Rab30 facilitates lipid homeostasis during fasting.

To facilitate inter-tissue communication and the exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Here, we show that Rab30 is induced in the mouse liver by fasting, which is amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2L-/-) lacking the ability to oxidize fatty acids, in a Pparα-dependent manner. Live-cell super-resolution imaging and in vivo proximity labeling demonstrates that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30; Cpt2 liver-specific double knockout (DKO) mice are viable with intact Golgi ultrastructure, although Rab30 deficiency in DKO mice suppresses the serum dyslipidemia observed in Cpt2L-/- mice. Corresponding with decreased serum triglyceride and cholesterol levels, DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels, particularly during times of excessive lipid burden.

Legionella pneumophila usurps host cell lipids for vacuole expansion and bacterial growth.

Vacuolar pathogens reside in membrane-bound compartments within host cells. Maintaining the integrity of this compartment is paramount to bacterial survival and replication as it protects against certain host surveillance mechanisms that function to eradicate invading pathogens. Preserving this compartment during bacterial replication requires expansion of the vacuole membrane to accommodate the increasing number of bacteria, and yet, how this is accomplished remains largely unknown. Here, we show that the vacuolar pathogen Legionella pneumophila exploits multiple sources of host cell fatty acids, including inducing host cell fatty acid scavenging pathways, in order to promote expansion of the replication vacuole and bacteria growth. Conversely, when exogenous lipids are limited, the decrease in host lipid availability restricts expansion of the replication vacuole membrane, resulting in a higher density of bacteria within the vacuole. Modifying the architecture of the vacuole prioritizes bacterial growth by allowing the greatest number of bacteria to remain protected by the vacuole membrane despite limited resources for its expansion. However, this trade-off is not without risk, as it can lead to vacuole destabilization, which is detrimental to the pathogen. However, when host lipid resources become extremely scarce, for example by inhibiting host lipid scavenging, de novo biosynthetic pathways, and/or diverting host fatty acids to storage compartments, bacterial replication becomes severely impaired, indicating that host cell fatty acid availability also directly regulates L. pneumophila growth. Collectively, these data demonstrate dual roles for host cell fatty acids in replication vacuole expansion and bacterial proliferation, revealing the central functions for these molecules and their metabolic pathways in L. pneumophila pathogenesis.

Proteomics identifies the developmental regulation of HKDC1 in liver of pigs and mice.

During the perinatal period, unique metabolic adaptations support energetic requirements for rapid growth. To gain insight into perinatal adaptations, quantitative proteomics was performed comparing the livers of Yorkshire pigs at postnatal day 7 and adult. These data revealed differences in the metabolic control of liver function including significant changes in lipid and carbohydrate metabolic pathways. Newborn livers showed an enrichment of proteins in lipid catabolism and gluconeogenesis concomitant with elevated liver carnitine and acylcarnitines levels. Sugar kinases were some of the most dramatically differentially enriched proteins compared with neonatal and adult pigs including galactokinase 1 (Galk1), ketohexokinase (KHK), hexokinase 1 (HK1), and hexokinase 4 (GCK). Interestingly, hexokinase domain containing 1 (HKDC1), a newly identified fifth hexokinase associated with glucose disturbances in pregnant women, was highly enriched in the liver during the prenatal and perinatal periods and continuously declined throughout postnatal development in pigs and mice. These changes were confirmed via Western blot and mRNA expression. These data provide new insights into the developmental and metabolic adaptations in the liver during the transition from the perinatal period to adulthood in multiple mammalian species.

Peroxisome proliferator activated receptor-γ in osteoblasts controls bone formation and fat mass by regulating sclerostin expression.

The nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) is a key contributor to metabolic function via its adipogenic and insulin-sensitizing functions, but it has negative effects on skeletal homeostasis. Here, we questioned whether the skeletal and metabolic actions of PPARγ are linked. Ablating Pparg expression in osteoblasts and osteocytes produced a high bone mass phenotype, secondary to increased osteoblast activity, and a reduction in subcutaneous fat mass because of reduced fatty acid synthesis and increased fat oxidation. The skeletal and metabolic phenotypes in Pparg mutants proceed from the regulation of sclerostin production by PPARγ. Mutants exhibited reductions in skeletal Sost expression and serum sclerostin levels while increasing production normalized both phenotypes. Importantly, disrupting the production of sclerostin synergized with the insulin-sensitizing actions of a PPARγ agonist while preventing bone loss. These data suggest that modulating sclerostin action may prevent bone loss associated with anti-diabetic therapies and augment their metabolic actions.

Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis.

To define the metabolic requirements of hematopoiesis, we examined blood lineages in mice conditionally deficient in genes required for long-chain fatty acid oxidation (Cpt2), glutaminolysis (Gls), or mitochondrial pyruvate import (Mpc2). Genetic ablation of Cpt2 or Gls minimally impacted most blood lineages. In contrast, deletion of Mpc2 led to a sharp decline in mature myeloid cells and a slower reduction in T cells, whereas other hematopoietic lineages were unaffected. Yet MPC2-deficient monocytes and neutrophils rapidly recovered due to a transient and specific increase in myeloid progenitor proliferation. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was progenitor intrinsic and accompanied by a metabolic switch to glutaminolysis. Myeloid recovery after loss of MPC2 or cyclophosphamide treatment was delayed in the absence of GLS. Reciprocally, MPC2 was not required for myeloid recovery after cyclophosphamide treatment. Thus, mitochondrial pyruvate metabolism maintains myelopoiesis under steady-state conditions, while glutaminolysis in progenitors promotes emergency myelopoiesis.

Mitochondrial ß-oxidation of adipose-derived fatty acids by osteoblasts fuels parathyroid hormone-induced bone formation.

The energetic costs of bone formation require osteoblasts to coordinate their activities with tissues, like adipose, that can supply energy-dense macronutrients. In the case of intermittent parathyroid hormone (PTH) treatment, a strategy used to reduce fracture risk, bone formation is preceded by a change in systemic lipid homeostasis. To investigate the requirement for fatty acid oxidation by osteoblasts during PTH-induced bone formation, we subjected mice with osteoblast-specific deficiency of mitochondrial long-chain ß-oxidation as well as mice with adipocyte-specific deficiency for the PTH receptor or adipose triglyceride lipase to an anabolic treatment regimen. PTH increased the release of fatty acids from adipocytes and ß-oxidation by osteoblasts, while the genetic mouse models were resistant to the hormone's anabolic effect. Collectively, these data suggest that PTH's anabolic actions require coordinated signaling between bone and adipose, wherein a lipolytic response liberates fatty acids that are oxidized by osteoblasts to fuel bone formation.

Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet.

Pyruvate has two major fates upon entry into mitochondria, the oxidative decarboxylation to acetyl-CoA via the pyruvate decarboxylase complex or the biotin-dependent carboxylation to oxaloacetate via pyruvate carboxylase (Pcx). Here, we have generated mice with a liver-specific KO of pyruvate carboxylase (PcxL-/-) to understand the role of Pcx in hepatic mitochondrial metabolism under disparate physiological states. PcxL-/- mice exhibited a deficit in hepatic gluconeogenesis and enhanced ketogenesis as expected but were able to maintain systemic euglycemia following a 24 h fast. Feeding a high-fat diet to PcxL-/- mice resulted in animals that were resistant to glucose intolerance without affecting body weight. However, we found that PcxL-/- mice fed a ketogenic diet for 1 week became severely hypoglycemic, demonstrating a requirement for hepatic Pcx for long-term glycemia under carbohydrate-limited diets. Additionally, we determined that loss of Pcx was associated with an induction in the abundance of lysine-acetylated proteins in PcxL-/- mice regardless of physiologic state. Furthermore, liver acetyl-proteomics revealed a biased induction in mitochondrial lysine-acetylated proteins. These data show that Pcx is important for maintaining the proper balance of pyruvate metabolism between oxidative and anaplerotic pathways.

Mitochondrial fatty acid ß-oxidation is important for normal osteoclast formation in growing female mice.

