Stress signaling between organs in metazoa.

Many organisms have developed a robust ability to adapt and survive in the face of environmental perturbations that threaten the integrity of their genome, proteome, or metabolome. Studies in multiple model organisms have shown that, in general, when exposed to stress, cells activate a complex prosurvival signaling network that includes immune and DNA damage response genes, chaperones, antioxidant enzymes, structural proteins, metabolic enzymes, and noncoding RNAs. The manner of activation runs the gamut from transcriptional induction of genes to increased stability of transcripts to posttranslational modification of important biosynthetic proteins within the stressed tissue. Superimposed on these largely autonomous effects are nonautonomous responses in which the stressed tissue secretes peptides and other factors that stimulate tissues in different organs to embark on processes that ultimately help the organism as a whole cope with stress. This review focuses on the mechanisms by which tissues in one organ adapt to environmental challenges by regulating stress responses in tissues of different organs.

Cryo-EM structure of the human chemerin receptor 1-Gi protein complex bound to the C-terminal nonapeptide of chemerin.

Chemerin is a processed protein that acts on G protein-coupled receptors (GPCRs) for its chemotactic and adipokine activities. The biologically active chemerin (chemerin 21-157) results from proteolytic cleavage of prochemerin and uses its C-terminal peptide containing the sequence YFPGQFAFS for receptor activation. Here we report a high-resolution cryo-electron microscopy (cryo-EM) structure of human chemerin receptor 1 (CMKLR1) bound to the C-terminal nonapeptide of chemokine (C9) in complex with Gi proteins. C9 inserts its C terminus into the binding pocket and is stabilized through hydrophobic interactions involving its Y1, F2, F6, and F8, as well as polar interactions between G4, S9, and several amino acids lining the binding pocket of CMKLR1. Microsecond scale molecular dynamics simulations support a balanced force distribution across the whole ligand-receptor interface that enhances thermodynamic stability of the captured binding pose of C9. The C9 interaction with CMKLR1 is drastically different from chemokine recognition by chemokine receptors, which follow a two-site two-step model. In contrast, C9 takes an "S"-shaped pose in the binding pocket of CMKLR1 much like angiotensin II in the AT1 receptor. Our mutagenesis and functional analyses confirmed the cryo-EM structure and key residues in the binding pocket for these interactions. Our findings provide a structural basis for chemerin recognition by CMKLR1 for the established chemotactic and adipokine activities.

A quantitative pipeline to assess secretion of human leptin coding variants reveals mechanisms underlying leptin deficiencies.

The hormone leptin, primarily secreted by adipocytes, plays a crucial role in regulating whole-body energy homeostasis. Homozygous loss-of-function mutations in the leptin gene (LEP) cause hyperphagia and severe obesity, primarily through alterations in leptin's affinity for its receptor or changes in serum leptin concentrations. Although serum concentrations are influenced by various factors (e.g., gene expression, protein synthesis, stability in the serum), proper delivery of leptin from its site of synthesis in the endoplasmic reticulum via the secretory pathway to the extracellular serum is a critical step. However, the regulatory mechanisms and specific machinery involved in this trafficking route, particularly in the context of human LEP mutations, remain largely unexplored. We have employed the Retention Using Selective Hooks (RUSH) system to elucidate the secretory pathway of leptin. We have refined this system into a medium-throughput assay for examining the pathophysiology of a range of obesity-associated LEP variants. Our results reveal that leptin follows the default secretory pathway, with no additional regulatory steps identified prior to secretion. Through screening of leptin variants, we identified three mutations that lead to proteasomal degradation of leptin and one variant that significantly decreased leptin secretion, likely through aberrant disulfide bond formation. These observations have identified novel pathogenic effects of leptin variants, which can be informative for therapeutics and diagnostics. Finally, our novel quantitative screening platform can be adapted for other secreted proteins.

ITIH5 inhibits proliferation, adipogenic differentiation, and secretion of inflammatory cytokines of human adipose stem cells-A new key in treating obesity?

Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is widely expressed in the human body, and it is detected to be particularly abundant in adipose tissue. ITIH5 expression is increased in people with obesity compared to lean persons and is decreased by diet-induced weight loss. This suggests that ITIH5 may be involved in the development of adiposity and clinical metabolic variables, although its exact function remains unknown. We measured the protein concentration of ITIH5 in adipose samples from patients undergoing abdominoplasty and tested for correlation with the subjects' BMI as well as inflammatory mediators. We stimulated human adipose stem cells (ASCs) with recombinant (r)ITIH5 protein and tested for an effect on proliferation, differentiation, and immunosuppressive properties when the cells were exposed to an artificial inflammatory environment. We found positive correlations between ITIH5 levels and the BMI (p < .001) as well as concentrations of inflammatory cytokines (TNF-α, IL-6, and MCP-1) in adipose tissue (p < .01). Application of the rITIH5 protein inhibited both proliferation (p < .001) and differentiation of ASCs. Especially, the development of mature adipocytes was reduced by over 50%. Moreover, rITIH5 decreased the release of IL-6 and MCP-1 when the cells were exposed to TNF-α and IL-1ß (p < .001). Our data suggest that ITIH5 is an adipokine that is increasingly released during human adipose tissue development, acting as a regulator that inhibits proliferation and adipogenic differentiation of ASCs. ITIH5 thus presents itself as a positive regulator of adipose tissue homeostasis, possibly protecting against both hyperplasia and hypertrophy of adipose tissue and the associated chronic inflammation.

Cellular Heterogeneity in Adipose Tissues.

Adipose tissue depots in distinct anatomical locations mediate key aspects of metabolism, including energy storage, nutrient release, and thermogenesis. Although adipocytes make up more than 90% of adipose tissue volume, they represent less than 50% of its cellular content. Here, I review recent advances in genetic lineage tracing and transcriptomics that reveal the identities of the heterogeneous cell populations constituting mouse and human adipose tissues. In addition to mature adipocytes and their progenitors, these include endothelial and various immune cell types that together orchestrate adipose tissue development and functions. One salient finding is the identification of progenitor subtypes that can modulate adipogenic capacity through paracrine mechanisms. Another is the description of fate trajectories of monocyte/macrophages, which can respond maladaptively to nutritional and thermogenic stimuli, leading to metabolic disease. These studies have generated an extraordinary source of publicly available data that can be leveraged to explore commonalities and differences among experimental models, providing new insights into adipose tissues and their role in metabolic disease.

Apelin-13 modulates the endometrial transcriptome of the domestic pig during implantation.

BACKGROUND: The peri-implantation period is a critical time during pregnancy that mostly defines the overall litter size. Most authors agree that the highest percentage of embryo mortality occurs during this time. Despite the brevity of the peri-implantation period, it is the most dynamic part of pregnancy in which the sequential and uninterrupted course of several processes is essential to the animal's reproductive success. Also then, the maternal uterine tissues undergo an intensive remodelling process, and their energy demand dramatically increases. It is believed that apelin, a member of the adipokine family, is involved in the control of female reproductive functions in response to the current metabolic state. The verified herein hypothesis assumed the modulatory effect of apelin on the endometrial tissue transcriptome on days 15 to 16 of gestation (beginning of implantation). RESULTS: The analysis of data obtained during RNA-seq (Illumina HiSeq2500) of endometrial slices treated and untreated with apelin (n = 4 per group) revealed changes in the expression of 68 genes (39 up-regulated and 29 down-regulated in the presence of apelin), assigned to 240 gene ontology terms. We also revealed changes in the frequency of alternative splicing events (397 cases), as well as single nucleotide variants (1,818 cases) in the presence of the adipokine. The identified genes were associated, among others, with the composition of the extracellular matrix, apoptosis, and angiogenesis. CONCLUSIONS: The obtained results indicate a potential role of apelin in the regulation of uterine tissue remodelling during the peri-implantation period.

Interorgan Communication Pathways in Physiology: Focus on Drosophila.

Studies in mammals and Drosophila have demonstrated the existence and significance of secreted factors involved in communication between distal organs. In this review, primarily focusing on Drosophila, we examine the known interorgan communication factors and their functions, physiological inducers, and integration in regulating physiology. Moreover, we describe how organ-sensing screens in Drosophila can systematically identify novel conserved interorgan communication factors. Finally, we discuss how interorgan communication enabled and evolved as a result of specialization of organs. Together, we anticipate that future studies will establish a model for metazoan interorgan communication network (ICN) and how it is deregulated in disease.

A novel RT-qPCR health assay reveals differential expression of stress and immunoregulatory genes between the seasonal migrations of humpback whales (Megaptera novaeangliae).

