Identification of the hub susceptibility genes and related common transcription factors in the skeletal muscle of Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and its related complications contribute to the high morbidity and mortality in worldwide. Skeletal muscle insulin resistance plays a critical role in the onset of T2DM due to the decreasing in the insulin-stimulated glucose uptake. T2DM is associated not only with the inherited factors but also with the noninherited factors. However, the susceptibility genes related with the two factors and the transcription factors (TF) regulating the susceptibility genes in skeletal muscle, which aggravate the development of T2DM were still ill-defined. METHODS: In the present study, the expression profiles by the array of GSE25462 were retrieved from the GEO database. GEO2R was performed to validate the susceptibility differentially expressed genes (SDEG) in skeletal muscle of T2DM. Gene Ontology (GO) analysis and The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted via The Database for Annotation, Visualization, and Integrated Discovery (DAVID). A Protein-Protein Interaction (PPI) network was performed with the STRING. RESULTS: With the performance of GEO2R, 229 SDEGs in skeletal muscle of T2DM were identified. The biological processes (BP) of SDEGs was enriched in the cellular response to UV-B most significantly. KEGG pathway analysis revealed that the SDEGs were most significantly enriched in glycosaminoglycan degradation. 5 hub susceptibility genes (GPR84, CALCB, GCG, PTGDR, GNG8) in the skeletal muscle of T2DM were identified. Eventually, the common transcription factors regulating the hub susceptibility genes were identified by means of the online tool PROMO. CONCLUSIONS: Five hub susceptibility genes (GPR84, CALCB, GCG, PTGDR, GNG8) in the skeletal muscle of T2DM and the common transcription factors were identified. The outputs would provide new clues on the novel potential targets and the therapeutic strategies for treating T2DM and its related diseases.

Heat shock protein 60 (HSP60) modulates adiponectin signaling by stabilizing adiponectin receptor.

Adiponectin, an adipokine produced and secreted by adipocytes, is involved in regulating the development and progression of insulin resistance, diabetes, and diabetic complications. Heat shock protein 60 (HSP60) is a molecular chaperone, most commonly presenting in mitochondria and participating in the maintenance of protein homeostasis. Accumulating studies have demonstrated that the elevated circulating HSP60 and the decreased intracellular HSP60 are closely associated with diabetic complications such as diabetic cardiomyopathy. However, the underlying mechanism remains poorly understood. In the present study, we reported that HSP60 interacted directly with adiponectin receptors. Its abundance was positively associated with adiponectin action. Furthermore, HSP60 depletion markedly mitigated the protective impacts of adiponectin on high glucose-induced oxidative stress and cell apoptosis in rat cardiac H9c2 cells. In addition, HSP60 knockdown significantly enhanced proteasome activity leading to the degradation of adiponectin receptor 1. Taken together, we showed for the first time that HSP60 interacted with adiponectin receptors and mediated adiponectin signaling through stabilizing adiponectin receptor. This in vitro study also provides an alternative explanation for mechanism by which adiponectin exerts its action. Video abstract.

LncRNA-HOST2 regulates cell biological behaviors in epithelial ovarian cancer through a mechanism involving microRNA let-7b.

Recently, a large number of long non-coding RNAs (lncRNAs) have been reported in mammalian genomes and are evolutionarily conserved and presumably function in many biological events, especially in the pathogenesis of diverse human cancers. A lncRNA, named HOST2 (human ovarian cancer-specific transcript 2), was once reported to specifically be expressed at high level in human ovarian cancer. However, how HOST2 acts to regulate gene functions in ovarian carcinogenesis has remained enigmatic. Here we report, for the first time, that HOST2 promotes tumor cell migration, invasion and proliferation in epithelial ovarian cancer by working in key aspects of biological behaviors. In the present study, bioinformatics analysis indicated that HOST2 binds with microRNA let-7b, a potent tumor suppressor, which was then verified to target HOST2. Our results showed that HOST2 harbors a let-7b binding site and modulates let-7b availability by acting as a molecular sponge. HOST2 inhibits let-7b functions, which post-transcriptionally suppress the expression of targets, including some oncogenes that regulate cell growth and motility. Additionally, understanding HOST2/let-7b-dependent regulation may lead to alternative approaches for the diagnosis and cure of this deadly disease.

Tiron ameliorates high glucose-induced cardiac myocyte apoptosis by PKCδ-dependent inhibition of osteopontin.

