Domestic cats are susceptible to obesity and chronic renal failure, leading to significant health risks. Nonsteroidal anti-inflammatory drug-activated gene (NAG-1), also known as growth differentiation factor 15 (GDF15), is a member of the transforming growth factor-β superfamily and has been associated with anti-obesity properties and preservation of kidney function. While the NAG-1 sequence has been extensively studied in several species, a comprehensive understanding of feline NAG-1 remains limited. This study aimed to investigate the nucleotide sequence of feline NAG-1 and its biological role in kidney protection through in-vitro experiments.

The feline NAG-1 cDNA was isolated from the feline uterus, and its sequence was analyzed and compared to sequences from other species, including humans. Expression patterns of feline NAG-1 in various tissues, particularly the liver and kidney, were determined. Furthermore, the effects of different phytochemicals and NSAIDs known to induce NAG-1 expression were assessed using Crandell-Rees Feline Kidney (CRFK) cells.

The analysis revealed that feline NAG-1 shares similarities with human NAG-1 and exhibits high expression levels in the liver and kidney of cats. Treatment with tolfenamic acid, quercetin, and resveratrol significantly increased NAG-1 expression in CRFK cells. Subsequently, CRFK cells overexpressing feline NAG-1 were utilized to investigate the functional roles of NAG-1 in feline kidney health. High-content screening analysis demonstrated that NAG-1 overexpression in cat kidney cells enhanced mitochondrial membrane potential, reduced reactive oxygen species (ROS) generation in both whole cells and mitochondria, and downregulated the expression of Bax, a pro-apoptotic protein, under conditions of ROS-induced stress. These findings indicate the renoprotective role of NAG-1.

This study highlights the significant role of NAG-1 in feline kidney cells, revealing its high expression in the liver and kidney and demonstrating its protective effects on kidney function. These results underscore the potential of NAG-1 as a key factor in kidney protection. Future research should focus on further elucidating the molecular pathways involved and exploring therapeutic strategies to harness NAG-1 for managing obesity-related renal dysfunction in cats.

Growth differentiation factor 15 (GDF15) is a stress-induced hepatokine with emerging roles in liver injury. Estrogen-related receptor γ (ERRγ), a nuclear receptor regulating mitochondrial function and metabolic stress, has also been implicated in various liver injury conditions. However, the regulatory interplay between ERRγ and GDF15 remains unclear. This study investigates the molecular mechanisms underlying GDF15 expression and secretion in the liver, focusing on the role of ERRγ during acute and chronic liver injury.

Wild-type and hepatocyte-specific ERRγ knockout (ERRγ-LKO) mice were administered with a single dose of carbon tetrachloride (CCl4) or fed an alcohol-containing diet for 4 weeks to establish acute or chronic liver injury models, respectively. ERRγ was overexpressed through an adenoviral construct (Ad-ERRγ). The ERRγ-specific inverse agonist GSK5182 was employed to inhibit the transactivation of ERRγ. The luciferase reporter assays were used to assess the binding of ERRγ protein to the regulatory region of GDF15 gene.

Hepatic ERRγ and GDF15 gene expression, and GDF15 protein secretion were significantly elevated in both acute and chronic liver injury. Adenovirus-mediated overexpression of ERRγ is sufficient to substantially increase hepatic GDF15 expression and secretion. Genetic ablation of ERRγ expression or pharmacological inhibition of ERRγ transactivation substantially inhibited the upregulation of hepatic GDF15 expression and production in both acute and chronic liver injury. Furthermore, reporter assays showed that ERRγ, but not ERRα or ERRβ, directly binds to and activates the GDF15 gene promoter.

Our findings highlight the crucial role of ERRγ in transcriptional regulation of GDF15 gene expression and production in response to liver damage. Understanding the regulatory mechanisms of GDF15 expression could lead to new therapeutic targets for protecting the liver from various types of injuries and associated diseases.

Liver regeneration is a well-organized and phase-restricted process that involves chromatin remodeling and transcriptional alterations. However, the specific transcription factors (TFs) that act as key "switches" to initiate hepatocyte regeneration and organoid formation remain unclear. Comprehensive integration of RNA sequencing and ATAC sequencing reveals that ATF3 representing "Initiation_on" TF and ONECUT2 representing "Initiation_off" TF transiently modulate the occupancy of target promoters to license liver cells for regeneration. Knockdown of Atf3 or overexpression of Onecut2 not only reduces organoid formation but also delays tissue-damage repair after PHx or CCl4 treatment. Mechanistically, we demonstrate that ATF3 binds to the promoter of Slc7a5 to activate mTOR signals while the Hmgcs1 promoter loses ONECUT2 binding to facilitate regenerative initiation. The results identify the mechanism for initiating regeneration and reveal the remodeling of transcriptional landscapes and chromatin accessibility, thereby providing potential therapeutic targets for liver diseases with regenerative defects.

Growth Differentiation Factor 15 (GDF15), a nonspecific inflammatory marker and member of the TGF-β superfamily, has a well-established role in both inflammation and metabolic modulation, but lacks a comprehensive paediatric literature review. In several adult disease states, including cancer cachexia and pregnancy, circulation and expression of GDF15 has been of clinical and scientific interest, but little published paediatric data exists. As such, we aim to summarize existing paediatric studies.

This review follows the PRISMA-ScR guidelines for reporting and aims to summarize existing paediatric studies including GDF15, describe disease entities in which GDF15 has been investigated including existing reference ranges, and identify literature gaps to present future clinical and research direction. Our search strategy queried Ovid MEDLINE, Ovid Embase, Cochrane Library and Scopus databases to find original scientific articles measuring GDF15 from birth through children up to age 18. Data relating to study participant demographic and disease pathology, GDF15 measurement methods and clinical outcomes of interest were extracted.