Health information is essential for the conservation management of whale species. However, assessing the health of free-ranging whales is challenging as samples are primarily limited to skin and blubber tissue. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) offers a method to measure health from blubber RNA, providing insights into energetic status, stress and immune activity. To identify changes in health, natural differences in baseline gene expression linked to an individual's sex, reproductive status and life-history stage must first be quantified. This study aimed to establish baseline gene expression indices of health in migrating humpback whales (Megaptera novaeangliae). To do this, we developed an assay to quantify seven health-related gene transcripts (Leptin, Leptin Receptor, Adiponectin, Aryl Hydrocarbon Receptor, Tumour Necrosis Factor-α, Interleukin-6, Heat Shock Protein-70) and used Bayesian mixed effect models to assess differential baseline expression based on sex, lactation status and migration stage (northbound to and southbound from the annual breeding grounds). Results showed no significant contribution of sex to differential baseline expression. However, lactating individuals exhibited downregulated AhR and HSP-70 compared to non-lactating conspecifics. Additionally, southbound individuals demonstrated significantly upregulated HSP-70 and downregulated TNF-alpha, suggesting a relationship between these inflammation-linked transcripts and migratory fasting. Our results suggest that baseline differences due to migratory stage and lactation status should be considered in health applications of this assay. Future monitoring efforts can use our baseline measurements to better understand how gene expression is tied to population-level impacts, such as reduced prey availability or migratory stressors.

Chemerin influences blood lipid of aged male mice under high fat diet and exercise states through regulating the distribution and browning of white adipose tissue.

BACKGROUND: With aging, white adipose tissue (WAT) undergoes distribution change and browning inhibition, which could be attenuated by exercise. Adipokine chemerin exerts roles in the above changes of WAT, and our previous studies demonstrated the effect of decreased chemerin on exercise-induced improvement of glucose and lipid metabolism in high fat diet (HFD) feeding male mice, so this study is to clarify whether chemerin's effects on glucose and lipid metabolism are associated with the distribution and browning of WAT. METHODS: After diet and exercise interventions, body weight and adipose tissue contents in different depots of male mice were weighed, body composition and energy metabolism parameters were determined by Echo MRI Body Composition Analyzer and metabolic cage, respectively. The levels of serum adiponectin and leptin were detected by ELISA, and the protein levels of PGC-1α, UCP1, adiponectin and leptin in WAT were measured by Western blot. RESULTS: Chemerin knockout exacerbated HFD-induced weight gain, upregulated the increases of visceral and subcutaneous WAT (vWAT and sWAT, especial in sWAT), and inhibited WAT browning, but improved blood lipid. Exercise reduced the body weight and WAT distribution, increased sWAT browning and further improved blood lipid in aged HFD male mice, which were abrogated by chemerin knockout. Detrimental alterations of leptin, adiponectin and adiponectin/leptin ratio were discovered in the serum and WAT of aged HFD chemerin(-/-) mice; and exercise-induced beneficial changes in these adipokines were blocked by chemerin knockout. CONCLUSION: Chemerin influences blood lipid of aged male mice under HFD and exercise states through regulating the distribution and browning of WAT, which might be related to the changes of adiponectin, leptin and adiponectin/leptin ratio.

Adipokines measured during pregnancy and at birth are associated with infant negative affect.

BACKGROUND: Increased adiposity during pregnancy may be related to offspring risk for mental health disorders, although the biological mechanisms are poorly understood. One promising hypothesis is that factors secreted from adipocytes such as leptin and adiponectin may explain this association. The current study examined whether pregnancy or umbilical cord blood concentrations of leptin and/or adiponectin a) predict elevated infant negative affect at 6 months (an early life marker of risk for psychopathology); and b) help explain the association between pregnancy adiposity and increased infant negative affect. METHODS: Data came from a prospective cohort (N = 305) of pregnant individuals and their offspring. Second trimester adiposity was assessed using air displacement plethysmography. Concentrations of leptin and adiponectin were measured in second trimester plasma and umbilical cord plasma. Infant negative affect was assessed by standardized observation at 6 months. Second trimester inflammation was assessed using a comprehensive panel of cytokines. RESULTS: Lower second trimester adiponectin was associated with elevated infant negative affect, and mediated the effect of pregnancy adiposity on infant negative affect. This association was independent of the effect of second trimester inflammation. Umbilical cord leptin also predicted higher infant negative affect and mediated the association between pregnancy adiposity and infant negative affect. CONCLUSIONS: This is the first study to link pregnancy adiponectin or cord blood leptin to infant markers of risk for psychopathology, and the first to demonstrate that these adipokines mediate the association between pregnancy adiposity and offspring behavioral outcomes, suggesting novel markers of risk and potential mechanisms of effect.

