Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data repository built on shared standards. This overdue initiative stands to markedly improve the accuracy and depth of efforts to interrogate mammalian metabolism. Data sharing according to established best practices will also accelerate the translation of basic findings into clinical applications for metabolic diseases afflicting global populations.

Mutations in the gene encoding Tectonic β-propeller repeat-containing repeat protein 2 (TECPR2) cause hereditary sensory and autonomic neuropathy subtype 9 (HSAN9) which is a fatal neurodevelopmental and neurodegenerative disorder involving the sensory and peripheral nervous system. TECPR2 is ubiquitously expressed and linked to trafficking and sorting within the cell, however, its functional role remains poorly defined. Moreover, molecular insights into pathogenic mechanisms underlying HSAN9 are lacking. Here, we report a novel mouse model which harbors a HSAN9-associated nonsense mutation that causes loss of TECPR2 expression. Mice show altered gait, highly region-specific axonal dystrophy, and extensive local gliosis. The affected medulla area prominently features swollen axons filled with amorphous protein aggregates, glycogen granules, single and double membrane vesicles as well as aberrant organelles including ER and mitochondria whose proteome is distinctly altered. Despite the locally restricted pathology the neuronal demise is detectable in the cerebrospinal fluid and responded to by damage-associated microglia. However, their capacity to clear neuronal debris seems attenuated. Overall, neuronal and microglia phenotypes point to a dysfunctional endolysosomal system when TECPR2 is missing. This was confirmed in TECPR2 knockout cells and linked to TECPR2's interaction with the homotypic fusion and protein sorting (HOPS)-tethering complex. Collectively, we uncovered a role of TECPR2 in endolysosome maintenance which seems relevant for healthy neurons in a particular brain region.

PURPOSE: This study investigates genes contributing to late-adult corneal dystrophies (LACDs) in aged mice, with potential implications for late-onset corneal dystrophies (CDs) in humans. METHODS: The International Mouse Phenotyping Consortium (IMPC) database, containing data from 8901 knockout mouse lines, was filtered to include late-adult mice (49+ weeks) with significant (P < 0.0001) CD phenotypes. Candidate genes were mapped to human orthologs using the Mouse Genome Informatics group, with expression analyzed via PLAE and a literature review for prior CD associations. Comparative analyses of LACD genes from IMPC and established human CD genes from IC3D included protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG). RESULTS: Analysis identified 14 genes linked to late-adult abnormal corneal phenotypes. Of these, 2 genes were previously associated with CDs in humans, while 12 were novel. Seven of the 14 genes (50%) were expressed in the human cornea based on single-cell transcriptomics. Protein-protein interactions via STRING showed several significant interactions with known human CD genes. PANTHER analysis identified six biological processes shared with established human CD genes. Two genes (Rgs2 and Galnt9) were involved in pathways related to human corneal diseases, including cGMP-PKG signaling, mucin-type O-glycan biosynthesis, and oxytocin signaling. Other candidates were implicated in pathways such as pluripotency of stem cells, MAPK signaling, WNT signaling, actin cytoskeleton regulation, and cellular senescence. CONCLUSIONS: This study identified 14 genes linked to LACD in knockout mice, 12 of which are novel in corneal biology. These genes may serve as potential therapeutic targets for treating corneal diseases in aging human populations.

Endurance exercise reduces the risk of metabolic diseases by improving skeletal muscle metabolism, particularly in individuals with overweight and obesity. As biological sex impacts glucose and fatty acid handling in skeletal muscle, we hypothesized sex differences at the transcriptomic and proteomic level in the acute response to exercise and after an 8-week exercise intervention. We analyzed skeletal muscle biopsies from 25 sedentary subjects (16f/9m) with overweight and obesity using transcriptomics and proteomics at baseline, after acute exercise, and following an 8-week endurance training program. Regulation of sex-specific differences was studied in primary myotubes from the donors. At baseline, differentially methylated CpG-sites potentially explain up to 59% of transcriptomic and 67% of proteomic sex differences. Differences were dominated by higher abundance of fast-twitch fiber type proteins, and transcripts and proteins regulating glycogen degradation and glycolysis in males. Females showed higher abundance of proteins regulating fatty acid uptake and storage. Acute exercise induced stress-responsive transcripts and serum myoglobin predominantly in males. Both sexes adapted to 8-week endurance training by upregulating mitochondrial proteins involved in TCA cycle, oxidative phosphorylation, and β-oxidation. Training equalized fast-twitch fiber type protein levels, mainly by reducing them in males. In vivo sex differences in autosomal genes were poorly retained in myotubes but partially restored by sex hormone treatment. In conclusion, our findings highlight sex-specific molecular signatures that reflect known differences in glucose and lipid metabolism between female and male skeletal muscle. After just 8 weeks of endurance training, these sex differences were attenuated, suggesting a convergence towards a shared beneficial adaptation at the molecular level.