Sixty-two studies were included, classified as cardiac, endocrine, mitochondrial, hematologic, neonatal, oncologic, infectious, rheumatologic, renal, neurologic or healthy. While several entities demonstrated elevated GDF15, the highest median GDF15 levels were observed in cardiac arrest 7089 pg/mL (interquartile range 3805-13 306) and mitochondrial diseases 4640 pg/mL (1896-14 064). In certain conditions, including cardiac stress, polycystic ovarian syndrome (PCOS), Kawasaki Disease (KD) and certain mitochondrial myopathies GDF15 can normalize with disease treatment or resolution. Of healthy children studied, GDF15 levels were highest in healthy neonates and followed a predictable pattern, decreasing over time. Mean and standard deviation values of GDF15 in healthy children were 343.8 ± 221.0 pg/mL, with a range of 90-1134 pg/mL for study averages.

Circulating GDF15 has been studied in a variety of paediatric diseases. However, variable evaluated outcome measures and GDF15 measurement methodologies prevent generalizability and direct comparison of these published studies. Validating normal GDF15 levels in children with standardized and reproducible methodology will help clarify GDF15's utility as a diagnostic marker of disease, a necessary step to elucidate clinical implications of GDF15 over expression and its potential as a therapeutic target.

Objective: This study investigated whether circulating growth differentiation factor 15 (GDF15) at diagnosis could estimate the Birmingham Vasculitis Activity Score (BVAS) and potentially predict all-cause mortality and end-stage kidney disease (ESKD) during follow-up in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: This study included 79 patients selected from a cohort of Korean patients with AAV. Circulating GDF15 was measured from patients' sera collected at diagnosis and stored at -80 °C. Clinical data at diagnosis and during follow-up were reviewed. Results: The median age was 64.0 years (40.5% men, and 59.5% women). Median circulating GDF15 was measured as 995.0 pg/mL. Of the 79 patients, 6 (7.6%) died and 20 (25.3%) progressed to ESKD during the disease course. Circulating GDF15 levels were significantly correlated with BVAS (r = 0.340) at diagnosis. Patients with circulating GDF15 ≥ 3350.5 pg/mL exhibited a significantly higher risk of the highest tertile of BVAS than those without (relative risk [RR], 11.229). Similarly, patients with circulating GDF15 ≥ 2239.5 pg/mL and ≥2208.5 pg/mL showed higher risks of all-cause mortality (RR, 7.733) and progression to ESKD (RR 7.125) than those without. Patients with circulating GDF15 ≥ 2239.5 pg/mL and ≥2208.5 pg/mL also showed significantly lower patient and ESKD-free survival rates than those without. Conclusions: Circulating GDF15 at diagnosis is useful in estimating BVAS and potentially predicts all-cause mortality and ESKD progression in patients with AAV.

Neurodegenerative diseases (ND) are complex diseases of still unknown etiology. Lately, long non-coding RNAs (lncRNAs) have become increasingly popular and implicated in several pathologies as they have several roles and appear to be involved in all biological processes such as cell signaling and cycle control as well as translation and transcription. MEG3 is one of these and acts by binding proteins or directly or competitively binding miRNAs. It has a crucial role in controlling cell death, inflammatory process, oxidative stress, endoplasmic reticulum stress, epithelial-mesenchymal transition and other processes. Recent reports showed that MEG3 is a major driving force of the necrosis phenomena in AD, causing the death of neurons, and its upregulation in cancer patients was linked to tumor suppression. Dysregulation of MEG3 affects neuronal cell death, inflammatory process, smooth muscle cell proliferation and consequently leads to the initiation or the acceleration of the disease. This review examines the current state of knowledge concerning the level of expression and the regulatory function of MEG3 in relation to several NDs. In addition, we examined the relation of MEG3 with neurotrophic factors such as Tumor growth factor β (TGFβ) and its possible mechanism of action. A comprehensive and in-depth analysis of the role of MEG3 in ND could give a clearer picture about the initiation of the process of neuronal death and help develop an alternative therapy that targets MEG3.

Non-obstructive coronary artery disease (NOCAD) is a condition in stable patients that experience angina despite not having significant coronary obstructive lesion. Knowledge on the role of certain biomarkers in patients with NOCAD is still limited. This study aimed to evaluate the roles of inflammation and adhesion molecules in the development of NOCAD. The correlations between the peripheral and coronary levels of the inflammatory biomarkers and adhesion molecules were also investigated.

In this cross-sectional study, symptomatic angina patients scheduled for coronary angiograms were recruited and separated into obstructive coronary artery disease (OCAD) and NOCAD groups based on those angiograms. Peripheral and coronary blood samples were taken to measure inflammation biomarkers [high sensitivity C-reactive protein (hsCRP) and growth differentiation factor 15 (GDF-15)], and adhesion molecules [vascular cell adhesion molecule-1 (VCAM-1)]. Subjects without angina symptoms were recruited for the control group.

The hsCRP, GDF-15, and VCAM-1 levels were higher in the OCAD and NOCAD groups than in the control group. VCAM-1 levels successfully predicted the incidence of NOCAD [p = 0.010, area under the curve (AUC) = 0.716]. All biomarkers' levels in the peripheral and coronary blood were correlated in OCAD and NOCAD patients (p < 0.001).

Elevated levels of the hsCRP, GDF-15, and VCAM-1 were found with NOCAD, despite the absent of significant coronary obstruction. VCAM-1 successfully predicted NOCAD and may thus serve as an early NOCAD biomarker. Significant correlations of hsCRP, GDF-15, and VCAM-1 level in peripheral and coronary blood indicate that the peripheral levels of these biomarkers reflect the levels and changes that occur at the coronary level.

Recent research has identified growth differentiation factor 15 (GDF15) as a crucial factor in various physiological and pathological processes, particularly in energy balance regulation. While the role of GDF15 in modulating energy metabolism through hindbrain GDNF family receptor alpha-like (GFRAL) signaling has been extensively studied, emerging evidence suggests direct peripheral metabolic actions of GDF15. Using knockout mouse models, we investigated GDF15 and GFRAL's roles in adipose tissue metabolism. Our findings indicate that C57BL/6/129/SvJ Gdf15-KO mice exhibit impaired expression of de novo lipogenesis enzymes in subcutaneous adipose tissue (sWAT). In contrast, C57BL/6J Gfral-KO mice showed no impairments compared to wild-type (WT) littermates. RNA-Seq analysis of sWAT in Gdf15-KO mice revealed a broad downregulation of genes involved in lipid metabolism. Importantly, our study uncovered sex-specific effects, with females being more affected by GDF15 loss than males. Additionally, we observed a fasting-induced upregulation of GDF15 gene expression in sWAT of both mice and humans, reinforcing this factor's role in adipose tissue lipid metabolism. In conclusion, our research highlights an essential role for GDF15 in sWAT lipid metabolic homeostasis. These insights enhance our understanding of GDF15's functions in adipose tissue physiology and underscore its potential as a therapeutic target for metabolic disorders.

