Nuclear receptors are key effectors of metabolic programs; however, the contribution of co-regulatory complexes in maintaining metabolic homeostasis is not fully understood. Here, we show that modulation of the constitutive androstane receptor (CAR) by the co-repressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) is required for bile acid (BA) homeostasis. Transcriptional changes in the livers of mice harboring a targeted disruption in one of the nuclear receptor-interacting domains (RIDs), SMRTmRID1 mice, revealed increased expression of CAR target genes involved in BA export. Consistent with this, SMRTmRID1 mice challenged with a high-fat diet showed increased BAs in serum and urine with commensurate decreases in the liver and intestines. Notably, the reduction in intestinal BAs led to decreased activity of the BA receptor farnesoid X receptor (FXR). This reduction in FXR activity compromised the integrity of the intestinal barrier, increased bacterial burden, and augmented intestinal inflammation. Moreover, SMRTmRID1 mice were susceptible to intestinal damage, with higher mortality rates in acute colitis and colitis-associated cancer models. Treatment with a synthetic FXR agonist (XL335) rescued SMRTmRID1 mice during acute colitis. Collectively, these studies highlight the importance of SMRT in maintaining BA homeostasis through direct and indirect regulation of hepatic CAR and intestinal FXR activity, respectively, and point to potential therapeutic routes for combating intestinal pathologies associated with a high-fat diet. Nuclear receptors (NRs) have a crucial role in gene transcription regulation, impacting metabolic homeostasis. This study explores the disruption of the silencing mediator for retinoid and thyroid hormone receptors (SMRT) network in high-fat diet (HFD)-fed SMRTmRID1 mice, revealing its impact on bile acid (BA) homeostasis and intestinal health. Researchers used SMRTmRID1 knock-in mice, which have mutations in the RID1 domain, to study the effects of impaired SMRT–NR interactions. They found that disrupted SMRT function derepresses hepatic constitutive androstane receptor activity, leading to altered BA metabolism and reduced intestinal BA levels. This reduction impairs farnesoid X receptor-mediated mucosal defense, increasing intestinal permeability and inflammation. The study highlights the importance of the SMRT–NR network in maintaining BA homeostasis and suggests that farnesoid X receptor activation could mitigate intestinal dysfunction. Future research could explore tissue-specific SMRT models to further understand these interactions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Chronic pancreatitis (CP) affects ∼3 million people worldwide, yet altering the course of the disease is challenging. We developed a patient-derived organoid (PDO) platform to investigate the molecular pathogenesis of this disease and identify therapeutic strategies. We generated 37 PDOs from patients with idiopathic, hereditary, and alcohol-related CP with a high genetic concordance. PDOs retained inflammation-associated transcriptional and proteomic features. Transcriptomic profiling revealed three molecular subtypes of CP independent of etiology. We discovered widespread dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in half of the CP PDOs, including those with wild-type CFTR. Clinically available CFTR modulators stabilized mutant or wild-type CFTR, restored CFTR function, and decreased mitogenic and inflammatory signaling. This work provides a comprehensive PDO platform for modeling CP. We demonstrate the utility of this platform for precision therapeutic investigations. Our findings reveal CFTR modulators as a broadly applicable and effective therapeutic strategy.

Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell-based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell-embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) represents a global health crisis associated with dysregulated hepatic triglyceride (TG) synthesis, oxidation and secretion. Despite progress in targeting hepatic lipid synthesis/oxidation for MASLD treatment and a well-documented relationship between circadian rhythms and lipid metabolism, the adaptive mechanisms coordinating TG secretion with circadian timing remain incompletely understood. Here we identify an autocrine regulatory pathway where circadian hepatic Fibroblast Growth Factor 1 (Fgf1) expression synchronizes diurnal TG secretion with the active phase. FGF1 activation of FGFR4 induces an mTORC1-IRE1-XBP1 signaling cascade involving atypical IRE1 activation that promotes TG secretion. Consistently, dietary-driven MASLD is exacerbated in liver-specific FGF1 knockout mice, while exogenous FGF1 halts disease progression in a Metabolic dysfunction-Associated Steatohepatitis (MASH) mouse model. This study causally associates FGF1 circadian rhythmicity with TG secretion to establish FGF1 as a crucial pacemaker in hepatic lipid homeostasis.

