerable activity even when carrying the W426A mutation, which allows Ire1 to form homo-dimers but not clusters. Unlike the Ire1 clusters, the nonclustered active form seems to be associated with BiP. An Ire1 mutant not carrying the BiP-association site continued to form clusters and to be activated strongly even after long-term stress. Similar observations were obtained when cells were ER-stressed by dithiothreitol. We thus propose that upon persistent ER stress, Ire1 is weakly and continuously activated in a nonclustered form through its (re)association with BiP, which disperses the Ire1 clusters.

Low myo-inositol indicating astrocytic damage in a case series of neuromyelitis optica.

Astrocytic necrosis is a prominent pathological feature of neuromyelitis optica (NMO) lesions and is clinically relevant. We report 5 NMO-related cases, all with longitudinally extensive lesions in the upper cervical cord, who underwent cervical cord (1) H-magnetic resonance spectroscopy. Lower myo-inositol/creatine values, suggesting astrocytic damage, were consistently found within the NMO lesions when compared with healthy controls and patients with multiple sclerosis (MS), who showed at least 1 demyelinating lesion at the same cord level. Therefore, the in vivo quantification of myo-inositol may distinguish NMO from MS. This is an important step toward developing imaging markers for clinical trials in NMO.

[The role of inositol deficiency in the etiology of polycystic ovary syndrome disorders]. / Rola niedoboru inozytolu w patofizjologii zaburzen wystepujacych w zespole policystycznych jajników.

Inositol acts as a second messenger in insulin signaling pathway Literature data suggest inositol deficiency in insulin-resistant women with the polycystic ovary syndrome. Supplementation of myo-inisitol decreases insulin resistance as it works as an insulin sensitizing agent. The positive role of myo-inositol in the treatment of polycystic ovary syndrome has been of increased evidence recently The present review presents the effects of myo-inositol on the ovarian, hormonal and metabolic parameters in women with PCOS.

Differential insulin response to myo-inositol administration in obese polycystic ovary syndrome patients.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, chronic anovulation, polycystic ovaries at ultrasound evaluation, and quite frequently by insulin resistance or compensatory hyperinsulinemia. Attention has been given to the role of inositol-phosphoglycan (IPG) mediators of insulin action and growing evidences suggest that a deficiency of D-chiro-inositol (DCI) containing IPG might be at the basis of insulin resistance, frequent in PCOS patients. On such basis, we investigated the efficacy on insulin sensitivity and hormonal parameters of 8 weeks treatment with myo-inositol (MYO) (Inofert, ItalPharmaco, Milano, Italy) at the dosage of 2 g day in a group (n = 42) of obese PCOS patients,. After the treatment interval body mass index (BMI) and insulin resistance decreased together with luteinizing hormone (LH), LH/FSH and insulin. When subdividing the patients according to their fasting insulin levels, Group A (n = 15) insulin below 12 µU/ml and Group B (n = 27) insulin above 12 µU/ml, MYO treatment induced similar changes in both groups but only patients of Group B showed the significant decrease of both fasting insulin plasma levels (from 20.3 ± 1.8 to 12.9 ± 1.8 µU/ml, p < 0.00001) and of area under the curve (AUC) of insulin under oral glucose tolerance test (OGTT). In conclusion, our study supports the hypothesis that MYO administration is more effective in obese patients with high fasting insulin plasma levels.

Inositol and Non-Alcoholic Fatty Liver Disease: A Systematic Review on Deficiencies and Supplementation.

Liver lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), broadly associated with insulin resistance. Inositols (INS) are ubiquitous polyols implied in many physiological functions. They are produced endogenously, are present in many foods and in dietary supplements. Alterations in INS metabolism seems to play a role in diseases involving insulin resistance such as diabetes and polycystic ovary syndrome. Given its role in other metabolic syndromes, the hypothesis of an INS role as a supplement in NAFLD is intriguing. We performed a systematic review of the literature to find preclinical and clinical evidence of INS supplementation efficacy in NAFLD patients. We retrieved 10 studies on animal models assessing Myoinosiol or Pinitol deficiency or supplementation and one human randomized controlled trial (RCT). Overall, INS deficiency was associated with increased fatty liver in animals. Conversely, INS supplementation in animal models of fatty liver reduced hepatic triglycerides and cholesterol accumulation and maintained a normal ultrastructural liver histopathology. In the one included RCT, Pinitol supplementation obtained similar results. Pinitol significantly reduced liver fat, post-prandial triglycerides, AST levels, lipid peroxidation increasing glutathione peroxidase activity. These results, despite being limited, indicate the need for further evaluation of INS in NAFLD in larger clinical trials.

IMPA1 is essential for embryonic development and lithium-like pilocarpine sensitivity.

Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1-/-) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1-/- mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1-/- mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1-/- mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1-/- mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

Generation and characterization of thiol-deficient Mycobacterium tuberculosis mutants.

