Semi-Supervised Clustering-Based DANA Algorithm for Data Gathering and Disease Detection in Healthcare Wireless Sensor Networks (WSN).

Wireless sensor networks (WSNs) have emerged as a promising technology in healthcare, enabling continuous patient monitoring and early disease detection. This study introduces an innovative approach to WSN data collection tailored for disease detection through signal processing in healthcare scenarios. The proposed strategy leverages the DANA (data aggregation using neighborhood analysis) algorithm and a semi-supervised clustering-based model to enhance the precision and effectiveness of data collection in healthcare WSNs. The DANA algorithm optimizes energy consumption and prolongs sensor node lifetimes by dynamically adjusting communication routes based on the network's real-time conditions. Additionally, the semi-supervised clustering model utilizes both labeled and unlabeled data to create a more robust and adaptable clustering technique. Through extensive simulations and practical deployments, our experimental assessments demonstrate the remarkable efficacy of the proposed method and model. We conducted a comparative analysis of data collection efficiency, energy utilization, and disease detection accuracy against conventional techniques, revealing significant improvements in data quality, energy efficiency, and rapid disease diagnosis. This combined approach of the DANA algorithm and the semi-supervised clustering-based model offers healthcare WSNs a compelling solution to enhance responsiveness and reliability in disease diagnosis through signal processing. This research contributes to the advancement of healthcare monitoring systems by offering a promising avenue for early diagnosis and improved patient care, ultimately transforming the landscape of healthcare through enhanced signal processing capabilities.

Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin.

BACKGROUND: Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy. METHODS: Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment. RESULTS: Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation. CONCLUSIONS: We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations. CLINICAL TRIAL REGISTRATION: NCT01266486.

Quantifying and Localizing the Mitochondrial Proteome Across Five Tissues in A Mouse Population.

We have used SWATH mass spectrometry to quantify 3648 proteins across 76 proteomes collected from genetically diverse BXD mouse strains in two fractions (mitochondria and total cell) from five tissues: liver, quadriceps, heart, brain, and brown adipose (BAT). Across tissues, expression covariation between genes' proteins and transcripts-measured in the same individuals-broadly aligned. Covariation was however far stronger in certain subsets than others: only 8% of transcripts in the lowest expression and variance quintile covaried with their protein, in contrast to 65% of transcripts in the highest quintiles. Key functional differences among the 3648 genes were also observed across tissues, with electron transport chain (ETC) genes particularly investigated. ETC complex proteins covary and form strong gene networks according to tissue, but their equivalent transcripts do not. Certain physiological consequences, such as the depletion of ATP synthase in BAT, are thus obscured in transcript data. Lastly, we compared the quantitative proteomic measurements between the total cell and mitochondrial fractions for the five tissues. The resulting enrichment score highlighted several hundred proteins which were strongly enriched in mitochondria, which included several dozen proteins were not reported in literature to be mitochondrially localized. Four of these candidates were selected for biochemical validation, where we found MTAP, SOAT2, and IMPDH2 to be localized inside the mitochondria, whereas ABCC6 was in the mitochondria-associated membrane. These findings demonstrate the synergies of a multi-omics approach to study complex metabolic processes, and this provides a resource for further discovery and analysis of proteoforms, modified proteins, and protein localization.

Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease.

BACKGROUND & AIMS: To date, no pharmacological therapy has been approved for non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the therapeutic potential of poly ADP-ribose polymerase (PARP) inhibitors in mouse models of NAFLD. METHODS: As poly ADP-ribosylation (PARylation) of proteins by PARPs consumes nicotinamide adenine dinucleotide (NAD+), we hypothesized that overactivation of PARPs drives NAD+ depletion in NAFLD. Therefore, we assessed the effectiveness of PARP inhibition to replenish NAD+ and activate NAD+-dependent sirtuins, hence improving hepatic fatty acid oxidation. To do this, we examined the preventive and therapeutic benefits of the PARP inhibitor (PARPi), olaparib, in different models of NAFLD. RESULTS: The induction of NAFLD in C57BL/6J mice using a high-fat high-sucrose (HFHS)-diet increased PARylation of proteins by PARPs. As such, increased PARylation was associated with reduced NAD+ levels and mitochondrial function and content, which was concurrent with elevated hepatic lipid content. HFHS diet supplemented with PARPi reversed NAFLD through repletion of NAD+, increasing mitochondrial biogenesis and ß-oxidation in liver. Furthermore, PARPi reduced reactive oxygen species, endoplasmic reticulum stress and fibrosis. The benefits of PARPi treatment were confirmed in mice fed with a methionine- and choline-deficient diet and in mice with lipopolysaccharide-induced hepatitis; PARP activation was attenuated and the development of hepatic injury was delayed in both models. Using Sirt1hep-/- mice, the beneficial effects of a PARPi-supplemented HFHS diet were found to be Sirt1-dependent. CONCLUSIONS: Our study provides a novel and practical pharmacological approach for treating NAFLD, fueling optimism for potential clinical studies. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the Western world and has no approved pharmacological therapy. PARP inhibitors given as a treatment in two different mouse models of NAFLD confer a protection against its development. PARP inhibitors may therefore represent a novel and practical pharmacological approach for treating NAFLD.

