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Formation of myelin by Schwann cells is tightly coupled to peripheral nervous system development and is important for neuronal function and long-term maintenance. Perturbation of myelin causes a number of specific disorders that are among the most prevalent diseases affecting the nervous system. Schwann cells synthesize myelin lipids de novo rather than relying on uptake of circulating lipids, yet one unresolved matter is how acetyl CoA, a central metabolite in lipid formation is generated during myelin formation and maintenance. Recent studies have shown that glucose-derived acetyl CoA itself is not required for myelination. However, the importance of mitochondrially-derived acetyl CoA has never been tested for myelination in vivo. Therefore, we have developed a Schwann cell-specific knockout of the ATP citrate lyase (Acly) gene to determine the importance of mitochondrial metabolism to supply acetyl CoA in nerve development. Intriguingly, the ACLY pathway is important for myelin maintenance rather than myelin formation. In addition, ACLY is required to maintain expression of a myelin-associated gene program and to inhibit activation of the latent Schwann cell injury program., (© 2024 The Author(s). GLIA published by Wiley Periodicals LLC.)

Agpat5 (1-acylglycerol-3-phosphate O-acyltransferase 5) is a broadly expressed lipid regulatory enzyme involved in glycerophospholipid metabolism. Multiple genetic studies in mice and humans have identified that Agpat5 is associated with plasma insulin, cholesterol, and alanine aminotransferase levels. Despite the strong genetic evidence on Agpat5, no study has investigated its liver-specific role in physiology. Here, we conducted a series of metabolic studies under four distinct dietary conditions to assess the impact of liver-specific Agpat5 deletion on plasma insulin levels, glucose tolerance, plasma cholesterol levels, and hepatic steatosis. Liver-specific deletion of Agpat5 did not affect plasma insulin levels, glucose tolerance, plasma cholesterol levels, or hepatic steatosis in mice fed a chow diet, high-fat diet, or Western diet. However, when mice consumed a chow diet combined with liquid sucrose, liver-specific deletion of Agpat5 resulted in significantly decreased plasma insulin levels and improved glucose tolerance without alterations in body weight or fat mass. Using global lipidomics, we identified that Agpat5 specifically modulated levels of phosphatidylglycerol and cardiolipin within the livers of mice consuming liquid sucrose. Overall, our findings indicate a liver-specific role of Agpat5 in contributing to hyperinsulinemia and glucose tolerance in the absence of body weight changes when consuming liquid sucrose., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Brian W. Parks reports financial support was provided by National Heart Lung and Blood Institute. Judith A. Simcox reports financial support was provided by Howard Hughes Medical Institute. Judith A. Simcox reports financial support was provided by Juvenile Diabetes Research Foundation Limited. Judith A. Simcox reports financial support was provided by National Institute of Diabetes and Digestive and Kidney Diseases. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Restricting the intake of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan in young or adult mice. However, their effects when initiated in aged animals are unknown. Here we investigate the consequences of consuming a diet with 67% reduction of all amino acids (low AA) or of isoleucine alone (low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. Both dietary regimens effectively promote overall metabolic health without reducing calorie intake. Both low AA and low Ile diets improve aspects of frailty and slow multiple molecular indicators of aging rate; however, the low Ile diet reduces grip strength in both sexes and has mixed, sexually dimorphic effects on the heart. These results demonstrate that low AA and low Ile diets can promote aspects of healthy aging in aged mice and suggest that similar interventions might promote healthy aging in older adults., Competing Interests: Competing interests: D.W.L. has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Skin has been shown to be a regulatory hub for energy expenditure and metabolism: mutations of skin lipid metabolism enzymes can change the rate of thermogenesis and susceptibility to diet-induced obesity. However, little is known about the physiological basis for this function. Here we show that the thermal properties of skin are highly reactive to diet: within three days, a high fat diet reduces heat transfer through skin. In contrast, a dietary manipulation that prevents obesity accelerates energy loss through skins. We found that skin was the largest target in a mouse body for dietary fat delivery, and that dietary triglyceride was assimilated both by epidermis and by dermal white adipose tissue. Skin from mice calorie-restricted for 3 weeks did not take up circulating lipids and showed a highly depleted stratum corneum. Dietary triglyceride acyl groups persist in skin for weeks after feeding. Using multi-modal lipid profiling, we have implicated both keratinocytes and sebocytes in the altered lipids which correlate with thermal function. In response to high fat feeding, wax diesters and ceramides accumulate, and triglycerides become more saturated. In contrast, in response to the dramatic loss of adipose tissue that accompanies restriction of the branched chain amino acid isoleucine, skin becomes more heat-permeable, resisting changes induced by Western diet feeding, with a signature of depleted signaling lipids. We propose that skin should be routinely included in physiological studies of lipid metabolism, given the size of the skin lipid reservoir and its adaptable functionality., Competing Interests: DWL has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases.

