Leptin Expression Research Articles

Leptin plays a role in the multiplication of and inflammation in ovarian granulosa cells in polycystic ovary syndrome through the JAK1/STAT3 pathway

ObjectivesThe authors determined the level of Expression of Leptin (LEP) in Polycystic Ovary Syndrome (PCOS) patients with or without obesity and in GCs treated with insulin. MethodsLEP expression was first assessed in ovary cortex specimens collected from women with PCOS with or without obesity as well as from healthy controls. Ovarian Granulosa Cells (OGCs) induced by insulin extracted from a mouse model were used in further functional research. ResultsReal-time PCR and western blotting indicated that LEP expression was upregulated in GCs induced by insulin, in comparison with that in GCs not induced by insulin. Furthermore, the knockdown of LEP resulted in a reduction in growth and multiplication and an increase in apoptosis and inflammation in GCs induced by insulin. Next, the authors evaluated the effect of LEP on three key pathways of inflammation (MAPK, NF-kB, and JAK1/STAT3); results showed that the JAK1/STAT3 pathway was induced by LEP knockdown, as evidenced by the upregulation of phosphor-JAK1, phosphor-STAT3, and nuclear STAT3 expression. Administration of curcumin, a specific inhibitor of STAT3, counteracted the effect of LEP knockdown on cell inflammation and apoptosis. ConclusionThe present data suggest that upregulation of LEP expression in the PCOS granulosa cell model is essential for reducing apoptosis and inflammation by modulating the JAK1/STAT3 pathway axis.

Nine kinds of novel cytokines identified in children with lead exposure

Lead (Pb) is a neurotoxic heavy metal element with many recognized adverse health side effects, and its main target of lead toxicity is the central nervous system. The mechanism of lead toxicity is still uncertain. However, there are few studies investigated the cytokines changes caused by lead exposure in children. The BLLs was quantified using flame atomic absorption spectroscopy. The novel cytokines were detected by RayBio@ Human Cytokine Antibody Array. A total of 4 children with elevated blood lead levels (BLLs) and 4 children with low BLLs were chosen in the study. Volcano plot analysis was performed to identify significant proteins, with the criteria: P value <0.05 and log2 fold change >1. The mean BLLs of children with elevated BLLs (5.675±1.018 μg/dL) has significant difference compared with those with low BLLs (1.975±0.3966 μg/dL) (P=0.0148, t=3.385). And 9 kinds of novel cytokines were identified. The expression of IL-6, IL-8 and IL-17 was significantly up-regulated, while the expression of BDNF, BMP-4, IGF-1, IL-7, IL-10 and Leptin was significantly down-regulated.

Correlations of Omentin-1 and Leptin with Bone Metabolism and Plasma Glucose Upon Type 2 Diabetes Mellitus and Osteoporosis.

The goal was to investigate the correlations of peripheral blood Omentin-1 and leptin (LEP) levels with bone metabolism and plasma glucose in patients with type 2 diabetes mellitus (T2DM) complicated with oste-oporosis (OP). One hundred patients with T2DM admitted from September 2019 to September 2021 were divided into group A (n = 36, OP with T-score ≤ -2.5), group B (n = 50, osteopenia with T-score between -1 and -2.5), and group C (n = 14, non-OP with T-score > -1) according to the values of bone mineral density (BMD). Thirty healthy adults physically examined in the same period were selected as group D. The levels of peripheral blood Omentin-1 and LEP, bone metabolism, and plasma glucose were compared among the four groups. The correlations of peripheral blood Omentin-1 and LEP levels with bone metabolism and plasma glucose were explored by Pearson's analysis. In group A, the levels of Omentin-1 and LEP in peripheral blood were lowest, the serum levels of beta C-terminal cross-linked telopeptides of type I collagen (β-CTX) and osteocalcin (OCN) were highest, the serum level of total N-terminal propeptide of type I procollagen (tPINP) was lowest, and the levels of fasting plasma glucose (FPG), 2-hours postprandial plasma glucose (2hPG) and glycosylated hemoglobin A1c (HbA1c) were highest, se-quentially followed by those of group B, group C, and group D (p < 0.05). Omentin-1 and LEP in peripheral blood were negatively correlated with β-CTX, OCN, 2hPG, and HbA1c and positively correlated with tPINP and FPG (p < 0.05). The expressions of Omentin-1 and LEP in peripheral blood have correlations with bone metabolism and plasma glucose in patients with T2DM complicated with OP.