The effect of curcumin supplementation on circulating adiponectin and leptin concentration in adults: a GRADE-assessed systematic review and meta-analysis of randomised controlled trials.

Curcumin is a phytocompound found in the root of turmeric, a common herbal ingredient in many Asian cuisines. The compound contains anti-inflammatory activity, which is mediated through an upregulation of adiponectin and reduction of leptin. Results of randomised controlled trials (RCT) have shown that the effects of curcumin on adipokines are conflicting. Therefore, the current systematic review and meta-analysis of RCT were conducted with the aim of elucidating the role of curcumin supplementation on serum adiponectin and leptin. The search included PubMed, Embase, Cochrane Library, Scopus, Web of Science and Google Scholar from inception to August 2023. For net changes in adipokines, standardised mean differences (SMD) were calculated using random effects models. Thirteen RCT with fourteen treatment arms were eligible for inclusion in this meta-analysis. Curcumin supplementation was effective in increasing serum adiponectin (SMD = 0·86, 95 % CI (0·33, 1·39), P < 0·001; I2 = 93·1 %, P < 0·001) and reducing serum leptin (SMD = -1·42, 95 % CI (-2·29, -0·54), P < 0·001; I2 = 94·7 %, P < 0·001). In conclusion, curcumin supplementation significantly increased circulating adiponectin and decreased leptin levels in adults.

Serum asprosin levels are increased in patients with periodontitis and ST-segment elevation myocardial infarction and correlated with periodontal parameters: A case-control study.

OBJECTIVE: The study aims to investigate whether patients with ST-elevation myocardial infarction (STEMI)-related periodontitis will experience any changes in asprosin levels. BACKGROUND: Periodontitis is a common, chronic infection of the periodontium that is epidemiologically associated with cardiovascular disease. Although asprosin, a hormone released from adipose tissue, is a protective role in cardiovascular diseases, its effectiveness in periodontitis is unknown. METHODS: The study was conducted on a total of 120 patients, divided into four groups; the group of healthy control (n = 35), the group of periodontitis (n = 35), the group of periodontitis+STEMI (n = 25), and the group of STEMI (n = 25). In each patient, age, serum asprosin, CRP, troponin-I, and clinical periodontal parameters [plaque index (PI), gingival index (GI), bleeding on probing (BOP), probing depth (PD), and clinical attachment level (CAL)] were evaluated. The results were analyzed statistically. RESULTS: Serum asprosin, CRP, and troponin-I levels were statistically higher in the STEMI+periodontitis group compared to the other groups. In addition, as a result of the study, it was observed that there was a correlation between serum asprosin levels, clinical periodontal parameters, and CRP levels. CONCLUSIONS: The results of this study show that STEMI and periodontitis are associated with high asprosin levels. Since the risk of periodontitis is high in STEMI patients, periodontitis should also be considered when evaluating asprosin levels in STEMI patients.

Circulating levels of asprosin in children with obesity: a systematic review and meta-analysis.

BACKGROUND: Prior studies reported that elevated asprosin level was associated with obesity in adults and animal models. However, the relationship between asprosin level and children with obeisty remains controversial. The aim of our analysis was to systematically review available literatures linking asprosin and children with obesity for a comprehensive understanding of the relationship between circulating asprosin level and obesity in children. METHODS: Eight databases were gleaned for studies published up to January 2024. Standard mean difference with 95% confidence interval (CI) and Fisher's Z transformation was calculated to evaluate the relationship between asprosin level and children with obesity using the Review Manager 5.4 Software. Other indicators were measured via mean difference with 95% CI. RESULTS: Six observational studies were included both in systematic review and meta-analysis. The current evidence indicated that no significant difference was observed in the level of circulating asprosin between the children with and without obesity (SMD = 0.37; 95% CI:-0.22-0.95, p = 0.22). However, Fisher's Z transformation suggested the positive association of circulating asprosin levels and clinical index measuring the degree of obesity: total cholesterol (Fisher's Z: 0.11, 95% CI: 0.02-0.20, p = 0.02). CONCLUSIONS: Circulating asprosin level was not independently related to childhood obesity currently. More rigorous longitudinal researches were required to disentangle the causations. However, the positive association of asprosin levels and total cholesterol indicated that asprosin might get involved in the lipid-metabolism of childhood obesity, asprosin might be a prospective bio-index and targeted treatment of total cholesterol metabolism besides the role of glucogenic and orexigenic. TRIAL REGISTRATION: Prospero ID: CRD42023426476.