GDF15 and FGF21, stress-responsive cytokines primarily secreted from the liver, are promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interaction between GDF15 and FGF21 remains unclear. We examined the effects of hepatocyte-specific GDF15 or FGF21 overexpression in high-fat diet (HFD)-fed mice for 8 weeks. Hydrodynamic injection of GDF15 or FGF21 sustained high circulating levels of GDF15 or FGF21, respectively, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and hepatic steatosis. In addition, GDF15 treatment led to early reduction in body weight despite no change in food intake, indicating the role of GDF15 other than appetite loss. GDF15 treatment increased liver-derived serum FGF21 levels, whereas FGF21 treatment did not affect GDF15 expression. GDF15 promoted eIF2α phosphorylation and XBP1 splicing, leading to FGF21 induction. In murine AML12 hepatocytes treated with free fatty acids (FFAs), GDF15 overexpression upregulated Fgf21 mRNA levels and promoted eIF2α phosphorylation and XBP1 splicing. Overall, continuous exposure to excess FFAs resulted in a gradual increase of β-oxidation-derived reactive oxygen species and endoplasmic reticulum stress, suggesting that GDF15 enhanced this pathway and induced FGF21 expression. GDF15- and FGF21-related crosstalk is an important pathway for the treatment of MASLD.

Growth differentiation factor 15 (GDF15) is a cell stress-response cytokine within the transforming growth factor-β (TGFβ) superfamily. It is known to exert diverse effects on many metabolic pathways through its receptor GFRAL, which is expressed in the hindbrain, and transduces signals through the downstream receptor tyrosine kinase Ret. Since the liver is the core organ of metabolism, summarizing the functions of GDF15 is highly important. In this review, we assessed the relevant literature regarding the main metabolic, inflammatory, fibrogenic, tumorigenic and other effects of GDF15 on different liver diseases, including Metabolic dysfunction-associated steatotic liver disease(MASLD), alcohol and drug-induced liver injury, as well as autoimmune and viral hepatitis, with a particular focus on the pathogenesis of MASLD progression from hepatic steatosis to MASH, liver fibrosis and even hepatocellular carcinoma (HCC). Finally, we discuss the prospects of the clinical application potential of GDF15 along with its research and development progress. With better knowledge of GDF15, increasing in-depth research will lead to a new era in the field of liver diseases.

Cardiovascular mortality is particularly high and increasing in patients with chronic kidney disease, with vascular calcification (VC) as a major pathophysiologic feature. VC is a highly regulated biological process similar to bone formation involving osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). We have previously demonstrated that loss of T-cell death-associated gene 51 (TDAG51) expression leads to an attenuation of medial VC. We now show a significant induction of circulating levels of growth differentiation factor 10 (GDF10) in TDAG51-/- mice, which was of interest due to its established role as an inhibitor of osteoblast differentiation. The objective of this study was to examine the role of GDF10 in the osteogenic transdifferentiation of VSMCs. Using primary mouse and human VSMCs, as well as ex vivo aortic ring cultures, we demonstrated that treatment with recombinant human (rh) GDF10 mitigated phosphate-mediated hydroxyapatite (HA) mineral deposition. Furthermore, ex vivo aortic rings from GDF10-/- mice exhibited increased HA deposition compared to C57BL/6J controls. To explain our observations, we identified that rhGDF10 treatment reduced protein expression of runt-related transcription factor 2, a key driver of osteogenic transdifferentiation of VSMCs and VC. In support of these findings, in vivo treatment with rhGDF10 attenuated VD3-induced VC. Furthermore, we demonstrated an increase in circulating GDF10 in patients with chronic kidney disease with clinically defined severe VC, as assessed by coronary artery calcium score. Thus, our studies identify GDF10 as a novel inhibitor of mineral deposition and as such, may represent a potential novel biomarker and therapeutic target for the detection and management of VC.

Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.

GDF15 is a stress response cytokine and a distant member of the transforming growth factor beta (TGFβ) superfamily, its levels increase in response to cell stress and certain diseases in the serum. To exert its effects, GDF15 binds to glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL), which was firstly identified in 2017 and highly expressed in the brain stem. Many studies have demonstrated that elevated serum GDF15 is associated with anorexia and weight loss. Herein, we focus on the biology of GDF15, specifically how this circulating protein regulates appetite and metabolism in influencing energy homeostasis through its actions on hindbrain neurons to shed light on its impact on diseases such as obesity and anorexia/cachexia syndromes. It works as an endocrine factor and transmits metabolic signals leading to weight reduction effects by directly reducing appetite and indirectly affecting food intake through complex mechanisms, which could be a promising target for the treatment of energy-intake disorders.

Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.

Cachexia is a wasting syndrome comprised of adipose, muscle, and weight loss observed in cancer patients. Tumor loss-of-function mutations in STK11/LKB1 , a regulator of the energy sensor AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are associated with cancer-related weight loss in NSCLC patients. Here we characterized the relevance of the NSCLC-associated cachexia factor growth differentiation factor 15 (GDF15) in several patient-derived and genetically engineered STK11/LKB1 -mutant NSCLC cachexia lines. Both tumor mRNA expression and serum concentrations of tumor-derived GDF15 were significantly elevated in multiple mice transplanted with patient-derived STK11/LKB1 -mutated NSCLC lines. GDF15 neutralizing antibody administered to mice transplanted with patient- or mouse-derived STK11/LKB1 -mutated NSCLC lines suppressed cachexia-associated adipose loss, muscle atrophy, and changes in body weight. The silencing of GDF15 in multiple human NSCLC lines was also sufficient to eliminate in vivo circulating GDF15 levels and abrogate cachexia induction, suggesting that tumor and not host tissues represent a key source of GDF15 production in these cancer models. Finally, reconstitution of wild-type STK11/LKB1 in a human STK11/LKB1 loss-of-function NSCLC line that normally induces cachexia in vivo correlated with the absence of tumor-secreted GDF15 and rescue from the cachexia phenotype. The current data provide evidence for tumor-secreted GDF15 as a conduit and a therapeutic target through which NSCLCs with STK11/LKB1 loss-of-function mutations promote cachexia-associated wasting.