Durable therapeutic efficacy remains a major barrier to improving outcomes for patients with pancreatic ductal adenocarcinoma (PDAC). An immunosuppressive tumor microenvironment (TME) is a hallmark of PDAC and has been demonstrated to be a dominant driver of therapeutic resistance. The aberrant glycan CA19-9 is prevalent in PDAC and drives tumor progression, but the paracrine mechanisms by which it contributes to TME remodeling are unknown. To address this, we mapped TME changes and performed functional analyses using a genetically engineered mouse model (GEMM) harboring KrasG12D mutation and inducible CA19-9 expression. Elevation of CA19-9 led to expansion of antigen-presenting cancer associated fibroblasts (apCAFs) and regulatory T cells (Tregs), which can drive immunosuppression. Antibody blockade of CA19-9 resulted in significant restoration of normal histology and decreased apCAF and Treg populations. We dissected the paracrine signaling mechanisms that drive this TME remodeling in vitro using mouse and human organoid mono- and co-culture models as well as in vivo using GEMMs and syngeneic orthotopic transplantation models. CA19-9 induced IL1a and TGFb expression, reprogramming pancreatic mesothelial cells into apCAFs in vitro, which in turn directly ligated naïve Cd4+ T cells resulting in Treg differentiation in co-cultures. Antibody blockade of IL1a and TGFb in mice led to reduced apCAF and Treg differentiation. We previously reported that CA19-9 modification of the secreted Fbln3 protein increased Egfr engagement and now find that the induction of IL1a and TGFb expression by CA19-9 is dependent on Fbln3 hyperactivation of EGFR signaling. Genetic depletion of Fbln3 led to reduced tumor progression and increased Cd8+ T cell infiltration in mice. Together these findings identify a previously unknown signaling axis driving immunosuppressive phenotypes in PDAC, uncovering multiple potential nodes to relieve the immunosuppressive pressures within the PDAC TME.

Abstract The ability of tumor cells to tolerate DNA damage through a robust DNA damage response (DDR) limits the efficacy of many anticancer therapies, including genotoxic agents; however, the epigenetic mechanisms that sustain DDR gene expression remain poorly understood. Here, we identify Class I histone deacetylases (HDACs) as critical regulators of the DDR in pancreatic ductal adenocarcinoma (PDAC). HDAC1/2 maintain a proper genome-wide distribution of H3K27 acetylation, ensuring efficient recruitment of BRD4 and RNA polymerase II to DDR gene promoters. Pharmacological HDAC inhibition with entinostat preferentially enriches H3K27 acetylation at intergenic regions, diverting transcriptional machinery away from promoters and suppressing DDR gene expression. Consequently, HDAC inhibition increases DNA damage and sensitizes PDAC to diverse DNA-damaging (e.g., platinum agents, topoisomerase inhibitors) and DDR-targeting therapies (e.g., PARP inhibitors). To overcome the systemic toxicity that has limited the clinical translation of HDAC inhibitors, we developed a bottlebrush prodrug (BPD) nanoparticle platform for tumor-selective entinostat delivery. Entinostat-BPD enables tumor-specific HDAC inhibition, reduces system toxicity, and achieves tumor suppression comparable to free entinostat with only one-seventh of the cumulative drug exposure, demonstrating enhanced translational potential of this platform. Together, these findings uncover an HDAC-directed epigenetic mechanism that drives resistance to DNA damage-inducing agents and further establish combinatorial and precision-targeting strategies to improve PDAC outcomes. Given the central role of the DDR across cancer types and the widespread use of DNA-damaging therapies, this work may have broad therapeutic relevance beyond pancreatic cancer. Citation Format: Gaoyang Liang, Hung V. Nguyen, Jonathan Zhu, Hervé Tiriac, Hadiqa Zafar, Daniel Y. Cao, Gabriela Estepa, Dylan C. Nelson, Yang Dai, Tae Gyu Oh, Christopher Liddle, Ruth T. Yu, Andrew M. Lowy, Weiwei Fan, Morgan L. Truitt, Annette R. Atkins, Jeremiah A. Johnson, Michael Downes, Ronald M. Evans. HDAC inhibition sensitizes pancreatic cancer to DNA-damaging therapies via genome-wide redistribution of transcriptional machinery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB097.

