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Objective Extensive research has explored the link between saturated fatty acids (SFAs) and cardiovascular diseases, alongside other biological dysfunctions. Yet, their association with cancer risk remains a topic of debate among scholars. The present study aimed to elucidate this association through a robust meta-analysis. Methods PubMed, Embase, Cochrane Library, and Web of Science databases were searched systematically to identify relevant studies published until December 2023. The Newcastle-Ottawa Scale was used as the primary metric for evaluating the quality of the included studies. Further, fixed- or random-effects models were adopted to determine the ORs and the associated confidence intervals using the Stata15.1 software. The subsequent subgroup analysis revealed the source of detection and the cancer types, accompanied by sensitivity analyses and publication bias evaluations. Results The meta-analysis incorporated 55 studies, comprising 38 case-control studies and 17 cohort studies. It revealed a significant positive correlation between elevated levels of total SFAs and the cancer risk (OR of 1.294; 95% CI: 1.182–1.416; P- value less than 0.001). Moreover, elevated levels of C14:0, C16:0, and C18:0 were implicated in the augmentation of the risk of cancer. However, no statistically significant correlation of the risk of cancer was observed with the elevated levels of C4:0, C6:0, C8:0, C10:0, C12:0, C15:0, C17:0, C20:0, C22:0, and C24:0. Subgroup analysis showed a significant relationship between excessive dietary SFA intake, elevated blood SFA levels, and heightened cancer risk. Increased total SFA levels correlated with higher risks of breast, prostate, and colorectal cancers, but not with lung, pancreatic, ovarian, or stomach cancers. Conclusion High total SFA levels were correlated with an increased cancer risk, particularly affecting breast, prostate, and colorectal cancers. Higher levels of specific SFA subtypes (C14:0, C16:0, and C18:0) are also linked to an increased cancer risk. The findings of the present study would assist in providing dietary recommendations for cancer prevention, thereby contributing to the development of potential strategies for clinical trials in which diet-related interventions would be used in combination with immunotherapy to alter the levels of SFAs in patients and thereby improve the outcomes in cancer patients. Nonetheless, further high-quality studies are warranted to confirm these associations.

ObjectiveOur previous results have shown that obesity-induced excessive palmitic acid (PA) can promote the expression of KLF7, which plays a vital role in regulation of inflammation, glucose metabolism. But the exact mechanism of PA up-regulating the expression of KLF7 is not clear yet. This study is intend to explore whether PA promoting KLF7 expression through GPRs/NF-κB signaling pathway, causing inflammation and glucose metabolism disorders.MethodsCells were blocked GPRs/NF-κB under PA stimulation in vitro to demonstrate the molecular mechanism of PA up-regulates KLF7 expression. The regulatory effect of p65 on KLF7 was detected by luciferase reporter gene assay. Blocking GPRs/NF-κB in diet-induced obesity mice to detect the expression of KLF7, inflammatory cytokines and glucose metabolism related factors, clarifying the effects of GPRs/NF-κB on KLF7 in vivo.ResultsIn 3T3-L1 adipocytes and HepG2 cells, PA could up-regulate the expression of KLF7 by promoting the GPR40/120-NF-κB signaling pathway, leading to inflammation and reduced glucose consumption (p < 0.05 for both). Luciferase reporter gene assay and ChIP assay showed that p65 could transcriptionally up-regulates the expression of KLF7. In high-fat diet (HFD) mice, after intraperitoneal injection of GPR40 or GPR120 blocker, the levels of p-p65 and KLF7 in epididymal white adipose tissue and liver were significantly decreased (p < 0.05 for both). Pharmacological inhibition of p-p65 significantly attenuated KLF7 expression and improved glucose tolerant and insulin sensitive (p < 0.05 for both).ConclusionsOur results indicate that obesity-induced elevated palmitic acid promotes inflammation and glucose metabolism disorders through GPRs/NF-κB/KLF7 signaling pathway.