Skeletal remodeling is an energy demanding process that is linked to nutrient availability and the levels of metabolic hormones. While recent studies have examined the metabolic requirements of bone formation by osteoblasts, much less is known about the energetic requirements of bone resorption by osteoclasts. The abundance of mitochondria in mature osteoclasts suggests that the production of an acidified micro-environment conducive to the ionization of hydroxyapatite, secretion of matrix-degrading enzymes, and motility during resorption requires significant energetic capacity. To investigate the contribution of mitochondrial long chain fatty acid ß-oxidation to osteoclast development, we disrupted the expression of carnitine palmitoyltransferase-2 (Cpt2) in myeloid-lineage cells. Fatty acid oxidation increases dramatically in bone marrow cultures stimulated with RANKL and M-CSF and microCT analysis revealed that the genetic inhibition of long chain fatty acid oxidation in osteoclasts significantly increases trabecular bone volume in female mice secondary to reduced osteoclast numbers. In line with these data, osteoclast precursors isolated from Cpt2 mutants exhibit reduced capacity to form large-multinucleated osteoclasts, which was not rescued by exogenous glucose or pyruvate, and signs of an energetic stress response. Together, our data demonstrate that mitochondrial long chain fatty acid oxidation by the osteoclast is required for normal bone resorption as its inhibition produces an intrinsic defect in osteoclast formation.

Progesterone receptor membrane component 1 (PGRMC1) binds and stabilizes cytochromes P450 through a heme-independent mechanism.

Progesterone receptor membrane component 1 (PGRMC1) is a heme-binding protein implicated in a wide range of cellular functions. We previously showed that PGRMC1 binds to cytochromes P450 in yeast and mammalian cells and supports their activity. Recently, the paralog PGRMC2 was shown to function as a heme chaperone. The extent of PGRMC1 function in cytochrome P450 biology and whether PGRMC1 is also a heme chaperone are unknown. Here, we examined the function of Pgrmc1 in mouse liver using a knockout model and found that Pgrmc1 binds and stabilizes a broad range of cytochromes P450 in a heme-independent manner. Proteomic and transcriptomic studies demonstrated that Pgrmc1 binds more than 13 cytochromes P450 and supports maintenance of cytochrome P450 protein levels posttranscriptionally. In vitro assays confirmed that Pgrmc1 KO livers exhibit reduced cytochrome P450 activity consistent with reduced enzyme levels. Mechanistic studies in cultured cells demonstrated that PGRMC1 stabilizes cytochromes P450 and that binding and stabilization do not require PGRMC1 binding to heme. Importantly, Pgrmc1-dependent stabilization of cytochromes P450 is physiologically relevant, as Pgrmc1 deletion protected mice from acetaminophen-induced liver injury. Finally, evaluation of Y113F mutant Pgrmc1, which lacks the axial heme iron-coordinating hydroxyl group, revealed that proper iron coordination is not required for heme binding, but is required for binding to ferrochelatase, the final enzyme in heme biosynthesis. PGRMC1 was recently identified as the causative mutation in X-linked isolated pediatric cataract formation. Together, these results demonstrate a heme-independent function for PGRMC1 in cytochrome P450 stability that may underlie clinical phenotypes.

Functional loss of ketogenesis in odontocete cetaceans.

Odontocete cetaceans exhibit genomic mutations in key ketogenesis genes. In order to validate an inferred lack of ketogenesis made by observations from genome sequencing, we biochemically analyzed tissues from several odontocete cetacean species and demonstrate that they indeed do not exhibit appreciable hepatic ß-hydroxybutyrate (ßHB) or its carnitine ester. Furthermore, liver tissue exhibited significantly lower long chain acylcarnitines and increased odd chain acylcarnitines indicative of a decreased reliance on hepatic long chain fatty acid oxidation in these carnivorous mammals. Finally, we performed single molecule, real-time next generation sequencing of liver and brain RNA of Tursiops truncatus and demonstrate that the succinyl-CoA transferase required for acetoacetate catabolism is expressed in the nervous system. These data show that odontocete cetaceans have lost the ability to perform ketogenesis and suggest a hepatocentric coenzyme A recycling function rather than a predominantly systemic-bioenergetic role for ketogenesis in other ketogenic competent mammals such as humans.

mTORC1 activation is not sufficient to suppress hepatic PPARα signaling or ketogenesis.