GDF15, also known as MIC1, is a member of the TGF-beta superfamily. Previous studies reported elevated serum levels of GDF15 in patients with kidney disorder, and its association with kidney disease progression, while other studies identified GDF15 to have protective effects. To investigate the potential protective role of GDF15 on podocytes, we first performed in vitro studies using a Gdf15-deficient podocyte cell line. The lack of GDF15 intensified puromycin aminonucleoside (PAN)-triggered endoplasmic reticulum stress and induced cell death in cultivated podocytes. This was evidenced by elevated expressions of Xbp1 and ER-associated chaperones, alongside AnnexinV/PI staining and LDH release. Additionally, we subjected mice to nephrotoxic PAN treatment. Our observations revealed a noteworthy increase in both GDF15 expression and secretion subsequent to PAN administration. Gdf15 knockout mice displayed a moderate loss of WT1+ cells (podocytes) in the glomeruli compared to wild-type controls. However, this finding could not be substantiated through digital evaluation. The parameters of kidney function, including serum BUN, creatinine, and albumin-creatinine ratio (ACR), were increased in Gdf15 knockout mice as compared to wild-type mice upon PAN treatment. This was associated with an increase in the number of glomerular macrophages, neutrophils, inflammatory cytokines, and chemokines in Gdf15-deficient mice. In summary, our findings unveil a novel renoprotective effect of GDF15 during kidney injury and inflammation by promoting podocyte survival and regulating endoplasmic reticulum stress in podocytes, and, subsequently, the infiltration of inflammatory cells via paracrine effects on surrounding glomerular cells.

Growth differentiation factor 15 (GDF15), a stress-sensitive cytokine, and a distant member of the transforming growth factor β superfamily, has been shown to exhibit increased levels with aging, and in various age-related pathologies. Although GDF15 levels are elevated in the aqueous humor (AH) of glaucoma (optic nerve atrophy) patients, the possible role of this cytokine in the modulation of intraocular pressure (IOP) or AH outflow is unknown. The current study addresses this question using transgenic mice expressing human GDF15 and GDF15 null mice, and by perfusing enucleated mouse eyes with recombinant human GDF15 (rhGDF15). Treatment of primary cultures of human trabecular meshwork cells with a telomerase inhibitor, an endoplasmic reticulum stress-inducing agent, hydrogen peroxide, or an autophagy inhibitor resulted in significant elevation in GDF15 levels relative to the respective control cells. rhGDF15 stimulated modest but significant increases in the expression of genes encoding the extracellular matrix, cell adhesion proteins, and chemokine receptors (C-C chemokine receptor type 2) in human trabecular meshwork cells compared with controls, as deduced from the differential transcriptional profiles using RNA-sequencing analysis. There was a significant increase in IOP in transgenic mice expressing human GDF15, but not in GDF15 null mice, compared with the respective wild-type control mice. The AH outflow facility was decreased in enucleated wild-type mouse eyes perfused with rhGDF15. Light microcopy-based histologic examination of the conventional AH outflow pathway tissues did not reveal identifiable differences between the GDF15-targeted and control mice. Taken together, these results reveal the modest elevation of IOP in mice expressing human GDF15 possibly stemming from decreased AH outflow through the trabecular pathway.

Over the past 4 decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, noncommunicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy, including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and antiretroviral therapy drugs. Adipocyte hypertrophy characterizes visceral and subcutaneous adipose tissue depot expansion, as well as ectopic lipid deposition that occurs diffusely in the liver, skeletal muscle, and heart. PLWH with excess visceral adipose tissue exhibit adipokine dysregulation coupled with increased insulin resistance, heightening their risk for cardiovascular disease above that of the HIV-negative population. However, conventional therapies are ineffective for the management of cardiometabolic risk in this patient population. Although the knowledge of complex cardiometabolic comorbidities in PLWH continues to expand, significant knowledge gaps remain. Ongoing studies aimed at understanding interorgan communication and energy balance provide insights into metabolic observations in PLWH and reveal potential therapeutic targets. Our review focuses on current knowledge and recent advances in HIV-associated adipose tissue dysfunction, highlights emerging adipokine paradigms, and describes critical mechanistic and clinical insights.

The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducing food intake through its hindbrain receptor GFRAL.

To examine how GDF15 regulates AMPK.

Wild-type and Gdf15-/- mice, mouse primary hepatocytes and the human hepatic cell line Huh-7 were used.

Gdf15-/- mice showed glucose intolerance, reduced hepatic phosphorylated AMPK levels, increased levels of phosphorylated mothers against decapentaplegic homolog 3 (SMAD3; a mediator of the fibrotic response), elevated serum levels of transforming growth factor (TGF)-β1, as well as upregulated gluconeogenesis and fibrosis. In line with these observations, recombinant (r)GDF15 promoted AMPK activation and reduced the levels of phosphorylated SMAD3 and the markers of gluconeogenesis and fibrosis in the liver of mice and in mouse primary hepatocytes, suggesting that these effects may be independent of GFRAL. Pharmacological inhibition of SMAD3 phosphorylation in Gdf15-/- mice prevented glucose intolerance, the deactivation of AMPK and the increase in the levels of proteins involved in gluconeogenesis and fibrosis, suggesting that overactivation of the TGF-β1/SMAD3 pathway is responsible for the metabolic alterations in Gdf15-/- mice.

Overall, these findings indicate that GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis by lowering the activity of the TGF-β1/SMAD3 pathway.

