Adipocyte-derived Cytokine Research Articles

Diagnostic and Prognostic Value of Serum Leptin in Critically Ill Patients with Acute versus Acute-on-Chronic Liver Failure.

Differentiation between acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) can be challenging in patients with de novo liver disease but is important to indicate the referral to a transplant center and urgency of organ allocation. Leptin, an adipocyte-derived cytokine that regulates energy storage and satiety, has multiple regulatory functions in the liver. We enrolled 160 critically ill patients with liver disease and 20 healthy individuals to measure serum leptin concentrations as a potential biomarker for diagnostic and prognostic purposes. Notably, patients with ALF had higher concentrations of serum leptin compared to patients with decompensated advanced chronic liver disease (dACLD) or ACLF (110 vs. 50 vs. 29 pg/mL, p < 0.001). Levels of serum leptin below 56 pg/mL excluded ALF in patients with acute hepatic disease, with a negative predictive value (NPV) of 98.8% in our cohort. Lastly, serum leptin did not show any dynamic changes within the first 48 h of ICU treatment, especially not in comparison with patients with ALF vs. ACLF or survivors vs. non-survivors. In conclusion, serum leptin may represent a helpful biomarker to exclude ALF in critically ill patients who present with acute liver dysfunction.

Adipokines and stroke: A systematic review and meta-analysis of disease risk and patient outcomes.

Obesity is reported to increase stroke risk, with adipocyte-derived cytokines or adipokines implicated as mediators. However, the relationship between adipokines and stroke is not well clarified. Thus, we aimed to evaluate the association of adipokines with stroke using fully adjusted risk estimates that incorporated body mass index in a meta-analysis. Data from 52 studies (62,428 patients) were pooled in a random-effects meta-analysis. Adiponectin was independently associated with a lower risk of pre-existing stroke (adjusted odds ratio: 0.64 [95% confidence interval: 0.46-0.88], p < 0.01), whereas leptin (1.08 [1.00-1.17], p = 0.04), resistin (1.06 [1.04-1.08], p < 0.01) and visfatin (1.04 [1.01-1.07], p = 0.01) are associated with a higher risk of stroke, but none with incident stroke. Adipokines independently associated with an ischaemic stroke subtype were adiponectin (0.48 [0.30-0.77], p < 0.01), leptin (1.10 [1.01-1.20], p = 0.04), and resistin (1.06 [1.04-1.08], p < 0.01). Fatty acid-binding protein-4 (FABP-4) independently predicted 6-month poor functional outcomes in stroke patients (adjusted hazard ratio: 1.09 [1.06-1.12], p < 0.01); whereas both FABP-4 (1.17 [1.03-1.34], p = 0.01) and visfatin (1.24 [1.00-1.55], p = 0.05) were predictive of 6-month mortality. Adipokines are associated with a greater risk of pre-existing stroke, but not with the relationship with incident stroke. Adipokines, such as FABP-4 and visfatin, may serve as biomarkers of stroke severity and worsening of stroke outcomes.

Biology and significance of leptin in animal production: A perspective

Leptin, an adipocyte-derived cytokine (adipokine) has plethora of physiological roles in the body, particularly in the onset of puberty, viz. reproduction and immune function of an animal. Moreover, body fatness which is a crucial determinant of meat quality is governed by blood leptin level. Since its discovery in 1994, various research groups have explored its potential role in animal production, reproductive fitness and immune function which ultimately determine the profitability of livestock rearing. Leptin binds with leptin receptor (LEPR) and activates different intracellular signaling pathways to activate downstream gene expression process to execute its functions. Intensive research works have shed light on the central role of this molecule in intricate circuitry of nutrition, metabolism, energy homeostasis and immune response. Single nucleotide polymorphisms (SNPs) detected on promoter or exon or intron region of leptin gene has been found to be associated with various key traits of animal productivity. The present review focusses to summarise about this gene structure and function in domestic mammalian species and need of future research efforts on leptin and related pathways for augmenting production of farm animals.

