Whole-body Homeostasis Research Articles

IL-17 has a role in whole-body homeostasis.

IL-17 has a role in whole-body homeostasis.

Mammalian colonic contribution of amino acids to whole-body homeostasis.

The colon is an effective bioreactor with auxotrophic microbiota that can serve by hydrolyzing dietary and endogenous protein, as well as by synthesizing essential amino acids through nitrogen salvage. Due to assumed negligible amino acid absorption, this colonic contribution was thought to be minimal, but this may not be true. Several studies that examined the colonic environment in health and disease, show the presence of proteases in the colonic lumen, which are of both host and microbial origin, along with indirect evidence of amino acid transporters in the colonic epithelium. There are also amino acid biosynthetic pathways in the microflora, and the contribution of colonic amino acid to host amino acid nutrition has been shown in wild animals. Yet, current direct and quantitative evidence on amino acid absorption in human colon is minimal. Although amino acid absorption in colon is not very well established, current studies show that substantial amounts of amino acid could possibly be contributed to the host by the colon. There is a need for assessing this contribution quantitatively using direct isotopic methods under different nutritional conditions, dietary intakes, and clinical conditions.

Exercise, disease state and sex influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1G93A amyotrophic lateral sclerosis (ALS) mouse model

BackgroundAmyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1G93A ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1G93A ALS mice could lead to differential and potentially improved benefits.MethodsWe thus investigated the contribution of Fn14 to disease phenotypes in the SOD1G93A ALS mice. To do so, Fn14 knockout mice (Fn14−/−) were crossed onto the SOD1G93A background to generate SOD1G93A;Fn14−/− mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14−/−, SOD1G93A and SOD1G93A;Fn14−/−).ResultsHere, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1G93A mice. We then show that Fn14-depleted SOD1G93A mice display increased lifespan, myofiber size, neuromuscular junction endplate area as well as altered expression of known molecular effectors of the TWEAK/Fn14 pathway, without an impact on motor function. Importantly, we also observe a complex interaction between exercise (rotarod and grid test), genotype, disease state and sex that influences the overall effects of Fn14 deletion on survival, expression of known molecular effectors of the TWEAK/Fn14 pathway, expression of myosin heavy chain isoforms and myofiber size.ConclusionsOur study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease, sex and exercise. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism, sex and exercise will be of importance in future studies.

What a wonderful world!

The world of cancer science is moving toward a paradigm shift in making connections with neuroscience. After decades of research on genetic instability and mutations or on the tumor microenvironment, emerging evidence suggests that a malignant tumor is able to hijack and use the brain and its network of peripheral and central neurons as disrupters of homeostasis in the body. Whole-body homeostasis requires brain-body circuits to maintain survival and health via the processes of interoception, immunoception, and nociception. It is now likely that cancer disturbs physiological brain-body communication in making bidirectional brain tumor connections.

Pregnancy alters fatty acid metabolism, glucose regulation, and detoxification of the liver in synchrony with biomechanical property changes

Pregnancy places a metabolic burden on the body including the liver, which is responsible for ensuring adequate nutrition for the maternal and fetal systems. To gain a better understanding of liver adaptation, this study investigates metabolic shifts occurring in livers of pregnant rats. Metabolic capacities of the livers of pregnant and non-pregnant female Wistar rats were assessed using comprehensive metabolic models. Kinetic metabolic models were generated for each animal based on protein abundance data from proteomics analysis allowing for a subject-specific assessment of hepatic metabolic functions. Data are available via ProteomeXchange with identifier PXD050758. Additionally, tissue stiffness, viscosity, and water diffusion obtained from magnetic resonance imaging and elastography were correlated with metabolic capabilities to study the relationship between metabolic function and biophysical properties. Proteome profiling revealed differences in protein expression in the livers of pregnant and non-pregnant animals. Functional analysis showed significant variations in metabolic capacities. Livers of pregnant rats had reduced capacities in carbohydrate and fatty acid metabolism, along with altered urea synthesis. Additionally, there were associations between metabolic functions and biophysical properties highlighting potential links between changes in liver structure and metabolic capacities during pregnancy. In summary, our work reveals extensive hepatic metabolic changes in pregnant rats. The liver adapts its metabolic capacities to ensure whole-body metabolic homeostasis but may struggle to counteract nutritional challenges, such as hypoglycemia. The study, employing a personalized approach combining proteomics, kinetic modeling, and advanced imaging, sheds light on the intricate interplay between hepatic adaptations and medical imaging markers, providing a foundation for further investigations into the implications for maternal and fetal health.

