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Worldwide, obesity rates have doubled since the 1980s and in the USA alone, almost 40% of adults are obese, which is closely associated with a myriad of metabolic diseases such as type 2 diabetes and arteriosclerosis. Obesity is derived from an imbalance between energy intake and consumption, therefore balancing energy homeostasis is an attractive target for metabolic diseases. One therapeutic approach consists of increasing the number of brown-like adipocytes in the white adipose tissue (WAT). Whereas WAT stores excess energy, brown adipose tissue (BAT) can dissipate this energy overload in the form of heat, increasing energy expenditure and thus inhibiting metabolic diseases. To facilitate BAT production a high-throughput screening approach was developed on previously known drugs using human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes. The screening allowed us to discover that zafirlukast, an FDA-approved small molecule drug commonly used to treat asthma, was able to differentiate adipocyte precursors and white-biased adipocytes into functional brown adipocytes. However, zafirlukast is toxic to human cells at higher dosages. Drug-Initiated Activity Metabolomics (DIAM) was used to investigate zafirlukast as a BAT inducer, and the endogenous metabolite myristoylglycine was then discovered to mimic the browning properties of zafirlukast without impacting cell viability. Myristoylglycine was found to be bio-synthesized upon zafirlukast treatment and was unique in inducing brown adipocyte differentiation, raising the possibility of using endogenous metabolites and bypassing the exogenous drugs to potentially alleviate disease, in this case, obesity and other related metabolic diseases.

Hypertension and kidney disease have been repeatedly associated with genomic variants and alterations of lysine metabolism. Here, we combined stable isotope labeling with untargeted metabolomics to investigate lysine's metabolic fate in vivo. Dietary 13 C 6 labeled lysine was tracked to lysine metabolites across various organs. Globally, lysine reacts rapidly with molecules of the central carbon metabolism, but incorporates slowly into proteins and acylcarnitines. Lysine metabolism is accelerated in a rat model of hypertension and kidney damage, chiefly through N-alpha-mediated degradation. Lysine administration diminished development of hypertension and kidney injury. Protective mechanisms include diuresis, further acceleration of lysine conjugate formation, and inhibition of tubular albumin uptake. Lysine also conjugates with malonyl-CoA to form a novel metabolite Nε-malonyl-lysine to deplete malonyl-CoA from fatty acid synthesis. Through conjugate formation and excretion as fructoselysine, saccharopine, and Nε-acetyllysine, lysine lead to depletion of central carbon metabolites from the organism and kidney. Consistently, lysine administration to patients at risk for hypertension and kidney disease inhibited tubular albumin uptake, increased lysine conjugate formation, and reduced tricarboxylic acid (TCA) cycle metabolites, compared to kidney-healthy volunteers. In conclusion, lysine isotope tracing mapped an accelerated metabolism in hypertension, and lysine administration could protect kidneys in hypertensive kidney disease., (© 2022. The Author(s).)

In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects. Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration. However, hyperactivation of IRE1 engages regulated IRE1-dependent decay (RIDD) and TRAF2/JNK pro-inflammatory signaling, which accelerate metabolic dysfunction. These pathologic IRE1-regulated processes have hindered efforts to pharmacologically harness the protective benefits of IRE1/XBP1s signaling in obesity-linked conditions. Here, we report the effects of a XBP1s-selective pharmacological IRE1 activator, IXA4, in diet-induced obese (DIO) mice. IXA4 transiently activates protective IRE1/XBP1s signaling in liver without inducing RIDD or TRAF2/JNK signaling. IXA4 treatment improves systemic glucose metabolism and liver insulin action through IRE1-dependent remodeling of the hepatic transcriptome that reduces glucose production and steatosis. IXA4-stimulated IRE1 activation also enhances pancreatic function. Our findings indicate that systemic, transient activation of IRE1/XBP1s signaling engenders multi-tissue benefits that integrate to mitigate obesity-driven metabolic dysfunction., (© 2022. The Author(s).)

