About

Judith Simcox is a researcher whose work focuses on the intersection of iron metabolism, adipocyte function, and glucose homeostasis, with significant implications for diabetes and obesity. Her research has explored how dietary iron restriction or iron chelation can protect against diabetes and beta-cell dysfunction in obese mouse models. She has contributed to understanding the role of adipocyte iron in regulating adiponectin, insulin sensitivity, leptin, and food intake, highlighting the importance of iron in metabolic regulation. Simcox's studies also investigate the molecular mechanisms by which iron influences glucose metabolism in liver and muscle, including the involvement of AMP-activated protein kinase and circadian hepatic glucose metabolism through heme synthesis. Her work extends to the study of mitochondrial function in adipocytes and brown fat thermogenesis, as well as the metabolic adaptations related to aging adipose tissue and mitochondrial lipid signaling. Through these contributions, Simcox has advanced knowledge of the metabolic pathways linking iron homeostasis, adipose tissue biology, and systemic energy balance.

Research topics

• Biology
• Endocrinology
• Physiology
• Biochemistry
• Medicine
• Internal medicine
• Cell biology
• Chemistry
• Genetics

Selected publications

• MassIVE MSV000100379 - diversity outbred mice untargeted lipidomics

  2026-01-01

  datasetOpen access1st authorCorresponding
  OA PDFDOI

• MassIVE MSV000100378 - Ceramide regulation of energy expenditure is dependent on acyl chain length and mechanism of cellular delivery

  2026-01-01

  datasetOpen access1st authorCorresponding
  OA PDFDOI

• Stearoyl-CoA desaturase 1 deficiency drives saturated lipid accumulation and increases liver and plasma acylcarnitines

  Journal of Lipid Research · 2025-05-09 · 6 citations

  articleOpen access

  Stearoyl-CoA desaturase-1 (SCD1) is a critical regulator of lipogenesis that catalyzes the synthesis of MUFAs, mainly oleate (18:1n-9) and palmitoleate (16:1n-7) from saturated fatty acids, stearoyl-CoA (18:0) and palmitoyl-CoA (16:0), respectively. Elevated SCD1 expression and its products are associated with obesity, metabolic dysfunction-associated steatotic liver disease, insulin resistance, and cancer. Conversely, Scd1 deficiency diminishes de novo lipogenesis and protects mice against adiposity, hepatic steatosis, and hyperglycemia. Yet, the comprehensive impact of Scd1 deficiency on hepatic and circulating lipids remains incompletely understood. To further delineate the effects of SCD1 on lipid metabolism, we employed lipidomics on the liver from mice under a lipogenic high carbohydrate, very low-fat diet. We found that Scd1 deficiency leads to an accumulation of saturated lipids and an increase in hepatic and plasma acylcarnitines. Remarkably, transgenic replenishment of de novo oleate synthesis by human SCD5 in the liver of Scd1-deficient mice not only restored hepatic lipid desaturation levels but also attenuated acylcarnitine accumulation, highlighting the distinct role of SCD1 and oleate in regulating intracellular lipid homeostasis.

  PublisherOA PDFDOI

• Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice

  Molecular Metabolism · 2025-09-10 · 3 citations

  articleOpen access

  The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, there are some reports that dietary supplementation with extra BCAAs has health benefits. Further, the interactions between sex, genetic background, and dietary isoleucine levels in response to a Western Diet (WD) remain incompletely understood. Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans, plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, an analysis of human NHANES data shows that isoleucine content varies widely across foods, and that individuals with higher Healthy Eating Index scores tend to consume lower amounts of isoleucine. Our results suggest that the dietary level of isoleucine is a potential mediator of the metabolic and molecular response to a WD, and imply that reducing dietary isoleucine may represent a theoretically translatable strategy to protect from the negative metabolic consequences of a WD.

  PublisherDOI

• Abstract 1508 ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism

  Journal of Biological Chemistry · 2025-05-01

  articleOpen access

  Background/Study Objective: Fatty acid β-oxidation (FAO) is a central catabolic pathway with broad implications for organismal health. However, various fatty acids are largely incompatible with FAO machinery before being modified by other enzymes. Such lipids include 4-hydroxy acids (4-HAs)-fatty acids hydroxylated at the 4 (γ) position-which can be provided from dietary intake, lipid peroxidation, and certain drugs of abuse. While the core enzymes of FAO were discovered several decades ago, the enzymes responsible for 4-HA catabolism in mammals remain unknown.

  PublisherOA PDFDOI

• Dietary lipids are largely deposited in skin and rapidly affect insulating properties

  Nature Communications · 2025-05-16 · 6 citations

  articleOpen access

  Skin is a regulatory hub for energy expenditure and metabolism, and alteration of lipid metabolism enzymes in skin impacts thermogenesis and obesogenesis in mice. Here we show that thermal properties of skin are highly reactive to diet: within three days, a high fat diet reduces heat transfer through skin. In contrast, a dietary manipulation that prevents obesity accelerates energy loss through skins. We find that skin is the largest target for dietary fat delivery, and that dietary triglyceride is assimilated by epidermis and dermal white adipose tissue, persisting for weeks after feeding. With caloric-restriction, mouse skins thin and assimilation of circulating lipids decreases. Using multi-modal lipid profiling, keratinocytes and sebocytes are implicated in lipid changes, which correlate with thermal function. We propose that skin should be routinely included in physiological studies of lipid metabolism, given the size of the skin lipid reservoir and its adaptable functionality. The mechanisms underlying the regulation of the skin thermal barrier are poorly understood. Here the authors show that the thermal properties of the skin are reactive to diet and that skin is a target for dietary fat delivery.