Intrinsic molecular proton sensitivity underlies GPR4 effects on retrotrapezoid nucleus (RTN) neuronal activation and CO2-stimulated breathing.

An interoceptive homeostatic reflex monitors levels of CO2/H+ to maintain blood gas homeostasis and rapidly regulate tissue acid-base balance by driving lung ventilation and CO2 excretion - this CO2-evoked increase in respiration is the hypercapnic ventilatory reflex (HCVR). Retrotrapezoid nucleus (RTN) neurons provide crucial excitatory drive to downstream respiratory rhythm/pattern-generating circuits, and their activity is directly modulated by changes in CO2/H+ RTN neurons express GPR4 and TASK-2, global deletion of which abrogates CO2/H+ activation of RTN neurons and the HCVR. It has not been determined if the intrinsic pH sensitivity of these proton detectors is required for these effects. We used CRISPR/Cas9 genome editing to generate mice with mutations in either of two pH-sensing histidine residues in GPR4 to determine effects on RTN neuronal CO2/H+ sensitivity and the HCVR. In global GPR4(H81F) and GPR4(H167F) mice, CO2-stimulated breathing and CO2-induced RTN neuronal activation were strongly blunted, with no effect on hypoxia-stimulated breathing. In brainstem slices from GPR4(H81F) mice, peak firing of RTN neurons during bath acidification was significantly reduced compared to GPR4 wild type mice, and a subpopulation of RTN neurons was rendered pH-insensitive, phenocopying previous results from GPR4-deleted mice. These effects were independent of changes in RTN number/distribution, neuronal excitability or transcript levels for GPR4 and TASK-2. CO2-stimulated breathing was reduced to a similar extent in GPR4(H81F) and TASK-2-deleted mice, with combined mutation yielding no additional deficit in the HCVR. Together, these data demonstrate that the intrinsic pH sensitivity of GPR4 is necessary for full elaboration of the HCVR.Significance Statement Among the critical mechanisms for whole-body homeostasis, the hypercapnic ventilatory reflex (HCVR) regulates lung ventilation in order to maintain physiological levels of arterial PCO2 and acid-base balance. GPR4 is a proton-activated receptor and putative molecular proton sensor in retrotrapezoid nucleus (RTN) neurons, which are a crucial neural component of this respiratory reflex. In this work, we developed multiple lines of mice in which the intrinsic pH sensitivity of GPR4 was globally disabled by mutations in key histidine residues; in those mice, CO2/H+-sensitivity of RTN neurons and the HCVR were strongly blunted. These data support a role for GPR4 as a direct molecular sensor for CO2/H+ in support of this important homeostatic reflex.

Interactions between toll-like receptors signaling pathway and gut microbiota in host homeostasis.