BACKGROUND:For patients with untreated pancreatic ductal adenocarcinoma (PDAC), chemotherapy before surgery ("neoadjuvant therapy") has shown benefit in reducing recurrence and prolonging survival. Targeting the vitamin D receptor (VDR) with analogs such as paricalcitol may improve chemotherapy effectiveness. This study evaluated the efficacy and safety of neoadjuvant albumin-bound paclitaxel (nab-paclitaxel) plus cisplatin plus gemcitabine (NABPLAGEM) plus paricalcitol (NCT03138720). METHODS:Participants were ≥18 years, had stage I-III PDAC without prior chemotherapy or radiation, Karnofsky Performance Status ≥70, and elevated CA 19-9. Study treatment included nab-paclitaxel (125 mg/m2), cisplatin (25 mg/m2), gemcitabine (1000 mg/m2), and paricalcitol (25 mcg) on days 1 and 8 of a 21-day cycle for up to 6 months. The primary outcome was CA 19-9 normalization. Secondary outcomes included margin-negative resection (R0), pathologic complete response (pCR), radiologic response, safety, and survival. Microbiome was analyzed as an exploratory outcome. RESULTS:Thirty-two participants were enrolled with median age 69.4 years, 56.2% male, and 93.8% white. Patients had resectable (cohort A, n = 10) and borderline resectable/locally advanced (cohort B, n = 22) tumors. CA 19-9 normalization occurred in 14 patients (43.8%). Two patients (6.2%) achieved pCR, and 19 (59.4%) achieved R0. Complete or partial radiologic response occurred in 39.3% of patients. Adverse events included grade 3-4 anemia (43.8%) and thrombocytopenia (59.4%). Median (95% CI) overall survival was 43.2 (7.5-upper bound not achieved) and 18.4 (10.9-41.2) months for cohorts A and B, respectively. CONCLUSION:Neoadjuvant NABPLAGEM plus paricalcitol demonstrated a high CA 19-9 normalization rate and was fairly well tolerated.

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes to the liver, which drives patient mortality. CA19-9 is elevated in most PDAC tumors and is widely used as a clinical biomarker. Elevated serum levels are associated with poor outcomes. However, whether CA19-9 functionally contributes to metastatic progression has not been fully defined, in part because mice lack endogenous CA19-9 expression. Here, using syngeneic murine PDAC cells engineered to express CA19-9, we investigated its functional role in liver metastasis. In splenic injection models, CA19-9 expression markedly increased liver metastatic burden by promoting both metastatic seeding and subsequent metastatic outgrowth. In vitro, CA19-9 enhanced tumor cell adhesion to endothelial cells through interaction with E-selectin. Metastatic seeding of CA19-9-expressing cells was reduced by genetic deletion of E-selectin or antibody neutralization of either CA19-9 or E-selectin in vivo. Therapeutic targeting of CA19-9 with a neutralizing antibody markedly reduced liver metastatic burden after metastatic seeding. CA19-9 expression increased AKT signaling in PDAC cells and liver metastases, and CA19-9 levels correlated with AKT activation in human PDAC tissues. These findings show that CA19-9 promotes PDAC liver metastasis through E-selectin-dependent metastatic seeding and AKT-associated metastatic outgrowth, highlighting CA19-9 as a functional mediator of PDAC metastasis and a potential therapeutic target.