Correlation between LRG1 and Adipokines in Psoriasis

Background and Objective. Patients with psoriasis may exhibit abnormal changes in serum adipokine levels, which are often related to disease severity of the disease. Leucine‐rich alpha‐2‐glycoprotein 1 (LRG1) is an acute‐phase inflammatory protein that may be linked to adipokines in psoriasis. In this study, we evaluated the differences in the expression of adipokines and LRG1 between patients with psoriasis and healthy individuals, analyzed the correlation between the expression of LRG1 and adipokines, and explored their relationship with psoriatic lesions. Methods. In this cross‐sectional study, patients with psoriasis (n = 54) and healthy controls (n = 26) were enrolled, and their clinical characteristics were recorded. Fasting venous blood samples were collected from each participant. The serum concentrations of leptin, resistin, adiponectin, and LRG1 in each sample were measured using the enzyme‐linked immunosorbent assay. Results. The study included 54 patients with psoriasis vulgaris and 26 healthy controls. The serum levels of LRG1, leptin, and resistin were significantly higher in patients with psoriasis than in healthy controls. Conversely, adiponectin levels were significantly lower in patients with psoriasis. The study showed that LRG1 expression was positively correlated with leptin and resistin expression but negatively correlated with adiponectin expression. Interestingly, only leptin, resistin, and LRG1 expression showed a linear correlation with the Psoriasis Area and Severity Index (PASI). When we categorized patients with psoriasis based on their LRG1 levels, we observed that the group with high LRG1 levels showed a higher PASI. Conclusions. We observed a significant correlation between LRG1 and adipokine expression in patients with psoriasis. In addition, the expression levels of LRG1, leptin, and resistin were observed to be correlated with the severity of psoriasis. We believe that the occurrence and development of psoriasis are collectively influenced by LRG1 and leptin/resistin expression.

The Effect of Supplementation with β-Hydroxy-β-Methylbutyric Acid (HMB) to Pregnant Sows on the Mucosal Structure, Immunolocalization of Intestinal Barrier Proteins, VIP and Leptin in the Large Intestine in their Offspring

Abstract The large intestine epithelium plays an important role in water absorption and participates in fluid, acid-base and electrolyte balance, and the removal of waste products. The large intestine is rich in microorganism-presented enzyme activity. Apart from energy supply, the colon also participates in the synthesis of trophic factors and the modulation of the immune system and the systemic inflammatory response. The current study investigated the effects of dietary HMB administration to pregnant sows on the postnatal development of the colon in their offspring, at weaning. From the 70th to the 90th day of gestation, sows received either a basal diet (n = 12) or the basal diet supplemented with HMB (n = 12) at a dose of 0.2 g/kg of body weight/day. Maternal HMB treatment increased serum IgG and glucose concentrations and decreased serum urea concentration in the piglets. Basal histomorphometric analysis of offspring large intestines showed that prenatal HMB treatment led to a reduction in the thickness of the mucosa, submucosa and both types of myenterons, as well as reduced crypt thickness. The immunoreaction performed to mark T0 lymphocytes and total T lymphocytes in the colon wall showed that prenatal HMB treatment decreased the number of both types of lymphocytes. Greater expression for cadherin was found in the colon of piglets delivered by the HMB-treated sows. The expression of both tight junction proteins (occludin and claudin-3), as well as that of leptin, was stronger in the HMB-treated group. Vasoactive intestinal peptide (VIP) expression was stronger in the submucosal plexuses in the HMB maternal treated piglets, while no changes were observed in the myenteric plexuses. The results obtained indicate that the administration of HMB to pregnant sows significantly influenced the expression of leptin, VIP and some proteins of the intestinal barrier in their offspring, with less influence on large intestine basal morphology.

Paternal dietary ratio of n-6: n-3 polyunsaturated fatty acids programs offspring leptin expression and gene imprinting in mice.