The pig is a valuable animal model in diabetes research; however, standardized protocols are essential for evaluating in vivo metabolism. Here, we present a protocol for in vivo assessment of glucose control and insulin secretion and sensitivity in the pig. We describe steps for catheter implantation, testing of intravenous glucose tolerance, performance of hyperinsulinemic-euglycemic clamps (HECs) and hyperglycemic clamps (HGCs), and blood processing. We then detail procedures for analysis of plasma glucose, insulin, glucagon, and C-peptide concentrations as well as data analysis. For complete details on the use and execution of this protocol, please refer to Renner et al.1 and Renner et al.2.

ABCB5 is a member of the ATP-binding cassette transporter superfamily that is expressed as a full transporter (ABCB5FL) and half transporter (ABCB5β). The ABCB5FL transporter mediates low-level multidrug resistance in cancer and is normally expressed in the prostate and testis, while ABCB5β has been found to be a marker of melanoma and limbal stem cells and is expressed in pigmented cells. To explore ABCB5’s role in normal physiology, we generated Abcb5-deficient C57BL/6J mice by the deletion of Abcb5 exon 2, knocking out both forms of ABCB5, which were completely phenotyped. The mice were fertile and demonstrated altered bioenergetics and fat metabolism, along with alterations in their blood composition, including anisocytosis and decreased white blood cells and platelet counts. This study uncovers further avenues of investigation into the role of Abcb5 in intermediary metabolism, particularly in relation to atherogenesis.

PURPOSE: Analyze phenotypic data from knockout mice with late-adult retinal pathologic phenotypes to identify genes associated with development of adult-onset retinal diseases. METHODS: The International Mouse Phenotyping Consortium (IMPC) database was queried for genes associated with abnormal retinal phenotypes in the late-adult knockout mouse pipeline (49-80 weeks postnatal age). We identified human orthologs and performed protein-protein analysis and biological pathways analysis with known inherited retinal disease (IRD) and age-related macular degeneration (AMD) genes using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), PLatform for Analysis of single cell Eye in a Disk (PLAE), Protein Analysis Through Evolutionary Relationships (PANTHER), and Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: Screening of 587 late-adult mouse genes yielded 12 with abnormal retinal phenotypes, which corresponded to 20 human orthologs. Three of the 12 mouse genes and two of the 20 human orthologs were previously implicated in retinal pathology or physiology in a literature review. Although all of the genes demonstrated retinal pathology when deleted from the mouse genome, most do not have established roles in human retinal disease. Furthermore, human protein-protein analysis and biological pathway analysis yielded only a few relationships between the candidate gene list and that of known IRD and AMD genes, suggesting they may represent novel retinal functions. CONCLUSIONS: We identified 12 mouse genes with significant late-adult abnormal retinal pathology, eight of which have not been previously implicated in either mouse or human retinal physiology or pathology. These serve as novel retinal disease gene candidates for late-onset retinal disease.