Leptin: an immunomodulatory molecule of animals

Leptin, an adipocyte-derived cytokine (adipokine), has plethora of physiological roles in the body, particularly in onset of puberty, reproduction and immune function of an animal. Leptin binds with leptin receptor (LEPR) and activates different intracellular signaling pathways to activate downstream gene expression process to execute its functions. The present mini-review focuses on our current understanding about the immunomodulatory and immunodiagnostic potential of leptin in domestic mammalian species. This warrants future research efforts to explore its immunological role that can be exploited for augmenting immunological protection of livestock.

Effects of Vitamin D Supplementation on Adipose Tissue Inflammation and NF-κB/AMPK Activation in Obese Mice Fed a High-Fat Diet.

Adipose tissue expansion is strongly associated with increased adipose macrophage infiltration and adipocyte-derived pro-inflammatory cytokines, contributing to obesity-associated low-grade inflammation. Individuals with vitamin D deficiency have an increased prevalence of obesity and increased circulating inflammatory cytokines. However, the effect of vitamin D supplementation on obesity-induced inflammation remains controversial. Male C57BL/6J mice received a low-fat (10% fat) or high-fat (HF, 60% fat diet) containing 1000 IU vitamin D/kg diet, or HF supplemented with 10,000 IU vitamin D/kg diet for 16 weeks (n = 9/group). Vitamin D supplementation did not decrease HF-increased body weight but attenuated obesity-induced adipose hypertrophy and macrophage recruitment as demonstrated by the number of crown-like structures. Vitamin D supplementation significantly reduced the mRNA expression of CD11c, CD68, and iNOS, specific for inflammatory M1-like macrophages, and decreased serum levels of NO. In addition, significant reductions in pro-inflammatory gene expression of IL-6, MCP-1, and TNFα and mRNA levels of ASC-1, CASP1, and IL-1β involved in NLRP3 inflammasome were found in obese mice supplemented with vitamin D. Vitamin D supplementation significantly increased obesity-decreased AMPK activity and suppressed HF-increased NF-κB phosphorylation in adipose tissue from obese mice. These observed beneficial effects of vitamin D supplementation on adipose tissue expansion, macrophage recruitment, and inflammation might be related to AMPK/NF-κB signaling.

Abstract 3128: Paracrine adipocyte signaling promotes colorectal cancer growth in vitro

Abstract Purpose: To identify candidate mediators of paracrine signaling between adipocytes and colorectal cancer cells contributing to the obesity-cancer link. Background: The worldwide prevalence of obesity has nearly tripled over the last few decades and is a major public health concern. Obesity-associated inflammation in adipose tissue correlates with colorectal tumorigenesis and tumor proliferation. The altered secretome of obesity-associated adipose tissue also affects colon cancer growth and development. Hence, we sought to determine the role of adipocyte-derived secreted factors in mediating the tumor-promoting paracrine signaling observed in obesity. Methods: Adipocytes were isolated from the gonadal fat pad of C57BL/6J male mice fed either a low-fat (10 kcal% fat) or high-fat (60 kcal% fat) diet and cultured for 24 hours. Cytokine production from the cultured adipocytes was quantified using the Bio-Plex Pro mouse chemokine 33-plex panel. To determine if adipocyte-derived metabolites or growth factors promote cancer cell proliferation, human SW620 colon cancer cells were grown for 24 hours in conditioned media and cell viability was assessed using the MTT assay. To test whether a subset of these cytokines directly impacted cancer cell growth, SW620 cells were cultured with or without the addition of 20 ng/mL recombinant IL-6 or 50 ng/mL CCL5 to the culture media. Proliferation was measured using the MTT assay and gene expression was assessed via qPCR. Results: Adipocyte-conditioned media contained 19 detectable cytokines, with CCL2, CCL7, and CCL5 being the most abundant. IL-6, CCL12, CCL11, and CXCL16 were all significantly elevated (p&amp;lt;0.05, fold enrichment &amp;gt;2.0) in adipocyte-conditioned media from obese relative to lean mice. SW620 cells demonstrated a &amp;gt;20% increase in proliferation when grown in conditioned media from adipocytes isolated from either low-fat or high-fat fed mice. CCL5 stimulation for 24 hours resulted in a ~17% increase in SW620 cell viability when cultured under replete (10% FBS) growth factor conditions, but a ~8% decrease under reduced (0.5% FBS) growth factor conditions. IL-6 stimulation did not impact SW620 cell growth. To understand the downstream cell signaling effects of IL-6 and CCL5 stimulation, we performed qPCR analysis on EMT and Wnt signaling markers in SW620 cells after 4-hour cytokine stimulation in media without growth factors (0% FBS). IL-6-stimulated cells exhibited a significant increase in SOCS3 and PTHLH while CCL5-stimulated cells exhibited a significant decrease in TCF7L1. Conclusions: Overall, these data indicate tumor-promoting paracrine signaling from adipose tissue may potentiate colon cancer growth in part via adipocyte-derived cytokine production. Further work to delineate the mechanisms through which such paracrine signaling acts will be important to develop interventions to reduce the growing burden of obesity-driven colon cancer. Citation Format: Nivetha S. Ramasamy, Elaine M. Glenny, Qing Shi, Stephen D. Hursting. Paracrine adipocyte signaling promotes colorectal cancer growth in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3128.