Toll-like receptors (TLRs) are a family of fundamental pattern recognition receptorsin the innate immune system, constituting the first line of defense against endogenous and exogenous antigens. The gut microbiota, a collection of commensal microorganisms in the intestine, is a major source of exogenous antigens. The components and metabolites of the gut microbiota interact with specific TLRs to contribute to whole-body immune and metabolic homeostasis. This review aims to summarize the interaction between the gut microbiota and TLRsignaling pathways and to enumerate the role of microbiota dysbiosis-induced TLR signaling pathways in obesity, inflammatory bowel disease (IBD), and colorectal cancer (CRC). Through the recognition of TLRs, the microbiota facilitates the development of both the innate and adaptive immune systems, while the immune system monitors dynamic changes in the commensal bacteria to maintain the balance of the host-microorganism symbiosis. Dysbiosis of the gut microbiota can induce a cascade of inflammatory and metabolic responses mediated by TLRsignaling pathways, potentially resulting in various metabolic and inflammatory diseases. Understanding the crosstalk between TLRs and the gut microbiota contributes to potential therapeutic applications in related diseases, offering new avenues for treatment strategies in conditions like obesity, IBD,and CRC.

Possible effect of exercise with anti-fatigue nutrition on ROS-induced depression and suicide risk: a review.

Epidemiological evidence shows that physical activity, including continuous stimulus changes and appropriate exercise programs, improves brain degeneration in the hippocampus, prefrontal cortex (PFC), and anterior cingulate cortex (ACC). Therefore, we investigated the possible synergistic effects of physical activity and nutrition in controlling chronic fatigue and reducing oxidative stress in patients at risk for depression and suicide. We systematically reviewed the literature on various systemic factors related to the effects of 1) suppressing oxidative stress and 2) improving depression through exercise and nutrition. To conduct this review, we searched the PubMed database for papers published until May 1, 2024, using the terms "physical activity OR exercise" and "fatigue" OR "anti-fatigue," "oxidative stress" and "depression" and "suicide." We then reviewed the resulting list of articles related to antioxidant mechanisms. Appropriate physical activity and natural product intake can substantially change whole-body homeostasis and provide a way to overcome the threat of depression and suicide by regulating metabolites, scavenging free radicals, and neurotransmitters. Suicide and depression prevention play crucial roles in improving patients' quality of life. Our review provides evidence supporting the idea that exercise and antioxidant nutrition diminish oxidative stress and fatigue by improving the degeneration of the hippocampus, PFC, and ACC.

Mechanobiology of Adipocytes.

The growing obesity epidemic necessitates increased research on adipocyte and adipose tissue function and disease mechanisms that progress obesity. Historically, adipocytes were viewed simply as storage for excess energy. However, recent studies have demonstrated that adipocytes play a critical role in whole-body homeostasis, are involved in cell communication, experience forces in vivo, and respond to mechanical stimuli. Changes to the adipocyte mechanical microenvironment can affect function and, in some cases, contribute to disease. The aim of this review is to summarize the current literature on the mechanobiology of adipocytes. We reviewed over 100 papers on how mechanical stress is sensed by the adipocyte, the effects on cell behavior, and the use of cell culture scaffolds, particularly those with tunable stiffness, to study adipocyte behavior, adipose cell and tissue mechanical properties, and computational models. From our review, we conclude that adipocytes are responsive to mechanical stimuli, cell function and adipogenesis can be dictated by the mechanical environment, the measurement of mechanical properties is highly dependent on testing methods, and current modeling practices use many different approaches to recapitulate the complex behavior of adipocytes and adipose tissue. This review is intended to aid future studies by summarizing the current literature on adipocyte mechanobiology.

PPA1 promotes adipogenesis by regulating the stability of C/EBPs.

Adipogenesis significantly contributes to healthy adipose tissue expansion in obesity. Increasing adipocyte number or function to alleviate adipose tissue overload could serve as a therapeutic strategy for both lipodystrophy and obesity-related metabolic syndrome. Inorganic pyrophosphatase (PPA1) is an enzyme that catalyzes the hydrolysis of pyrophosphate (PPi) and is involved in many biochemical reactions, but its function in adipose tissue has not been studied previously. In this study, we demonstrated that adipose-specific PPA1 knockout (PPA1AKO) mice showed lipodystrophy and spontaneously developed hepatic steatosis and severe insulin resistance under normal chow diet feeding. PPA1 deficiency suppressed the differentiation of primary adipocyte precursors and 3T3-L1 cells. Notably, PPA1 overexpression can restore inhibited adipogenesis in preadipocytes isolated from db/db mice and type 2 diabetes patients. Mechanistic studies have revealed that PPA1 acts as a positive regulator of early adipocyte differentiation by promoting CCAAT/enhancer-binding proteinβ and δ (C/EBPβ and δ) protein stability. Moreover, the function of PPA1 in adipogenesis is independent of its PPi catalytic activity. Collectively, our in vivo and in vitro findings demonstrated that PPA1 is a novel critical upstream regulator of adipogenesis, controlling adipose tissue development and whole-body metabolic homeostasis.

