Claudio Javier Villanueva

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Verified

Claudio verified their affiliation via an institutional email.

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• PhD @ UCSF Postdoc @UCLA
• Professor (Associate) at University of California, Los Angeles

Cold-induced thermogenesis is an energy-demanding process that protects endotherms against a reduction in ambient temperature. Using non-targeted liquid chromatography-mass spectrometry-based lipidomics, we identified elevated levels of plasma acylcarnitines in response to the cold. We found that the liver undergoes a metabolic switch to provide fu...

Adipose tissue regulates energy homeostasis and metabolic function, but its adaptability is impaired in obesity. In this study, we investigate the impact of acute PPARγ agonist treatment in obese mice and find significant transcriptional remodeling of cells in the stromal vascular fraction (SVF). Using single-cell RNA sequencing, we profile the SVF...

Disclosure: S. Patel: None. K. Ganbold: None. C. Cho: None. N. Sparman: None. S. Sadeh: None. R. Yildiz: None. C. Nyugen: None. J. Wang: None. J. Whitelegge: None. S.K. Fried: None. W. Hironori: None. C.J. Villanueva: None. M. Seldin: None. S. Sakaguchi: None. W. Ellmeier: None. P.J. Tontonoz: None. P. Rajbhandari: None. In caloric excess, the lack...

White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic...

Interplay between energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of specialized niche, adipocytes require the activity of the nuclear receptor PPARγ for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that a...

Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white...

Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (...

In cell models, changes in the ‘accessible’ pool of plasma membrane (PM) cholesterol are linked with the regulation of endoplasmic reticulum sterol synthesis and metabolism by the Aster family of nonvesicular transporters; however, the relevance of such nonvesicular transport mechanisms for lipid homeostasis in vivo has not been defined. Here we re...

Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of ATP synthase. Here we provide evidence that mitochondrial phosphatidylethanolamine (PE) directly...

White adipose tissues (WAT) play a central role in lipid storage and systemic energy, lipid, and glucose homeostasis. Understanding the intricacies of adipocyte formation could inform therapies for obesity and metabolic disorders. We have identified the POZ/BTB and AT Hook Containing Zinc Finger 1 (PATZ1) protein as an adipogenic transcription fact...

Adipose tissue, colloquially known as “fat,” is an extraordinarily flexible and heterogeneous organ. While historically viewed as a passive site for energy storage, we now appreciate that adipose tissue regulates many aspects of whole-body physiology, including food intake, maintenance of energy levels, insulin sensitivity, body temperature, and im...

In a new study, Zhang et al. (2021) show that reducing iron levels in adipose tissue improves metabolic function. This occurs through an interorgan communication system where signals from the adipocyte reduce intestinal lipid absorption.

Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to help maintain a constant body temperature and counteract metabolic disease in mammals. The metabolic adaptations required for thermogenesis are not fully understood. Here we explore how steady state levels of metabolic intermediates are altered in...

Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to maintain a constant body temperature and counteract metabolic disease. The metabolic adaptations required for thermogenesis are not fully understood. Here, we explore how steady state levels of metabolic intermediates are altered in brown adipose t...

Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to maintain a constant body temperature and counteract metabolic disease. The metabolic adaptations required for thermogenesis are not fully understood. Here, we explore how steady state levels of metabolic intermediates are altered in brown adipose t...

Oguri and colleagues use single-cell RNA sequencing to identify a beige adipocyte precursor cell that gives rise to thermogenic adipocytes in subcutaneous adipose tissue. These beige fat progenitors are marked by PDGFRα, Sca1, and CD81 and proliferate upon activation of FAK-signaling in response to the cold and irisin.

Although metabolic adaptations have been demonstrated to be essential for tumor cell proliferation, the metabolic underpinnings of tumor initiation are poorly understood. We found that the earliest stages of colorectal cancer (CRC) initiation are marked by a glycolytic metabolic signature, including downregulation of the mitochondrial pyruvate carr...

Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to help maintain a constant body temperature and counteract metabolic disease. Metabolite profiling of BAT showed increased pyruvate levels with cold exposure. Using U13C-glucose labeling experiments, we found that activated brown adipocytes increased...

The biophysical environment of membrane phospholipids affects structure, function, and stability of membrane-bound proteins.1,2 Obesity can disrupt membrane lipids, and in particular, alter the activity of sarco/endoplasmic reticulum (ER/SR) Ca2+-ATPase (SERCA) to affect cellular metabolism.3-5 Recent evidence suggests that transport efficiency (Ca...