This study determined the effects of the paternal dietary ratio of n-6: n-3 polyunsaturated fatty acids (PUFAs) on leptin expression in the offspring and associated gene imprinting in a mouse model. Three- to four-week-old male C57BL/6J mice (F0) were fed an n-3 PUFA-deficient (n-3 D) diet, a diet with normal n-3 PUFA content (n-3 N; n-6: n-3 = 4.3:1), or a diet with a high n-3 PUFA content (n-3 H; n-6: n-3 = 1.5:1) for 8 weeks. Two subsequent generations were generated by mating F0 and F1 male mice with 10-week-old virgin female C57 BL/6J mice, to produce F1 and F2 offspring. Compared to the paternal n-3 D diet, paternal n-3 N and n-3 H diets reduced adipose mRNA expression of leptin (Lep) and its plasma concentrations in juvenile F1 male and female offspring, and adult F1 male and F2 female offspring, with upregulated Lep receptor mRNA expression in the hypothalamus. Meanwhile, paternal n-3 N and n-3 H diets altered the expression of the imprinted genes H19, Igf2, Igf2r, Plagl1, Cdkn1c, Kcnq1ot1, Peg3, and Grb10 in the adipose tissue of juvenile and adult F1 males, with almost no effects on F1 females, while more effects were observed in the adult F2 females than F2 males. Principal component analysis verified that Plagl1, Cdkn1c, and Kcnq1ot1 contributed the most to variation in adipose tissue expression in all offspring. Some of these genes (Plagl1, Cdkn1c, Kcnq1ot1, Peg3, and Grb10) were altered by the paternal n-3 N and n-3 H diets in the F1 and F2 generation testes as well. Furthermore, adipose Lep expression was positively correlated with expressions of H19, Igf2r, Plagl1, and Kcnq1ot1 in juvenile F1 males and females, negatively correlated with the Kcnq1ot1 expression in adult F1 males, and positively correlated with the Plagl1 expression in adult F2 females. These data imply that paternal Plagl1, Cdkn1c, and Kcnq1ot1 might be part of the pathways involved in offspring leptin programming. Therefore, a lower ratio of n-6: n-3 PUFAs, with higher intake of n-3 PUFAs in paternal pre-conception, may help maintain the offspring's optimal leptin pattern in a sex-specific manner through multiple generations, and thereby, be beneficial for the offspring's long-term health.

Depletion of Zinc Causes Osteoblast Apoptosis with Elevation of Leptin Secretion and Phosphorylation of JAK2/STAT3.

Zinc (Zn) has been reported to mediate leptin secretion, and thus leptin can be an important candidate molecule linking Zn with bone formation. The present study investigated whether zinc deficiency induces leptin secretion by activating a JAK2/STAT3 signaling pathway and leads to osteoblastic apoptosis. MC3T3-E1 cells were incubated for 24 h in normal osteogenic differentiation medium (OSM) or OSM treated with either 1 μM (Low Zn) or 15 μM (High Zn) of ZnCl2 containing 5 μM TPEN (Zn chelator). Our results demonstrated that low Zn stimulated extracellular leptin secretion and increased mRNA and protein expression of leptin in osteoblastic MC3T3-E1 cells. The OB-Rb (long isoform of leptin receptor) expressions were also elevated in osteoblasts under depletion of Zn. Leptin-signaling proteins, JAK2 and p-JAK2 in the cytosol of low Zn osteoblast conveyed leptin signaling, which ultimately induced higher p-STAT3 expression in the nucleus. Apoptotic effects of JAK2/STAT3 pathway were shown by increased caspase-3 in low Zn osteoblasts as well as apoptotic morphological features observed by TEM. Together, these data suggest that low Zn modulates leptin secretion by activating JAK2/STAT3 signaling pathway and induces apoptosis of osteoblastic MC3T3-E1 cells.