INTRODUCTION: Maturity-onset Diabetes of the Young (MODY) is a rare form of diabetes and arises from mutations in key regulatory genes of the pancreatic beta cell, leading to their functional impairment and early-onset diabetes. Research into PDX1-MODY, a form of MODY caused by mutations in the PDX1 gene, enhances understanding of gene-specific mechanisms underlying glucose dysregulation and provides insights into possible approaches to restore normal metabolic function. However, no currently published mouse model accurately depicts the genetic cause of PDX1-MODY in human patients. METHODS: Using CRISPR-Cas9 technology, we generated the first mouse model carrying one of the most prevalent pathological PDX1 point mutation found in human patients, P33T, and conducted an 18-week in vivo phenotyping experiment assessing homozygous PDX1P33T and wild-type littermates on both chow and high fat diet (HFD). Additionally, transcriptomic and proteomic analyses were performed on isolated pancreatic islets. Islet architecture was investigated via fluorescent microscopy. RESULT: Contrary to expectations, our comprehensive phenotypic analysis of the mouse model carrying the homozygous PDX1P33T mutation revealed no significant differences in metabolic parameters compared to wild-type controls, and no pathological outcomes were observed as seen in human patients. Notably, male PDX1P33T mice exhibited an increase in islet size and number on chow diet, with omics analyses suggesting reprogramming toward stress resilience, but failed to adapt respectively on HFD. DISCUSSION: Our work indicates substantial differences between mouse and human PDX1 function in the pancreas. Further refinement of animal models is necessary to better elucidate the pathophysiology of PDX1-MODY.

BACKGROUND AND AIMS: Fasting hypoglycemia has clinical implications for children with growth hormone (GH)-insensitivity syndrome. This study investigates the pathophysiology of juvenile hypoglycemia in a large animal model for GH receptor (GHR) deficiency (the GHR-KO pig) and elucidates mechanisms underlying the transition to normoglycemia in adulthood. METHODS: Insulin sensitivity was assessed in juvenile and adult GHR-KO pigs and wild-type (WT) controls via hyperinsulinemic-euglycemic clamp (HEC) tests. Glucose turnover was measured using D-[6,6-2H2] glucose and 2H2O. Clinical chemical and targeted metabolomics parameters in blood serum were correlated with qPCR and western blot analyses of liver and adipose tissue. RESULTS: GHR-KO pigs showed increased insulin sensitivity (p=0.0019), especially at young age (M-value +34% vs. WT), insignificantly reduced insulin levels, and reduced endogenous glucose production (p=0.0007), leading to fasting hypoglycemia with depleted liver glycogen, elevated β-hydroxybutyrate, but no increase in NEFA levels. Low hormone-sensitive lipase phosphorylation in adipose tissue suggested impaired lipolysis in young GHR-KO pigs. Metabolomics indicated enhanced fatty acid beta-oxidation and use of glucogenic amino acids, likely serving as compensatory pathways to maintain energy homeostasis. In adulthood, insulin sensitivity remained elevated but less pronounced (M-value +20%), while insulin levels were significantly reduced, enabling normoglycemia and improved NEFA availability. Increased fat mass, not sex hormones, appeared key to this metabolic transition, as early castration had no effect. CONCLUSION: Juvenile hypoglycemia in GH insensitivity results from excessive insulin sensitivity, reduced glucose production, and impaired lipolysis. Normoglycemia in adulthood emerges through increased adiposity and moderated insulin sensitivity, independently of sex hormones. These findings elucidate the age-dependent metabolic adaptations in GH insensitivity.

In cancer cachexia, the presence of a tumor triggers systemic metabolic disruption that leads to involuntary body weight loss and accelerated mortality in affected patients. Here, we conducted transcriptomic and epigenomic profiling of the liver in various weight-stable cancer and cancer cachexia models. An integrative multilevel analysis approach identified a distinct gene expression signature that included hepatocyte-secreted factors and the circadian clock component REV-ERBα as key modulator of hepatic transcriptional reprogramming in cancer cachexia. Notably, hepatocyte-specific genetic reconstitution of REV-ERBα in cachexia ameliorated peripheral tissue wasting. This improvement was associated with decreased levels of specific cachexia-controlled hepatocyte-secreted factors. These hepatokines promoted catabolism in multiple cell types and were elevated in cachectic cancer patients. Our findings reveal a mechanism by which the liver contributes to peripheral tissue wasting in cancer cachexia, offering perspectives for future therapeutic interventions.

