About

Claudio Villanueva leads a research lab focused on understanding the molecular mechanisms that regulate adipocyte programming and biology. The lab investigates the complex processes involved in adipose tissue expansion, adipocyte differentiation, and the adipocyte life cycle, with an emphasis on how these processes impact systemic energy metabolism and metabolic diseases. The research aims to identify critical regulators of adipocyte differentiation using advanced techniques such as CRISPR-Cas9, which will help uncover factors that promote healthy or pathological expansion of adipose tissue. This work is crucial for developing interventions to treat metabolic diseases like type 2 diabetes and fatty liver disease. The lab also studies nutrient-sensing genes and their role in maintaining adipose tissue homeostasis, as well as how adipose tissue communicates with other organs such as the liver to regulate metabolism. Overall, Claudio Villanueva's research contributes to a deeper understanding of adipose tissue biology and its systemic effects on energy metabolism and metabolic health.

Research topics

• Biology
• Cell biology
• Endocrinology
• Chemistry
• Biochemistry
• Biophysics
• Internal medicine

Selected publications

• Very long-chain ceramides promote energy expenditure in brown adipose tissue

  Research Square · 2026-02-27

  preprintOpen access
  PublisherOA PDFDOI

• Fat cells burn energy to make heat – making them the next frontier of weight loss therapies

  2026-03-11

  article1st authorCorresponding
  PublisherDOI

• Mapping the Glycogen Synthase 1 Interactome in Brown Adipocytes

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-03

  articleSenior authorCorresponding

  ABSTRACT Brown adipose tissue (BAT) is distinguished by its ability to dissipate energy through thermogenesis, a process with considerable therapeutic potential for obesity, type 2 diabetes, and related metabolic disorders. Although glycogen represents a relatively minor energy reserve in adipocytes compared with liver and muscle, emerging evidence shows that glycogen turnover increases sharply during metabolic transitions and is required for full thermogenic activation in brown adipocytes. The rate-limiting enzyme glycogen synthase 1 (GYS1) catalyzes glycogen chain elongation, and adipose-specific Gys1 deletion impairs adaptive thermogenesis, highlighting the importance of GYS1 in coordinating glucose and lipid metabolism; however, the mechanisms regulating GYS1 in BAT remain poorly defined. To address this gap, we used an unbiased proximity-labeling strategy in brown adipocytes by fusing GYS1 to the biotin ligase TurboID and identifying biotinylated proteins through mass spectrometry, revealing 425 putative interactors. These included canonical glycogen-handling proteins such as glycogenin and glycogen phosphorylase, validating the approach, while gene ontology analysis uncovered broader enrichment in cytoskeletal remodeling, vesicle trafficking, and transcriptional regulation, suggesting previously unrecognized roles for GYS1 beyond glycogen synthesis. Notably, we identified several novel candidate interactors, including CAST, PDAP1, and CCDC102A. Together, these findings define the most comprehensive GYS1 interactome reported to date and provide new insights into the molecular mechanisms linking glycogen metabolism to thermogenic function in BAT.

  PublisherDOI

• Protocol to perform polysome profiling in primary differentiating murine adipocytes

  STAR Protocols · 2025-05-01 · 2 citations

  articleOpen accessSenior author

  .

  PublisherDOI

• PPARγ-dependent remodeling of translational machinery in adipose progenitors is impaired in obesity

  Cell Reports · 2024-11-22 · 18 citations

  articleOpen accessSenior author

  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 of inguinal and epididymal adipose tissue of obese mice following rosiglitazone treatment and find an induction of ribosomal factors in both progenitor and preadipocyte populations, while expression of ribosomal factors is reduced with obesity. Notably, the expression of a subset of ribosomal factors is directly regulated by PPARγ. Polysome profiling of the epididymal SVF shows that rosiglitazone promotes translational selectivity of mRNAs that encode pathways involved in adipogenesis and lipid metabolism. Inhibition of translation using a eukaryotic translation initiation factor 4A (eIF4A) inhibitor is sufficient in blocking adipogenesis. Our findings shed light on how PPARγ agonists promote adipose tissue plasticity in obesity.