AM-879, a PPARy non-agonist and Ser273 phosphorylation blocker, promotes insulin sensitivity without adverse effects in mice

Obesity is one of the main risk factors for type 2 diabetes, and peroxisome proliferator-activated receptor γ (PPARγ) is considered a promising pathway on insulin sensitivity and adipose tissue metabolism. The search for molecules acting as insulin sensitizers have increased, especially for molecules that block PPARγ-Ser273 phosphorylation, without reaching full agonism. We evaluated the in vivo effects of AM-879, a PPARγ non-agonist, and found that AM-879 exerts different effects in mice depending on the dose. At lower doses, this ligand decreased BAT, increased leptin and Crh expression. However, at a higher dose, it promoted improvement on insulin sensitivity, ameliorates expression of metabolism-related genes, decreased the expression of genes related to liver toxicity, maintaining body weight and adipocyte size. These results present a new lead molecule to ameliorates insulin resistance and confirm AM-879 as a PPARγ non-agonist which blocks Ser273 phosphorylation as a good strategy to modulate insulin sensitivity without developing the adverse effects promoted by PPARγ full agonists.

Musical therapy attenuates neuroma pain by modifying leptin expression

BackgroundAccumulating evidence reveals that music therapy appears to help patients with pain. However, there is a limited understanding of the underlying mechanisms. Several studies indicate that leptin level has a crucial relationship with acute and chronic pain. Herein, we evaluated the effects of music stimulation and the potential roles of adipokines (leptin) in pain behaviors.MethodsWe used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. Adult male Sprague–Dawley rats were randomly assigned to one of the three groups (n = 6):group 1 (GC), TNT with white noise; group 2(GM), TNT with music; and group 3(GH), TNT. White noise and music stimulation was given once a day following surgery until the end of the study (42nd day). Pain behavioral tests were carried out before surgery and on the 3rd, 10th, 14th, 21st, 28th, 35th, and 42nd days after surgery. At the end of the observation period, we analyzed the histological samples of blood, spinal cord, and prefrontal cortex to investigate the role of leptin in pain behaviors modulated by white noise and sound stimulation.ResultMusic therapy might improve the pain of TNT rats. Music stimulation ameliorated paw withdrawal thermal latency (PWTL) from the 3rd day after the surgery while the mechanical pain was improved 21 days after the operation.Music stimulation also increased leptin expression in the spinal cord, prefrontal cortex.White noise had no obvious effect.ConclusionMusic therapy might improve the pain of TNT rats. Besides, music stimulation ameliorated TNT-induced pain behaviors and affected leptin expression.

A new perspective: Fat tissue and adipokines in rheumatic heart valves.

To observe fat tissue and the expression of adipokines in rheumatic heart valves and explore the possible role of fat tissue and adipokines in the pathology of rheumatic heart disease (RHD). In this retrospective study, a total of 29 patients who received mitral valve replacement surgery were included. The study group consisted of 25 patients with RHD while the control group consisted of 4 patients with secondary mitral insufficiency caused by coronary heart disease (CAD). The clinical data of the patients including medical history, age, body mass index (BMI), fasting blood glucose (FBG), total triglycerides (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein(a) [apo(a)], apolipoprotein(b) [apo(b)] were collected and compared. Cardiac ultrasonography was used to assess valve conditions before surgery. The removed valves were collected. The hematoxylin-eosin (HE) staining, oil-red O staining, and Masson's trichrome staining were adopted to evaluate the histological changes in the mitral valve. Immunohistochemical (IMC) staining was performed to evaluate the expression of adiponectin, leptin, and chemerin. There was no significant difference in general information and blood lipid levels between the two groups (all p > .05). Preoperative ultrasonography showed adipose tissue in the mitral valve of RHD patients. In the study group, rheumatic mitral valve samples showed thickening, adherence at the junction of the leaflets, calcification, and yellowish or fat mass by naked observation. The HE staining showed that there was calcification, inflammatory cell infiltration, fibrous tissue arranged disorder, and neovascularization. The oil-red O staining suggested fatty infiltration. Masson's trichrome staining suggested disorderly arrangement of collagen fiber and elastic fiber in rheumatic lesions, and the lesions were dominated by collagen fiber hyperplasia and less elastic fiber hyperplasia. The results of IMC indicated that chemerin was not expressed in valves of the control group. Most of the valve samples from the study group also did not show leptin and the leptin was seen in only a few rheumatic mitral valves with vascular hyperplasia. Adiponectin was not found in the valves of the study group and the control group. Adipose tissue in the rheumatic mitral valve could be observed by ultrasound. The fat mass and adipokines existed in rheumatic mitral valves, the adipocytokine chemerin is involved in the progression of the pathology in RHD.