The mitochondrial multi-omic response to exercise training across rat tissues

Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes andcirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction.

Abstract 2151: VascularRegulationbySuper Enhancer-DerivedLINC00607

Vascular endothelial cells (ECs) play a pivotal role in whole-body homeostasis. Recent advances have revealed enhancer-associated long non-coding RNAs (lncRNAs) as essential regulators in EC function. We investigated LINC00607, a super enhancer-derived lncRNA (SE-lncRNA) in human arteries with an emphasis on ECs. Based on public databases and our single-cell RNA-sequencing (scRNA-seq) data from human arteries collected from healthy and diabetic donors, we found that LINC00607 is abundantly expressed in the arteries and its level is increased in diabetic patients. Furthermore, through transcriptomic and promoter analysis, we identified c-Myc as an upstream transcription factor of LINC00607 in diabetic conditions. Interestingly, we found that N6-methyladenosine modification also contributes to the induced abundance in diabetic patients. Using RNA sequencing, we characterized the transcriptomes regulated by LINC00607 in ECs and vascular smooth muscle cells (VSMCs) and in basal and diabetic conditions in ECs. Finally, using scRNA-seq, we demonstrated that the modified antisense oligonucleotide inhibitor of LINC00607 can reverse dysfunctional changes induced by high glucose and TNF alpha in ECs. Collectively, our study demonstrates a multi-pronged approach to characterize LINC00607 in vascular cells and its gene regulatory networks in ECs and VSMCs. Our findings provide new insights into the regulation and function of SE-derived lncRNAs in both vascular homeostasis and dysfunction in a cell-type and context-dependent manner, which could have a significant impact on our understanding of epigenetic regulation implicated in cardiovascular health and diseases like diabetes.

Understanding osteokine biology

Bone is an endocrine organ that participates in whole-body homeostasis. The biology of bone-derived osteokines, however, remains unclear. Liang etal. integrate experimental and computational methods to discover new osteokines, establish their cell of origin and target site, and study their role in aging and during mechanical stress.

Exploring the role of pyroptosis in the pathogenicity of heart disease.

Cell death is an essential cellular mechanism that ensures quality control and whole-body homeostasis. Various modes of cell death have been studied and detailed. Unbalanced cell death can lead to uncontrolled cell proliferation (i.e., tumors) or excessive loss of cells (i.e., ischemia injury tissue loss). Thus, it is imperative for modes of cell death to be balanced and controlled. Here, we will focus on a recent mode of cell death called pyroptosis. While extensive studies have shown the role of this route of cell death in macrophages and monocytes, evidence for pyroptosis have expanded to encompass other pathologies, including cancer and cardiac diseases. Herein, we provide a brief review on pyroptosis and discuss current gaps in knowledge and scientific advances in cardiac pyroptosis in recent years. Lastly, we provide conclusions and prospective on the relevance to various cardiac diseases.