The mechanistic target of rapamycin (mTOR) is often referred to as a master regulator of the cellular metabolism that can integrate the growth factor and nutrient signaling. Fasting suppresses hepatic mTORC1 activity via the activity of the tuberous sclerosis complex (TSC), a negative regulator of mTORC1, to suppress anabolic metabolism. The loss of TSC1 in the liver locks the liver in a constitutively anabolic state even during fasting, which was suggested to regulate peroxisome proliferator-activated receptor alpha (PPARα) signaling and ketogenesis, but the molecular determinants of this regulation are unknown. Here, we examined if the activation of the mTORC1 complex in mice by the liver-specific deletion of TSC1 (TSC1L-/-) is sufficient to suppress PPARα signaling and therefore ketogenesis in the fasted state. We found that the activation of mTORC1 in the fasted state is not sufficient to repress PPARα-responsive genes or ketogenesis. Furthermore, we examined whether the activation of the anabolic program mediated by mTORC1 complex activation in the fasted state could suppress the robust catabolic programming and enhanced PPARα transcriptional response of mice with a liver-specific defect in mitochondrial long-chain fatty acid oxidation using carnitine palmitoyltransferase 2 (Cpt2L-/-) mice. We generated Cpt2L-/-; Tsc1L-/- double-KO mice and showed that the activation of mTORC1 by deletion of TSC1 could not suppress the catabolic PPARα-mediated phenotype of Cpt2L-/- mice. These data demonstrate that the activation of mTORC1 by the deletion of TSC1 is not sufficient to suppress a PPARα transcriptional program or ketogenesis after fasting.

The role of ethanolamine phosphate phospholyase in regulation of astrocyte lipid homeostasis.

Dietary lipid composition has been shown to impact brain morphology, brain development, and neurologic function. However, how diet uniquely regulates brain lipid homeostasis compared with lipid homeostasis in peripheral tissues remains largely uncharacterized. To evaluate the lipid response to dietary changes in the brain, we assessed actively translating mRNAs in astrocytes and neurons across multiple diets. From this data, ethanolamine phosphate phospholyase (Etnppl) was identified as an astrocyte-specific fasting-induced gene. Etnppl catabolizes phosphoethanolamine (PEtN), a prominent headgroup precursor in phosphatidylethanolamine (PE) also found in other classes of neurologically relevant lipid species. Altered Etnppl expression has also previously been associated with humans with mood disorders. We evaluated the relevance of Etnppl in maintaining brain lipid homeostasis by characterizing Etnppl across development and in coregulation with PEtN-relevant genes, as well as determining the impact to the brain lipidome after Etnppl loss. We found that Etnppl expression dramatically increased during a critical window of early brain development in mice and was also induced by glucocorticoids. Using a constitutive knockout of Etnppl (EtnpplKO), we did not observe robust changes in expression of PEtN-related genes. However, loss of Etnppl altered the phospholipid profile in the brain, resulting in increased total abundance of PE and in polyunsaturated fatty acids within PE and phosphatidylcholine species in the brain. Together, these data suggest that brain phospholipids are regulated by the phospholyase action of the enzyme Etnppl, which is induced by dietary fasting in astrocytes.

Remodeling glycerophospholipids affects obesity-related insulin signaling in skeletal muscle.

It has long been known that fatty acids can either adversely or positively affect insulin signaling in skeletal muscle, depending on chain length or saturation, and can therefore be primary drivers of systemic insulin sensitivity. However, the detailed mechanisms linking fatty acids to insulin signaling in skeletal muscle have been elusive. In this issue of the JCI, Ferrara et al. suggest a model whereby membrane lipid remodeling mediates skeletal muscle insulin sensitivity. The authors demonstrate that membrane glycerophospholipid fatty acid remodeling by lysophosphatidylcholine acyltransferase 3 (LPCAT3) in skeletal muscle from subjects with obesity was induced, suppressing insulin signaling and glucose tolerance. Loss or gain of LPCAT3 function in mouse models showed that Lpcat3 was both required and sufficient for high-fat diet-induced muscle insulin resistance. These results suggest that the physiochemical properties of muscle cell membranes may drive insulin sensitivity and, therefore, systemic glucose intolerance.

The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism.