Tiron functions as an effective antioxidant alleviating the intracellular reactive oxygen species (ROS) or the acute toxic metal overload. Previous studies have shown that cardiac myocyte apoptosis can be effectively inhibited by tiron administration in streptozotocin (STZ)-induced diabetic rats, primary neonatal rat cardiomyocytes (NRVMs), and H9c2 embryonic rat cardiomyocytes. However, the underlying signalling mechanism is ill-defined. In the present study, we found that tiron supplementation significantly inhibited apoptosis of high glucose (HG)-treated NRVMs and the left ventricular cardiomyocytes from STZ-diabetic rat, accompanied with a reduction of osteopontin (OPN) levels as well as an inhibition of PKCδ phosphorylation. OPN knockdown protected NRVMs against HG-induced cell apoptosis. In addition, genetic inhibition of PKCδ mitigated HG-stimulated enhancement of intracellular OPN levels in NRVMs. These findings indicate that ROS-mediated activation of PKCδ upregulated OPN expression, leading to cardiac myocyte apoptosis. Interfering with ROS/PKCδ pathway by antioxidants such as tiron provides an optional therapeutic strategy for treatment and prevention of apoptosis-related cardiovascular diseases including diabetic cardiomyopathy.

Wogonin enhances intracellular adiponectin levels and suppresses adiponectin secretion in 3T3-L1 adipocytes.

As an insulin sensitizer and modulator of inflammatory responses, adiponectin has become a therapeutic target for insulin resistance, diabetes, and diabetes-related complications. Wogonin possesses anti-oxidative, anti-inflammatory, and anti-diabetic abilities. However, its effect on generation and secretion of adiponectin is ill-defined in adipocytes. Here, we demonstrated that wogonin administration augmented intracellular adiponectin levels and attenuated adiponectin release in a dose- and time-dependent manner in mature 3T3-L1 adipocytes, along with a suppression of PKCδ phosphorylation. Wogonin treatment also prevented PKCδ overexpression-induced reduction of intracellular adiponectin levels and enhancement of adiponectin release. In addition, wogonin supplementation dramatically increased AMPK phosphorylation and SirT1 expression. Inhibition of either AMPK or SirT1 mitigated wogonin action on adiponectin production and release. Furthermore, inhibition of AMPK by its specific inhibitor markedly reduced wogonin-enhanced mRNA and protein expressions of SirT1. These results suggested that wogonin regulated expression and secretion of adiponectin via PKCδ/AMPK/SirT1 signaling pathway in mature 3T3-L1 adipocytes.

Nickel-Catalyzed Borylation of Aryl- and Benzyltrimethylammonium Salts via C-N Bond Cleavage.

By developing a mild Ni-catalyzed system, a method for direct borylation of sp(2) and sp(3) C-N bonds has been established. The key to this hightly efficient C-N bond borylative cleavage depends on the appropriate choice of the nickel catalyst Ni(COD)2, ICy·HCl as a ligand, and the use of 2-ethoxyethanol as the cosolvent. This transformation shows good functional group compatibility and can serve as a powerful synthetic tool for gram-scale synthesis and late-stage C-N borylation of complex compounds.

Nickel-Catalyzed Decarbonylative Borylation of Amides: Evidence for Acyl C-N Bond Activation.

A nickel/N-heterocyclic carbene catalytic system has been established for decarbonylative borylation of amides with B2 nep2 by C-N bond activation. This transformation shows good functional-group compatibility and can serve as a powerful synthetic tool for late-stage borylation of amide groups in complex compounds. More importantly, as a key intermediate, the structure of an acyl nickel complex was first confirmed by X-ray analysis. Furthermore, the decarbonylative process was also observed. These findings confirm the key mechanistic features of the acyl C-N bond activation process.

Functional vesicles formed by anticancer drug assembly.

In this Letter, a new type of nitrogen mustard conjugate vesicles is developed to improve the stability and efficiency of anticancer drug. Benzoic acid nitrogen mustard-peptide (AAAK) conjugate was designed and synthesized, which was found to self-assemble into vesicles in water. The formation of the vesicles was confirmed by dynamic light scattering (DLS), transmission electron microscopy (TEM) and circular dichroism (CD). The degradation data revealed that the benzoic acid nitrogen mustard peptide (AAAK) conjugate vesicles are more stable than the parent drug in aqueous solution. Furthermore, MTT assay revealed that the free drug conjugate has similar antitumor activity against MCF-7, Hela, HepG-2 cell lines compared with the parent drug. The benzoic acid nitrogen mustard-peptide conjugate vesicles may have potential in the treatment of cancers.