Pyridoxine-dependent epilepsy due to recessive ALDH7A1 mutations is characterized byintractable epilepsy that is often unresponsive to antiseizure medications. Irrespective ofpyridoxine (vitamin B6) supplementation and lysine reduction therapy, patients present severeresidual neurocognitive deficits. We evaluated upstream inhibition of 2-aminoadipicsemialdehyde synthase as a novel therapeutic strategy to reduce the accumulating metabolites (α-aminoadipic semialdehyde , Δ1-piperideine-6-carboxylate, pipecolic acid, 6-oxo-pipecolic acid,and 2S,6S-/2s,6R-oxopropylpiperidine-2-carboylic acid) considered neurotoxic.We utilized an existing mouse knockout model of hyperlysinemia (Aass-knockout) andgenerated a PDE model, a Aldh7a1 single knockout model via CRISPR/Cas (clustered regularlyinterspaced short palindromic repeats and CRISPR-associated protein) and generated the double-knockout Aass/Aldh7a1 mice. Next-Generation metabolomics screening was performed tomeasure all known biomarkers in brain, liver, and plasma of wildtype and mutant mice.Metabolomics confirmed the known metabolite markers for Aldh7a1-knockout and Aassknockout mice in all samples. The potentially neurotoxic metabolites (Δ1-piperideine-6-carboxylate, pipecolic acid, 6-oxo-pipecolic acid, and 2S,6S-/2s,6R-oxopropylpiperidine-2-carboylic acid) significantly decreased in double knock-out Aass/Aldh7a1 mice brain and livertissues compared to Aldh7a1-knockout mice. Plasma analysis revealed a significant reduction ofknown biomarkers, suggesting a reliable monitoring option in human patients.We demonstrate the first mammalian evidence that AASS inhibition is a viable strategy to rescueabnormal brain metabolism associated with pyridoxine-dependent epilepsy. This may target theintellectual disability and neurologic deficits caused by persistent lysine catabolic-relatedneurotoxicity despite adequate vitamin B6 supplementation.

Hutchinson–Gilford progeria syndrome (HGPS) is a rare, fatal, and premature aging disorder caused by progerin, a truncated form of lamin A that disrupts nuclear architecture, induces systemic inflammation, and accelerates senescence. While the farnesyltransferase inhibitor lonafarnib extends the lifespan by limiting progerin farnesylation, it does not address the chronic inflammation or the senescence-associated secretory phenotype (SASP), which worsens disease progression. In this study, we investigated the combined effects of baricitinib (BAR), a JAK1/2 inhibitor, and lonafarnib (FTI) in a LmnaG609G/G609G mouse model of HGPS. BAR + FTI therapy synergistically extended the lifespan by 25%, surpassing the effects of either monotherapy. Treated mice showed improved health, as evidenced by reduced kyphosis, better fur quality, decreased incidence of cataracts, and less severe dysgnathia. Histological analyses indicated reduced fibrosis in the dermal, hepatic, and muscular tissues, restored cellularity and thickness in the aortic media, and improved muscle fiber integrity. Mechanistically, BAR decreased the SASP and inflammatory markers (e.g., IL-6 and PAI-1), complementing the progerin-targeting effects of FTI. This preclinical study demonstrates the synergistic potential of BAR + FTI therapy in addressing HGPS systemic and tissue-specific pathologies, offering a promising strategy for enhancing both lifespan and health.

Metalloenzyme inhibitors often incorporate a hydroxamic acid moiety to bind the bivalent metal ion cofactor within the enzyme's active site. Recently, inhibitors of Zn2+-dependent histone deacetylases (HDACs), including clinically advanced drugs, have been identified as potent inhibitors of the metalloenzyme MBLAC2. However, selective chemical probes for MBLAC2, which are essential for studying its inhibitory effects, have not yet been reported. To discover highly selective MBLAC2 inhibitors, we conducted chemoproteomic target deconvolution and selectivity profiling of a library of hydroxamic acid-type molecules and other metal-chelating compounds. This screen revealed MBLAC2 as a frequent off-target of supposedly selective HDAC inhibitors, including the HDAC6 inhibitor SW-100. Profiling a focused library of SW-100-related phenylhydroxamic acids led to identifying two compounds, KV-65 and KV-79, which exhibit nanomolar binding affinity for MBLAC2 and over 60-fold selectivity compared to HDACs. Interestingly, some phenylhydroxamic acids were found to bind additional off-targets. We identified KV-30 as the first drug-like inhibitor of the histidine triad nucleotide-binding protein HINT1 and confirmed its mode of inhibition through a cocrystal structure analysis. Furthermore, we report the discovery of the first inhibitors for the undrugged nucleoside diphosphate kinases NME1, NME2, NME3, and NME4. Overall, this study maps the target and off-target landscape of 53 metalloenzyme inhibitors, providing the first selective MBLAC2 inhibitors. Additionally, the discovery of pharmacophores for NME1-4 and HINT1 establishes a foundation for the future design of potent and selective inhibitors for these targets.