Prostate cancer (PCa) continues to be the most common, noncutaneous cancer in men. Bone is the most frequent site of PCa metastases, and up to 90% of patients with advanced PCa develop bone metastases. An altered bone marrow microenvironment, induced by obesity, is a significant mediator for the bone tropism of PCa. However, the specific molecular mechanisms by which obesity causes changes in the bone marrow microenvironment, leading to PCa bone metastasis, are not fully understood. Our results demonstrate that a high‐fat diet (HFD) leads to dyslipidemia and changes in bone marrow of nude mice: an increase in the area and number of adipocytes and a reduction in the area and number of osteoblasts. Moreover, a HFD promoted cyclooxygenase 2 (COX2) expression and inhibited osteoprotegerin (OPG) expression in the bone microenvironment. Additionally, the total level of free fatty acids (FFAs) and caprylic acid (C8:0) was significantly higher in PCa patients with bone metastases. In vitro, caprylic acid (C8:0) promoted bone mesenchymal stem cell (MSC)‐derived adipocytic differentiation, COX2 expression, and prostaglandin E2 (PGE2) secretion, whereas osteoblastic differentiation and OPG expression were reduced. Furthermore, caprylic acid (C8:0)‐treated adipocytes promoted the invasion and migration of PCa cells. Taken together, our findings suggest caprylic acid (C8:0) promotes bone metastasis of PCa by dysregulated adipo‐osteogenic balance of bone marrow. Obesity‐induced high level of free fatty acids could change the bone marrow microenvironment that provides \"fertile soil\" for bone metastasis of prostate cancer. It was found for the first time that increased caprylic acid (C8:0) could promote the area and number of adipocytes and the level of cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) in the bone marrow cavity, which causes prostate cancer bone metastasis.

Aims/introduction Previous studies have found that miR‐4472 is overexpressed in the serum of individuals with obesity and type 2 diabetes mellitus (T2DM), which may participate in the process of obesity‐induced T2DM. However, a role for miR‐4472 in the process has not been demonstrated. Here, we aim to investigate whether the increased content of miR‐4472 in adipose tissue derived from exosomes inhibits glucose uptake in skeletal muscle by downregulating the expression of its target gene. Materials and methods In vitro C2C12 and 3T3‐L1 cells, and in vivo diet‐induced obesity mouse models and AT‐Dicer KO mice were used to assess the impact of miR‐4472 on glucose uptake and insulin sensitivity. We also evaluated the effects of serum exosomes from normal and obese individuals on insulin sensitivity in mice and the expression of miR‐4472 and target genes in skeletal muscle. Results miR‐4472 exhibits a strong positive correlation with BMI, waist circumference, hip circumference, and FPG. The content of miR‐4472 derived from adipose tissue exosomes increases in the circulation in a state of obesity, which can induce insulin resistance by targeting the expression of MEF2D/GLUT4, inhibiting the glucose consumption and uptake ability of skeletal muscle cells. Both exosome inhibitors and miR‐4472 inhibitors can reverse the inhibitory effect of miR‐4472 on MEF2D/GLUT4 expression and glucose intake and uptake ability. Additionally, they can improve insulin resistance caused by increased miR‐4472 levels in mice with obesity. Conclusions Adipocyte exosome miR‐4472 inhibits glucose uptake in skeletal muscle through downregulating the expression of MEF2D/GLUT4. Adipocyte exosome miR‐4472 inhibits glucose uptake in skeletal muscle through downregulating the expression of MEF2D/GLUT4.

Background Obesity-induced abnormal bone marrow microenvironment is one of the important risk element for bone metastasis in prostate cancer (PCa). The present study aimed to determine whether obesity-induced elevation in palmitic acid (PA), which is the most abundant of the free fatty acids (FFAs), increased CCL2 via the GPRs/KLF7 pathway in bone marrow adipocytes (BMA) to facilitate PCa growth and metastasis. Methods We constructed a bone-tumor bearing mouse model with obesity through high-fat diet, and observed the tumor formation ability of PCa cells. In vitro, observe the effect of PA on the expression level of CCL2 in BMA through GPRs/KLF7 signaling pathway. After co-culture of BMA and PCa cells, CCK8 assay and transwell experiment were used to detect the changes in biological behavior of PCa cells stimulated by BMA. Results The BMA distribution in the bone marrow cavity of BALB/c nude mice fed with the high-fat diet (HFD) was evidently higher than that in the mice fed with the normal diet (ND). Moreover, HFD-induced obesity promoted KLF7/CCL2 expression in BMA and PCa cell growth in the bone marrow cavity of the mice. In the vitro experiment, a conditioned medium with increased CCL2 obtained from the BMA cultured with PA (CM-BMA-PA) was used for culturing the PCa cell lines, which evidently enhanced the proliferation, invasion, and migration ability. KLF7 significantly increased the CCL2 expression and secretion levels in BMA by targeting the promoter region of the CCL2 gene. In addition, GPR40/120 engaged in the PA-induced high KLF7/CCL2 levels in BMA to facilitate the malignant progression of PC-3 cells. Conclusions PA-activated GPRs/KLF7/CCL2 pathway in BMA facilitates prostate cancer growth and metastasis.