Vitamin D receptor (VDR) agonists promote quiescence of cancer-associated fibroblasts and improve efficacy of chemotherapy in preclinical models of pancreatic cancer. We conducted a run-in phase trial with primary endpoint of safety when the VDR agonist paricalcitol is given with first-line gemcitabine and albumin-bound paclitaxel (GA) in patients with metastatic pancreatic cancer. Secondary endpoints included pharmacodynamic analyses. Thirty-six patients were randomized to GA plus placebo, GA plus intravenous paricalcitol or GA plus oral paricalcitol with pretreatment and on-treatment tumor biopsies. Paricalcitol was safely administered with GA, although five patients (42%) receiving oral paricalcitol had grade 2-4 hypercalcemia and required dose reduction. Nuclear VDR protein expression was heterogeneous across patients, and VDR was expressed in tumor, immune and stromal cells. Compared to pretreatment specimens, on-treatment biopsies had decreased proportion of αSMA+ fibroblasts, altered fibroblast VDR activation signature and greater density and spatial colocalization of CD8+ T cells with tumor cells in the GA-plus-paricalcitol arms. VDR expression was predictive of tumor response in the GA-plus-paricalcitol arms. Paricalcitol can be safely administered with chemotherapy to patients with metastatic pancreatic cancer, and on-treatment biopsies indicated favorable modulation of the tumor microenvironment by paricalcitol as predicted by preclinical models. ClinicalTrials.gov identifier: NCT03520790 .

While glucose uptake is a surrogate marker of brown fat activation, its role in thermogenesis remains uncertain. To ascertain when and how glucose can fuel thermogenesis, we generated brown adipocyte-specific RalGAPB knockout (KO) mice, which have constitutively active RalA and dramatically elevated glucose uptake due to the translocation of the glucose transporter Glut4 to the plasma membrane (PM). Lean mice with RalGAPB KO showed increased lipid accumulation in brown adipocytes through elevated de novo lipogenesis (DNL) and reduced oxidative metabolism; these mice exhibited markedly reduced energy expenditure and cold tolerance. DNL inhibitors rescued the defective oxidation and energy expenditure in the KO mice. Surprisingly, brown adipocyte DNL was not increased in obese RalGAPKO mice, but energy expenditure was. Moreover, obese KO mice lost more fat than controls during fasting, due to a combination of increased energy expenditure and reduced insulin levels that favored systemic lipid oxidation. RalA was activated in brown fat by β adrenergic stimulation due to increased insulin secretion, an effect that was required for cold tolerance. This process was repressed in obesity. Together, these findings reveal that increasing glucose uptake drives energy expenditure when DNL is restricted, underscoring the context-dependent role of glucose metabolism in brown fat thermogenesis.

The DNA damage response (DDR) is critical for pancreatic ductal adenocarcinoma (PDAC) development and therapeutic responses, including to genotoxic agents. While epigenetic modulators have been shown to contribute to the DDR, how chromatin regulation dictates responses to DNA damage in PDAC remains incompletely understood. Here, we identify Class I histone deacetylases (HDACs) as critical regulators of the DDR. HDAC1/2 direct the genomic distribution of H3K27ac, ensuring sufficient BRD4 and RNA polymerase II (Pol II) occupancy at DDR gene promoters. HDAC inhibition by entinostat shifts the balance of H3K27 acetylation preferentially toward intergenic regions, diverting BRD4 and Pol II from promoters, thereby suppressing DDR gene expression. In line with this, HDAC inhibition heightens DNA damage and sensitizes PDAC to diverse DNA-damaging and DDR-targeting agents. Since the clinical development of HDAC inhibitors has been limited by systemic toxicity, we developed bottlebrush prodrug (BPD) nanoparticles for tumor-selective entinostat delivery. Entinostat-BPD achieved tumor-specific HDAC inhibition while displaying potent efficacy and reduced systemic toxicity. These findings reveal an HDAC-dependent DDR vulnerability and offer combinational and precision targeting strategies to facilitate clinical translation and improve PDAC patient outcomes.