WD40 and SOCS box protein-2 (WSB2), a member of the large family of suppressor of cytokine signaling (SOCS)-box proteins, has recently been identified as a substrate receptor of cullin 5 E3 ligase that plays an important role in proteomic regulation through substrate ubiquitination and proteasomal degradation. Here we report five patients from four unrelated families presenting with neurodevelopmental delay, dysmorphic features, brain structural abnormalities with or without growth restriction, hypotonia, and microcephaly, all of whom are homozygous for extremely rare and predicted loss-of-function (pLoF) or missense variants in WSB2, inherited from consanguineous parents. The Wsb2-mutant mice exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina. Our findings suggest that homozygous LoF WSB2 variants cause a novel neurodevelopmental disorder in humans with similar neurologic and developmental findings seen in Wsb2-mutant mouse models.

Reproductive biology is often considered in three siloed research areas; humans, agriculture and wildlife. Yet, each demand solutions for treatment of subfertility, fertility biomarkers, development of assisted reproductive technologies and effective contraception. To efficiently develop solutions applicable to all species, we must improve our understanding of the common biology underpinning reproductive processes. Accordingly, we integrate proteomic data from 29 publicly available datasets (>2 TB of data) to characterize mature sperm proteomes spanning 12 vertebrate species, identifying 13,853 proteins. Although human and mouse have relatively wellannotated sperm proteomes, many non-model species rely heavily on predicted or homologyinferred identifications. Despite variation in proteome size, composition and reproductive strategies, comparative analyses revealed that vertebrates share a fundamental molecular framework essential for sperm function. A core set of 45 species-level and 135 order-level conserved proteins mapped to critical processes, including energy generation, acrosome function, as well as novel signalling pathways (BAG2 and FAT10). Knockout mouse models further validate the significance of these conserved proteins, demonstrating that their disruption impairs sperm motility and fertilization capacity. Moreover, we discovered loss-of-function variants of two additional core sperm proteins in clinical samples, linking them to severe sperm defects. Intriguingly, in-silico analysis reveals function-driven, context-dependent diversity surpassing evolutionary patterns. Collectively, these results highlight the value of integrating publicly available datasets and underscore the need for improved genome/proteome annotation in nonmodel species in mammals. This work provides a foundation for developing cross-species strategies to enhance fertility treatments, assisted reproductive technologies, and conservation efforts.

Clinical practice guidelines recommend defined weight loss goals for the prevention of type 2 diabetes (T2D) in those individuals with increased risk, such as prediabetes. However, achieving prediabetes remission, that is, reaching normal glucose regulation according to American Diabetes Association criteria, is more efficient in preventing T2D than solely reaching weight loss goals. Here we present a post hoc analysis of the large, multicenter, randomized, controlled Prediabetes Lifestyle Intervention Study (PLIS), demonstrating that prediabetes remission is achievable without weight loss or even weight gain, and that it also protects against incident T2D. The underlying mechanisms include improved insulin sensitivity, β-cell function and increments in β-cell-GLP-1 sensitivity. Weight gain was similar in those achieving prediabetes remission (responders) compared with nonresponders; however, adipose tissue was differentially redistributed in responders and nonresponders when compared against each other-while nonresponders increased visceral adipose tissue mass, responders increased adipose tissue in subcutaneous depots. The findings were reproduced in the US Diabetes Prevention Program. These data uncover essential pathways for prediabetes remission without weight loss and emphasize the need to include glycemic targets in current clinical practice guidelines to improve T2D prevention.