Adiponectin and cardiometabolic trait and mortality: where do we go?

Adiponectin is an adipocyte-derived cytokine known for its cardioprotective effects in preclinical studies. Early epidemiologic studies replicated these findings and drew great interest. Subsequent large-scale prospective cohorts, however, showed that adiponectin levels seemed not to relate to incident coronary artery disease (CAD). Even more surprisingly, a paradoxical increase of all-cause and cardiovascular (CV) mortality with increased adiponectin levels was reported. The adiponectin-mortality paradox has been explained by some groups asserting that adiponectin secretion is promoted by elevated natriuretic peptides (NP). Other groups have proposed that adiponectin is elevated due to adiponectin resistance in subjects with metabolic syndrome or heart failure (HF). However, there is no unifying theory that can clearly explain this paradox. In patients with HF with reduced ejection fraction (HFrEF), stretched cardiomyocytes secrete NPs, which further promote release of adiponectin from adipose tissue, leading to adiponectin resistance. On the other hand, adiponectin biology may differ in patients with heart failure with preserved ejection fraction (HFpEF), which constitutes 50% of all of HF. Most HFpEF patients are obese, which exerts inflammation and myocardial stiffness, i.e. likely to prevent myocardial stretch and subsequent NP release. This segment of the patient population may display different adiponectin biology from its HFrEF counterpart. Dissecting the adiponectin-mortality relationship in terms of different HF subtypes may help to comprehensively understand this paradox. Mendelian randomization (MR) analyses claimed that adiponectin levels are not causally related to CAD or metabolic syndrome. Results from MR studies, however, should be interpreted with great caution because the underlying history of CAD or CHF was not taken into account in these analyses, an issue that may substantially confound the results. Here, we discuss many aspects of adiponectin; cardiometabolic traits, therapeutic interventions, and the ongoing debate about the adiponectin paradox, which were recently described in basic, epidemiologic, and clinical studies.

Rodent Models of Spondyloarthritis Have Decreased White and Bone Marrow Adipose Tissue Depots.

Bone marrow adipose tissue (BMAT) has recently been recognized as a distinct fat depot with endocrine functions. However, if and how it is regulated by chronic inflammation remains unknown. Here, we investigate the amount of white fat and BMAT in HLA-B27 transgenic rats and curdlan-challenged SKG mice, two well-established models of chronic inflammatory spondyloarthritis (SpA). Subcutaneous and gonadal white adipose tissue and BMAT was reduced by 65-70% and by up to 90% in both experimental models. Consistently, B27 rats had a 2-3-fold decrease in the serum concentrations of the adipocyte-derived cytokines adiponectin and leptin as well as a 2-fold lower concentration of triglycerides. The bone marrow of B27 rats was further characterized by higher numbers of neutrophils, lower numbers of erythroblast precursors, and higher numbers of IL-17 producing CD4+ T cells. IL-17 concentration was also increased in the serum of B27 rats. Using a cell culture model, we show that high levels of IL-17 in the serum of B27 rats negatively impacted adipogenesis (-76%), an effect that was reversed in the presence of neutralizing anti-IL-17 antibody. In summary, these findings show BMAT is severely reduced in two experimental models of chronic inflammatory SpA and suggest that IL-17 is involved in this process.