It has been hypothesized that reducing the bioenergetic costs of gut inflammation as an explanation for the effect of antibiotic growth promoters (AGPs) on animal efficiency, framing some observations but not explaining the increase in growth rate or the prevention of infectious diseases. The host's ability to adapt to alterations in environmental conditions and to maintain health involves managing all physiological interactions that regulate homeostasis. Thus, metabolic pathways are vital in regulating physiological health as the energetic demands of the host guides most biological functions. Mitochondria are not only the metabolic heart of the cell because of their role in energy metabolism and oxidative phosphorylation, but also a central hub of signal transduction pathways that receive messages about the health and nutritional states of cells and tissues. In response, mitochondria direct cellular and tissue physiological alterations throughout the host. The endosymbiotic theory suggests that mitochondria evolved from prokaryotes, emphasizing the idea that these organelles can be affected by some antibiotics. Indeed, therapeutic levels of several antibiotics can be toxic to mitochondria, but subtherapeutic levels may improve mitochondrial function and defense mechanisms by inducing an adaptive response of the cell, resulting in mitokine production which coordinates an array of adaptive responses of the host to the stressor(s). This adaptive stress response is also observed in several bacteria species, suggesting that this protective mechanism has been preserved during evolution. Concordantly, gut microbiome modulation by subinhibitory concentration of AGPs could be the result of direct stimulation rather than inhibition of determined microbial species. In eukaryotes, these adaptive responses of the mitochondria to internal and external environmental conditions, can promote growth rate of the organism as an evolutionary strategy to overcome potential negative conditions. We hypothesize that direct and indirect subtherapeutic AGP regulation of mitochondria functional output can regulate homeostatic control mechanisms in a manner similar to those involved with disease tolerance.

Mitochondria function as platforms for bioenergetics, nutrient metabolism, intracellular signaling, innate immunity regulators, and modulators of stem cell activity. Thus, the decline in mitochondrial functions causes or correlates with diabetes mellitus and many aging-related diseases. Upon stress or damage, the mitochondria elicit a series of adaptive responses to overcome stress and restore their structural integrity and functional homeostasis. These adaptive responses to low-level or transient mitochondrial stress promote health and resilience to upcoming stress. Beneficial effects of low-grade mitochondrial stress, termed mitohormesis, have been observed in various organisms, including mammals. Accumulated evidence indicates that treatments boosting mitohormesis have therapeutic potential in various human diseases accompanied by mitochondrial stress. Here, we review multiple cellular signaling pathways and interorgan communication mechanisms through which mitochondrial stress leads to advantageous outcomes. We also discuss the relevance of mitohormesis in obesity, diabetes, metabolic liver disease, aging, and exercise.

Liver fibrosis is prevalent among chronic diseases of the liver and represents a major health burden worldwide. Growth differentiation factor 7 (GDF7), a member of the TGFβ protein superfamily, has been recently investigated for its role in repair of injured organs, but its role in chronic liver diseases remains unclear. Here, we examined hepatic GDF7 expression and its association with development and progression of human liver fibrosis. Moreover, we determined the source and target cells of GDF7 in the human liver.

GDF7 expression was analyzed in fibrotic and healthy human liver tissues by immunohistochemistry and qPCR. Cell-specific accumulation of GDF7 was examined by immunofluorescence through co-staining of cell type-specific markers on formalin-fixed paraffin-embedded human liver tissues. Public single cell RNA sequence databases were analyzed for cell type-specific expression of GDF7. In vitro, human liver organoids and LX-2 hepatic stellate cells (LX-2) were treated with recombinant human GDF7. Human liver organoids were co-cultured with activated LX-2 cells to induce an autocrine signaling circuit of GDF7 in liver organoids.

GDF7 protein levels were elevated in fibrotic liver tissue, mainly detected in hepatocytes and cholangiocytes. In line, GDF7 mRNA was mainly detected in liver parenchymal cells. Expressions of BMPR1A and BMPR2, encoding GDF7 receptors, were readily detected in hepatocytes, cholangiocytes and stellate cells in vivo and in vitro. In vitro, recombinant GDF7 promoted liver organoid growth and enhanced expression of the progenitor cell markers (LGR5, AXIN2), but failed to activate LX-2 cells. Still, activated LX-2 cells induced GDF7 and LGR5 expression in co-cultured human liver organoids.

Collectively, this study reveals a role of GDF7 in liver fibrosis and suggests a potential pro-regenerative function that can be utilized for amelioration of hepatic fibrosis caused by chronic liver disease.

Adipokines are biologically active factors secreted by adipose tissue that act on local and distant tissues through autocrine, paracrine, and endocrine mechanisms. However, adipokines are believed to be involved in an increased risk of atherosclerosis. Classical adipokines include leptin, adiponectin, and ceramide, while newly identified adipokines include visceral adipose tissue-derived serpin, omentin, and asprosin. New evidence suggests that adipokines can play an essential role in atherosclerosis progression and regression. Here, we summarize the complex roles of various adipokines in atherosclerosis lesions. Representative protective adipokines include adiponectin and neuregulin 4; deteriorating adipokines include leptin, resistin, thrombospondin-1, and C1q/tumor necrosis factor-related protein 5; and adipokines with dual protective and deteriorating effects include C1q/tumor necrosis factor-related protein 1 and C1q/tumor necrosis factor-related protein 3; and adipose tissue-derived bioactive materials include sphingosine-1-phosphate, ceramide, and adipose tissue-derived exosomes. However, the role of a newly discovered adipokine, asprosin, in atherosclerosis remains unclear. This article reviews progress in the research on the effects of adipokines in atherosclerosis and how they may be regulated to halt its progression.

There is an increasing proportion of hospitalized heart failure (HF) patients classified as HF with preserved ejection fraction (HFpEF) around the world. Growth differentiation factor 15 (GDF-15) is a promising biomarker in HFpEF prognostication; however, the majority of the existing data has been derived from the research on undifferentiated HF, whereas the studies focusing on HFpEF are still limited. This study aimed to determine the prognostic power of GDF-15 in the hospitalized patients with HFpEF in a Chinese cohort.