Telomere length regulation is essential for genome stability as short telomeres can trigger cellular senescence and apoptosis constituting an integral aspect of biological aging. Telomere biology disorders (TBDs) such as dyskeratosis congenita (DC) are rare, inherited diseases with known mutations in at least 16 different genes encoding components of the telomere maintenance complexes. The precise role of TEN1, part of the CST complex (CTC1, STN1, and TEN1), and the consequences of its loss of function in vivo are not yet known. We investigated the first viable murine model of Ten1 deficiency created by CRISPR-Cas9-mediated exon 3 deletion. Ten1 homozygous knockout mice present with telomere attrition, short life span, skin hyperpigmentation, aplastic anemia, and cerebellar hypoplasia. Molecular analyses revealed a reduction of proliferating cells, increased apoptosis, and stem cell depletion with activation of the p53/p21 signaling pathway. Our data demonstrate that Ten1 deficiency causes telomere shortening and associates with accelerated aging.

Infrared ion spectroscopy (IRIS) is a tandem mass spectrometry (MS) technique that generates structurally diagnostic vibrational spectra for mass-selected ions trapped in a mass spectrometer. Until now, IRIS applications for biological samples have primarily focused on solution-based analyses, such as body fluids (e.g., plasma and urine) and tissue homogenates, using electrospray ionization (ESI) coupled with liquid chromatography-mass spectrometry (LC-MS). In this study, we have combined matrix-assisted laser desorption/ionization (MALDI) with IRIS for the direct analysis of small molecules from biological tissues on a Fourier-transform ion cyclotron resonance mass spectrometer. We applied this technique alongside MALDI mass spectrometry imaging to analyse brain tissue from two knockout mouse models of l-lysine catabolism disorders: pyridoxine-dependent epilepsy (ALDH7A1) and glutaric aciduria type 1 (GCDH). The MALDI-IRIS platform, now available for users at HFML-FELIX, represents a significant advance in the direct structural characterization of metabolites in complex biological tissues and opens new possibilities for structure elucidation in the field of MALDI mass spectrometry imaging.

Glutaric aciduria type I (GA1) is an inherited disorder caused by the enzymatic defect of glutaryl-CoA dehydrogenase in the lysine degradation pathway, characterized by the accumulation of toxic metabolites in the central nervous system. We reasoned that substrate reduction therapy targeting the alpha-Aminoadipic Semialdehyde Synthase (AASS), the first enzyme in the catabolism of lysine, could provide an attractive therapeutic alternative. We explored to reduce the expression of AASS by an artificial microRNA with AASS target sequences embedded in a miR-16 backbone (miR_AASS). We analyzed several delivery routes and AAV serotypes and evaluated the therapeutic efficacy of a systemic neonatal delivery of AAV9_miR_AASS in the Gcdh-/- mouse model of GA1. We detected dose-dependent miR-AASS expression and AASS inhibition in liver and striatum, the main tissues affected in GA1. Treatment with AAV9_miR_AASS in lysine overload challenged mice reduced the accumulation of neurotoxic metabolites, up to six months post-treatment in the striatum, prevented the neuropathological alterations and improved mouse survival. Our results show that AAV9_miR_AASS supports AASS-lowering as a potential gene therapy strategy for GA1.

Adipose tissue is a central organiser of systemic lipid homeostasis and a pharmacological target in obesity, orchestrating cellular responses to environmental cues. Nutritionally regulated adipose and cardiac enriched protein (NRAC) is a small adipocyte-specific transmembrane protein with unknown function. Here, we show that Nrac directly interacts with scavenger receptor CD36 via its first transmembrane domain. Forming a complex with CD36 and caveolin-1 under low extracellular fatty acid (FA) concentrations, NRAC modulates CD36-dependent fatty acid uptake in adipocytes. Upon increase in extracellular FA levels, NRAC is ubiquitinated and internalised, leading to CD36's dissociation from caveolin-1 and clathrin-mediated endocytosis. This results in increased fatty acid uptake into fat cells, adipocyte hypertrophy, increased fat mass and elevated lipid clearance from the blood in chow-diet-fed mice. Finally, human NRAC expression and the intronic SNP rs12878589 are associated with body fat distribution and obesity. Together, these findings reveal a novel regulatory mechanism by which adipocytes sense and respond to extracellular fatty acid availability to fine-tune lipid uptake and storage at cellular and organismal level.