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα.

AIM: Wogonin (5,7-dihydroxy-8-methoxyflavone), a major bioactive compound of the flavonoid family, is commonly extracted from the traditional Chinese medicine Scutellaria baicalensis and possesses antioxidant and anti-inflammatory activities and is assumed to have anti-diabetes function. Indeed, a current study has shown that it can possibly treat metabolic disorders such as those found in db/db mice. However, the underlying molecular mechanism remains largely unclear. The aim of this study was to investigate the impact of wogonin on osteopontin (OPN) expression in adipose tissue from type 1 diabetic mice and in 3T3-L1 adipocytes. METHODS: Type 1 diabetes was induced by streptozotocin (STZ) injection. 3T3-L1 preadipocytes were converted to 3T3-L1 adipocytes through treatment with insulin, dexamethasone, and 3-isobutyl-1-methylxanthine (IBMX). Western blot analysis and RT-PCR were performed to detect protein expression and mRNA levels, respectively. RESULTS: Wogonin treatment suppressed the increase in serum OPN levels and reduced OPN expression in adipose tissue from STZ-induced type 1 diabetic mice. Administration of wogonin enhanced PPARα expression and activity. Silencing of PPARα diminished the inhibitory effects of wogonin on OPN expression in 3T3-L1 adipocytes. Furthermore, the levels of c-Fos and phosphorylated c-Jun were reduced in wogonin-treated adipose tissue and 3T3-L1 adipocytes. In addition, wogonin treatment dramatically mitigated p38 MAPK phosphorylation. Pharmacological inhibition of p38 MAPK by its specific inhibitor SB203580 increased PPARα activity and decreased OPN expression. CONCLUSION: Our results suggest that wogonin downregulated OPN expression in adipocytes through the inhibition of p38 MAPK and the sequential activation of the PPARα pathway. Given the adverse effects of high OPN levels on metabolism, our results provide evidence for the potential administration of wogonin as a treatment for diabetes.

Role of the ubiquitin-proteasome system and autophagy in regulation of insulin sensitivity in serum-starved 3T3-L1 adipocytes.

The ubiquitin-proteasome system (UPS) and autophagy are two conserved intracellular proteolytic pathways, responsible for degradation of most cellular proteins in living cells. Currently, both the UPS and autophagy have been suggested to be associated with pathogenesis of insulin resistance and diabetes. However, underlying mechanism remains largely unknown. The purpose of the present study is to investigate the impact of the UPS and autophagy on insulin sensitivity in serum-starved 3T3-L1 adipocytes. Our results show that serum depletion resulted in activation of the UPS and autophagy, accompanied with increased insulin sensitivity. Inhibition of the UPS with bortezomib (BZM), a highly selective, reversible 26S proteasome inhibitor induced compensatory activation of autophagy but did not affect significantly insulin action. Genetic and pharmacological inhibition of autophagy dramatically mitigated serum starvation-elevated insulin sensitivity. In addition, autophagy inhibition compromised UPS function and led to endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Inability of the UPS by BMZ exacerbated autophagy inhibition-induced ER stress and UPR. These results suggest that protein quality control maintained by the UPS and autophagy is required for preserving insulin sensitivity. Importantly, adaptive activation of autophagy plays a critical role in serum starvation-induced insulin sensitization in 3T3-L1 adipocytes.

Treatment of Tislelizumab-Induced Toxic Epidermal Necrolysis and Agranulocytosis: A Case Report and Literature Review.

BACKGROUND: Non-small Cell Lung Cancer (NSCLC) makes up about 85% of lung cancer cases, mainly adenocarcinoma and squamous cell carcinoma. Recently, PD-1 inhibitors have become crucial in NSCLC treatment, significantly enhancing survival for some. However, side effects, like skin reactions and hematotoxicity, limit their use, with drug-induced TEN and immunotherapy-induced agranulocytosis as severe adverse effects. CASE PRESENTATION: Herein, we have reported the case of a 75-year-old male diagnosed with metastatic Lung Squamous cell Carcinoma (LUSC) in the left lung. He received first-line treatment with one cycle of tislelizumab in combination with nab-paclitaxel and carboplatin, after which he developed Toxic Epidermal Necrolysis (TEN) and granulocytopenia. To address these two serious immune-related Adverse Events (irAEs), the patient was administered methylprednisolone in combination with gamma globulin for TEN and dexamethasone in combination with G-CSF for agranulocytosis. Antibiotics were also administered according to the patient's medication regimen. After treatment, the patient recovered and was discharged from the hospital. It was also noted that the lung tumor condition improved. CONCLUSION: Effective management of severe immune-related side effects from tislelizumab, including TEN and agranulocytosis, can be partly achieved through steroids, gamma globulin, GCSF, and antibiotics. This strategy not only alleviates these adverse effects, but also potentially improves tumor conditions, highlighting the crucial role of vigilant monitoring and management in immunotherapy.