  PublisherOA PDFDOI

• Abstract 2261 Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis in human cells

  Journal of Biological Chemistry · 2025-05-01

  articleOpen access

  NADPH is a cell-essential coenzyme that provides the major source of reducing equivalents to power macromolecule biosynthesis and antioxidant defense. The rate-limiting substrate for NADPH production is its oxidized form, NADP+, which is generated from NAD+ by NAD kinases. NADP+ and NADPH (NADP(H)) each exist in mutually exclusive pools in the mitochondria and cytosol of human cells, with compartmentalized levels of NADP(H) being controlled by two distinct NAD kinases (NADK, cytosolic; NADK2, mitochondrial).

  PublisherOA PDFDOI

• Stearoyl-CoA Desaturases regulate stem and progenitor cell metabolism and function in response to nutrient abundance

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-20

  preprintOpen access

  SUMMARY Dietary components and metabolites play a critical role in regulating intestinal stem and progenitor cell function and proliferation. Here we show that Stearoyl-CoA Desaturases (SCDs), which regulate intracellular saturated to monounsaturated fatty acids ratios, are induced in response to nutrient abundance, especially in the distal intestine, and regulate intestinal homeostasis. Genetic or pharmacological inhibition of SCDs altered lipid metabolism, increased ER stress, and reduced proliferative intestinal stem and progenitor cells in intestinal organoids. These effects were largely mitigated by oleic acid supplementation. Intestinal epithelium-specific deletion of Scd1 and Scd2 led to metabolic rewiring, leading to expansion of progenitor cell populations. DSS-induced epithelial damage revealed a dependence on SCD enzymes during regeneration, accelerating epithelial damage and inflammation in intestines lacking epithelial Scd1 and Scd2 . These findings underscore key metabolic pathways and dependencies that enable intestinal stem and progenitor cells to adapt to nutrient fluctuations and support epithelial tissue regeneration following injury.

  PublisherOA PDFDOI

• PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease

  Nature · 2025-05-07 · 21 citations

  articleOpen access

  Lysosomes catabolize lipids and other biological molecules, maintaining cellular and organismal homeostasis. Bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles, stimulates lipid-degrading enzymes and is altered in various human conditions, including neurodegenerative diseases1,2. Although lysosomal BMP synthase was recently discovered3, the enzymes mediating BMP turnover remain elusive. Here we show that lysosomal phospholipase PLA2G15 is a physiological BMP hydrolase. We further demonstrate that the resistance of BMP to lysosomal hydrolysis arises from its unique sn2, sn2′ esterification position and stereochemistry, as neither feature alone confers resistance. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes. Furthermore, PLA2G15 efficiently hydrolyses synthesized BMP stereoisomers with primary esters, challenging the long-held thought that BMP stereochemistry alone ensures resistance to acid phospholipases. Conversely, BMP with secondary esters and S,S stereoconfiguration is stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient cells and tissues accumulate several BMP species, a phenotype reversible by supplementing wild-type PLA2G15 but not its inactive mutant. Targeting PLA2G15 reduces the cholesterol accumulation in fibroblasts of patients with Niemann–Pick disease type C1 and significantly ameliorates disease pathologies in Niemann–Pick disease type C1-deficient mice, leading to an extended lifespan. Our findings established the rules governing BMP stability in lysosomes and identified PLA2G15 as a lysosomal BMP hydrolase and a potential target for therapeutic intervention in neurodegenerative diseases. Lysosomal phospholipase PLA2G15 was identified as a physiological BMP hydrolase whose activity depends on unique esterification and stereochemistry of BMP and offers a potential therapeutic target for Niemann–Pick disease type C1 and other neurodegenerative conditions.

  PublisherOA PDFDOI

• Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV

  Cell Metabolism · 2025-05-14 · 12 citations

  articleOpen accessSenior author

  Cold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state, shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of Tfeb in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB-binding sites of lysosomal genes and determined that the phospholipase a2 group XV (PLA2G15) regulates BMP lipid catabolism. Decreasing Pla2g15 levels in mice increased BMP lipids, ablated the cold-induced rise in BMP lipids, and improved cold tolerance. Mutation of the catalytic site of PLA2G15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through PLA2G15 catabolism. • Liver bis(monoacylglycerol)phosphate (BMP) lipids are increased with cold exposure • BMP lipids regulate liver lysosomal function and metabolic adaptation to cold • Phospholipase A2 group XV (PLA2G15) regulates BMP lipids in cold exposure • PLA2G15 loss increases BMP lipids, lysosomal lipid processing, and energy expenditure Davidson et al. demonstrated that liver lysosomes orchestrate the metabolic adaptation to cold by rewiring lipid processing. They show that phospholipase A2 group XV (PLA2G15) breaks down bis(monoacylglycerol)phosphate (BMP) lipids to shift lysosomal function and metabolism in response to direct transcription factor EB regulation.

  PublisherDOI

Frequent coauthors

• Dudley W. Lamming

  William S. Middleton Memorial Veterans Hospital

  36 shared

• Raghav Jain

  University of Wisconsin–Madison

  29 shared

• Cara L. Green

  University of Wisconsin–Madison

  23 shared

• Reji Babygirija

  William S. Middleton Memorial Veterans Hospital

  21 shared

• Heidi H. Pak

  University of Wisconsin–Madison

  20 shared

• Chung-Yang Yeh

  University of Wisconsin–Madison

  19 shared

• Michelle M. Sonsalla

  University of Wisconsin–Madison

  19 shared

• Mariah F. Calubag

  William S. Middleton Memorial Veterans Hospital

  18 shared

Labs

• Biochemistry Computational Research Facility (BCRF)PI

Education

• PhD, Biochemistry

  University of Utah

  2014

• BA, Biology

  Carroll College

  2007

Awards & honors

• HHMI Freeman Hrabowski Scholar