Role of adipose tissue in methionine-choline-deficient model of non-alcoholic steatohepatitis (NASH).

UNLABELLED: Methionine-choline-deficient (MCD) diet is a widely used dietary model of non-alcoholic steatohepatitis (NASH) in rodents. However, the contribution of adipose tissue to MCD-induced steatosis, and inflammation as features of NASH are not fully understood. The goal of this study was to elucidate the role of adipose tissue fatty acid (FA) metabolism, adipogenesis, lipolysis, inflammation and subsequent changes in FA profiles in serum and liver in the pathogenesis of steatohepatitis. We therefore fed ob/ob mice with control or MCD diet for 5 weeks. MCD-feeding increased adipose triglyceride lipase and hormone sensitive lipase activities in all adipose depots which may be attributed to increased systemic FGF21 levels. The highest lipase enzyme activity was exhibited by visceral WAT. Non-esterified fatty acid (NEFA)-18:2n6 was the predominantly elevated FA species in serum and liver of MCD-fed ob/ob mice, while overall serum total fatty acid (TFA) composition was reduced. In contrast, an overall increase of all FA species from TFA pool was found in liver, reflecting the combined effects of increased FA flux to liver, decreased FA oxidation and decrease in lipase activity in liver. NAFLD activity score was increased in liver, while WAT showed no changes and BAT showed even reduced inflammation. CONCLUSION: This study demonstrates a key role for adipose tissue lipases in the pathogenesis of NASH and provides a comprehensive lipidomic profiling of NEFA and TFA homeostasis in serum and liver. Our findings provide novel mechanistic insights for the role of WAT in progression of MCD-induced liver injury.

Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity.

BACKGROUND & AIMS: Bile acids (BAs) are major regulators of hepatic BA and lipid metabolism but their mechanisms of action in non-alcoholic fatty liver disease (NAFLD) are still poorly understood. Here we aimed to explore the molecular and biochemical mechanisms of ursodeoxycholic acid (UDCA) in modulating the cross-talk between liver and visceral white adipose tissue (vWAT) regarding BA and cholesterol metabolism and fatty acid/lipid partitioning in morbidly obese NAFLD patients. METHODS: In this randomized controlled pharmacodynamic study, we analyzed serum, liver and vWAT samples from 40 well-matched morbidly obese patients receiving UDCA (20 mg/kg/day) or no treatment three weeks prior to bariatric surgery. RESULTS: Short term UDCA administration stimulated BA synthesis by reducing circulating fibroblast growth factor 19 and farnesoid X receptor (FXR) activation, resulting in cholesterol 7α-hydroxylase induction mirrored by elevated C4 and 7α-hydroxycholesterol. Enhanced BA formation depleted hepatic and LDL-cholesterol with subsequent activation of the key enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl-CoA reductase. Blunted FXR anti-lipogenic effects induced lipogenic stearoyl-CoA desaturase (SCD) in the liver, thereby increasing hepatic triglyceride content. In addition, induced SCD activity in vWAT shifted vWAT lipid metabolism towards generation of less toxic and more lipogenic monounsaturated fatty acids such as oleic acid. CONCLUSION: These data demonstrate that by exerting FXR-antagonistic effects, UDCA treatment in NAFLD patients strongly impacts on cholesterol and BA synthesis and induces neutral lipid accumulation in both liver and vWAT.

Role of adipose triglyceride lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia.