Astragalus polysaccharide stimulates glucose uptake in L6 myotubes through AMPK activation and AS160/TBC1D4 phosphorylation.

AIM: To establish the mechanism responsible for the stimulation of glucose uptake by Astragalus polysaccharide (APS), extracted from Astragalus membranaceus Bunge, in L6 myotubes in vitro. METHODS: APS-stimulated glucose uptake in L6 myotubes was measured using the 2-deoxy-[(3)H]-D-glucose method. The adenine nucleotide contents in the cells were measured by HPLC. The phosphorylation of AMP-activated protein kinase (AMPK) and Akt substrate of 160 kDa (AS160) was examined using Western blot analysis. The cells transfected with 4P mutant AS160 (AS160-4P) were constructed using gene transfer approach. RESULTS: Treatment of L6 myotubes with APS (100-1600 µg/mL) significantly increased glucose uptake in time- and concentration-dependent manners. The maximal glucose uptake was reached in the cells treated with APS (400 µg/mL) for 36 h. The APS-stimulated glucose uptake was significantly attenuated by pretreatment with Compound C, a selective AMPK inhibitor or in the cells overexpressing AS160-4P. Treatment of L6 myotubes with APS strongly promoted the activation of AMPK. We further demonstrated that either Ca(2+)/calmodulin-dependent protein kinase kinase ß (CaMKKß) or liver kinase B1 (LKB1) mediated APS-induced activation of AMPK in L6 myotubes, and the increased cellular AMP: ATP ratio was also involved. Treatment of L6 myotubes with APS robustly enhanced the phosphorylation of AS160, which was significantly attenuated by pretreatment with Compound C. CONCLUSION: Our results demonstrate that APS stimulates glucose uptake in L6 myotubes through the AMP-AMPK-AS160 pathway, which may contribute to its hypoglycemic effect.

Revealing the contribution of iron overload-brown adipocytes to iron overload cardiomyopathy: Insights from RNA-seq and exosomes coculture technology.

Iron overload has been demonstrated to be associated with insulin resistance, iron overload cardiomyopathy (IOC). Brown adipose tissue (BAT) is emerging as a novel therapeutic target for the treatment of various diseases, not only because of its capacity for dissipating excess energy via non-shivering thermogenesis, but also because of its implication in physiological and pathophysiological processes. However, little attention has been devoted to the precise alterations and impacts of iron overload-BAT. We conducted RNA-Seq analysis on BAT samples obtained from mice subjected to a high iron diet (HID) or a normal chow diet (CON), respectively. The RNA-seq transcriptomic analysis revealed that 1,289 differentially expressed RNAs (DEGs) were identified, with a higher number of the downregulated genes (910 genes) compared to the upregulated genes (379 genes). The results of Gene Ontology (GO) and The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the downregulated DEGs were primarily involved in hypertrophic cardiomyopathy, dilated cardiomyopathy, which were defined as IOC under the iron overload condition. The association between iron overload-BAT with cardiomyopathy was further investigated using exosome coculture technology. Our results demonstrated that the exosomes derived from ferric citrate treated-mature HIB 1B brown adipocytes, could be internalized by HL-1 cardiomyocytes, and contributed to the dysfunction in these cells. The present study has revealed the alterations and impacts of iron overload-BAT, particularly on the onset of IOC via not only RNA-seq but also exosomes coculture technology. The outputs might shed light on the novel therapeutic strategies for the treatment of IOC.

Functional role of frontal electroencephalogram alpha asymmetry in the resting state in patients with depression: A review.