Untargeted metabolomics of disease-associated intestinal microbiota can detect quantitative changes in metabolite profiles and complement other methodologies to reveal the full effect of intestinal dysbiosis. Here, we used the T cell transfer mouse model of colitis to identify small-molecule metabolites with altered abundance due to intestinal inflammation. We applied untargeted metabolomics to detect metabolite signatures in cecal, colonic, and fecal samples from healthy and colitic mice and to uncover differences that would aid in the identification of colitis-associated metabolic processes. We provided an unbiased spatial survey of the GI tract for small molecules, and we identified the likely source of metabolites and biotransformations. Several prioritized metabolites that we detected as being altered in colitis were evaluated for their ability to induce inflammatory signaling in cultured macrophages, such as NF-κB signaling and the expression of cytokines and chemokines upon LPS stimulation. Multiple previously uncharacterized anti-inflammatory and inflammation-augmenting metabolites were thus identified, with phytosphingosine showing the most effective anti-inflammatory activity in vitro. We further demonstrated that oral administration of phytosphingosine decreased inflammation in a mouse model of colitis induced by the compound TNBS. The collection of distinct metabolites we identified and characterized, many of which have not been previously associated with colitis, may offer new biological insight into IBD-associated inflammation and disease pathogenesis.

The EAT-Lancet Commission promulgated a universal reference diet. Subsequently, researchers constructed an EAT-Lancet diet score (0-14 points), with minimum intake values for various dietary components set at 0 g/d, and reported inverse associations with risks of major health outcomes in a high-income population. We assessed associations between EAT-Lancet diet scores, without or with lower bound values, and the mean probability of micronutrient adequacy (MPA) among nutrition-insecure women of reproductive age (WRA) from low- and middle-income countries (LMIC). We analysed single 24-h diet recall data (n 1950) from studies in rural DRC, Ecuador, Kenya, Sri Lanka and Vietnam. Associations between EAT-Lancet diet scores and MPA were assessed by fitting linear mixed-effects models. Mean EAT-Lancet diet scores were 8·8 (SD 1·3) and 1·9 (SD 1·1) without or with minimum intake values, respectively. Pooled MPA was 0·58 (SD 0·22) and energy intake was 10·5 (SD 4·6) MJ/d. A one-point increase in the EAT-Lancet diet score, without minimum intake values, was associated with a 2·6 (SD 0·7) percentage points decrease in MPA (P < 0·001). In contrast, the EAT-Lancet diet score, with minimum intake values, was associated with a 2·4 (SD 1·3) percentage points increase in MPA (P = 0·07). Further analysis indicated positive associations between EAT-Lancet diet scores and MPA adjusted for energy intake (P < 0·05). Our findings indicate that the EAT-Lancet diet score requires minimum intake values for nutrient-dense dietary components to avoid positively scoring non-consumption of food groups and subsequently predicting lower MPA of diets, when applied to rural WRA in LMIC.

The understanding of the mechanisms underlying adipocyte differentiation and function has greatly benefited from the use of immortalized white preadipocyte cell lines. These cultured cell lines, however, have limitations. They do not fully capture the diverse functional spectrum of the heterogenous adipocyte populations that are now known to exist within white adipose depots. To provide a more physiologically relevant model to study the complexity of white adipose tissue, a protocol has been developed and optimized to enable simultaneous isolation of primary white and brown adipocyte progenitors from newborn mice, their rapid expansion in culture, and their differentiation in vitro into mature, fully functional adipocytes. The primary advantage of isolating primary cells from newborn, rather than adult mice, is that the adipose depots are actively developing and are, therefore, a rich source of proliferating preadipocytes. Primary preadipocytes isolated using this protocol differentiate rapidly upon reaching confluence and become fully mature in 4-5 days, a temporal window that accurately reflects the appearance of developed fat pads in newborn mice. Primary cultures prepared using this strategy can be expanded and studied with high reproducibility, making them suitable for genetic and phenotypic screens and enabling the study of the cell-autonomous adipocyte phenotypes of genetic mouse models. This protocol offers a simple, rapid, and inexpensive approach to study the complexity of adipose tissue in vitro.

Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse-small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1-a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1's catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of signaling lipids with anti-inflammatory and anti-diabetic properties. However, the endogenous regulation of FAHFAs remains a pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS-based lipidomics analyses, and activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolases, control FAHFA levels in vivo in both genetic and pharmacologic mouse models. Tissues from mice lacking ADTRP ( Adtrp -KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs particularly isomers with the ester bond at the 9 th carbon due to decreased FAHFA hydrolysis activity. The levels of other lipid classes were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs. Complementing these genetic studies, we also identified a dual AIG1/ADTRP inhibitor, ABD-110207, which is active in vivo Acute treatment of WT mice with ABD-110207 resulted in elevated FAHFA levels, further supporting the notion that AIG1 and ADTRP activity control endogenous FAHFA levels. However, loss of AIG1/ADTRP did not mimic the changes associated with pharmacologically administered FAHFAs on extent of upregulation of FAHFA levels, glucose tolerance, or insulin sensitivity in mice, indicating that therapeutic strategies should weigh more on FAHFA administration. Together, these findings identify AIG1 and ADTRP as the first endogenous FAHFA hydrolases identified and provide critical genetic and chemical tools for further characterization of these enzymes and endogenous FAHFAs to unravel their physiological functions and roles in health and disease., (© 2020 Erikci Ertunc et al.)

Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes 1,2 . The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown 3,4 . Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined 3,4 . Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.

Objectives: Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes., Methods: KDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling., Results: We show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone., Conclusions: Activation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Defects in adipocyte function associated with obesity drive the development of systemic insulin resistance and type 2 diabetes. Agents that correct obesity-linked adipocyte dysfunction serve as useful insulin sensitizers in humans, as is exemplified by the thiazolidinediones (TZDs). We have developed a new platform that integrates advanced chemoproteomics with phenotypic screening to identify small molecules that promote differentiation and lipid storage in adipocytes, and, in tandem, their molecular target(s). These molecules mimic the activity of TZDs in culture and thus may also serve as insulin sensitizers in vivo. Central to this platform is the use of fully functionalized fragment (FFF) probes that consist of a variable, fragment-like recognition element linked to an alkyne-diazirine group that enables the photoactivated capture of probe-bound proteins directly in living cells and subsequent copper-catalyzed azide-alkyne cycloaddition to reporter tags for enrichment and identification of these probe-bound proteins by mass spectrometry. This platform, which can be adapted to diverse screens and cell types beyond adipocytes, has the potential to uncover new biological pathways amenable to pharmacological modulation that may impact human disease.

The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells. Principal among these is NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of KEAP1-mutant NSCLC cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Our findings designate NR0B1 as a druggable transcriptional regulator that supports NRF2-dependent lung cancers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: In a phase II clinical trial in nine obese, insulin-resistant humans, we observed that treatment with KDT501, a novel isohumulone drug, increased total and high-molecular weight (HMW) adiponectin in plasma. The objective was to determine whether KDT501 increased adiponectin secretion from subcutaneous white adipose tissue (SC WAT) and the underlying mechanism(s)., Methods: Nine obese participants with either prediabetes or with normal glucose tolerance plus three features of metabolic syndrome were part of the study. SC WAT biopsies were performed before and after 28 days of KDT501 treatment in a clinical research setting. In addition, a cold stimulus was used to induce thermogenic gene expression. Adiponectin secretion was measured, and gene expression of 130 genes involved in adipose tissue function was determined. The effect of KDT501 on adipocyte mitochondrial function was analyzed in vitro ., Results: SC WAT explants secreted more total and HMW adiponectin after KDT501 treatment ( P  < 0.05). After KDT501 treatment, a number of genes involved in thermogenesis and lipolysis were induced by cold ( P  < 0.05). KDT501 also potentiated β-adrenergic signaling ( P  < 0.001) and enhanced mitochondrial function in adipocytes ( P  < 0.001)., Conclusion: KDT501 induced adiponectin secretion posttranscriptionally and increased gene expression of thermogenic and lipolytic genes in response to cold stimulation. These beneficial effects on SC WAT may be explained by the ability of KDT501 to potentiate β-adrenergic signaling and enhance mitochondrial function in adipocytes., Clinical Trial Registration: https://www.ClinicalTrials.gov, ID number: NCT02444910.

Objective: Evaluation of the effectiveness of a workplace health promotion program on employees' vitality, health, and work-related outcomes, and exploring the influence of organizational support and the supervisors' role on these outcomes., Methods: The 5-month intervention included activities at management, team, and individual level targeting self-management to perform healthy behaviors: a kick-off session, vitality training sessions, workshops, individual coaching, and intervision. Outcome measures were collected using questionnaires, health checks, and sickness absence data at baseline, after the intervention and at 10 months follow-up. For analysis linear and generalized mixed models were used., Results: Vitality, work performance, sickness absence, and self-management significantly improved. Good organizational support and involved supervisors were significantly associated with lower sickness absence., Conclusions: Including all organizational levels and focusing on increasing self-management provided promising results for improving vitality, health, and work-related outcomes.