UNLABELLED: Hepatic inflammation is a key feature of progressive liver disease. Alterations of fatty acid (FA) metabolism and signaling may play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). Moreover, FAs activate peroxisome proliferator-activated receptor α (PPARα) as a key transcriptional regulator of hepatic FA metabolism and inflammation. Since adipose triglyceride lipase (ATGL/PNPLA2) is the key enzyme for intracellular hydrolysis of stored triglycerides and determines FA signaling through PPARα, we explored the role of ATGL in hepatic inflammation in mouse models of NASH and endotoxemia. Mice lacking ATGL or hormone-sensitive lipase (HSL) were challenged with a methionine-choline-deficient (MCD) diet as a nutritional model of NASH or lipopolysaccharide (LPS) as a model of acute hepatic inflammation. We further tested whether a PPARα agonist (fenofibrate) treatment improves the hepatic phenotype in MCD- or LPS-challenged ATGL-knockout (KO) mice. MCD-fed ATGL-KO mice, although partially protected from peripheral lipolysis, showed exacerbated hepatic steatosis and inflammation. Moreover, ATGL-KO mice challenged by LPS showed enhanced hepatic inflammation, increased mortality, and torpor, findings which were attributed to impaired PPARα DNA binding activity due to reduced FABP1 protein levels, resulting in impaired nuclear FA import. Notably, liganding PPARα through fenofibrate attenuated hepatic inflammation in both MCD-fed and LPS-treated ATGL-KO mice. In contrast, mice lacking HSL had a phenotype similar to the WT mice on MCD and LPS challenge. CONCLUSION: These findings unravel a novel protective role of ATGL against hepatic inflammation which could have important implications for metabolic and inflammatory liver diseases.

Development of gluten free biscuits utilizing fruits and starchy vegetable powders.

Gluten free biscuits, also suitable during fasting were developed utilizing different levels of fruits (water chestnut and makhana) and starchy vegetable (potato) powders. Biscuits were developed using creamery method and evaluated for physical properties, proximate composition, sensory characteristics and storability for 90 days at room temperature. Expansion in diameter of biscuits with different level of potato and makhana powder varied between 1.026 to 1.059 and 1.046 to 1.059, respectively as compared to 1.075 for biscuits prepared using water chestnut only. Breaking hardness and toughness of different biscuit was increased with increasing level of potato or makhana powder in flour blends and higher in potato powder incorporated biscuits. Whiteness (L values) of biscuits was decreased with increasing level of potato powder while a reverse trend was observed in case of makhana powder incorporated biscuits. Protein content in biscuits with makhana powder was higher than the biscuits prepared using potato powder in flour blends. Biscuits prepared using hundred percent water chestnut showed the maximum crude fibre content in them. Results indicated that gluten free biscuits for fasting people can be prepared using potato powder or makhana powder up to 50 % with water chestnut powder. The overall sensory acceptability of biscuits with makhana powder was better than for biscuits with potato powder with maximum overall acceptability scores for biscuits developed using 70:30 parts of water chestnut and makhana powders in flour blend, which were storable for 90 days period at room temperature.

The PPARα agonist fenofibrate suppresses B-cell lymphoma in mice by modulating lipid metabolism.

Obesity is associated with an increased risk for malignant lymphoma development. We used Bcr/Abl transformed B cells to determine the impact of aggressive lymphoma formation on systemic lipid mobilization and turnover. In wild-type mice, tumor size significantly correlated with depletion of white adipose tissues (WAT), resulting in increased serum free fatty acid (FFA) concentrations which promote B-cell proliferation in vitro. Moreover, B-cell tumor development induced hepatic lipid accumulation due to enhanced hepatic fatty acid (FA) uptake and impaired FA oxidation. Serum triglyceride, FFA, phospholipid and cholesterol levels were significantly elevated. Consistently, serum VLDL/LDL-cholesterol and apolipoprotein B levels were drastically increased. These findings suggest that B-cell tumors trigger systemic lipid mobilization from WAT to the liver and increase VLDL/LDL release from the liver to promote tumor growth. Further support for this concept stems from experiments where we used the peroxisome proliferator-activated receptor α (PPARα) agonist and lipid-lowering drug fenofibrate that significantly suppressed tumor growth independent of angiogenesis and inflammation. In addition to WAT depletion, fenofibrate further stimulated FFA uptake by the liver and restored hepatic FA oxidation capacity, thereby accelerating the clearance of lipids released from WAT. Furthermore, fenofibrate blocked hepatic lipid release induced by the tumors. In contrast, lipid utilization in the tumor tissue itself was not increased by fenofibrate which correlates with extremely low expression levels of PPARα in B-cells. Our data show that fenofibrate associated effects on hepatic lipid metabolism and deprivation of serum lipids are capable to suppress B-cell lymphoma growth which may direct novel treatment strategies. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.