Mycothiol (MSH) and ergothioneine (ERG) are thiols able to compensate for each other to protect mycobacteria against oxidative stress. Gamma-glutamylcysteine (GGC), another thiol and an intermediate in ERG biosynthesis has detoxification abilities. Five enzymes are involved in ERG biosynthesis, namely EgtA, EgtB, EgtC, EgtD and EgtE. The role of these enzymes in the production of ERG had been unclear. On the other hand, the enzyme MshA is known to be essential for MSH biosynthesis. In this manuscript, we describe the raw data of the generation and characterization of Mycobacterium tuberculosis (M.tb) mutants harbouring a deletion of the gene coding for each of these enzymes, and the raw data of the phenotypic characterization of the obtained thiol-deficient M.tb mutants. High throughput screening (HTS) of off-patent drugs and natural compounds revealed few compounds that displayed a higher activity against the thiol-deficient mutants relative to the wild-type strain. The mode of action of these drugs was further investigated. Raw data displaying these results are described here.

Lithium-pilocarpine seizures as a model for lithium action in mania.

Lithium (Li) pre-treatment of rats or mice given low dose pilocarpine induces a unique limbic seizure syndrome. This syndrome is stereospecifically reversed by myo-inositol, which suggests that it is a behavioral model for Li depletion of brain inositol. However, this syndrome has little face validity because seizures are not a component of bipolar disorder. Moreover, other animal species that maintain higher brain inositol levels than mice or rats do not show Li-pilocarpine seizures and a study in humans suggests that humans do not show this syndrome as well. It could be suggested that Li-pilocarpine seizures are an in vivo bioassay for inositol depletion. Recent studies of knockout mice lacking inositol monophosphatase-1 or the sodium myo-inositol transporter-1 found that both these knockout mice given pilocarpine develop limbic seizures as if they had been pre-treated with Li. These mice in addition to such pilocarpine sensitivity have other behaviors such as decreased immobility in the Porsolt forced swim test that suggests that their inositol depletion has Li-like effects. Thus, the Li-pilocarpine seizure model may, despite its lack of face validity, be a biochemical marker for a model of mania treatment in animals.

Behavioural phenotyping of sodium-myo-inositol cotransporter heterozygous knockout mice with reduced brain inositol.

Inositol plays a key role in dopamine, serotonin, noradrenaline and acetylcholine neurotransmission, and inositol treatment is reported to have beneficial effects in depression and anxiety. Therefore, a reduction in brain intracellular inositol levels could be a cause of some psychiatric disorders, such as depression or anxiety. To determine the behavioural consequences of inositol depletion, we studied the behaviour of sodium-dependent myo-inositol cotransporter-1 heterozygous knockout mice. In heterozygous mice, free inositol levels were reduced by 15% in the frontal cortex and by 25% in the hippocampus, but they did not differ from their wild-type littermates in cholinergic-mediated lithium-pilocarpine seizures, in the apomorphine-induced stereotypic climbing model of dopaminergic system function, in the Porsolt forced-swimming test model of depression, in amphetamine-induced hyperactivity, or in the elevated plus-maze model of anxiety. Reduction of brain inositol by more than 25% may be required to elicit neurobehavioural effects.

Quantification of plasma myo-inositol using gas chromatography-mass spectrometry.

BACKGROUND: Myo-inositol (MI) deficiency is associated with an increased risk for neural tube defects (NTDs), mental disorders and metabolic diseases. We developed a gas chromatography-mass spectrometry (GC-MS) method to detect MI in human plasma, which was accurate, relatively efficient and convenient for clinical application. METHODS: An external standard method was used for determination of plasma MI. Samples were analyzed by GC-MS after derivatization. The stable-isotope labeled internal standard approach was used to validate the method's accuracy. Alpha fetal protein (AFP) was detected by chemiluminescence immunoassay. RESULTS: The method was validated by determining the linearity, sensitivity and recovery rate. There was a good agreement between the internal standard approach and the present method. The NTD-affected pregnancies showed lower plasma MI (P=0.024) and higher AFP levels (P=0.001) than control. Maternal MI level showed a better discrimination in spina bifida subgroup, while AFP level showed a better discrimination in anencephaly subgroup after stratification analysis. CONCLUSIONS: We developed a sensitive and reliable method for the detection of clinical plasma MI, which might be a marker for NTDs screening, and established fundamental knowledge for clinical diagnosis and prevention for the diseases related to disturbed MI metabolism.

Early effect of myo-inositol deficiency on fatty acid synthetic enzymes of rat liver.

Young rats (100 g) were fed either a purified myo-inositol-deficient balanced diet or a control diet containing 0.5% by weight myo-inositol, ad libitum, for up to 2 weeks following a 48 h fast. Weight gain was the same for animals in both groups. Liver triacylglycerol levels in the deficient animals were 1.8-, 3.5- and 3.0-fold higher than the corresponding levels in the control animals after 4, 8 and 14 days of feeding, respectively. In the myo-inositol-deficient group the specific activities of liver fatty acid synthetase and acetyl-CoA carboxylase were elevated 1.5-2.0-fold over controls, reaching a maximum after 3-4 days of feeding. Subsequently, activities declined to control levels. Rates of fatty acid synthetase synthesis in the deficient group, as measured by [3H]leucine incorporation into immunoprecipitable fatty acid synthetase polypeptide, were significantly higher (1.5-2.0-fold) than controls after 12-18 h of feeding and then declined to control levels by 1 day. No difference was noted between groups in either the rate of total, soluble liver protein synthesis or the half-life of fatty acid synthetase over this time period. These results suggest that the liver lipodystrophy observed during myo-inositol deficiency in rats may be due in part to elevated levels of lipogenic enzymes in this tissue in the early stage of the deficiency.