T cells help keep you lean The gut microbiota is a critical factor regulating mammalian metabolism. The host immune system, in turn, can shape the microbiome, in part via immunoglobulin A (IgA) antibodies. Petersen et al. report that mice defective in T follicular helper cell development and gut IgA production show hallmarks of metabolic syndrome w...

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional...

Objective Activation of the Wnt-signaling pathway is known to inhibit differentiation in adipocytes. However, there is a gap in our understanding of the transcriptional network regulated by components of the Wnt-signaling pathway during adipogenesis and in adipocytes during postnatal life. The key intracellular effectors of the Wnt-signaling pathwa...

Identifying regulatory mechanisms that influence inflammation in metabolic tissues is critical for developing novel metabolic disease treatments. Here, we investigated the role of microRNA-146a (miR-146a) during diet-induced obesity in mice. miR-146a is reduced in obese and type 2 diabetic patients and our results reveal that miR-146a-/- mice fed a...

miR-146a and BAT weight and gene expression. (A-C) qRT-PCR expression data from BAT samples of young, untreated WT (blue) or miR-146a-/- (green) mice relative to L32 expression in (A) BAT activation genes, (B) Lipogenesis genes, and (C) inflammatory immune genes. (D) Weight (g) of BAT samples from WT or miR-146a-/- mice. (E) qRT-PCR expression of m...

miR-146a protects against high blood glucose levels during diet-induced obesity but does not alter pancreatic architecture. (A) WT and miR-146a-/- mice on NCD or HFD were injected with glucose at 0 minutes and blood glucose levels were measured over time for 120 minutes. (B) Blood glucose of 6-hour fasted WT and miR-146a-/- mice on NCD or HFD. (C)...

GSEA of RNA-seq data from miR-146a-/- and WT mouse ATMs on NCD or HFD. (A) Percentages of live, singlet CD45+ cells positive for CD11b and F4/80 markers, collected from the SVF of VAT in WT and miR-146a-/- mice fed NCD or HFD. (B) Total number of live, singlet, CD45+ cells positive for CD11b and F4/80 markers, collected from the SVF of VAT in WT an...

Underlying numeric data. (XLSX)

miR-146a is required to prevent weight gain and Leptin accumulation during HFD. (A) Each line shows average percent weight gain over time during an individual experimental repeat of young female WT (blue) and miR-146a-/- (red) mice on HFD. (B) Percent weight gain over time of WT and miR-146a-/- mice on NCD. (C) Body weight gain (in grams) over time...

Increased weight gain by miR-146a-/- mice during DIO is not dependent upon miR-155. (A) Percent weight gain over time of diet in WT, miR-155-/-, miR-146a-/-, and DKO mice on HFD. (B) Body weight (in grams) of WT, miR-155-/-, miR-146a-/-, and DKO mice over time of diet. (C) Blood glucose levels of WT, miR-155-/-, miR-146a-/-, and DKO mice following...

Materials table listing all materials used in this publication. (PDF)

Animals must adjust their metabolism as they progress through development in order to meet the needs of each stage in the life cycle. Here, we show that the dHNF4 nuclear receptor acts at the onset of Drosophila adulthood to direct an essential switch in lipid metabolism. Lipid stores are consumed shortly after metamorphosis but contribute little t...

Adipocyte differentiation is controlled by multiple signaling pathways. To identify new adipogenic factors, C3H10T1/2 adipocytes were treated with previously known antiadipogenic phytochemicals (resveratrol, butein, sulfuretin, and fisetin) for 24 hours. Commonly regulated genes were then identified by transcriptional profiling analysis. Three gene...

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue are not well understood. Here we demonstrate that the transcriptional coregulator TLE3...

Stimulation of white adipose tissue (WAT) browning is considered as a potential approach to treat obesity and metabolic diseases. Our previous studies have shown that phytochemical butein can stimulate WAT browning through induction of Prdm4 in adipocytes. Here, we investigated the effects of butein on diet-induced obesity and its underlying molecu...

The common genetic variation at rs8004664 in the FOXN3 gene is independently and significantly associated with fasting blood glucose, but not insulin, in non-diabetic humans. Recently, we reported that primary hepatocytes from rs8004664 hyperglycemia risk allele carriers have increased FOXN3 transcript and protein levels and liver-limited overexpre...

Calcium (Ca²⁺) influx into the mitochondrial matrix stimulates ATP synthesis. Here, we investigate whether mitochondrial Ca²⁺ transport pathways are altered in the setting of deficient mitochondrial energy synthesis, as increased matrix Ca²⁺ may provide a stimulatory boost. We focused on mitochondrial cardiomyopathies, which feature such dysfunctio...