Lysosomes catabolize lipids and other biological molecules, a function essential for cellular and organismal homeostasis. Key to lipid catabolism in the lysosome is bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles (ILVs) and a stimulator of lipid-degrading enzymes. BMP levels are altered in a broad spectrum of human conditions, including neurodegenerative diseases. Although BMP synthase was recently discovered, it has long been thought that BMP's unique stereochemistry confers resistance to acid phospholipases, a requirement for its role in the lysosome. Here, we demonstrate that PLA2G15, a major lysosomal phospholipase, efficiently hydrolyzes BMP with primary esters regardless of stereochemistry. Interestingly, we discover that BMP's unique esterification position is what confers resistance to hydrolysis. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes under acidic conditions. Furthermore, PLA2G15 catalytic activity against synthesized BMP stereoisomers with primary esters was comparable to its canonical substrates. Conversely, BMP with secondary esters is intrinsically stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient tissues and cells accumulate multiple BMP species, a phenotype reversible by supplementing wildtype PLA2G15 but not its catalytically dead mutant. Increasing BMP levels by targeting PLA2G15 reverses the cholesterol accumulation phenotype in Niemann Pick Disease Type C (NPC1) patient fibroblasts and significantly ameliorate disease pathologies in NPC1-deficient mice leading to extended lifespan. Our findings establish the rules that govern the stability of BMP in the lysosome and identify PLA2G15 as a lysosomal BMP hydrolase and as a potential target for modulating BMP levels for therapeutic intervention.

The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, it is unknown how sex, strain, and dietary isoleucine intake may interact to impact the response to a Western Diet (WD). Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain- independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, we find that foods contain a range of isoleucine levels, and that consumption of dietary isoleucine is lower in humans with healthy eating habits. Our results demonstrate that the dietary level of isoleucine is critical in the metabolic and molecular response to a WD, and suggest that lowering dietary levels of isoleucine may be an innovative and translatable strategy to protect from the negative metabolic consequences of a WD., Competing Interests: DECLARATION OF INTERESTS DWL has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases.

Fatty acid β-oxidation (FAO) is a central catabolic pathway with broad implications for organismal health. However, various fatty acids are largely incompatible with standard FAO machinery until they are modified by other enzymes. Included among these are the 4-hydroxy acids (4-HAs)-fatty acids hydroxylated at the 4 (γ) position-which can be provided from dietary intake, lipid peroxidation, and certain drugs of abuse. Here, we reveal that two atypical and poorly characterized acyl-CoA dehydrogenases (ACADs), ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains N-terminal to their ACAD domains that phosphorylate the 4-OH position as a requisite step in the conversion of 4-hydroxyacyl-CoAs into 2-enoyl-CoAs-conventional FAO intermediates. Our ACAD11 cryo-EM structure and molecular modeling reveal a unique binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma while comparable 3- and 5-hydroxy acids remain unchanged. Collectively, this work defines ACAD10 and ACAD11 as the primary gatekeepers of mammalian 4-HA catabolism and sets the stage for broader investigations into the ramifications of aberrant 4-HA metabolism in human health and disease., Competing Interests: Competing interest declaration Authors declare no conflicts of interest in this study.

Cold exposure is an environmental stress that elicits a rapid metabolic shift in endotherms and is required for survival. The liver provides metabolic flexibility through its ability to rewire lipid metabolism to respond to an increased demand in energy for thermogenesis. We leveraged cold exposure to identify novel lipids contributing to energy homeostasis and found that lysosomal bis(monoacylglycero)phosphate (BMP) lipids were significantly increased in the liver during acute cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of TFEB in hepatocytes decreased BMP lipid levels. Through molecular biology and biochemical assays, we found that TFEB regulates lipid catabolism during cold exposure and that TFEB knockdown mice were cold intolerant. To identify how TFEB regulates BMP lipid levels, we used a combinatorial approach to identify TFEB target Pla2g15 , a lysosomal phospholipase, as capable of degrading BMP lipids in in vitro liposome assays. Knockdown of Pla2g15 in hepatocytes led to a decrease in BMP lipid species. Together, our studies uncover a required role of TFEB in mediating lipid liver remodeling during cold exposure and identified Pla2g15 as an enzyme that regulates BMP lipid catabolism.