Increased Expression of Retinol-Binding Protein 4 in Ovarian Endometrioma and Its Possible Role in the Pathogenesis of Endometriosis.

Although endometriosis is a benign disease characterized by the presence of endometrial tissues outside the uterus, ectopic endometrial cells can exhibit malignant biological behaviors. Retinol-binding protein4 (RBP4) is a novel adipocyte-derived cytokine, which has important roles in regulating insulin sensitivity and energy metabolism. RBP4 is a potent modulator of gene transcription, and acts by directly controlling cell growth, invasiveness, proliferation and differentiation. Here, we evaluated the possible role of RBP4 in the pathogenesis of endometriosis. We compared the levels of RBP4 in the tissues and peritoneal fluid (PF) of women with and without endometriosis and evaluated the in vitro effects of RBP4 on the viability, invasiveness, and proliferation of endometrial stromal cells (ESCs). RBP4 levels were significantly higher in the PF of the women in the endometriosis group than in the controls. RBP4 immunoreactivity was significantly higher in the ovarian endometriomas of women with advanced stage endometriosis than those of controls. In vitro treatment with human recombinant-RBP4 significantly increased the viability, bromodeoxyuridine expression, and invasiveness of ESCs. Transfection with RBP4 siRNA significantly reduced ESC viability and invasiveness. These findings suggest that RBP4 partakes in the pathogenesis of endometriosis by increasing the viability, proliferation and invasion of endometrial cells.

Resistin; a physiological overview

Resistin is a novel peptide which is known to be an adipocyte-derived cytokine. It belongs to resistin like molecule family. It was revealed that resistin is an important link between obesity, insulin resistance and type 2 Diabetes Mellitus. After that, several investigations showed the important physiological activities of resistin apart from its role in insulin resistance and diabetes in many pathological conditions as cardiovascular diseases (as coronary thrombosis), malignancy, endothelial dysfunction, hypertension, thrombosis, angiogenesis, inflammation, asthma, autoimmune disease, atherosclerosis and chronic kidney disease. Moreover, several studies have underlined it’s participation in reproductive functions. It is well known that resistin expression is recorded in murine white adipose tissue but in human its expression is noticed in monocytes and macrophages. The mechanism of action, receptors and signaling pathways are beginning to be distinguished. In the present review, the present data concerning the discovery, structure, tissue distribution and functional role of resistin is summarized.

Obesity, kidney dysfunction, and inflammation: interactions in hypertension.

Obesity contributes 65-75% of the risk for human primary (essential) hypertension (HT) which is a major driver of cardiovascular and kidney diseases. Kidney dysfunction, associated with increased renal sodium reabsorption and compensatory glomerular hyperfiltration, plays a key role in initiating obesity-HT and target organ injury. Mediators of kidney dysfunction and increased blood pressure include (i) elevated renal sympathetic nerve activity (RSNA); (ii) increased antinatriuretic hormones such as angiotensin II and aldosterone; (iii) relative deficiency of natriuretic hormones; (iv) renal compression by fat in and around the kidneys; and (v) activation of innate and adaptive immune cells that invade tissues throughout the body, producing inflammatory cytokines/chemokines that contribute to vascular and target organ injury, and exacerbate HT. These neurohormonal, renal, and inflammatory mechanisms of obesity-HT are interdependent. For example, excess adiposity increases the adipocyte-derived cytokine leptin which increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway. Excess visceral, perirenal and renal sinus fat compress the kidneys which, along with increased RSNA, contribute to renin-angiotensin-aldosterone system activation, although obesity may also activate mineralocorticoid receptors independent of aldosterone. Prolonged obesity, HT, metabolic abnormalities, and inflammation cause progressive renal injury, making HT more resistant to therapy and often requiring multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes, and inflammation. More effective anti-obesity drugs are needed to prevent the cascade of cardiorenal, metabolic, and immune disorders that threaten to overwhelm health care systems as obesity prevalence continues to increase.