Mitochondrial diseases often feature early onset of dilated cardiomyopathy, due to the large energetic demand placed by the heart. Among regulators of mitochondrial respiration, we focus on calcium, which potently stimulates ATP synthesis. We assessed the hypothesis that cells boost mitochondrial calcium to stimulate respiration as this declines in...

Adipose tissue is a central metabolic organ that controls energy homeostasis of the whole body. White adipose tissue (WAT) stores excess energy in the form of triglycerides, whereas brown adipose tissue (BAT) dissipates energy in the form of heat through mitochondrial uncoupling protein 1 (Ucp1). A newly identified adipose tissue called ‘beige fat’...

Cold induced thermogenesis is an energy demanding process that protects endotherms against a reduction in ambient temperature. Using non-targeted LC-MS based lipidomics, we identified plasma acylcarnitines as the most significantly changed lipid class in response to the cold. Here we show that acylcarnitines provide fuel for brown fat thermogenesis...

A highly orchestrated gene expression program establishes the properties that define mature adipocytes, but the contribution of posttranscriptional factors to the adipocyte phenotype is poorly understood. Here we have shown that the RNA-binding protein PSPC1, a component of the paraspeckle complex, promotes adipogenesis in vitro and is important fo...

Quantification of the Pax7+ and MyoG+ cell numbers and the fusion index in Wdr5S49E expressing cells.DOI: http://dx.doi.org/10.7554/eLife.17985.019

Numerical values from graphs represennted in Figure 1.DOI: http://dx.doi.org/10.7554/eLife.17985.003

Numerical data from qPCR analysis off WT vs Pask-/- satellite cells from the graph represented in Figure 2B and quantification of Pax7+ and MyoG+ cell numbers.DOI: http://dx.doi.org/10.7554/eLife.17985.009

Numerical values from the ChIP analysis represented in Figure 6.DOI: http://dx.doi.org/10.7554/eLife.17985.022

Numerical values from the ChIP analysis represented in Figure 7.DOI: http://dx.doi.org/10.7554/eLife.17985.024

Numerical values from qPCR analysis in Figure 3A and quantification of MyoD+ and MyoG+ cell numbers from Figure 3D.DOI: http://dx.doi.org/10.7554/eLife.17985.014

Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of the estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissue-specific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To...

Transcriptional effectors of white adipocyte-selective gene expression have not been described. Here we show that TLE3 is a white-selective cofactor that acts reciprocally with the brown-selective cofactor Prdm16 to specify lipid storage and thermogenic gene programs. Occupancy of TLE3 and Prdm16 on certain promoters is mutually exclusive, due to t...

Histone modifications and their modifying enzymes are fundamentally involved in the epigenetic regulation of adipogenesis. This study aimed to define the roles of various histone modifications and their "division of labor" in fat cell differentiation. To achieve these goals, we examined the distribution patterns of eight core histone modifications...

PPARγ and Wnt signaling are central positive and negative regulators of adipogenesis, respectively. Here we identify the groucho family member TLE3 as a transcriptional integrator of the PPARγ and Wnt pathways. TLE3 is a direct target of PPARγ that participates in a feed-forward loop during adipocyte differentiation. TLE3 enhances PPARγ activity an...

Macrophages are central components of the innate immune system that are critical for host defense. Found in almost all tissues, they exhibit wide heterogeneity and acquire a variety of functional phenotypes depending on the external milieu. For example, dendritic cells and macrophages present foreign antigens and coordinate inflammatory responses t...

Unlabelled: Nonalcoholic fatty liver disease, characterized by the accumulation of triacylglycerols (TGs) and other lipids in the liver, often accompanies obesity and is a risk factor for nonalcoholic steatohepatitis and fibrosis. To treat or prevent fatty liver, a thorough understanding of hepatic fatty acid and TG metabolism is crucial. To inves...

Members of the nuclear receptor 4A (NR4A) subgroup of nuclear receptors have been implicated in the regulation of glucose and lipid metabolism in insulin-sensitive tissues such as liver and skeletal muscle. However, their function in adipocytes is not well defined. Previous studies have reported that these receptors are rapidly up-regulated after t...

We previously identified the small molecule harmine as a regulator of peroxisome proliferator activated-receptor gamma (PPARgamma) and adipocyte differentiation. In an effort to identify signaling pathways mediating harmine's effects, we performed transcriptional profiling of 3T3-F442A preadipocytes. Inhibitor of DNA biding 2 (Id2) was identified a...

The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. Ho...

Mice lacking acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the terminal step in triacylglycerol synthesis, have enhanced insulin sensitivity and are protected from obesity, a result of increased energy expenditure. In these mice, factors derived from white adipose tissue (WAT) contribute to the systemic changes in meta...