Depression is a psychological disorder that affects the general public worldwide. It is particularly important to make an objective and accurate diagnosis of depression, and the measurement methods of brain activity have gradually received increasing attention. Resting electroencephalogram (EEG) alpha asymmetry in patients with depression shows changes in activation of the alpha frequency band of the left and right frontal cortices. In this paper, we review the findings of the relationship between frontal EEG alpha asymmetry in the resting state and depression. Based on worldwide studies, we found the following: (1) Compared with individuals without depression, those with depression showed greater right frontal EEG alpha asymmetry in the resting state. However, the pattern of frontal EEG alpha asymmetry in the resting state in depressive individuals seemed to disappear with age; (2) Compared with individuals without maternal depression, those with maternal depression showed greater right frontal EEG alpha asymmetry in the resting state, which indicated that genetic or experience-based influences have an impact on frontal EEG alpha asymmetry at rest; and (3) Frontal EEG alpha asymmetry in the resting state was stable, and little or no change occurred after antidepressant treatment. Finally, we concluded that the contrasting results may be due to differences in methodology, clinical characteristics, and participant characteristics.

Analysis of the different characteristics between omental preadipocytes and differentiated white adipocytes using bioinformatics methods.

Obesity is emerging as an epidemiological issue, being associated with the onset and progress of various metabolism-related disorders. Obesity is characterized by the white adipose expansion, which encounters white adipocyte hypertrophy and hyperplasia. White adipocyte hyperplasia is defined as adipogenesis with the increase in the number of the white adipocytes from the preadipocytes. Adipogenesis contributes to distributing excess triglycerides among the smaller newly formed adipocytes, reducing the number of hypertrophic adipocytes and secreting anti-inflammatory factor. Therefore, adipogenesis is emerging as a new therapeutic target for the treatment of obesity. In the present study, for a better understanding of the contribution of the alteration of the omental differentiated white adipocytes to the systemic metabolic disorders, we downloaded the mRNA expression profiles from GEO database GSE1657, 328 differentially expressed genes (DEGs) were screened between the undifferentiated preadipocytes (UNDIF) and omental differentiated white adipocytes (DIF). The contributions of the upregulated and downregulated DEGs to the system were performed via the Gene Ontology (GO) analysis, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Protein-Protein Interaction (PPI) network, respectively. The potential contribution of the whole altered genes in the differentiated white adipocytes was explored with the performance of Gene Set Enrichment Analysis (GSEA), especially on the GO analysis, KEGG analysis, hallmark analysis, oncogenic analysis and related miRNA analysis. The output of the current study will shed light on the new targets for the treatment of obesity and obesity-related disorders.

Promotion of PDGF-induced endothelial cell migration by phosphorylated VASP depends on PKA anchoring via AKAP.

Vasodilator-stimulated phosphoprotein (VASP), an important substrate of PKA, plays a critical role in remodeling of actin cytoskeleton and actin-based cell motility. However, how PKA accurately transfers extracellular signals to VASP and then how phosphorylation of VASP regulates endothelial cell migration have not been clearly defined. Protein kinase A anchoring proteins (AKAPs) are considered to regulate intracellular-specific signal targeting of PKA via AKAP-mediated PKA anchoring. Thus, our study investigated the relationship among AKAP anchoring of PKA, PKA activity, and VASP phosphorylation, which is to clarify the exact role of VASP and its upstream regulatory mechanism in PKA-dependent migration. Our results show that chemotactic factor PDGF activated PKA, increased phosphorylation of VASP at Ser157, and enhanced ECV304 endothelial cell migration. However, phosphorylation site-directed mutation of VASP at Ser157 attenuated the chemotactic effect of PDGF on endothelial cells, suggesting phosphorylation of VASP at Ser157 promotes PKA-mediated endothelial cell migration. Furthermore, disrupting PKA anchoring to AKAP or PKA activity significantly attenuated the PKA activity, VASP phosphorylation, and subsequent cell migration. Meanwhile, disrupting PKA anchoring to AKAP abolished PDGF-induced lamellipodia formation and special VASP accumulation at leading edge of lamellipodia. These results indicate that PKA activation and PKA-mediated substrate responses in VASP phosphorylation and localization depend on PKA anchoring via AKAP in PDGF-induced endothelial cell migration. In conclusion, AKAP anchoring of PKA is an essential upstream event in regulation of PKA-mediated VASP phosphorylation and subsequent endothelial cell migration, which contributes to explore new methods for controlling endothelial cell migration related diseases and angiogenesis.

Identification of differentially expressed mRNA and the Hub mRNAs modulated by lncRNA Meg3 as a competing endogenous RNA in brown adipose tissue of mice on a high-fat diet.