Leptin-producing monocytes in the airway submucosa may contribute to asthma pathogenesis

BackgroundObesity leads to an increase in the incidence and severity of asthma. Adipokines, such as leptin, secreted by adipocytes induce systemic inflammation, causing airway inflammation. We previously reported that leptin activates both inflammatory and structural cells, including lung fibroblasts. However, little is known about the differential leptin expression and responsiveness to leptin in asthmatic individuals and healthy controls (HC). In this study, we investigated the expression and origin of leptin in asthmatic airways. We also compared the effect of leptin on asthmatic and HC fibroblasts. MethodsLung specimens from asthmatic and non-asthmatic patients were analyzed by immunohistochemical staining using anti-leptin and anti-CD163 antibodies. Leptin mRNA and protein levels in human monocytes were detected by real-time PCR and western blotting and ELISA, respectively. We used flow cytometry to analyze asthmatic and HC lung fibroblasts for leptin receptor (Ob-R) expression. Further, we determined cytokine levels using cytometric bead array and ELISA and intracellular phosphorylation of specific signaling molecules using western blotting. ResultsAsthma specimens displayed accumulation of leptin-positive inflammatory cells, which were also positive for CD163, a high-affinity scavenger receptor expressed by monocytes and macrophages. Leptin expression was observed at both transcript and protein levels in human blood-derived monocytes. No significant differences were observed between asthmatic and HC lung fibroblasts in Ob-R expression, cytokine production, and intracellular phosphorylation of p38 mitogen-activated protein kinase. ConclusionsOur findings reveal similar responsiveness of control and asthmatic fibroblasts to leptin. However, the accumulation of inflammatory leptin-producing monocytes in the airway may contribute to the pathogenesis of asthma.

PSUN311 JTV-519 Alleviates the Impairment of FGF21 Axis Signaling after Spinal Cord Contusion in Mice

Abstract Spinal cord injury (SCI) causes adverse changes in body composition and metabolic profile due to dramatic loss of skeletal muscle mass and an extremely sedentary lifestyle. These abrupt and permanent changes increase the risk for cardiovascular disease, liver disorders, and type 2 diabetes compared to the general population. We have reported that metabolic dysregulation following SCI due to transection is associated with impaired fibroblast growth factor 21 (FGF21) and adiponectin (ADPN) signaling [1], two important regulators of metabolism [2, 3]. JTV519, which stabilizes ryanodine receptors and blocks calcium uptake via SERCA [4], has been reported to have a strong cardioprotective effect via stabilization of ryanodine receptor 2. We examined the effects of SCI caused by contusion (a more common cause of SCI), with or without JTV519 administration, on FGF21 and ADPN signaling in tissues collected from mice at 56 days after SCI. SCI reduced serum and hepatic mRNA levels of FGF21 by 75% and 45%, respectively, compared to sham mice. SCI also significantly diminished FGF21 receptor (FGF-R1) and coreceptor (beta-klotho, KLB) mRNA expression in adipose tissue. In addition, SCI decreased serum ADPN levels, particularly its high molecular weight (HMW) isoform which is the most potent form of the protein. These inhibitory effects were associated with decreased hepatic mRNA expression for PPARalpha (55%), type-2 adiponectin receptor (AdipoR2; 70%), and Glut4 (75%). In addition, SCI reduced mRNA expression of leptin (by 85%) and UCP1 (by 95%) in adipose tissue. In skeletal muscle (gastrocnemius), SCI lowered mRNA expression of PGC1alpha (by 38%), ADPN (by 80%), FGF-R1 (by 35%) and AdipoR1 (by 20%) compared to sham mice. Treating sham-mice with JTV519 upregulated FGF21 and ADPN serum and mRNA levels as well as the expression of the associated metabolic genes of interest (mentioned above). Likewise, SCI-mice treated with JTV519 also demonstrated upregulation of serum levels of FGF21, the HMW isoform of ADPN, and hepatic FGF21 mRNA expression compared to vehicle-treated SCI-mice. Decreased hepatic mRNA expression of PPARalpha, AdipoR2, Glut4 and FGF-R1 and KLB mRNA in adipose tissue were also reversed after JTV519 administration, with levels approximately equivalent to those observed in sham-vehicle treated mice but lower than sham-JTV519 treated mice. Moreover, JTV519 treatment protected against SCI-induced decreases of PGC1alpha, ADPN and FGF-R1 mRNA expression in the gastrocnemius. These data imply that JTV-519 is able to alleviate SCI-induced impairments of FGF21/ADPN signaling. Therefore, JTV519 could be a potential pharmacological agent to treat metabolic dysfunction after SCI.