Obesity is a high‐risk factor in the development of endometrial cancer (EC). Our previous study observed that miR‐548ag was significantly overexpressed in the sera of obese individuals. Here, we report the function of miR‐548ag and its mechanism in promoting the obesity‐related progression of EC. The content of miR‐548ag was increased in the serum of obese EC individuals. Bioinformatics analysis indicated that the survival rate of EC patients with a higher expression of miR‐548ag was significantly reduced. The Mps One Binder Kinase Activator 1B (MOB1B, the core member of the Hippo signaling pathway) is a direct target gene of miR‐548ag, which is inversely correlated with the expression of miR‐548ag. The overexpression of miR‐548ag enhances the proliferation, invasion, and migration, and inhibits apoptosis by downregulating the expression of MOB1B, leading to the deactivation of the Hippo pathway in EC cell lines and contributing to tumor progression in vivo. Our study has established that miR‐548ag functions as an oncogene by suppressing MOB1B in the development of obesity‐related EC. Our results indicate that miR‐548ag is a promising diagnostic biomarker to understand the role of the MOB1B/YAP1/CCND1/XIAP axis in promoting obesity‐related EC progression. Starting from clinical issues, this study clarified the molecular mechanism of high expression miR‐548ag in the occurrence and development of obesity‐related EC through in vitro and in vivo experiments, which will provide a theoretical basis for the prevention and treatment of EC.

Aim/Introduction Obesity is considered an important risk factor for many metabolic disorders, especially type 2 diabetes mellitus, and microRNAs (miRNAs) play a vital role in the development of type 2 diabetes mellitus. Therefore, we conducted this study to investigate the role of miR‐4431 in the obesity‐associated pathobiology of type 2 diabetes mellitus. Materials and methods Subjects were divided into normal control (n = 36), obese (n = 36), and type 2 diabetes mellitus (n = 12) groups, and serum miR‐4431 levels were analyzed. Adenovirus‐vectored miR‐4431 mimic or sponge was intraperitoneally injected into the normal diet group and the high‐fat diet group (HFD) mice to investigate glucose tolerance, insulin sensitivity, and lipid levels. The downstream target genes of miR‐4431 were predicted using bioinformatics, and they were verified in vitro. Results Serum miR‐4431 levels were significantly high in obese and type 2 diabetes mellitus individuals, and positively correlated with the body mass index and fasting plasma glucose levels. In HFD mice, miR‐4431 levels in the serum, white adipose tissue, and liver were significantly increased. Moreover, miR‐4431 impaired glucose tolerance, insulin sensitivity, and lipid metabolism in mice. Bioinformatic prediction suggested that TRIP10 and PRKD1 could be the downstream target genes of miR‐4431. The HFD mice showed a remarkable reduction in the mRNA levels of TRIP10 and PRKD1 in the liver, which were countered by blocking miR‐4431. In HepG2 and L02 cells, miR‐4431 could downregulate TRIP10 and PRKD1 while blocking glucose uptake. The luciferase reporter assay showed that miR‐4431 could bind TRIP10 and PRKD1 3′‐UTR. Conclusion miR‐4431 targets TRIP10/PRKD1 and impairs glucose metabolism. Serum miR‐4431 was significantly overexpressed in obese and type 2 diabetes mellitus individuals, and it was positively correlated with BMI and FPG. miR‐4431 impaired glucose tolerance, insulin sensitivity, and lipid metabolism in mice. miR‐4431 targeted to bind TRIP10 and PRKD1.

Objective. To investigate the role and possible molecular mechanism of Krüppel-like factor 7 (KLF7) in the TLR4/NF-κB/IL-6 inflammatory signaling pathway activated by free fatty acids (FFA). Methods. The mRNA and protein expression levels of KLF7 and the factors of TLR4/NF-κB/IL-6 inflammatory signal pathways were detected by qRT-PCR and Western blotting after cell culture with different concentrations of palmitic acid (PA). The expression of KLF7 or TLR4 in adipocytes was upregulated or downregulated; after that, the mRNA and protein expression levels of these key factors were detected. KLF7 expression was downregulated while PA stimulated adipocytes, and then the mRNA and protein expressions of KLF7/p65 and downstream inflammatory cytokine IL-6 were detected. The luciferase reporter assay was used to determine whether KLF7 had a transcriptional activation effect on IL-6. Results. (1) High concentration of PA can promote the expression of TLR4, KLF7, and IL-6 in adipocytes. (2) TLR4 positively regulates KLF7 expression in adipocytes. (3) KLF7 positively regulates IL-6 expression in adipocytes. (4) PA promotes IL-6 expression via KLF7 in adipocytes. (5) KLF7 has a transcriptional activation on IL-6. Conclusion. PA promotes the expression of the inflammatory cytokine IL-6 by activating the TLR4/KLF7/NF-κB inflammatory signaling pathway. In addition, KLF7 may directly bind to the IL-6 promoter region and thus activate IL-6.