Mitochondrial carriers (MCs) mediate the passage of small molecules across the inner mitochondrial membrane (IMM), enabling regulated crosstalk between compartmentalized reactions. Despite MCs representing the largest family of solute carriers in mammals, most have not been subjected to a comprehensive investigation, limiting our understanding of their metabolic contributions. Here, we functionally characterize SFXN1, a member of the non-canonical, sideroflexin family. We find that SFXN1, an integral IMM protein with an uneven number of transmembrane domains, is a TIM22 complex substrate. SFXN1 deficiency leads to mitochondrial respiratory chain impairments, most detrimental to complex III (CIII) biogenesis, activity, and assembly, compromising coenzyme Q levels. The CIII dysfunction is independent of one-carbon metabolism, the known primary role for SFXN1 as a mitochondrial serine transporter. Instead, SFXN1 supports CIII function by participating in heme and α-ketoglutarate metabolism. Our findings highlight the multiple ways that SFXN1-based amino acid transport impacts mitochondrial and cellular metabolic efficiency.

Discordant hepatic fatty acid oxidation and triglyceride hydrolysis leads to liver disease.

To extract energy from stored lipids, fatty acids must first be liberated from triglyceride before their ß-oxidation in mitochondria in a coordinated and stepwise manner. To determine the independent and interdependent roles of hepatic triglyceride hydrolysis and fatty acid oxidation, mice were generated with a liver-specific defect in triglyceride hydrolysis (AtglL-/-), fatty acid oxidation (Cpt2L-/-), or both (double knockout). The loss of either gene resulted in the compensatory increase in the other, demonstrating their coordination. The loss of individual components of fatty acid catabolism (carnitine palmitoyl transferase 2 [Cpt2], adipose triglyceride lipase [Atgl], and Pparα) resulted in largely independent effects on hepatocyte morphology, intermediary metabolism, and gene expression in response to fasting. However, high-fat feeding revealed the interdependent role of Atgl and Cpt2, as the loss of only one of the genes resulted in steatosis (fatty liver) but the loss of both components resulted in significant steatohepatitis (inflammation and fibrosis). Lipolysis and ß-oxidation are intimately linked within a continuous pathway, and disruption of their coordination leads to unique cellular and molecular phenotypes that ultimately result in liver disease.

Reducing Fatty Acid Oxidation Improves Cancer-free Survival in a Mouse Model of Li-Fraumeni Syndrome.

Germline mutations of TP53, which cause the cancer predisposition disorder Li-Fraumeni syndrome (LFS), can increase mitochondrial activity as well as fatty acid ß-oxidation (FAO) in mice. Increased fatty acid metabolism can promote cancer malignancy, but its specific contribution to tumorigenesis in LFS remains unclear. To investigate this, we crossed LFS mice carrying the p53 R172H knock-in mutation (p53172H/H , homolog of the human TP53 R175H LFS mutation) with myoglobin-knockout (MB-/- ) mice known to have decreased FAO. MB-/- p53172H/H double-mutant mice also showed mildly reduced FAO in thymus, a common site of T lymphoma development in LFS mice, in association with an approximately 40% improvement in cancer-free survival time. RNA sequencing profiling revealed that the p53 R172H mutation promotes mitochondrial metabolism and ribosome biogenesis, both of which are suppressed by the disruption of MB. The activation of ribosomal protein S6, involved in protein translation and implicated in cancer promotion, was also inhibited in the absence of MB. To further confirm the role of FAO in lymphomagenesis, mitochondrial FAO enzyme, carnitine palmitoyltransferase 2 (CPT2), was specifically disrupted in T cells of p53172H/H mice using a Cre-loxP-mediated strategy. The heterozygous knockout of CPT2 resulted in thymus FAO haploinsufficiency and an approximately 30% improvement in survival time, paralleling the antiproliferative signaling observed with MB disruption. Thus, this study demonstrates that moderating FAO in LFS can suppress tumorigenesis and improve cancer-free survival with potential implications for cancer prevention. PREVENTION RELEVANCE: Mildly inhibiting the increased fatty acid oxidation observed in a mouse model of Li-Fraumeni syndrome, a cancer predisposition disorder caused by inherited mutations of TP53, dampens aberrant pro-tumorigenic cell signaling and improves the survival time of these mice, thereby revealing a potential strategy for cancer prevention in patients.

Regulation of maternal-fetal metabolic communication.