Calcium (Ca 2+ ) influx into the mitochondrial matrix stimulates ATP synthesis. Here, we investigate whether mitochondrial Ca 2+ transport pathways are altered in the setting of deficient mitochondrial energy synthesis, as increased matrix Ca 2+ may provide a stimulatory boost. We focused on mitochondrial cardiomyopathies, which feature such dysfunction of oxidative phosphorylation. We study a mouse model where the main transcription factor for mitochondrial DNA (transcription factor A, mitochondrial, Tfam) has been disrupted selectively in cardiomyocytes. By the second postnatal week (10-15day old mice), these mice have developed a dilated cardiomyopathy associated with impaired oxidative phosphorylation. We find evidence of increased mitochondrial Ca 2+ during this period using imaging, electrophysiology, and biochemistry. The mitochondrial Ca 2+ uniporter, the main portal for Ca 2+ entry, displays enhanced activity, whereas the mitochondrial sodium-calcium (Na + -Ca 2+ ) exchanger, the main portal for Ca 2+ efflux, is inhibited. These changes in activity reflect changes in protein expression of the corresponding transporter subunits. While decreased transcription of Nclx, the gene encoding the Na + -Ca 2+ exchanger, explains diminished Na + -Ca 2+ exchange, the mechanism for enhanced uniporter expression appears to be post-transcriptional. Notably, such changes allow cardiac mitochondria from Tfam knockout animals to be far more sensitive to Ca 2+ -induced increases in respiration. In the absence of Ca 2+ , oxygen consumption declines to less than half of control values in these animals, but rebounds to control levels when incubated with Ca 2+ . Thus, we demonstrate a phenotype of enhanced mitochondrial Ca 2+ in a mitochondrial cardiomyopathy model, and show that such Ca 2+ accumulation is capable of rescuing deficits in energy synthesis capacity in vitro., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Dietary iron supplementation is associated with increased appetite. Here, we investigated the effect of iron on the hormone leptin, which regulates food intake and energy homeostasis. Serum ferritin was negatively associated with serum leptin in a cohort of patients with metabolic syndrome. Moreover, the same inverse correlation was observed in mice fed a high-iron diet. Adipocyte-specific loss of the iron exporter ferroportin resulted in iron loading and decreased leptin, while decreased levels of hepcidin in a murine hereditary hemochromatosis (HH) model increased adipocyte ferroportin expression, decreased adipocyte iron, and increased leptin. Treatment of 3T3-L1 adipocytes with iron decreased leptin mRNA in a dose-dependent manner. We found that iron negatively regulates leptin transcription via cAMP-responsive element binding protein activation (CREB activation) and identified 2 potential CREB-binding sites in the mouse leptin promoter region. Mutation of both sites completely blocked the effect of iron on promoter activity. ChIP analysis revealed that binding of phosphorylated CREB is enriched at these two sites in iron-treated 3T3-L1 adipocytes compared with untreated cells. Consistent with the changes in leptin, dietary iron content was also directly related to food intake, independently of weight. These findings indicate that levels of dietary iron play an important role in regulation of appetite and metabolism through CREB-dependent modulation of leptin expression.

The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbα) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1α variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Iron overload is a risk factor for diabetes. The link between iron and diabetes was first recognized in pathologic conditions-hereditary hemochromatosis and thalassemia-but high levels of dietary iron also impart diabetes risk. Iron plays a direct and causal role in diabetes pathogenesis mediated both by β cell failure and insulin resistance. Iron also regulates metabolism in most tissues involved in fuel homeostasis, with the adipocyte in particular serving an iron-sensing role. The underlying molecular mechanisms mediating these effects are numerous and incompletely understood but include oxidant stress and modulation of adipokines and intracellular signal transduction pathways., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In Chuvash polycythemia, a homozygous 598C>T mutation in the von Hippel-Lindau gene (VHL) leads to an R200W substitution in VHL protein, impaired degradation of α-subunits of hypoxia-inducible factor (HIF)-1 and HIF-2, and augmented hypoxic responses during normoxia. Chronic hypoxia of high altitude is associated with decreased serum glucose and insulin concentrations. Other investigators reported that HIF-1 promotes cellular glucose uptake by increased expression of GLUT1 and increased glycolysis by increased expression of enzymes such as PDK. On the other hand, inactivation of Vhl in murine liver leads to hypoglycemia associated with a HIF-2-related decrease in the expression of the gluconeogenic enzyme genes Pepck, G6pc, and Glut2. We therefore hypothesized that glucose concentrations are decreased in individuals with Chuvash polycythemia. We found that 88 Chuvash VHL ( R200W ) homozygotes had lower random glucose and glycosylated hemoglobin A1c levels than 52 Chuvash subjects with wild-type VHL alleles. Serum metabolomics revealed higher glycerol and citrate levels in the VHL ( R200W ) homozygotes. We expanded these observations in VHL ( R200W ) homozygote mice and found that they had lower fasting glucose values and lower glucose excursions than wild-type control mice but no change in fasting insulin concentrations. Hepatic expression of Glut2 and G6pc, but not Pdk2, was decreased, and skeletal muscle expression of Glut1, Pdk1, and Pdk4 was increased. These results suggest that both decreased hepatic gluconeogenesis and increased skeletal uptake and glycolysis contribute to the decreased glucose concentrations. Further study is needed to determine whether pharmacologically manipulating HIF expression might be beneficial for treatment of diabetic patients.