We analysed the levels of serum GDF-15 in 380 patients hospitalized for acute onset of HFpEF measured by heart ultrasound at admission in a prospective cohort. The associations of GDF-15 with 1 year risk of all-cause death and 1 year HF readmission were assessed by the Cox proportional hazards model. Area under the receiver operating characteristic curves was used to compare predictive accuracy. GDF-15 was strongly correlated with 1 year HF readmission and 1 year all-cause death, with event rates of 24.8%, 40.0%, and 50.0% for 1 year HF readmission (P < 0.001), respectively, and with 11.2%, 13.6%, and 24.6% for 1 year all-cause death (P = 0.004) in the corresponding tertile, respectively. In the multivariate linear regression model, GDF-15 had a significantly negative correlation with haemoglobin (P = 0.01) and a positive correlation with creatinine (P = 0.01), alanine transaminase (P = 0.001), and therapy of aldosterone antagonist (P = 0.018). The univariate Cox regression model of GDF-15 showed that c-statistic was 0.632 for 1 year HF readmission and 0.644 for 1 year all-cause death, which were superior to the N-terminal pro-brain natriuretic peptide (NT-proBNP) model with c-statistics of 0.595 and 0.610, respectively. In the multivariable Cox regression model, GDF-15 tertiles independently predicted 1 year HF readmission (hazard ratio 2.25, 95% confidence interval: 1.43-3.54, P < 0.001) after adjusting for baseline Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) risk score, history of HF, NT-proBNP, and high-sensitivity cardiac troponin T. Compared with the model including all the adjusted variables, the model with the addition of GDF-15 improved predictive power, with c-statistic increasing from 0.643 to 0.657 for 1 year HF readmission and from 0.638 to 0.660 for 1 year all-cause death.

In hospitalized patients with HFpEF, GDF-15 measured within 48 h of admission is a strong independent biomarker for 1 year HF readmission and even better than NT-proBNP. GDF-15 combined with the traditional indicators provided incremental prognostic value in this population.

Background GDF15 (growth differentiation factor 15) is a potent predictor of bleeding in people with cardiovascular disease. However, whether GDF15 is associated with bleeding in individuals without a history of cardiovascular disease is unknown. Methods and Results The study population was from the ARIC (Atherosclerosis Risk in Communities) study. We studied the association of GDF15 with hospitalized bleeding events among 9205 participants (1993-1995) without prior bleeding and cardiovascular disease (mean age 60 years, 57% women, 21% Black). Plasma levels of GDF15 were measured in relative fluorescence units using DNA-based aptamer technology. Bleeding was ascertained using discharge codes. We examined hazard ratios (HRs) of incident bleeding using Cox models and risk prediction with the addition of GDF15 to clinical predictors of bleeding. There were 1328 hospitalizations with bleeding during a median follow-up of 22.5 years. The majority (76.5%) were because of gastrointestinal bleeding. The absolute incidence rate of bleeding per 1000 person-years was 11.64 in the highest quartile of GDF15 versus 5.22 in the lowest quartile. The highest versus lowest quartile of GDF15 demonstrated an adjusted HR of 2.00 (95% CI, 1.69-2.35) for total bleeding. The findings were consistent when we examined bleeding as the primary discharge diagnosis. The addition of GDF15 to clinical predictors of bleeding improved the C-statistic by 0.006 (0.002-0.011) from 0.684 to 0.690, P=0.008. Conclusions Higher levels of GDF15 were associated with bleeding events and improved the risk prediction beyond clinical predictors in individuals without cardiovascular disease.

High serum NEFA and GDF-15 are risk factors for CAD and have been linked to detrimental cardiovascular events. It has been hypothesized that hyperuricemia causes CAD via the oxidative metabolism and inflammation. The current study sought to clarify the relationship between serum GDF-15/NEFA and CAD in individuals with hyperuricemia.

Blood samples collected from 350 male patients with hyperuricemia(191 patients without CAD and 159 patients with CAD, serum UA > 420 μmol/L) to measure serum GDF-15 and NEFA concentrations with baseline parameters.

Serum circulating GDF-15 concentrations(pg/dL) [8.48(6.67,12.73)] and NEFA levels(mmol/L) [0.45(0.32,0.60)] were higher in hyperuricemia patients with CAD. Logistic regression analysis revealed that the OR (95% CI) for CAD were 10.476 (4.158, 26.391) and 11.244 (4.740, 26.669) in quartile 4 (highest) respectively. The AUC of the combined serum GDF-15 and NEFA was 0.813 (0.767,0.858) as a predictor of whether CAD occurred in male with hyperuricemia.

Circulating GDF-15 and NEFA levels correlated positively with CAD in male patients with hyperuricemia and measurements may be a useful clinical adjunct.

Our aim in this study was to identify the associations between growth differentiation factor 15 (GDF15) and type 2 diabetes mellitus (T2DM) complications in a community-based population in China.

Based on a cross-sectional study registered in the National Basic Public Health Service for disease management of Changshu in China, a total of 1,689 T2DM patients were enrolled and tested further for plasma GDF15 levels. Macrovascular (cardiovascular disease and diabetic foot) and microvascular (diabetic kidney disease [DKD], diabetic retinopathy, and neuropathy) complications were evaluated. Logistic regression models were conducted to identify the associations of GDF15 with the risk of diabetes complications, and linear regression models were used to assess relationships between GDF15 and other clinical features.

Overall, 459 of the 1,689 T2DM patients (27.18%) had complications. GDF15 levels were significantly higher in patients with any type of complication compared with their counterparts. With each standard deviation increase of base 10 logarithms of GDF15 (lg-GDF15), the risk of overall complications increased by 1.17-fold (95% confidence interval [CI], 1.03 to 1.32). In contrast to macrovascular complications, associations of GDF15 with microvascular complications appeared to be stronger (adjusted odds ratio [OR], 1.24; 95% CI, 1.08 to 1.43), especially for DKD (adjusted OR, 1.51; 95% CI, 1.19 to 1.93). Subgroup analyses showed that the strength of association between GDF15 and complications varied by distinct age and T2DM duration subgroups. Patients with 2 or more types of complications had higher levels of GDF15 than those with fewer types of complications. Also, linear relationships were identified between GDF15 and several liver and kidney function indices.