An integrated multi-omics analysis reveals osteokines involved in global regulation

Bone secretory proteins, termed osteokines, regulate bone metabolism and whole-body homeostasis. However, fundamental questions as to what the bona fide osteokines and their cellular sources are and how they are regulated remain unclear. In this study, we analyzed bone and extraskeletal tissues, osteoblast (OB) conditioned media, bone marrow supernatant (BMS), and serum, for basal osteokines and those responsive to aging and mechanical loading/unloading. We identified 375 candidate osteokines and their changes in response to aging and mechanical dynamics by integrating data from RNA-seq, scRNA-seq, and proteomic approaches. Furthermore, we analyzed their cellular sources in the bone and inter-organ communication facilitated by them (bone-brain, liver, and aorta). Notably, we discovered that senescent OBs secrete fatty-acid-binding protein 3 to propagate senescence toward vascular smooth muscle cells (VSMCs). Taken together, we identified previously unknown candidate osteokines and established a dynamic regulatory network among them, thus providing valuable resources to further investigate their systemic roles.

Long non-coding RNA variability in porcine skeletal muscle.

Recently, numerous studies including various tissues have been carried out on long non-coding RNAs (lncRNAs), but still, its variability has not yet been fully understood. In this study, we characterised the inter-individual variability of lncRNAs in pigs, in the context of number, length and expression. Transcriptomes collected from muscle tissue belonging to six Polish Landrace boars (PL1-PL6), including half-brothers (PL1-PL3), were investigated using bioinformatics (lncRNA identification and functional analysis) and statistical (lncRNA variability) methods. The number of lncRNA ranged from 1289 to 3500 per animal, and the total number of common lncRNAs among all boars was 232. The number, length and expression of lncRNAs significantly varied between individuals, and no consistent pattern has been found between pairs of half-brothers. In detail, PL5 exhibits lower expression than the others, while PL4 has significantly higher expression than PL2-PL3 and PL5-PL6. Noteworthy, comparing the inter-individual variability of lncRNA and mRNA expression, they exhibited concordant patterns. The enrichment analysis for common lncRNA target genes determined a variety of biological processes that play fundamental roles in cell biology, and they were mostly related to whole-body homeostasis maintenance, energy and protein synthesis as well as dynamics of multiple nucleoprotein complexes. The high variability of lncRNA landscape in the porcine genome has been revealed in this study. The inter-individual differences have been found in the context of three aspects: the number, length and expression of lncRNAs, which contribute to a better understanding of its complex nature.

Cold exposure affects glucose metabolism, lipid droplet deposition and mitophagy in skeletal muscle of newborn goats

Cold exposure is a common stressor for newborn goats. Skeletal muscle plays an important role in maintaining whole-body homeostasis of glucose and lipid metabolism. However, the molecular mechanisms underlying regulation of skeletal muscle of newborn goats by cold exposure remains unclear. In this study, we found a significant increase (P < 0.01) in serum glucagon levels after 24 h of cold exposure (COLD, 6°C), while glucose and insulin concentrations were significantly decreased (P < 0.01) compared to room temperature (RT, 25°C). Additionally, we found that cold exposure reduced glycogen content (P < 0.01) in skeletal muscle. Pathway enrichment analysis revealed that cold exposure activated skeletal muscle glucose metabolism pathways (including insulin resistance and the insulin signaling pathway) and mitophagy-related pathways. Cold exposure up-regulated the expression of genes involved in fatty acid and triglyceride synthesis, promoting skeletal muscle lipid deposition. Notably, cold exposure induced mitophagy in skeletal muscle.

FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions.

Fibroblast growth factor (FGF) signalling via FGF receptors (FGFR1-4) orchestrates fetal development and contributes to tissue and whole-body homeostasis, but can also promote tumorigenesis. Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. Erdafitinib is approved for patients with urothelial carcinoma harbouring FGFR2/3 alterations, and futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harbouring FGFR2 fusions and/or rearrangements. Clinical benefit from these agents is in part limited by hyperphosphataemia owing to off-target inhibition of FGFR1 as well as the emergence of resistance mutations in FGFR genes, activation of bypass signalling pathways, concurrent TP53 alterations and possibly epithelial-mesenchymal transition-related isoform switching. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.