Asprosin: its function as a novel endocrine factor in metabolic-related diseases.

BACKGROUND AND PURPOSE: Asprosin was discovered as a new endocrine hormone originating from fibrillin-1 cleavage that plays a crucial role in various metabolic-related diseases, such as obesity, nonalcoholic fatty liver disease (NAFLD), diabetes, polycystic ovary syndrome (PCOS), and cardiovascular diseases. The purpose of this review is to describe the recent advancements of asprosin. METHOD: Narrative review. RESULT: This comprehensive review explores its tissue-specific functions, focusing on white adipose tissue, liver, hypothalamus, testis, ovary, heart, pancreas, skeletal muscle, and kidney. CONCLUSION: Asprosin is a multifaceted protein with tissue-specific roles in various physiological and pathological processes. Further research is needed to fully understand the mechanisms and potential of asprosin as a therapeutic target. These insights could provide new directions for treatments targeting metabolic-related diseases.

The association between adipokines and pulmonary diseases: a mendelian randomization study.

BACKGROUND: The role of adipokines in the development of lung diseases is significant, yet their specific relationship with different lung diseases remains unclear. METHODS: In our research, we analyzed genetic variations associated with adipokines and various lung conditions such as interstitial lung disease, chronic obstructive pulmonary disease, asthma, lung cancer, sleep apnea, pneumonia, and tuberculosis, using data from public genome-wide studies. We employed Mendelian randomization techniques, including inverse variance weighting, weighted median, and MR-Egger regression methods, and conducted sensitivity checks to validate our findings. RESULTS: A study using the FinnGen database, which included 198,955 participants, identified 13 SNPs associated with adiponectin. Notably, adiponectin was found to significantly reduce the risk of interstitial lung disease and idiopathic pulmonary fibrosis. However, little evidence was found to establish a direct cause-effect relationship between the six adipokines and several other lung conditions, including sarcoidosis, asthma, chronic obstructive pulmonary disease, lung cancer, tuberculosis, pneumonia, and sleep apnea syndrome. CONCLUSION: This study reveals a reverse link between adiponectin levels and the likelihood of interstitial lung disease, including idiopathic pulmonary fibrosis.

Association between serum omentin-1 and mucosal disease activity in patients with ulcerative colitis.

PURPOSE: Mucosal inflammation is a key feature of ulcerative colitis (UC), a chronic relapsing and remitting form of inflammatory bowel disease. Omentin-1, a newly discovered adipokine, is reported to have anti-inflammatory effects and has been found to be decreased in patients with inflammatory bowel disease. The aim of our study was to investigate the association between serum omentin-1 levels and mucosal disease activity in patients with UC. STUDY DESIGN: A total of 126 patients with UC and 77 healthy volunteers were enrolled in the study. Serum omentin-1 expression levels were measured using enzyme-linked immunosorbent assay to evaluate its potential for monitoring disease activity, including clinical and endoscopic activity. RESULTS: Serum omentin-1 levels were significantly lower in patients with UC compared to healthy controls (HC) (UC, 61.7 interquartile range: 51.5-72.6 versus healthy controls, 103.5 interquartile range: 48.3-156.2 ng/ml; P < .001). Furthermore, serum omentin-1 levels were associated with both clinical and endoscopic activity in patients with UC. Notably, omentin-1 levels were significantly lower in patients who achieved mucosal healing. Receiver operating characteristic curves indicated that serum omentin-1 levels could potentially serve as an activity index for evaluating UC. CONCLUSIONS: These findings provide further insight into the association between omentin-1 and UC, suggesting that omentin-1 may be a useful biomarker for monitoring mucosal disease activity in patients with UC.

Effect of non-surgical periodontal treatment on visfatin and chemerin concentration in the gingival crevicular fluid.