Higher GDF15 levels were associated with T2DM complications, especially DKD. GDF15 may serve as a biomarker for monitoring the deterioration of T2DM.

Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine, which is involved in the cellular stress response following acute damage. However, the functional role of GDF15 in triple-negative breast cancer (TNBC) has not been fully elucidated. ELISA, Western blot, and PCR assays as well as bioinformatics analyses were conducted to observe the expression of GDF15. Cell Counting Kit-8, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet staining assays were conducted to evaluate paclitaxel resistance and cell viability. Cell apoptosis was analyzed by Western blotting. Murine xenograft model assay was employed to evaluate tumor growth in vivo . Our data indicate that GDF15 is markedly elevated in paclitaxel-resistant TNBC cells, which is significantly associated with unfavorable prognosis. Silencing of GDF15 robustly inhibits the proliferation of tumor cells and increases their sensitivity to paclitaxel in vitro and in vivo , whereas the treatment of purified GDF15 protein confers breast cancer cells with chemoresistance ability. Moreover, GDF15 activates protein kinase B (AKT) /mammalian target of rapamycin (mTOR) signaling, inhibition of AKT or mTOR reverses the prosurvival effect of GDF15 and enhances the antitumor efficacy of paclitaxel in TNBC cells. Altogether, our study uncovers the role of GDF15 in tumor growth and paclitaxel resistance, implicating a potential therapeutic target for TNBC.

Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the β2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.

A cytokine storm drives the pathogenesis of severe COVID-19 infection and several biomarkers have been linked to mortality. Chronic kidney disease (CKD) emerged as a risk factor for severe COVID-19. We investigated the association between selected biomarkers and mortality in 77 patients hospitalized for COVID-19, and whether they differ in patients with eGFR higher and lower than 45 mL/min. The association between patients’ characteristics, plasma biomarkers and mortality was conducted by univariate logistic regression models and independent predictors of mortality were then used to create a multivariate prediction model through Cox regression. Patients with lower eGFR had a significant increase of GDF-15, CD-25 and RAGE, with higher plasma levels in non-survivors and in patients who needed ventilation. At univariate analysis, low and mid-low GDF-15 quartiles (<4.45 ng/mL) were associated with lower mortality risk, while mid-high and high quartiles (>4.45 ng/mL) were associated with higher mortality risk. Independent association between GDF-15 quartiles and mortality risk was confirmed in the Cox model and adjusted for eGFR, age, fever and dyspnea (HR 2.28, CI 1.53−3.39, p < 0.0001). The strength of the association between GDF-15 quartiles and mortality risk increased in patients with lower compared to higher eGFR (HR 2.53, CI 1.34−4.79 versus HR 1.99, CI 1.17−3.39). Our findings may suggest a further investigation of the effect of GDF-15 signaling pathway inhibition in CKD.

Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. Here, we identify proteins in sera of patients and mouse models with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT. The severity of neuropathy in the patients was assessed by the CMT Neuropathy Examination Score (CMTES). We performed multitargeted proteomics on both sample sets to identify proteins elevated across multiple mouse models and CMT patients. Selected proteins and additional potential biomarkers, such as growth differentiation factor 15 (GDF15) and cell free mitochondrial DNA, were validated by ELISA and quantitative PCR, respectively. We propose that neural cell adhesion molecule 1 (NCAM1) is a candidate biomarker for CMT, as it was elevated in Gjb1-null, Hspb8K141N, GarsC201R and GarsP278KY mice as well as in patients with both demyelinating (CMT1A) and axonal (CMT2D, CMT2N) forms of CMT. We show that NCAM1 may reflect disease severity, demonstrated by a progressive increase in mouse models with time and a significant positive correlation with CMTES neuropathy severity in patients. The increase in NCAM1 may reflect muscle regeneration triggered by denervation, which could potentially track disease progression or the effect of treatments. We found that member proteins of the complement system were elevated in Gjb1-null and Hspb8K141N mouse models as well as in patients with both demyelinating and axonal CMT, indicating possible complement activation at the impaired nerve terminals. However, complement proteins did not correlate with the severity of neuropathy measured on the CMTES scale. Although the complement system does not seem to be a prognostic biomarker, we do show complement elevation to be a common disease feature of CMT, which may be of interest as a therapeutic target. We also identify serum GDF15 as a highly sensitive diagnostic biomarker, which was elevated in all CMT genotypes as well as in Hspb8K141N, Gjb1-null, GarsC201R and GarsP278KY mouse models. Although we cannot fully explain its origin, it may reflect increased stress response or metabolic disturbances in CMT. Further large and longitudinal patient studies should be performed to establish the value of these proteins as diagnostic and prognostic molecular biomarkers for CMT.

Radiotherapy is one of the conventional methods for the clinical treatment of breast cancer. However, radioresistance has an adverse effect on the prognosis of breast cancer patients after radiotherapy. In this study, using bioinformatic analysis of GSE59732 and GSE59733 datasets in the Gene Expression Omnibus (GEO) database together with the prognosis database of breast cancer patients after radiotherapy, the GDF15 gene was screened out to be related to the poor prognosis of breast cancer after radiotherapy. Compared with radiosensitive parental breast cancer cells, breast cancer cells with acquired radioresistance exhibited a high level of GDF15 expression and enhanced epithelial-to-mesenchymal transition (EMT) properties of migration and invasion, as well as obvious stem-like traits, including the increases of mammosphere formation ability, the proportion of stem cells (CD44⁺ CD24^- cells), and the expressions of stem cell-related markers (SOX2, NANOG). Moreover, knockdown of GDF15 sensitized the radioresistance cells to irradiation and significantly inhibited their EMT and stem-like traits, indicating that GDF15 promoted the radioresistance of breast cancer by enhancing the properties of EMT and stemness. Conclusively, GDF15 may be applicable as a novel prognosis-related biomarker and a potential therapeutic target for breast cancer radiotherapy.