We examined mouse models with altered adipocyte expression of mitoNEET, a protein residing in the mitochondrial outer membrane, to probe its impact on mitochondrial function and subsequent cellular responses. We found that overexpression of mitoNEET enhances lipid uptake and storage, leading to an expansion of the mass of adipose tissue. Despite the resulting massive obesity, benign aspects of adipose tissue expansion prevail, and insulin sensitivity is preserved. Mechanistically, we also found that mitoNEET inhibits mitochondrial iron transport into the matrix and, because iron is a rate-limiting component for electron transport, lowers the rate of β-oxidation. This effect is associated with a lower mitochondrial membrane potential and lower levels of reactive oxygen species-induced damage, along with increased production of adiponectin. Conversely, a reduction in mitoNEET expression enhances mitochondrial respiratory capacity through enhanced iron content in the matrix, ultimately corresponding to less weight gain on a high-fat diet. However, this reduction in mitoNEET expression also causes heightened oxidative stress and glucose intolerance. Thus, manipulation of mitochondrial function by varying mitoNEET expression markedly affects the dynamics of cellular and whole-body lipid homeostasis.

Iron overload is associated with increased diabetes risk. We therefore investigated the effect of iron on adiponectin, an insulin-sensitizing adipokine that is decreased in diabetic patients. In humans, normal-range serum ferritin levels were inversely associated with adiponectin, independent of inflammation. Ferritin was increased and adiponectin was decreased in type 2 diabetic and in obese diabetic subjects compared with those in equally obese individuals without metabolic syndrome. Mice fed a high-iron diet and cultured adipocytes treated with iron exhibited decreased adiponectin mRNA and protein. We found that iron negatively regulated adiponectin transcription via FOXO1-mediated repression. Further, loss of the adipocyte iron export channel, ferroportin, in mice resulted in adipocyte iron loading, decreased adiponectin, and insulin resistance. Conversely, organismal iron overload and increased adipocyte ferroportin expression because of hemochromatosis are associated with decreased adipocyte iron, increased adiponectin, improved glucose tolerance, and increased insulin sensitivity. Phlebotomy of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores.

Iron overload can cause insulin deficiency, but in some cases this may be insufficient to result in diabetes. We hypothesized that the protective effects of decreased iron would be more significant with increased beta-cell demand and stress. Therefore, we treated the ob/ob mouse model of type 2 diabetes with an iron-restricted diet (35 mg/kg iron) or with an oral iron chelator. Control mice were fed normal chow containing 500 mg/kg iron. Neither treatment resulted in iron deficiency or anemia. The low-iron diet significantly ameliorated diabetes in the mice. The effect was long lasting and reversible. Ob/ob mice on the low-iron diet exhibited significant increases in insulin sensitivity and beta-cell function, consistent with the phenotype in mouse models of hereditary iron overload. The effects were not accounted for by changes in weight or feeding behavior. Treatment with iron chelation had a more dramatic effect, allowing the ob/ob mice to maintain normal glucose tolerance for at least 10.5 wk despite no effect on weight. Although dietary iron restriction preserved beta-cell function in ob/ob mice fed a high-fat diet, the effects on overall glucose levels were less apparent due to a loss of the beneficial effects of iron on insulin sensitivity. Beneficial effects of iron restriction were minimal in wild-type mice on normal chow but were apparent in mice on high-fat diets. We conclude that, even at "normal" levels, iron exerts detrimental effects on beta-cell function that are reversible with dietary restriction or pharmacotherapy.