  PublisherDOI

• 7623 Transcriptional control of biogenesis and maintenance of adipocytes

  Journal of the Endocrine Society · 2024-10-01

  articleOpen access

  Abstract 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 of functional adipocytes can cause lipid mishandling and altered adipokine production, leading to lipid accumulation in non-adipose organs (lipotoxicity) and insulin resistance. Proper adipocyte function is vital for metabolic health, as healthy adipocytes can mitigate the adverse effects of obesity; therefore, identifying factors involved in adipocyte formation and maintenance holds immense promise for combating the global epidemics of obesity and diabetes. Adipogenesis, a highly orchestrated program involving commitment and terminal differentiation phases, is driven by complex transcriptional events triggered by several transcription factors that drive the CEBPβ-PPARγ-CEBPα feed-forward circuitry. Through an unbiased high-throughput cDNA screen, we have identified the zinc finger protein PATZ1 as a novel transcription factor crucial for adipogenesis. In vitro studies have validated PATZ1's role in promoting both early and late differentiation phases of adipogenesis via its DNA binding ability. Genome-wide DNA binding analyses have uncovered PATZ1's interactions with the promoter regulatory regions of crucial adipogenic factors and histone modifiers, including CEBPβ, MED1, and p300, to maintain the CEBPβ-PPARγ and CEBPβ-PPARγ-CEBPα feed-forward circuitry for adipogenesis and maintenance of adipocytes, respectively. In vivo, analysis using three distinct mouse models has demonstrated that PATZ1 knockdown in adipocyte precursor cells leads to decreased fat mass and impaired expression of early adipogenesis factors, while PATZ1 knockdown in mature adipocytes results in reduced fat mass and a lipodystrophic-like phenotype. Intriguingly, the deletion of PATZ1 in brown adipose tissue precursors shows no significant differences compared to controls. Moreover, we have identified General Transcription Factor 2I (GTF2I) as a binding partner of PATZ1, which potentially forms a repressive complex that regulates PATZ1's adipogenic function. Notably, the knockdown of GTF2I enhances adipogenic programming, suggesting its role in limiting adipogenesis. These exciting findings position PATZ1 as a pivotal regulator of adipocyte differentiation and metabolic programs. By unveiling the intricate interplay between transcriptional programs and adipocyte-specific phenotypes, our study could inform future therapeutic interventions in adipose tissue to address obesity and its associated comorbidities. Presentation: 6/1/2024

  PublisherOA PDFDOI

• Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors

  Nature Communications · 2024-10-02 · 11 citations

  articleOpen access

  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 transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1’s function during differentiation. These findings underscore PATZ1’s regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development. Adipogenesis is important for white adipose tissue function. Here the authors identify the transcription factor PATZ1 as a regulator of adipogenesis and adipocyte maintenance, and report that adipose-tissue specific loss of PATZ1 leads to reduced fat mass and larger adipocytes in mice.

  PublisherOA PDFDOI

• Mitochondrial phosphatidylethanolamine modulates UCP1 to promote brown adipose thermogenesis

  Science Advances · 2023 · 62 citations

  • Biology
  • Cell biology
  • Biochemistry

  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 (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PE-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.

  PublisherOA PDFDOI

• Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis

  Nature Metabolism · 2023-01-16 · 60 citations

  articleOpen access
  PublisherOA PDFDOI

• Acute activation of adipocyte lipolysis reveals dynamic lipid remodeling of the hepatic lipidome

  Journal of Lipid Research · 2023-08-26 · 30 citations

  articleOpen accessSenior author

  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 adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte-secreted lipidome and show that there is interorgan crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome showed that free fatty acids increase within 30 min of β3-adrenergic receptor activation and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of adipose tissue triglyceride lipase exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together, these data highlight critical role of adipocyte lipolysis in interorgan crosstalk between adipocytes and liver.

  PublisherOA PDFDOI

Recent grants

• Role of TLE3 in the transcriptional regulation of beige adipocytes

  NIH · $1.7M · 2015–2021

• NIH Grant F31DK065312

  NIH · $87k · 2007

• NIH Grant R03DK103089

  NIH · $149k · 2016

• NIH Grant K01DK097285

  NIH · $480k · 2016

Frequent coauthors

• Jared Rutter

  University of Saskatchewan

  23 shared

• Peter Tontonoz

  23 shared

• Judith Simcox

  University of Wisconsin–Madison

  13 shared

• James E. Cox

  12 shared

• Vanja Panic

  University of Utah

  12 shared

• Kevin Wroblewski

  University of California, Los Angeles

  9 shared

• Lily C. Chao

  Children's Hospital of Los Angeles

  9 shared

• Hironori Waki

  The University of Tokyo

  9 shared

Labs

• Claudio Villanueva LabPI

Education

• Postdoctoral Fellow, Pathology

  University of California Los Angeles

  2012

• PhD/Biomedical Sciences, Gladstone Institute of Cardiovascular Research

  University of California San Francisco

  2007

• B.A./Biology, Biology

  California State University San Bernardino

  2001