LESSONS LEARNED:Intravenous paricalcitol did not improve the efficacy of pembrolizumab, likely related to the short half-life. BACKGROUND:Immunotherapy has limited benefit in the treatment of advanced pancreatic cancer with the tumor microenvironment playing a key role in immune resistance. In preclinical studies, vitamin D receptor (VDR) agonists have been shown to sensitize pancreatic tumors to PD-1 blockade. METHODS:This was a randomized, double-blinded, placebo-controlled, phase II trial to evaluate pembrolizumab with or without paricalcitol as maintenance therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants were ≥18 years; histologically or cytologically confirmed metastatic PDAC showing no disease progression after frontline systemic therapy, and achieving maximal cytoreduction (eg, with no further antitumor effect), Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; adequate organ function. Study treatment included: pembrolizumab 200 mg IV every 3 weeks and either paricalcitol 25 mcg IV 3 times per week or placebo. The primary objective was to evaluate 6-month progression free survival (PFS). Secondary objectives include evaluating the toxicity of the combination and overall survival (OS). RESULTS:There was no significant difference in 6-month PFS, median PFS, median OS, nor treatment-related AEs between the 2 arms. CONCLUSIONS AND RELEVANCE:Paricalcitol did not improve the efficacy of pembrolizumab likely related to its short half-life of only 5-7 hours. Microbiome analysis revealed significant difference between long-term (>12 weeks) and short-term (<12 weeks) survival groups across treatment arms. Modulation of the tumor microenvironment will likely require more sustained VDR activity. TRIAL REGISTRATION:Clinicaltrials.gov, ID: NCT03331562.

Mitochondrial energy metabolism is vital for muscle function and is tightly controlled at the transcriptional level, both in the basal state and during adaptive muscle remodeling. The importance of the transcription factors estrogen-related receptors (ERRs) in controlling innate mitochondrial energetics has been recently demonstrated. However, whether different ERR isoforms display distinct functions in glycolytic versus oxidative myofibers is largely unknown. Moreover, their roles in regulating exercise-induced adaptive mitochondrial biogenesis remain unclear. Using muscle-specific single and combinatorial knockout mouse models, we have identified both cooperative and distinct roles of the ERR isoforms ERRα and ERRγ in regulating mitochondrial energy metabolism in different muscles. We demonstrate the essential roles of both these ERRs in mediating adaptive mitochondrial biogenesis in response to exercise training. We further show that PGC1α-induced mitochondrial biogenesis is completely abolished in primary myotubes with ERRα deletion but not ERRγ, highlighting distinct roles of these two isoforms in adaptive mitochondrial remodeling. Mechanistically, we find that both ERRs directly bind to the majority of mitochondrial energetic genes and control their expression, largely through collaborative binding to the same genomic loci. Collectively, our findings reveal critical and direct regulatory roles of ERRα and ERRγ in governing both innate and adaptive mitochondrial energetics in skeletal muscle.

BACKGROUND:Preclinical studies suggest that cancer cells take up oxidized vitamin C (dehydroascorbate, DHA) via the GLUT1 transporter, leading to oxidative stress and glutathione depletion. This mechanism may offer a therapeutic strategy for KRAS-mutated cancers. This Phase IB trial evaluated high-dose intravenous ascorbic acid (AA) combined with nab-paclitaxel, cisplatin, and gemcitabine (NABPLAGEM) in patients with untreated metastatic pancreatic ductal adenocarcinoma (PDAC). METHODS:Eligible patients (≥18 years, ECOG 0-1, measurable PDAC, adequate organ function) received AA (25, 37.5, or 56.25 g/m2 twice weekly) plus NABPLAGEM on Days 1 and 8 of 21-day cycles. The primary endpoint was determining the maximum tolerated dose (MTD) of AA. RESULTS:Seventeen patients were enrolled (median age 63.9; 70.6 % female; 82.4 % white). No MTD was reached; AA up to 56.25 g/m2 twice weekly was feasible. Patients on the lowest AA dose remained on treatment longer. Grade ≥3 treatment-related adverse events (TRAEs) included thrombocytopenia (82.4 %), anemia (35.3 %), neutropenia (29.4 %), hypokalemia (29.4 %), diarrhea (11.8 %), and colitis (11.8 %), with no significant differences between dose groups. Peak AA levels >20 mM were achieved in 57 % of patients at the highest dose. Median progression-free survival (PFS) and overall survival (OS) were 7.1 and 14.2 months, respectively, with no significant differences by AA dose. Textural imaging showed decreased liver fat in 3 of 4 patients with baseline steatosis. CONCLUSION:High-dose AA with NABPLAGEM was tolerable in patients with advanced PDAC but did not improve disease response compared to historical data for chemotherapy alone. A separate study suggests AA may enhance gemcitabine and nab-paclitaxel efficacy without cisplatin. AA and cisplatin may have overlapping DNA-damaging effects, or differences in AA dosing frequency and exposure may influence outcomes - variables to consider in future trials. TRIAL REGISTRATION:NCT03410030.