The effectiveness of the "Extra Fit!" (EF!) education program in promoting healthy diet and physical activity to prevent and reduce overweightness among primary school children aged 9 to 11 was evaluated. A randomized controlled design was carried out in 45 primary schools (n = 1112) in the Netherlands, 23 intervention and 22 control schools. The intervention schools received the education program for two successive school years in grades (U.S. system) 4, 5, and 6 (mean 7.6 h during 16 weeks per school per year). The control schools followed their usual curriculum. No positive effects of EF! were found with regard to behavior and anthropometric measures when follow-up measurements were compared to the baseline. However, from baseline to follow-up after one and two school years, the intervention group improved their knowledge score significantly compared to the control group. Moreover, an effect was observed for mean time spent inactively that increased more in the control group than in the intervention group. In conclusion, limited intervention effects were found for the intervention on knowledge and inactivity. To improve the effectiveness of education programs, we advise focusing on parental involvement, attractive lessons to enlarge the acceptability of the program, and multi-component environmental strategies.

Diterpene derivatives of the natural product acanthoic acid have potent anti-inflammatory effects in vivo. In this issue of Chemistry & Biolgy, Través and colleagues report that the primary molecular mechanism of action of diterpenes structurally related to acanthoic acid is the direct activation of PI3-kinase signaling in macrophages, which in turn inhibits NF-κB activation and suppresses proinflammatory gene expression., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Autotaxin is a secreted enzyme that produces most extracellular lysophosphatidate, which stimulates 6 G-protein-coupled receptors. Lysophosphatidate promotes cancer cell survival, growth, migration, invasion, metastasis, and resistance to chemotherapy and radiotherapy. The present work investigated whether inhibiting autotaxin could decrease breast tumor growth and metastasis. We used a new autotaxin inhibitor (ONO-8430506; IC90=100 nM), which decreased plasma autotaxin activity by >60% and concentrations of unsaturated lysophosphatidates by >75% for 24 h compared with vehicle-treated mice. The effects of ONO-8430506 on tumor growth were determined in a syngeneic orthotopic mouse model of breast cancer following injection of 20,000 BALB/c mouse 4T1 or 4T1-12B cancer cells. We show for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastatic nodules both by 60% compared with vehicle-treated mice. Significantly, 4T1 cells express negligible autotaxin compared with the mammary fat pad. Autotaxin activity in the fat pad of nontreated mice was increased 2-fold by tumor growth. Our results emphasize the importance of tumor interaction with its environment and the role of autotaxin in promoting breast cancer growth and metastasis. We also established that autotaxin inhibition could provide a novel therapeutic approach to blocking the adverse effects of lysophosphatidate in cancer., (© FASEB.)

Background: Biofortification of cassava with pro-vitamin A can potentially reduce vitamin A deficiency in low-income countries. However, little is known about consumer acceptance of this deep yellow variety of cassava compared to the commonly available white varieties. We aimed to determine the sensory and cultural acceptability of the consumption of pro-vitamin A rich cassava in order to identify key factors predicting the intention to consume pro-vitamin A rich cassava by families with school-aged children in Eastern Kenya., Methods: Sensory acceptability was measured by replicated discrimination tests and paired preference tests among 30 children (7-12 yr) and 30 caretakers (18-45 yr) in three primary schools. Cultural acceptability was assessed with a questionnaire based on the combined model of The Theory of Planned Behavior and The Health Belief Model in one primary school among 140 caretakers of children aged 6 to 12 years. Correlations and multivariate analyses were used to determine associations between summed scores for model constructs., Results: Caretakers and children perceived a significant difference in taste between white and pro-vitamin A rich cassava. Both preferred pro-vitamin A rich cassava over white cassava because of its soft texture, sweet taste and attractive color. Knowledge about pro-vitamin A rich cassava and it's relation to health ('Knowledge' ((β = 0.29, P = <.01)) was a strong predictor of 'Health behavior identity'. Worries related to bitter taste and color ('Perceived barriers 1' (β = -0.21, P = .02)), the belief of the caretaker about having control to prepare cassava ('Control beliefs' (β = 0.18, P = .02)) and activities like information sessions about pro-vitamin A rich cassava and recommendations from health workers ('Cues to action'(β = 0.51, P = <.01)) were the best predictors of intention to consume pro-vitamin A rich cassava., Conclusions: Pro-vitamin A rich cassava is well accepted by school children in our study population.