Crosstalk between brown adipocytes and macrophages

There are two types of adipose tissue (AT): white adipose tissue (WAT), which is involved in energy storage, and brown adipose tissue (BAT) that dissipates energy in the form of heat (non‐shivering‐thermogenesis). AT acts as an endocrine organ that secretes hormones or cytokines known as adipokines. Dysregulation of secretion of adipokines, caused by adipocyte hypertrophy and dysfunction, is directly linked to chronic inflammation. Inflammation of WAT during obesity leads to increased expression and secretion of pro‐inflammatory cytokines such as TNF‐α, IL‐6, MCP‐1 (Villarroya et al., 2018). This increase in adipocyte‐derived pro‐inflammatory cytokines causes a dramatic shift in the immune cell population, especially in macrophages, and leads to metaflammation. On the other hand, adipose tissue‐resident macrophages (ATMs) play a very important role in innervation and energy expenditure of BAT (Wolf et al., 2017). All these facts are the reason why we investigate signal pathways as well as secreted molecules that play a role in the communication between brown adipocytes and ATM. We are focusing on the crosstalk between brown adipocytes and macrophages. We used three in vitro models: direct co‐cultivation, transwell system and conditioned medium. In our experiments, we used two different types of macrophages: fetal liver derived macrophages (FLDMs) and bone marrow derived macrophages (BMDMs). We found that macrophages regulate expression of adipogenic (e.g. PPARg) as well as thermogenic (e.g. UCP1) markers. Interestingly, we observed that brown adipocytes produce different factors that regulate macrophages and their pro‐ versus anti‐inflammatory phenotype. These data indicate a crosstalk between macrophages and adipocytes in BAT.Support or Funding InformationInstitute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany Research Training Group 1873, University of Bonn, 53127 Bonn, Germany

Adipose-Derived Molecules-Untouched Horizons in Alzheimer's Disease Biology.

The global incidence of Alzheimer’s disease (AD) is on the rise with the increase in obesity and metabolic disease epidemic. Obesity is co-morbid with the increase in mass of adipose tissue, which secretes numerous molecules that are biologically important. Obesity and its associated conditions are perhaps involved in the causative pathway of AD. Immunologically important cytokines such as IL-1β, IL-10, and IL-18, which are released by adipose tissue, are also found to be associated with AD. Besides, the expression of IL-6, IFNγ, and TNF alpha are also associated with AD. Ang-I and Ang-II are found to mediate the progression of AD. Complement factors B, C4b, and H are differentially expressed in AD. Overall, several adipocyte-derived cytokines are found to be dysregulated in AD, and their role in AD remains to be studied. The induction of autophagy is a very promising strategy in the treatment of AD. A variety of adipose-derived molecules have been shown to modulate autophagy. However, very little literature is available on the role of adipose-derived molecules in inducing autophagy in microglial cells of AD. Understanding the role of adipose-derived molecules in the development of AD, especially in the induction of autophagy, would open up new avenues in devising strategies for the treatment of AD.

Cyclin-Dependent Kinase 5 Inhibitor Butyrolactone I Elicits a Partial Agonist Activity of Peroxisome Proliferator-Activated Receptor γ.

Adiponectin is an adipocyte-derived cytokine having an insulin-sensitizing activity. During the phenotypic screening of secondary metabolites derived from the marine fungus Aspergillus terreus, a poly cyclin-dependent kinase (CDK) inhibitor butyrolactone I affecting CDK1 and CDK5 was discovered as a potent adiponectin production-enhancing compound in the adipogenesis model of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). CDK5 inhibitors exhibit insulin-sensitizing activities by suppressing the phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ). However, the adiponectin production-enhancing activities of butyrolactone I have not been correlated with the potency of CDK5 inhibitor activities. In a target identification study, butyrolactone I was found to directly bind to PPARγ. In the crystal structure of the human PPARγ, the ligand-binding domain (LBD) in complex with butyrolactone I interacted with the amino acid residues located in the hydrophobic binding pockets of the PPARγ LBD, which is a typical binding mode of the PPARγ partial agonists. Therefore, the adiponectin production-enhancing effect of butyrolactone I was mediated by its polypharmacological dual modulator activities as both a CDK5 inhibitor and a PPARγ partial agonist.