Objective The release of adipose tissue-derived miRNAs is increased under conditions of obesity, but the exact molecular mechanisms involved have not been elucidated. This study investigated whether obesity-induced increases in palmitic acid (PA) content could activate the NF-κB/endoplasmic reticulum stress (ER stress) pathway and promote the expression and release of exosomal miRNAs in adipocytes. Methods Abdominal adipose tissue and serum samples were collected from normal weight individuals and people with obesity to clarify the correlation of serum PA content with NF-κB/ER stress and the release of exosomal miRNAs. NF-κB and ER stress were blocked in obese mice and in vitro cultured adipocytes to demonstrate the molecular mechanisms by which PA promotes the release of exosomal miRNAs.The morphology, particle size and distribution of the exosomes were observed via transmission electron microscopy and NTA. Results Accompanied by increased serum PA levels, the NF-κB/ER stress pathway was activated in the adipose tissue of people with obesity and in high-fat diet (HFD)-induced obese mice; moreover, the levels of miRNAs in both adipose tissue and serum were increased. P-p65 (Bay11-7082) and ER stress (TUDCA) blockers significantly reduced the levels of miRNAs in abdominal adipose tissue and serum, decreased blood glucose levels, and improved glucose tolerance and insulin sensitivity in obese mice. In 3T3-L1 adipocytes, high concentrations of PA activated the NF-κB/ER stress pathway and increased the expression and release of miRNAs in exosomes. P-p65 (Bay11-7082) and ER stress (TUDCA) blockers significantly reversed the increased release exosomal miRNAs cause by PA. Conclusions Obesity-induced increases in PA content increase the expression and release of miRNAs in adipocyte exosomes by activating the NF-κB/ER stress pathway.

Objective Recent studies have revealed a link between toll-like receptors (TLRs), Kruppel-like factors (KLFs), and the adipose tissue inflammation associated with obesity. TLR4 is associated with chronic inflammation in obesity. KLF7 is known to play an important role in the differentiation of adipocytes, but its role in visceral adipose tissue inflammation has not yet been investigated. Thus, the objective of this study was to determine the correlation of TLR4 and KLF7 in inflammation induced by obesity. Methods A total of 32 Wistar male rat subjects were fed in the center for experimental animals of Shihezi University. The rats were divided into normal control (NC) and high-fat diet (HFD) group. Surgical instruments were used to collect rats’ visceral adipose tissue samples in the 10th week after HFD feeding. Ninety-five Uygur subjects between 20 and 90 years old were enrolled in the present study. The subjects were divided into two groups: the normal control group (NC, 18.0 kg/m 2  ≤ BMI ≤ 23.9 kg/m 2 , n  = 50) and the obesity group (OB, BMI ≥ 28 kg/m 2 , n  = 45), and visceral adipose tissue was collected from the subjects. Anthropometric and clinical parameters were measured using standard procedures; biochemical indices were detected using the glucose oxidase-peroxidase method and a standardized automatic biochemistry analyzer; the plasma levels of inflammatory factors and adipocytokines were measured by enzyme-linked immunosorbent assay (ELISA); the mRNA and protein expression levels of key genes involved in the inflammatory signaling pathway were measured by real-time PCR and Western blot. Results In rats, compared with the NC group, the weight, Lee’s index, waist circumference, visceral fat mass, and the plasma level of Glu, TG, FFA, and TNF-α were higher in the HFD group, while the plasma levels of LPT and APN were significantly lower in the HFD group in the 10th week. Furthermore, compared with the NC group, visceral adipose tissue’s mRNA expression levels of TLR4, KLF7, and SRC were higher in the HFD group, and KLF7 was significantly positively correlated with LDL, TLR4, SRC, and IL-6 ( P  < 0.05). Meanwhile, in the Uygur population, the plasma levels of TG, LDL, and TNF-α in the OB group were significantly higher than those in the NC group ( P  < 0.05). Moreover, compared with the NC group, visceral adipose tissue’s mRNA expression levels of TLR4, KLF7, and SRC were significantly higher in the OB group ( P  < 0.05), and KLF7 was significantly positively correlated with TC, TLR4, MYD88, SRC, and IL-6 ( P  < 0.05); the protein expression levels of TLR4 and KLF7 were significantly higher than those in the NC group ( P  < 0.05). Conclusion Higher expression of TLR4 and KLF7 may play a vital role in the process of inflammation induced by obesity in visceral adipose tissue.