A one month high fat diet disrupts the gut microbiome and integrity of the colon inducing adiposity and behavioral despair in male Sprague Dawley rats

High-fat diet (HFD) is associated with gut microbiome dysfunction and mental disorders. However, the time-dependence as to when this occurs is unclear. We hypothesized that a short-term HFD causes colonic tissue integrity changes resulting in behavioral changes. Rats were fed HFD or low-fat diet (LFD) for a month and gut microbiome, colon, and behavior were evaluated. Behavioral despair was found in the HFD group. Although obesity was absent, the HFD group showed increased percent weight gain, epididymal fat tissue, and leptin expression. Moreover, the HFD group had increased colonic damage, decreased expression of the tight junction proteins, and higher lipopolysaccharides (LPS) in serum. Metagenomic analysis revealed that the HFD group had more Bacteroides and less S24-7 which correlated with the decreased claudin-5. Finally, HFD group showed an increase of microglia percent area, increased astrocytic projections, and decreased phospho-mTOR. In conclusion, HFD consumption in a short period is still sufficient to disrupt gut integrity resulting in LPS infiltration, alterations in the brain, and behavioral despair even in the absence of obesity.

Serum leptin differs in children with obstructive sleep apnea: A meta-analysis and PRISMA compliant article.

Background:Obstructive sleep apnea (OSA) as an independent cardiovascular risk factor has been proposed, but the mechanisms underlying cardiovascular disease is far from being completely elucidated. Leptin, an inflammatory cytokine produced by adipocytes, contributes to the modulation of metabolism, respiratory control, and inflammation, which are factors associated with cardiovascular disease. Serum levels of leptin in children with OSA have shown conflicting results in previous studies.Methods:We performed a meta-analysis to clarify the correlation between leptin expression of the OSA patients following the PRISMA. PubMed, Embase, and Web of Science were systematically searched for relevant studies, and then independently screened by two researchers, and analyzed the data through STATA version 12.0.Results:In a total of 5 articles including 469 participants, the data analysis showed that serum leptin levels were elevated in children with OSA (MD, 6.36; 95% CI, 0.24–12.49, P < .001), compared to the control group. Subgroup analysis were performed based on body mass index. The results of subgroup analysis demonstrated that the serum leptin concentration was correlated with body mass index in children with OSA (MD, 9.70; 95% CI, 0.22–11.18, P < .001).Conclusions:The serum leptin levels were elevated in children with OSA, compared to the control group. It could add to our developing understanding of the pathogenesis and potential treatments for children with OSA, and help us to recognize the relevance of OSA in determining cardiovascular issues among children.

Effects of temperature on food intake and the expression of appetite regulators in three Characidae fish: The black-skirted tetra (Gymnocorymbus ternetzi), neon tetra (Paracheirodon innesi) and Mexican cavefish (Astyanax mexicanus)