Adipose tissue maintains energy homeostasis by storing lipids during nutrient surplus and releasing them through lipolysis in times of energy demand. While lipolysis is essential for short term metabolic adaptation, prolonged metabolic stress requires adaptive changes that preserve energy reserves. Here, we report that β-adrenergic activation of adipocytes induces a transient and depot-specific infiltration of neutrophils into white adipose tissue (WAT), particularly in lipid-rich visceral WAT. Neutrophil recruitment requires the stimulation of both lipolysis and p38 MAPK activation in adipocytes. Recruited neutrophils locally secrete IL-1β, which suppresses lipolysis and limits excessive energy expenditure. Neutrophil depletion or blockade of IL-1β production increased lipolysis, leading to reduced WAT mass upon repeated β3-adrenergic stimulation. Together, these findings reveal an unexpected role of neutrophil-derived IL-1β in preserving lipid stores during metabolic stress, highlighting a physiological function of innate immune cells in maintaining energy homeostasis.

Thermogenic activation of subcutaneous white adipocytes requires glycogen synthesis and turnover. Here we show that β-adrenergic stimulation induces a distinct glycogen metabolism gene program in inguinal white adipose tissue in a cell-autonomous and adipocyte-specific manner. Among these, Gys2 and Ppp1r3c are rapidly induced following acute β3-adrenergic receptor activation. We identify Gys2 as a direct transcriptional target of PKA-CREB signaling. In contrast, sustained expression of glycogen metabolism genes under chronic β3-adrenergic activation requires the coactivator PGC1α, whose loss blunts glycogen accumulation and thermogenic capacity. Mechanistically, PGC1α cooperates with estrogen-related receptors (ERRs) to regulate chromatin accessibility and gene transcription. Although deletion of ERRα is compensated by ERRγ, combined deletion of ERRα/β/γ abolishes expression of glycogen metabolism and thermogenic genes. Chromatin profiling confirm that ERRs directly control the glycogen metabolic program in beige adipocytes. Together, our results identify a multilayered transcriptional axis that sustains glycogen metabolism during β-adrenergic activation in male mice.

Adipose tissue maintains energy homeostasis by storing lipids during nutrient surplus and releasing them through lipolysis in times of energy demand1,2. While lipolysis is essential for short-term metabolic adaptation, prolonged metabolic stress requires adaptive changes that preserve energy reserves2,3. Here we report that β3-adrenergic activation of adipocytes induces a transient and depot-specific infiltration of neutrophils into white adipose tissue (WAT), particularly in lipid-rich visceral WAT. Neutrophil recruitment requires the stimulation of both lipolysis and p38 MAPK in adipocytes, and is mediated by the secretion of leukotriene B4. Recruited neutrophils undergo activation in situ, and locally secrete IL-1β, which suppresses lipolysis and limits excessive energy loss. Neutrophil depletion or blockade of IL-1β production increases lipolysis, leading to reduced WAT mass after repeated β3-adrenergic stimulation. Together, these findings reveal a role of neutrophil-derived IL-1β in preserving lipid stores during metabolic stress, highlighting a physiological function of innate immune cells in limiting lipid loss and maintaining energy homeostasis.