The Role of Adiponectin in Maintaining Metabolic Homeostasis.

Adiponectin is an adipocyte-derived cytokine closely associated with obesity, altered body adipose tissue distribution, insulin resistance, and cardiovascular diseases. Evidence from animal and human studies demonstrate that adiponectin plays an important role in the regulation of glucose and lipid metabolism. Adiponectin increases insulin sensitivity and improves systemic lipid metabolism. Although research efforts on adiponectin mostly aim towards its endocrine functions, this adipocyte-derived molecule also has profound autocrine and paracrine functions. In this review, our aim is to discuss the role of adiponectin in maintaining metabolic homeostasis and its association with cardiovascular health. The proper identification of these roles is of great importance, which has the potential to identify a wealth of novel targets for the treatment of diabetes and related cardio-metabolic diseases.

CTRP9 induces iNOS expression through JAK2/STAT3 pathway in Raw 264.7 and peritoneal macrophages

The C1q tumor necrosis factor (TNF)-related proteins 9 (CTRP9), an adipocyte-derived cytokine, affects a number of physiological processes, including immune function and inflammation. We investigated whether CTRP9 affects the expression of inflammation-related genes in Raw 264.7 and peritoneal macrophages. The CTRP9-induced expression of iNOS increased in a time- and dose-dependent manner. LPS and CTRP9 promote the expression of iNOS jointly in Raw 264.7 and peritoneal macrophages. CTRP9 induced the phosphorylation of JAK2 and STAT3 in Raw 264.7 and peritoneal macrophages. VX509 (JAK2 inhibitor) reduced the CTRP9-induced iNOS protein production. In addition, the CTRP9-induced phosphorylation of JAK2 and STAT3 was dramatically reduced by VX509. Collectively, these results suggest that JAK2/STAT3 signaling is involved in the CTRP9-induced expression of iNOS.

Dysregulated homeostatic pathways in sarcopenia among frail older adults.

Sarcopenia, a core feature of the physical frailty syndrome, is characterized by multisystem physiological dysregulation. No study has explored qualitatively the hierarchical network of relationships among different dysregulated pathways involved in the pathogenesis of sarcopenia. We used 40 blood biomarkers belonging to community‐dwelling prefrail and frail older persons to derive measures of multiple physiological pathways, and structural equation modeling to generate path network models of the multisystem physiological dysregulations associated with muscle mass and function (MMF). Insulin–leptin signaling and energy regulation, anabolic sex steroid regulation (testosterone, leptin), and tissue oxygenation (hemoglobin, red cell count) appear to be primary mediating factors exerting direct influences on MMF. There was additionally secondary mediatory involvement of myocyte‐ and adipocyte‐derived cytokines, hypothalamic pituitary adrenal (HPA) stress hormones (cortisol, DHEAS), glomerular function, and immune cell regulatory and inflammatory cytokines and glycoproteins. We conclude that within a hierarchical network of multisystem physiological dysregulations in sarcopenia, dysregulated anabolic and catabolic pathways via sex steroids and insulin–leptin dual signaling and tissue hypoxemia are primary physiological dysregulations responsible for sarcopenia and frailty.

Globular adiponectin acts as a melanogenic signal in human epidermal melanocytes.

Adiponectin is an adipocyte-derived cytokine that circulates as a full-length protein and a fragment containing the globular domain of adiponectin (gAd). A recent study has reported the antimelanogenic effects of full-length adiponectin. To examine the involvement of gAd in melanogenesis and its mechanisms of action. The effects of gAd on melanogenesis and its mechanisms of action were investigated in human epidermal melanocytes and reconstructed epidermis, including melanin content, cellular tyrosinase activity, cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activity, expression and phosphorylation of signalling molecules. Exogenous gAd increased melanin content, and the mRNA levels of microphthalmia-associated transcription factor (MITF) and its downstream genes TRP1, but not TRP2, were increased by gAd. However, cAMP production and PKA activity were not affected by gAd. Moreover, attempts to elucidate the underlying mechanism behind the gAd-mediated effect revealed that gAd could regulate melanogenesis by upregulating MITF through phosphorylation of the cAMP response element-binding protein (CREB). In addition, upregulation of MITF was mediated by activation of adenosine monophosphate-activated protein kinase (AMPK)-p38 mitogen-activated protein kinase (MAPK) signalling. Taken together, these findings indicate that promotion of melanogenesis by gAd occurs through increased expression of MITF, which is mediated by activation of the AMPK-p38 MAPK-CREB pathway. These findings suggest that gAd contributes to epidermal homeostasis via its effect on melanocyte biology, and products of adipose tissue could affect epidermal biology.