Conditional hepatocyte ablation of PDIA1 uncovers indispensable roles in both APOB and MTTP folding to support VLDL secretion

ObjectivesThe assembly and secretion of hepatic very low-density lipoprotein (VLDL) plays pivotal roles in hepatic and plasma lipid homeostasis. Protein disulfide isomerase A1 (PDIA1/P4HB) is a molecular chaperone whose functions are essential for protein folding in the endoplasmic reticulum. Here we investigated the physiological requirement in vivo for PDIA1 in maintaining VLDL assembly and secretion. MethodsPdia1/P4hb was conditionally deleted in adult mouse hepatocytes and the phenotypes characterized. Mechanistic analyses in primary hepatocytes determined how PDIA1 ablation alters MTTP synthesis and degradation as well as altering synthesis and secretion of Apolipoprotein B (APOB), along with complementary expression of intact PDIA1 vs a catalytically inactivated PDIA1 mutant. ResultsHepatocyte-specific deletion of Pdia1/P4hb inhibited hepatic MTTP expression and dramatically reduced VLDL production, leading to severe hepatic steatosis and hypolipidemia. Pdia1-deletion did not affect mRNA expression or protein stability of MTTP but rather prevented Mttp mRNA translation. We demonstrate an essential role for PDIA1 in MTTP synthesis and function and show that PDIA1 interacts with APOB in an MTTP-independent manner via its molecular chaperone function to support APOB folding and secretion. ConclusionsPDIA1 plays indispensable roles in APOB folding, MTTP synthesis and activity to support VLDL assembly. Thus, like APOB and MTTP, PDIA1 is an obligatory component of hepatic VLDL production.

Zinc finger protein ZNF638 regulates triglyceride metabolism via ANGPTL8 in an estrogen dependent manner

Background and aimTriglyceride (TG) levels are closely related to obesity, fatty liver and cardiovascular diseases, while the regulatory factors and mechanism for triglyceride homeostasis are still largely unknown. Zinc Finger Protein 638 (ZNF638) is a newly discovered member of zinc finger protein family for adipocyte function in vitro. The aim of the present work was to investigate the role of ZNF638 in regulating triglyceride metabolism in mice. MethodsWe generated ZNF638 adipose tissue specific knockout mice (ZNF638 FKO) by cross-breeding ZNF638 flox to Adiponectin-Cre mice and achieved adipose tissue ZNF638 overexpression via adenoviral mediated ZNF638 delivery in inguinal adipose tissue (iWAT) to examined the role and mechanisms of ZNF638 in fat biology and whole-body TG homeostasis. ResultsAlthough ZNF638 FKO mice showed similar body weights, body composition, glucose metabolism and serum parameters compared to wild-type mice under chow diet, serum TG levels in ZNF638 FKO mice were increased dramatically after refeeding compared to wild-type mice, accompanied with decreased endothelial lipoprotein lipase (LPL) activity and increased lipid absorption of the small intestine. Conversely, ZNF638 overexpression in iWAT reduced serum TG levels while enhanced LPL activity after refeeding in female C57BL/6J mice and obese ob/ob mice. Specifically, only female mice exhibited altered TG metabolism upon ZNF638 expression changes in fat. Mechanistically, RNA-sequencing analysis revealed that the TG regulator angiopoietin-like protein 8 (Angptl8) was highly expressed in iWAT of female ZNF638 FKO mice. Neutralizing circulating ANGPTL8 in female ZNF638 FKO mice abolished refeeding-induced TG elevation. Furthermore, we demonstrated that ZNF638 functions as a transcriptional repressor by recruiting HDAC1 for histone deacetylation and broad lipid metabolic gene suppression, including Angptl8 transcription inhibition. Moreover, we showed that the sexual dimorphism is possibly due to estrogen dependent regulation on ZNF638-ANGPTL8 axis. ConclusionWe revealed a role of ZNF638 in the regulation of triglyceride metabolism by affecting Angptl8 transcriptional level in adipose tissue with sexual dimorphism.