The Characidae family of fish is composed of commercially important species for which little is known about the regulation of feeding. Fish are ectotherms so that their body temperature fluctuates with the temperature of the surrounding water. Changes in water temperature can thus have major effects on the physiology of fish, in particular their feeding. The mechanisms by which appetite is influenced by changes in temperatures in fish remain unclear. In this study, we examined the effects of temperature on feeding behavior, food intake and the expression of appetite regulators in three characid fish (black tetra, neon tetra and cavefish) by submitting them to four different temperatures for 2 weeks (20°C, 24°C, 28°C, 32°C). In all species, food intake increased with increasing temperature. In neon and black tetras, increasing temperatures decreased expressions of orexin and leptin and increased that of cocaine and amphetamine regulated transcript (CART). In cavefish, temperature had no effect on brain orexin, leptin or CART. In all three species, higher temperatures induced increases in intestine expression of cholecystokinin (CCK), but no effects were seen for intestine ghrelin and peptide YY expressions. Our results show that temperature affects feeding in Characidae fish and induces species-specific changes in the expression of appetite regulators.

Are we approaching a holistic view of leptin's role in arthritis?

Adipokines—in particular, leptin, the forerunner of this superfamily—are receiving increasing attention for their role in exerting both beneficial and harmful actions in musculoskeletal inflammatory diseases. Leptin has been extensively associated with cartilage metabolism and OA. OA human chondrocytes have been shown to produce higher levels of leptin than normal cartilage1, with the pattern of leptin expression related to the level of cartilage destruction2,3. Moreover, elevated leptin levels have been found in serum, IPFP, synovial tissues, and cartilage of OA patients compared with healthy controls4,5.

Decreased Expression of Leptin among Patients with Shoulder Stiffness.

Shoulder stiffness (SS) is a disease that is fibroblastic and inflammatory in nature. Leptin is an adipokine-mediating the fibroblastic and inflammatory processes of various diseases. Our study tried to investigate the role of leptin in SS pathogenesis. Subacromial bursa from stiff and non-stiff shoulders were obtained for reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunoblotting. Subacromial fluid was obtained for enzyme-linked immunosorbent assay. We showed that the expression level of leptin was lower in the subacromial bursae from the stiff shoulders in RT-PCR analysis (p < 0.001) and immunoblotting (p < 0.001). The concentration of leptin was also lower in the subacromial fluid derived from stiff shoulders. The leptin level in the subacromial fluid was positively associated with the constant score, total range of motion, flexion, abduction, and external rotation. The synovial fibroblasts derived from stiff shoulder-retrieved subacromial bursa were treated by 0, 1, and 3 μM leptin. Under RT-qPCR analysis, leptin was shown to dose-dependently decrease the transcription of IL-6, IL-10, and IL-13, but without impact on IL-1β and IL-4 (p < 0.001, p = 0.001, p = 0.001, p = 0.137, and p = 0.883 by ANOVA test, respectively). These results shed light on the role of leptin in orchestrating the disease processes of SS.

Alcohol self-administration and nicotine withdrawal alter biomarkers of stress and inflammation and prefrontal cortex changes in Gβ subunits

ABSTRACT Background: Although alcohol and nicotine are often used together, the biological consequences of these substances are not well understood. Identifying shared targets will inform cessation pharmacotherapies and provide a deeper understanding of how co-use of alcohol and nicotine impacts health, including biomarkers of stress and inflammation. Objective: We examined the effects of nicotine exposure and withdrawal on alcohol self-administration (SA), stress and inflammatory biomarkers, and a G-protein coupled receptor subunit (Gβ) in brain areas associated with drug use. Methods: Male rats were trained to SA alcohol and then received a nicotine pump (n = 7–8 per group). We assessed alcohol intake for 12 days during nicotine exposure and then following pump removal to elicit withdrawal. After the behavioral studies, we assessed plasma leptin, corticosterone, and interleukin-1β (IL-1β), and Gβ protein expression in the amygdala, nucleus accumbens (NAc), and prefrontal cortex (PFC). Results: Nicotine exposure or withdrawal did not alter alcohol intake (p > .05). Alcohol and nicotine withdrawal elevated corticosterone levels (p = .015) and decreased Gβ levels in the PFC (p = .004). In the absence of nicotine, alcohol SA suppressed IL-1β levels (p = .039). Chronic exposure to nicotine or withdrawal during alcohol SA did not alter leptin levels or Gβ expression in the amygdala or NAc (p’s > .05). Conclusions: The combination of alcohol SA and nicotine withdrawal produced a persistent increase in stress biomarkers and a suppression in Gβ expression in the PFC, providing an important first step toward understanding the common biological mechanisms of alcohol/nicotine misuse.