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious chronic liver disease with limited therapeutic options. Fibroblast growth factor (FGF) analogs show promising therapeutic benefits for MASLD, yet the underlying mechanisms remain incompletely understood. Here, we studied the mechanism underlying the anti-steatotic properties of FGF1, the prototype member of the FGF family. Methods: The effect of FGF1 was studied in human and rodent hepatocytes and in obese mouse models exhibiting acute or chronic endoplasmic reticulum (ER) stress characteristic of MASLD. Metabolic analysis and proteomics were applied to evaluate liver physiology, ER stress and signaling. Results: We show that FGF1 reduces hepatic triglyceride (TG) levels in obese mice (51%, p <0.01, n = 8) via acute stimulation of very-low-density lipoprotein (VLDL, 3.9-fold, p <0.01, n = 8) secretion in an ER stress-dependent manner. This anti-steatotic effect was independent of adipose FGF receptor 1, which is required for the glucose-lowering effect of FGF1. Mechanistically, activation of the unfolded protein response (UPR), resulting in stabilization of apolipoprotein B (ApoB, 1.8-fold, p <0.01, n = 8), the main structural protein component of atherogenic lipoprotein particles, was identified as the key mechanism by which FGF1 drives VLDL secretion. Post-translational control of ApoB by FGF1 was potentiated by pre-existing ER stress. FGF1 stimulated major regulators of protein synthesis, and during ER stress, all three branches of the UPR were activated. In ER stress-primed lean mice, FGF1 adopted novel TG secretion activity (2.2-fold, p <0.05, n = 6). Conversely, alleviation of ER stress in obese mice suppressed FGF1-stimulated VLDL-TG production (49%, n = 11, p <0.05). Conclusion: These results define ER stress-dependent modulation of VLDL secretion as a mechanism underlying the anti-steatotic activity of FGF1. Targeting the FGF-UPR pathway may thus have therapeutic potential for treating MASLD. Impact and implications: Fibroblast growth factors show therapeutic potential in both preclinical models and clinical trials for treating metabolic dysfunction-associated steatotic liver disease, a highly prevalent condition with limited treatment options. Identifying the mechanisms underlying their anti-steatotic effects may accelerate clinical development. Our finding that triglyceride secretion is the major driver of the anti-steatotic action of FGF1, together with the involvement of an adaptive unfolded protein response, provides deeper insight into the therapeutic potential of this pathway. These results also highlight possible implications for liver physiology and for the circulating lipoprotein profile, with relevance for both efficacy and safety considerations.

Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS.

Nutritional status is a determining factor for growth during development and homeostatic maintenance in adulthood. In the context of muscle, growth hormone (GH) coordinates growth with nutritional status; however, the detailed mechanisms remain to be fully elucidated. Here, we show that the transcriptional repressor B cell lymphoma 6 (BCL6) maintains muscle mass by sustaining GH action. Muscle-specific genetic deletion of BCL6 at either perinatal or adult stages profoundly reduces muscle mass and compromises muscle strength. Conversely, muscle-directed viral overexpression of BCL6 significantly reverses the loss of muscle mass and strength. Mechanistically, we show that BCL6 transcriptionally represses the suppressor of cytokine signaling 2 to sustain the anabolic actions of GH in muscle. Additionally, we find that GH itself transcriptionally inhibits BCL6 through the Janus kinase and signal transducer and activator of transcription 5 (JAK/STAT5) pathway. Supporting the physiologic relevance of this feedback regulation, we show the coordinated suppression of muscle Bcl6 expression with the induction of GH in the fasted state. These findings reveal the complexity of the feedback controls modulating GH signaling and identify BCL6 as a key homeostatic regulator coordinating muscle mass with nutrient availability. Moreover, these studies open avenues for targeted therapeutic strategies to combat muscle-wasting conditions.