Management of diabetes and insulin resistance in the setting of cardiovascular disease has become an important issue in an increasingly obese society. Besides the development of hypertension and buildup of atherosclerotic plaques, the derangement of fatty acid and lipid metabolism in the heart plays an important role in promoting cardiac dysfunction and oxidative stress. This review discusses the mechanisms by which metabolic inflexibility in the use of fatty acids as the preferred cardiac substrate in diabetes produces detrimental effects on mechanical efficiency, mitochondrial function, and recovery from ischemia. Lipid accumulation and the consequences of toxic lipid metabolites are also discussed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Lipin-1 is the major phosphatidate phosphatase (PAP) in the heart and a transcriptional coactivator that regulates fatty acid (FA) oxidation in the liver. As the control of FA metabolism is essential for maintaining cardiac function, we investigated whether lipin-1 deficiency affects cardiac metabolism and performance. Cardiac PAP activity in lipin-1 deficient [fatty liver dystrophy (fld)] mice was decreased by >80% compared with controls. Surprisingly, oleate oxidation and incorporation in triacylglycerol (TG), as well as glucose oxidation, were not significantly different in perfused working fld hearts. Despite this, [³H]oleate accumulation in phosphatidate and phosphatidylinositol was increased in fld hearts, reflecting the decreased PAP activity. Phosphatidate accumulation was linked to increased cardiac mammalian target of rapamycin complex 1 (mTORC1) signaling and endoplasmic reticulum (ER) stress. Transthoracic echocardiography showed decreased cardiac function in fld mice; however, cardiac dysfunction was not observed in ex vivo perfused working fld hearts. This showed that changes in systemic factors due to the global absence of lipin-1 could contribute to the decreased cardiac function in vivo. Collectively, this study shows that fld hearts exhibit unchanged oleate esterification, as well as oleate and glucose oxidation, despite the absence of lipin-1. However, lipin-1 deficiency increases the accumulation of newly synthesized phosphatidate and induces aberrant cell signaling.

Excessive fatty acid (FA) uptake by cardiac myocytes is often associated with adverse changes in cardiac function. This is especially evident in diabetic individuals, where increased intramyocardial triacylglycerol (TG) resulting from the exposure to high levels of circulating FA has been proposed to be a major contributor to diabetic cardiomyopathy. At present, our knowledge of how the heart regulates FA storage in TG and the hydrolysis of this TG is limited. This review concentrates on what is known about TG turnover within the heart and how this is likely to be regulated by extrapolating results from other tissues. We also assess the evidence as to whether increased TG accumulation protects against FA-induced lipotoxicity through limiting the accumulations of ceramides and diacylglycerols versus whether it is a maladaptive response that contributes to cardiac dysfunction.

Mammalian lipins (lipin-1, lipin-2, and lipin-3) are Mg2+-dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin-1 also functions as a transcriptional coactivator in conjunction with members of the peroxisome proliferator-activated receptor family. An S734L mutation in LPIN2 causes Majeed syndrome, a human inflammatory disorder characterized by recurrent osteomyelitis, fever, dyserythropoietic anemia, and cutaneous inflammation. Here we demonstrate that mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis. We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine. Therefore, our results indicate that the symptoms of the Majeed syndrome result from a loss of lipin-2 PAP activity. To characterize sites of lipin-2 action, we detected lipin-2 expression by in situ hybridization on whole mouse sections and by quantitative PCR of tissues relevant to Majeed syndrome. Lipin-2 was most prominently expressed in liver, where levels were much higher than lipin-1, and also in kidney, lung, gastrointestinal tract, and specific regions of the brain. Lipin-2 was also expressed in circulating red blood cells and sites of lymphopoiesis (bone marrow, thymus, and spleen). These results raise the possibility that the loss of lipin-2 PAP activity in erythrocytes and lymphocytes may contribute to the anemia and inflammation phenotypes observed in Majeed syndrome patients.