CARDPSoML: Comparative approach to analyze and predict cardiovascular disease based on medical report data and feature fusion approach.

Background and Aims: Diabetes patients are at high risk for cardiovascular disease (CVD), which makes early identification and prompt management essential. To diagnose CVD in diabetic patients, this work attempts to provide a feature-fusion strategy employing supervised learning classifiers. Methods: Preprocessing patient data is part of the method, and it includes important characteristics connected to diabetes including insulin resistance and blood glucose levels. Principal component analysis and wavelet transformations are two examples of feature extraction techniques that are used to extract pertinent characteristics. The supervised learning classifiers, such as neural networks, decision trees, and support vector machines, are then trained and assessed using these characteristics. Results: Based on the area under the receiver operating characteristic curve, sensitivity, specificity, and accuracy, these classifiers' performance is closely evaluated. The assessment findings show that the classifiers have a good accuracy and area under the receiver operating characteristic curve value, suggesting that the suggested strategy may be useful in diagnosing CVD in patients with diabetes. Conclusion: The recommended method shows potential as a useful tool for developing clinical decision support systems and for the early detection of CVD in diabetes patients. To further improve diagnostic skills, future research projects may examine the use of bigger and more varied datasets as well as different machine learning approaches. Using an organized strategy is a crucial first step in tackling the serious problem of CVD in people with diabetes.

Pineal Parenchymal Tumors With Intermediate Differentiation to Pineoblastoma: A Transitional Neuroectodermal Tumor of the Pineal Gland.

Pineal tumors are quite rare and are fairly aggressive tumors seen in young adults and children. These tumors arise from the pineal region or recess from various types of cells in the gland and structures located in close propinquity to the gland. Pineal gland tumors have a heterogeneous spectrum that includes pineal parenchymal tumors (PPTs) and papillary tumors of the pineal region (PTPR). The PPTs are further subclassified into pineocytomas (Grade 1), PPTs of intermediate differentiation (grade 2 or 3), and pineoblastomas (grade 4) based on the World Health Organization (WHO) grades and histopathological features. We discuss the case of an 11-year-old male child who presented with complaints of headache for 15 days, vomiting for seven days, and diplopia for four days. On magnetic resonance imaging (MRI), a soft tissue density lesion was noticed in the posterior third ventricle region. Based on the location and the MRI findings, the differential diagnosis considered were a pineal lesion, a choroid plexus papilloma, or a meningioma. He underwent a right occipital ventriculoperitoneal shunt followed by total excision of the tumor, and the resected specimen was sent for histopathological examination. After pathologic examination, the diagnosis of pineoblastoma (grade 4) with features of a PPT of intermediate differentiation (grades 2-3) was revealed, and the same was confirmed on immunohistochemistry.

The mouse metallomic landscape of aging and metabolism.

Organic elements make up 99% of an organism but without the remaining inorganic bioessential elements, termed the metallome, no life could be possible. The metallome is involved in all aspects of life, including charge balance and electrolytic activity, structure and conformation, signaling, acid-base buffering, electron and chemical group transfer, redox catalysis energy storage and biomineralization. Here, we report the evolution with age of the metallome and copper and zinc isotope compositions in five mouse organs. The aging metallome shows a conserved and reproducible fingerprint. By analyzing the metallome in tandem with the phenome, metabolome and proteome, we show networks of interactions that are organ-specific, age-dependent, isotopically-typified and that are associated with a wealth of clinical and molecular traits. We report that the copper isotope composition in liver is age-dependent, extending the existence of aging isotopic clocks beyond bulk organic elements. Furthermore, iron concentration and copper isotope composition relate to predictors of metabolic health, such as body fat percentage and maximum running capacity at the physiological level, and adipogenesis and OXPHOS at the biochemical level. Our results shed light on the metallome as an overlooked omic layer and open perspectives for potentially modulating cellular processes using careful and selective metallome manipulation.

COX7A2L genetic variants determine cardiorespiratory fitness in mice and human.

Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3' untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality.

Gene-by-environment modulation of lifespan and weight gain in the murine BXD family.

How lifespan and body weight vary as a function of diet and genetic differences is not well understood. Here we quantify the impact of differences in diet on lifespan in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow diet (CD, n = 663) or a high-fat diet (HFD, n = 685). We further generate key metabolic data in a parallel cohort euthanized at four time points. HFD feeding shortens lifespan by 12%: equivalent to a decade in humans. Initial body weight and early weight gains account for longevity differences of roughly 4-6 days per gram. At 500 days, animals on a HFD typically gain four times as much weight as control, but variation in weight gain does not correlate with lifespan. Classic serum metabolites, often regarded as health biomarkers, are not necessarily strong predictors of longevity. Our data indicate that responses to a HFD are substantially modulated by gene-by-environment interactions, highlighting the importance of genetic variation in making accurate individualized dietary recommendations.