Visfatin, as a novel adipokine, is considered to play a role in periodontal inflammation. Chemerin is another newly identified adipokine that is possible to have a role in periodontitis firstly reported in our previous study. The aim of the current study is to evaluate the gingival crevicular fluid (GCF) levels of visfatin and chemerin in periodontitis and and compare these adipokine levels with before and after non-surgical periodontal treatment. Twenty-nine patients with Stage III Grade B periodontitis and eighteen healthy subjects included in this cross-sectional cohort study. Clinical periodontal parameters and GCF were obtained from all subjects. Eight weeks after the following non-surgical periodontal treatment including scaling and root planning, samples and clinical periodontal parameters were collected again in the periodontitis group. The levels of adipokines were analyzed with standard enzyme-linked immunosorbent assay. The levels of visfatin and chemerin were statistically significantly higher at periodontitis group as compared to healthy group (P < 0.001). Although, no changes were observed in visfatin levels after periodontal treatment (P > 0.05), chemerin levels were significantly decreased (P < 0.001). Also, no differences were observed as compared to the healthy group (P > 0.05). Visfatin and chemerin may play a role in the periodontal disease process. In addition, it can be considered that the decreased chemerin levels after non-surgical periodontal treatment may play an important role for developing host modulation strategies.

Visfatin Affects the Transcriptome of Porcine Luteal Cells during Early Pregnancy.

Visfatin/NAMPT (VIS), the hormone exerting a pleiotropic effect, is also perceived as an important factor in the regulation of reproductive processes and pregnancy maintenance. Previous studies confirmed its involvement in the control of porcine pituitary and ovary function. In this study, we hypothesized that VIS may affect the global transcriptome of luteal cells and thus regulate the functioning of the ovaries. Illumina's NovaSeq 6000 RNA sequencing was performed to investigate the differentially expressed genes (DEGs) and long non-coding RNAs (DELs) as well as the occurrence of differential alternative splicing events (DASs) in the porcine luteal cells exposed to VIS (100 ng/mL) during the implantation period. The obtained results revealed 170 DEGs (99 up- and 71 downregulated) assigned to 45 functional annotations. Moreover, we revealed 40 DELs, of which 3 were known and 37 were described for the first time. We identified 169 DASs events. The obtained results confirmed a significant effect of VIS on the transcriptome and spliceosome of luteal cells, including the genes involved in the processes crucial for successful implantation and pregnancy maintenance as angiogenesis, steroidogenesis, inflammation, cell development, migration, and proliferation.

Cornelian Cherry (Cornus mas L.) Fruit Extract Lowers SREBP-1c and C/EBPα in Liver and Alters Various PPAR-α, PPAR-γ, LXR-α Target Genes in Cholesterol-Rich Diet Rabbit Model.

Cornelian cherry (Cornus mas L.) fruits, abundant in iridoids and anthocyanins, are natural products with proven beneficial impacts on the functions of the cardiovascular system and the liver. This study aims to assess and compare whether and to what extent two different doses of resin-purified cornelian cherry extract (10 mg/kg b.w. or 50 mg/kg b.w.) applied in a cholesterol-rich diet rabbit model affect the levels of sterol regulatory element-binding protein 1c (SREBP-1c) and CCAAT/enhancer binding protein α (C/EBPα), and various liver X receptor-α (LXR-α), peroxisome proliferator-activated receptor-α (PPAR-α), and peroxisome proliferator-activated receptor-γ (PPAR-γ) target genes. Moreover, the aim is to evaluate the resistive index (RI) of common carotid arteries (CCAs) and aortas, and histopathological changes in CCAs. For this purpose, the levels of SREBP-1c, C/EBPα, ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), fatty acid synthase (FAS), endothelial lipase (LIPG), carnitine palmitoyltransferase 1A (CPT1A), and adiponectin receptor 2 (AdipoR2) in liver tissue were measured. Also, the levels of lipoprotein lipase (LPL), visceral adipose tissue-derived serine protease inhibitor (Vaspin), and retinol-binding protein 4 (RBP4) in visceral adipose tissue were measured. The RI of CCAs and aortas, and histopathological changes in CCAs, were indicated. The oral administration of the cornelian cherry extract decreased the SREBP-1c and C/EBPα in both doses. The dose of 10 mg/kg b.w. increased ABCA1 and decreased FAS, CPT1A, and RBP4, and the dose of 50 mg/kg b.w. enhanced ABCG1 and AdipoR2. Mitigations in atheromatous changes in rabbits' CCAs were also observed. The obtained outcomes were compared to the results of our previous works. The beneficial results confirm that cornelian cherry fruit extract may constitute a potentially effective product in the prevention and treatment of obesity-related disorders.

Differential Modulation of Catecholamine and Adipokine Secretion by the Short Chain Fatty Acid Receptor FFAR3 and α2-Adrenergic Receptors in PC12 Cells.

Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α2-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α2-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gßγ-activated phospholipase C (PLC)-ß/Ca2+ signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α2A-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α2A-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α2A-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action.