Pregnancy may be the most nutritionally sensitive stage in the life cycle, and improved metabolic health during gestation and early postnatal life can reduce the risk of chronic disease in adulthood. Successful pregnancy requires coordinated metabolic, hormonal, and immunological communication. In this review, maternal-fetal metabolic communication is defined as the bidirectional communication of nutritional status and metabolic demand by various modes including circulating metabolites, endocrine molecules, and other secreted factors. Emphasis is placed on metabolites as a means of maternal-fetal communication by synthesizing findings from studies in humans, non-human primates, domestic animals, rabbits, and rodents. In this review, fetal, placental, and maternal metabolic adaptations are discussed in turn. (1) Fetal macronutrient needs are summarized in terms of the physiological adaptations in place to ensure their proper allocation. (2) Placental metabolite transport and maternal physiological adaptations during gestation, including changes in energy budget, are also discussed. (3) Maternal nutrient limitation and metabolic disorders of pregnancy serve as case studies of the dynamic nature of maternal-fetal metabolic communication. The review concludes with a summary of recent research efforts to identify metabolites, endocrine molecules, and other secreted factors that mediate this communication, with particular emphasis on serum/plasma metabolomics in humans, non-human primates, and rodents. A better understanding of maternal-fetal metabolic communication in health and disease may reveal novel biomarkers and therapeutic targets for metabolic disorders of pregnancy.

Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor.

Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen.

Determining the Bioenergetic Capacity for Fatty Acid Oxidation in the Mammalian Nervous System.

The metabolic state of the brain can greatly impact neurologic function. Evidence of this includes the therapeutic benefit of a ketogenic diet in neurologic diseases, including epilepsy. However, brain lipid bioenergetics remain largely uncharacterized. The existence, capacity, and relevance of mitochondrial fatty acid ß-oxidation (FAO) in the brain are highly controversial, with few genetic tools available to evaluate the question. We have provided evidence for the capacity of brain FAO using a pan-brain-specific conditional knockout (KO) mouse incapable of FAO due to the loss of carnitine palmitoyltransferase 2, the product of an obligate gene for FAO (CPT2B-/-). Loss of central nervous system (CNS) FAO did not result in gross neuroanatomical changes or systemic differences in metabolism. Loss of CPT2 in the brain did not result in robustly impaired behavior. We demonstrate by unbiased and targeted metabolomics that the mammalian brain oxidizes a substantial quantity of long-chain fatty acids in vitro and in vivo Loss of CNS FAO results in robust accumulation of long-chain acylcarnitines in the brain, suggesting that the mammalian brain mobilizes fatty acids for their oxidation, irrespective of diet or metabolic state. Together, these data demonstrate that the mammalian brain oxidizes fatty acids under normal circumstances with little influence from or on peripheral tissues.

Deletion of translin (Tsn) induces robust adiposity and hepatic steatosis without impairing glucose tolerance.

OBJECTIVE: Translin knockout (KO) mice display robust adiposity. Recent studies indicate that translin and its partner protein, trax, regulate the microRNA and ATM kinase signaling pathways, both of which have been implicated in regulating metabolism. In the course of characterizing the metabolic profile of these mice, we found that they display normal glucose tolerance despite their elevated adiposity. Accordingly, we investigated why translin KO mice display this paradoxical phenotype. METHODS: To help distinguish between the metabolic effects of increased adiposity and those of translin deletion per se, we compared three groups: (1) wild-type (WT), (2) translin KO mice on a standard chow diet, and (3) adiposity-matched WT mice that were placed on a high-fat diet until they matched translin KO adiposity levels. All groups were scanned to determine their body composition and tested to evaluate their glucose and insulin tolerance. Plasma, hepatic, and adipose tissue samples were collected and used for histological and molecular analyses. RESULTS: Translin KO mice show normal glucose tolerance whereas adiposity-matched WT mice, placed on a high-fat diet, do not. In addition, translin KO mice display prominent hepatic steatosis that is more severe than that of adiposity-matched WT mice. Unlike adiposity-matched WT mice, translin KO mice display three key features that have been shown to reduce susceptibility to insulin resistance: increased accumulation of subcutaneous fat, increased levels of circulating adiponectin, and decreased Tnfα expression in hepatic and adipose tissue. CONCLUSIONS: The ability of translin KO mice to retain normal glucose tolerance in the face of marked adipose tissue expansion may be due to the three protective factors noted above. Further studies aimed at defining the molecular bases for this combination of protective phenotypes may yield new approaches to limit the adverse metabolic consequences of obesity.