Bilateral ovarian edema with unilateral ovarian leiomyoma and double inferior vena cava: a case report.

BACKGROUND: Ovarian edema, ovarian leiomyoma, and double inferior vena cava are all rare clinical entities. The coexistence of all these entities has not been yet reported in the literature. CASE PRESENTATION: We report a case of a 25-year-old nulliparous tamang woman with all these rare clinical entities, who presented with a complaint of right-sided lower abdominal pain. After examination and investigation, an ovarian tumor was suspected and laparotomy was performed during which bilateral ovarian edema with a solid tumor on the left side was identified and left salpingo-oophorectomy was done preserving her right ovary. A histopathological examination confirmed the clinical findings. CONCLUSIONS: As ovarian edema is a rare entity, due to lack of clinical suspicion it is often overdiagnosed as a malignant tumor leading to radical surgery with subsequent loss of hormonal function and early infertility. A high degree of clinical suspicion during the intraoperative period is helpful for diagnosis to avoid unnecessary oophorectomy and infertility.

The Gene-Regulatory Footprint of Aging Highlights Conserved Central Regulators.

Many genes and pathways have been linked to aging, yet our understanding of underlying molecular mechanisms is still lacking. Here, we measure changes in the transcriptome, histone modifications, and DNA methylome in three metabolic tissues of adult and aged mice. Transcriptome and methylome changes dominate the liver aging footprint, whereas heart and muscle globally increase chromatin accessibility, especially in aging pathways. In mouse and human data from multiple tissues and regulatory layers, age-related transcription factor expression changes and binding site enrichment converge on putative aging modulators, including ZIC1, CXXC1, HMGA1, MECP2, SREBF1, SREBF2, ETS2, ZBTB7A, and ZNF518B. Using Mendelian randomization, we establish possible epidemiological links between expression of some of these transcription factors or their targets, including CXXC1, ZNF518B, and BBC3, and longevity. We conclude that conserved modulators are at the core of the molecular footprint of aging, and variation in tissue-specific expression of some may affect human longevity.

Genetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes.

The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for ∼94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies. Lipid species from different classes provided signatures of metabolic health, including seven plasma triglyceride species that associated with either healthy or fatty liver. This observation was further validated in an independent mouse model of non-alcoholic fatty liver disease (NAFLD) and in plasma from NAFLD patients. This work provides a resource to identify plausible genes regulating the measured lipid species and their association with metabolic traits.

Systems Analyses Reveal Physiological Roles and Genetic Regulators of Liver Lipid Species.

The genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 strains of the BXD mouse population fed chow or high-fat diet and integrated these data with complementary multi-omics datasets. We identified several lipid species and lipid clusters with specific phenotypic and molecular signatures and, in particular, cardiolipin species with signatures of healthy and fatty liver. Genetic analyses revealed quantitative trait loci for 68% of the lipids (lQTL). By multi-layered omics analyses, we show the reliability of lQTLs to uncover candidate genes that can regulate the levels of lipid species. Additionally, we identified lQTLs that mapped to genes associated with abnormal lipid metabolism in human GWASs. This work provides a foundation and resource for understanding the genetic regulation and physiological significance of lipid species.

ERRγ Preserves Brown Fat Innate Thermogenic Activity.

Brown adipose tissue (BAT) adaptively transfers energy from glucose and fat into heat by inducing a gene network that uncouples mitochondrial electron transport. However, the innate transcription factors that enable the rapid adaptive response of BAT are unclear. Here, we identify estrogen-related receptor gamma (ERRγ) as a critical factor for maintaining BAT identity. ERRγ is selectively expressed in BAT versus WAT, in which, in the absence of PGC1α, it drives a signature transcriptional network of thermogenic and oxidative genes in the basal (i.e., thermoneutral) state. Mice lacking ERRγ in adipose tissue (ERRγKO mice) display marked downregulation of BAT-selective genes that leads to a pronounced whitening of BAT. Consistent with the transcriptional changes, the thermogenic capacity of ERRγKO mice is severely blunted, such that they fail to survive an acute cold challenge. These findings reveal a role for ERRγ as a critical thermoneutral maintenance factor required to prime BAT for thermogenesis.