Metformin is a blood-glucose-lowering medication with physiological effects that extend beyond its anti-diabetic indication. Recently, it was reported that metformin lowers body weight via induction of growth differentiation factor 15 (GDF15), which suppresses food intake by binding to the GDNF family receptor α-like (GFRAL) in the hindbrain. Here, we corroborate that metformin increases circulating GDF15 in mice and humans, but we fail to confirm previous reports that the GDF15-GFRAL pathway is necessary for the weight-lowering effects of metformin. Instead, our studies in wild-type, GDF15 knockout, and GFRAL knockout mice suggest that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. The data presented here question whether metformin is a sufficiently strong stimulator of GDF15 to drive anorexia and weight loss and emphasize that additional work is needed to untangle the relationship among metformin, GDF15, and energy balance.

Hormonal factors behind weight regain (WR) after surgical weight loss remain inadequately understood. Growth/differentiation factor 15 (GDF15) has emerged as a potential therapeutic target in obesity treatment. Cortisol, another stress hormone, has also been associated with weight gain at both low and high circulating concentrations. We aimed to compare meal-stimulated GDF15 and cortisol response in adults with and without WR after sleeve gastrectomy (SG). We hypothesized that GDF15 and cortisol response to meal tolerance test (MTT) will be lower in those with versus without WR after SG.

Cross-sectional study comprised 21 adults without diabetes, who underwent SG. WR was defined as 100 × (current weight - nadir)/(preoperative weight - nadir) > 10%. GDF15, cortisol, insulin, glucose, and incretins (total glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) circulating concentrations) were measured during MTT (0-240 min) after 3-6 years post-bariatric surgery.

All participants were 48% White, 85% female, with mean (SD) age: 43(10) years, and BMI: 36.2(7.6) kg/m². Compared to the non-WR group (n = 6), the WR group (n = 15) had significantly higher BMI (WR: 38.6 ± 7.6 kg/m², non-WR: 30.3 ± 3.5 kg/m², p = 0.02) and showed lower GDF15 response (WR AUC vs non-WR AUC (116143 ± 13973 vs 185798 ± 38884 ng*min/L, p = 0.047)) and lower cortisol response (WR AUC vs non-WR AUC (3492 ± 210 vs 4880 ± 655 µg*min/dL, p = 0.015)). Incretin response did not differ between the groups.

GDF15 and cortisol responses to MTT were lower in those who regained the weight after SG compared to those who did not, suggesting that dysregulation in GDF15 and cortisol response following bariatric surgery.

Growth differentiation factor 15 (GDF15) has been reported to be associated with fibrosis and cancer in liver disease. Diagnosis of autoimmune hepatitis (AIH) is often difficult because of the lack of specific markers. We investigated whether GDF15 is useful for diagnosing AIH and determined its therapeutic effects. We enrolled 171 Japanese patients as follows: AIH (n = 45), hepatitis B (HB) (n = 17), hepatitis C (HC) (n = 15), primary biliary cholangitis (PBC) (n = 20), and 74 healthy controls. Serum GDF15 levels were measured, and immunohistological analyses of GDF15 were performed using liver tissue of AIH patients. (1) GDF15 levels (pg/ml) were higher in AIH (1994.3 ± 1258.0) and HC (1568.0 ± 822.3) than in HB (953.2 ± 871.4), PBC (643.9 ± 247.0), and controls (475.3 ± 145.3) (p < 0.0001), as well as in cirrhosis patients (n = 31) than in non-cirrhosis patients (n = 66) (1926.6 ± 1026.0 vs. 1249.1 ± 1124.1, p < 0.0001). In non-cirrhosis patients, GDF15 levels were higher in AIH (1914.0 ± 1327.2) than in HC (955.7 ± 502.7), HB (519.3 ± 197.5), and PBC (643.9 ± 247.0) (p < 0.0001). (2) GDF15 was positively correlated with M2BPGi (r = 0.7728), total bilirubin (r = 0.6231), and PT-INR (r = 0.6332). (3) GDF15 levels could be used to distinguish AIH from other liver diseases in non-cirrhosis patients, with an area under the curve of 0.9373 (sensitivity 93.6%, specificity 79.3%, cut-off value 931.3). (4) GDF15 in AIH decreased after treatment. (5) Immunohistological analyses in AIH liver tissues revealed that GDF15 was strongly expressed in inflammatory cells, hepatic cytoplasm, and sinusoidal endothelial cells, but decreased after treatment. GDF15 is a novel diagnostic marker for AIH and is also expected to be a therapeutic marker for AIH.Clinical Trials Registration: The study protocol was approved by the institutional review board of Kurume University (Approval No.: 19049).

Plasma biomarkers that reflect energy balance disorders in people living with HIV (PLWH) remain limited. Growth differentiation factor 15 (GDF15) abundance in plasma of mice and humans induces negative energy balance but also becomes highly elevated in obesity and other metabolic diseases. We sought to compare plasma GDF15 levels in PLWH and HIV-negative persons and mouse models expressing the HIV accessory protein Vpr (that recapitulate HIV-associated metabolic disorders) and determine their relationship to metabolic parameters. We measured liver Gdf15 mRNA levels and plasma GDF15 levels in male Vpr mice and littermate controls. In parallel, we analyzed plasma GDF15 levels in 18 male PLWH on stable, long-term antiretroviral therapy and 13 HIV-negative men (6 healthy controls and 7 with metabolic syndrome). Plasma GDF15 levels were correlated with anthropometric and immune cell parameters in humans. Gene expression analysis of Vpr mouse liver demonstrated elevated Gdf15 mRNA. Plasma GDF15 levels were also higher in Vpr mouse models. Levels of plasma GDF15 in PLWH were greater than in both HIV-negative groups and correlated positively with the CD4/CD8 T cell ratio in PLWH. Plasma GDF15 levels correlated positively with age in the HIV-negative subjects but not in PLWH. Since GDF15 levels predict fatty liver disease and energy balance disorders, further studies are warranted to determine the effect of GDF15 in mediating the metabolic disturbances that occur in Vpr mice and PLWH.