Obesity is associated with insulin resistance, diabetes, and obesity-related metabolic disorders. Brown adipocytes have emerged as potential targets for the treatment of obesity and obesity-related diseases. However, changes that occur in brown adipose tissue during various stages of high fat diet (HFD)-induced obesity remain poorly understood. The present study aimed to determine the changes occurring in brown adipose tissue during various stages of an HFD by analyzing two microarray expression profiles. A total of 1,337 differentially expressed RNAs (DE RNAs) were identified between the HFD and ND groups, using the limma package in R. The DE RNAs included 1,249 mRNAs, 74 long non coding RNAs (lncRNAs), and 14 pseudogenes. Functional annotation of the DE mRNAs, including GO terms and KEGG pathways were identified using the Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction network was constructed using STRING and clusters were obtained through the Molecular Complex Detection plug-in. In the present study, the lncRNA,maternally expressed gene 3 (Meg3), was identified as the DE lncRNA with a significant fold change. The network of Meg3 as a ceRNA was constructed, which demonstrated that Meg3 modulated five hub DE mRNAs via competitive binding to microRNAs.

Icariin Attenuates Amyloid-ß (Aß)-Induced Neuronal Insulin Resistance Through PTEN Downregulation.

Neuronal insulin resistance is implicated in neurodegenerative diseases. Icariin has been reported to improve insulin resistance in skeletal muscle cells and to restore impaired hypothalamic insulin signaling in the rats with chronic unpredictable mild stress. In addition, icariin can exert the neuroprotective effects in the mouse models of neurodegenerative diseases. However, the molecular mechanisms by which icariin affects neuronal insulin resistance are poorly understood. In the present study, amyloid-ß (Aß) was used to induce insulin resistance in human neuroblastoma SK-N-MC cells. Insulin sensitivity was evaluated by measuring insulin-stimulated Akt T308 phosphorylation and glucose uptake. We found that the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mediated Aß-induced insulin resistance. Icariin treatment markedly reduced Aß-enhanced PTEN protein levels, leading to an improvement in Aß-induced insulin resistance. Accordingly, PTEN overexpression obviously abolished the protective effects of icariin on Aß-induced insulin resistance. Furthermore, icariin activated proteasome activity. The proteasome inhibitor MG132 attenuated the effects of icariin on PTEN protein levels. Taken together, these results suggest that icariin protects SK-N-MC cells against Aß-induced insulin resistance by activating the proteasome-dependent degradation of PTEN. These findings provide an experimental background for the identification of novel molecular targets of icariin, which may help in the development of alternative therapeutic approaches for neurodegenerative diseases.

APPL1 knockdown blocks adipogenic differentiation and promotes adipocyte lipolysis.

Adipocyte dysfunction is closely associated with the development of obesity, insulin resistance, and type 2 diabetes. In addition to having a positive effect on adiponectin pathway and insulin signaling through direct and/or indirect mechanisms, adapter protein APPL1 has also been reported to regulate body weight, brown fat tissues thermogenesis, and body fat distribution in diabetic individuals. However, there is dearth of data on the specific role of APPL1 on adipogenic differentiation and adipocyte lipolysis. In this study, APPL1's function in adipocyte differentiation and adipocyte lipolysis was evaluated, and the possible mechanisms were investigated. We found that APPL1 knockdown (KD) impeded differentiation of 3T3-L1 preadipocytes into mature 3T3-L1 adipocytes and enhanced basal and insulin-suppressed lipolysis in mature 3T3-L1 adipocytes. APPL1 KD cells presented a reduced autophagic activity in 3T3-L1 preadipocytes and mature 3T3-L1 adipocytes. In 3T3-L1 preadipocytes, APPL1 KD reduced PPARγ protein levels, which was prevented by administration with proteasome inhibitor MG132. Furthermore, APPL1 KD-reduced autophagic activity in mature 3T3-L1 adipocytes was markedly restored by inhibition of PKA, accompanied with prevention of APPL1-induced lipolysis. In addition, APPL1 KD caused insulin resistance in mature 3T3-L1 adipocytes. Unexpectedly, we found that APPL1 overexpression did not appear to play a role in adipogenic differentiation and adipocyte lipolysis. Our results confirmed that APPL1 KD inhibits adipogenic differentiation by suppressing autophagy and enhances adipocyte lipolysis through activating PKA respectively. These findings may deepen our understanding of APPL1 function, especially its regulation on adipocyte biology.