Paeoniflorin Ameliorates Colonic Fibrosis in Rats with Postinfectious Irritable Bowel Syndrome by Inhibiting the Leptin/LepRb Pathway.

Postinfectious irritable bowel syndrome (PI-IBS) is a highly prevalent gastrointestinal disorder associated with immune dysregulation and depression- and anxiety-like behaviors. Through traditional medicine, the active ingredient of Paeoniae Radix called paeoniflorin (PF) was previously found to prevent the symptoms of PI-IBS. However, there is limited information on the effects of PF on intestinal function and depression- and anxiety-like symptoms in PI-IBS animal models. Here, we aimed to determine the effects of PF treatment on the symptoms of PI-IBS in a rat model. The PI-IBS rat model was established via early postnatal sibling deprivation (EPSD), trinitrobenzenesulfonic acid (TNBS), and chronic unpredictable mild stress (CUMS) stimulation and then treated with different dosages of PF (10, 20, and 40 mg/kg) and leptin (1 and 10 mg/kg). The fecal water content and body weight were measured to evaluate the intestinal function, while the two-bottle test for sucrose intake, open field test (OFT), and elevated plus maze test (EMT) were performed to assess behavioral changes. The serum leptin levels were also measured using an enzyme-linked immunosorbent assay. Furthermore, the expressions of leptin and its receptor, LepRb, were detected in colonic mucosal tissues through an immunohistochemical assay. The activation of the PI3K/AKT signaling pathway and the expression of brain-derived neurotrophic factor (BDNF) were also detected via western blotting. After the experimental period, the PI-IBS rats presented decreased body weight and increased fecal water content, which coincided with elevated leptin levels and heightened depression- and anxiety-like behaviors (e.g., low sucrose intake, less frequency in the center areas during OFT, and fewer activities in the open arms during EMT). However, the PF treatment ameliorated these observed symptoms. Furthermore, PF not only inhibited leptin/LepRb expression but also reduced the PI3K/AKT phosphorylation and BDNF expression in PI-IBS rats. Notably, cotreatment with leptin (10 mg/kg) reduced the effects of PF (20 mg/kg) on colonic fibrosis, leptin/LepRb expression, and PI3K/AKT activation. Therefore, our findings suggest that leptin is targeted by PF via the leptin/LepRb pathway, consequently ameliorating the symptoms of PI-IBS. Our study also contributes novel insights for elucidating the pharmacological action of PF on gastrointestinal disorders and may be used for the clinical treatment of PI-IBS in the future.

Inhibitory Effect of Bacterial Lysates Extracted from Pediococcus acidilactici on the Differentiation of 3T3-L1 Pre-Adipocytes.

Postbiotics, including bacterial lysates, are considered alternatives to probiotics. The aim of the current study was to investigate the effect of bacterial lysates (BLs) extracted from Pediococcus acidilactici K10 (K10 BL) and P. acidilactici HW01 (HW01 BL) on the differentiation of 3T3-L1 pre-adipocytes. Both K10 and HW01 BLs significantly reduced the accumulation of lipid droplets and the amounts of cellular glycerides in 3T3-L1 cells (p < 0.05). However, another postbiotic molecule, peptidoglycan of P. acidilactici K10 and P. acidilactici HW01, moderately inhibited the accumulation of lipid droplets, whereas heat-killed P. acidilactici did not effectively inhibit the lipid accumulation. The mRNA and protein levels of the transcription factors, peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α, responsible for the differentiation of 3T3-L1 cells, were significantly inhibited by K10 BL and HW01 BL (p < 0.05). Both K10 and HW01 BLs decreased adipocyte-related molecules, adipocyte fatty acid-binding protein and lipoprotein lipase, at the mRNA and protein levels. Furthermore, both K10 and HW01 BLs also downregulated the mRNA expression of leptin, but not resistin. Taken together, these results suggest that P. acidilactici BLs mediate anti-adipogenic effects by inhibiting adipogenic-related transcription factors and their target molecules.