Roles and mechanisms of leptin in osteogenic stimulation in cervical ossification of the posterior longitudinal ligament

BackgroundHyperleptinemia is a common feature of obese people, and leptin, an adipocyte-derived cytokine, is believed to be an important factor in the pathogenesis of cervical ossification of the posterior longitudinal ligament(C-OPLL). So this research was to identify the relation between the serum leptin and bone metabolic markers and how the leptin induced osteogenic effect in C-OPLL.MethodsSixty-four samples were selected to determine the concentration of leptin, insulin, and alkaline phosphatase. And the association of leptin with these factors was also examined. We also evaluate the effect of leptin on the development of C-OPLL and further explored the possible underlying mechanism in vitro.ResultsWe found that serum leptin concentrations were higher in females than in males. Serum leptin and ALP concentrations were increased significantly in C-OPLL females compared to non-OPLL females. In OPLL subjects, the serum leptin concentration corrected for body mass index correlated negatively with the ALP concentrations. In C-OPLL cells, leptin treatment led to a significant increase in mRNA expressions of ALP and OCN and formation of mineralized nodule. Our experiments reported here that osteogenic effect of leptin in C-OPLL cells could be mediated via ERK1/2, p38 MAPK, and/or JNK signaling pathways.ConclusionsFrom this research, we got that leptin treatment led to a significant increase in mRNA expressions of ALP and OCN and formation of mineralized nodule. And the osteogenic effect of leptin in C-OPLL cells could be mediated via ERK1/2, p38 MAPK, and/or JNK signaling pathways.

Adiponectin Attenuates NLRP3 Inflammasome by Modulating AMPK-ROS Pathway

Adiponectin is an adipocyte-derived cytokine that exerts antidiabetic and anti-atherogenic properties and has been shown to enhance insulin sensitivity and promote lipid metabolism in obesity-linked diseases through the anti-inflammatory action. However, the detail mechanism of the anti-inflammatory effect of adiponectin remains unknown. In the present study, we found that in 50 patients with newly diagnosed type 2 diabetes (T2D), the circulating levels of adiponectin correlate inversely with IL-18 (r = -0.64, P &amp;lt; 0.01). On this basis and in vitro, we demonstrated that adiponectin significantly attenuates IL-18 secreation from LPS+PA-induced THP-1 cells (P &amp;lt; 0.01). In addition, we reported here that adiponectin inhibits IL-18 by suppressing NLRP3 inflammasome activation. Importantly, we found that adiponectin suppressed LPS+PA (palmitic acid)-induced ROS production, which is required for NLRP3 inflammasome activation. Furtherly, we, for the first time, described that adiponectin attenuates NLRP3 inflammasome activation by modulating AMPK-ROS signaling pathway, as the reason that suppression of AMPK with small interfering RNA (siRNA) abolished adiponectin-mediated inhibition of ROS and NLRP3 inflammasome. In vivo studies with STZ-induced diabetic mice models, we showed that adenovirus-mediated overexpression of adiponectin decreased triglycerides and cholesterol in the serum of diabetic mice. Meanwhile, adiponectin decreased CD68 positive macrophages infiltrated in adipose tissue. Furthermore, adiponectin reduced activation of NLRP3 inflammasome in liver and white adipose tissue (WAT) with western blot assay. Taken together, we report a new mechanism that adiponectin alleviates inflammation through NLRP3 inflammasome inhibition by modulating AMPK-ROS pathway, which may have therapeutic implications for T2D and the related metabolic diseases. Disclosure F. Wang: None. L. Wang: None. Y. Liu: None. J. Yuan: None. Z. Mo: None.