Prenylated Chrysin Derivatives as Partial PPARγ Agonists with Adiponectin Secretion-Inducing Activity.

Decreased circulating adiponectin levels are associated with an increased risk of human metabolic diseases. The chemical-mediated upregulation of adiponectin biosynthesis has been proposed as a novel therapeutic approach to managing hypoadiponectinemia-associated diseases. In preliminary screening, the natural flavonoid chrysin (1) exhibited adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Here, we provide the 7-prenylated chrysin derivatives, chrysin 5-benzyl-7-prenylether compound 10 and chrysin 5,7-diprenylether compound 11, with the improved pharmacological profile compared with chrysin (1). Nuclear receptor binding and ligand-induced coactivator recruitment assays revealed that compounds 10 and 11 functioned as peroxisome proliferator-activated receptor (PPAR)γ partial agonists. These findings were supported by molecular docking simulation, followed by experimental validation. Notably, compound 11 showed PPARγ binding affinity as potent as that of the PPARγ agonists pioglitazone and telmisartan. This study presents a novel PPARγ partial agonist pharmacophore and suggests that prenylated chrysin derivatives have therapeutic potential in various human diseases associated with hypoadiponectinemia.

In vitro and in vivo suppression of SARS-CoV-2 replication by a modified, short, cell-penetrating peptide targeting the C-terminal domain of the viral spike protein.

Peptides are promising therapeutic agents for COVID-19 because of their specificity, easy synthesis, and ability to be fine-tuned. We previously demonstrated that a cell-permeable peptide corresponding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike C-terminal domain (CD) inhibits the interaction between viral spike and nucleocapsid proteins that results in SARS-CoV-2 replication in vitro. Here, we used docking studies to design R-t-Spike CD(D), a more potent short cell-penetrating peptide composed of all D-form amino acids and evaluated its inhibitory effect against the replication of SARS-CoV-2 S clade and other variants. R-t-Spike CD(D) was internalized into Vero cells and Calu-3 cells and suppressed the replication of SARS-CoV-2 S clade, delta variant, and omicron variant with higher potency than the original peptide. In hemizygous K18-hACE2 mice, intratracheal administration of R-t-Spike CD(D) effectively delivered the peptide to the trachea and lungs, whereas intranasal administration delivered the peptide mostly to the upper respiratory system and stomach, and a small amount to the lungs. Administration by either route reduced viral loads in mouse lungs and turbinates. Furthermore, intranasally administered R-t-Spike CD(D) mitigated pathological change in the lungs and increased the survival of mice after infection with the SARS-CoV-2 S clade or delta variant. Our data suggest that R-t-Spike CD(D) has potential as a therapeutic agent against SARS-CoV-2 infection.

Structure-Activity Relationships of Truncated 1'-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs.

Peroxisome proliferator-activated receptors (PPARs) are associated with the regulation of metabolic homeostasis. Based on a previous report that 1'-homologated 4'-thionucleoside acts as a dual PPARγ/δ modulator, carbocyclic nucleosides 2-5 with various sugar conformations were synthesized to determine whether sugar puckering affects binding to PPARs. (S)-conformer 2 was synthesized using Charette asymmetric cyclopropanation, whereas (N)-conformer 3 was synthesized using stereoselective Simmons-Smith cyclopropanation. All synthesized nucleosides did not exhibit binding affinity to PPARα but exhibited significant binding affinities to PPARγ/δ. The binding affinity of final nucleosides to PPARγ did not differ significantly based on their conformation, but their affinity to PPARδ depended greatly on their conformation, correlated with adiponectin production. (N)-conformer 3h was discovered to be the most potent PPARδ antagonist with good adiponectin production, which exhibited the most effective activity in inhibiting the mRNA levels of LPS-induced IL-1ß expression in RAW 264.7 macrophages, implicating its anti-inflammatory activity.

Computational Prediction of the Phenotypic Effect of Flavonoids on Adiponectin Biosynthesis.

In silico machine learning applications for phenotype-based screening have primarily been limited due to the lack of machine-readable data related to disease phenotypes. Adiponectin, a nuclear receptor (NR)-regulated adipocytokine, is relatively downregulated in human metabolic diseases. Here, we present a machine-learning model to predict the adiponectin-secretion-promoting activity of flavonoid-associated phytochemicals (FAPs). We modeled a structure-activity relationship between the chemical similarity of FAPs and their bioactivities using a random forest-based classifier, which provided the NR activity of each FAP as a probability. To link the classifier-predicted NR activity to the phenotype, we next designed a single-cell transcriptomics-based multiple linear regression model to generate the relative adiponectin score (RAS) of FAPs. In experimental validation, estimated RAS values of FAPs isolated from Scutellaria baicalensis exhibited a significant correlation with their adiponectin-secretion-promoting activity. The combined cheminformatics and bioinformatics approach enables the computational reconstruction of phenotype-based screening systems.

Hepatic TREM2+ macrophages express matrix metalloproteinases to control fibrotic scar formation.

Liver cirrhosis is characterized by the extensive deposition of extracellular matrix such as fibril collagen, causing dysfunction and failure of the liver. Hepatic macrophages play pivotal roles in the transition from inflammatory to restorative properties upon hepatic injury. In particular, scar-associated macrophages (SAMacs) control liver fibrosis with the representative expression of matrix metalloproteinase (MMP). However, the heterogenic SAMac population has not been well characterized yet. This study profiled heterogeneous liver macrophages using public databases of single-cell transcriptomics and found T-cell immunoglobulin and mucin containing (TIM)4- macrophages exhibited elevated expression of MMPs. Scar-associated triggering receptor expressed on myeloid cells (TREM)2 was positively correlated with MMP expression, suggesting that TREM2+ subsets exert their fibrotic role via MMPs. During the progression of diet-induced nonalcoholic steatohepatitis and drug-induced liver cirrhosis, monocyte-derived TREM2+ macrophages accumulate in the liver with the distinct expression of MMPs. A noticeable expansion of MMP- and TREM2- double positive macrophages was observed in fibrotic scar regions. Consistently, the analysis of single-cell transcriptomics for human cirrhotic livers supported the theory that TREM2+ SAMacs are strongly associated with MMPs. The results could expand the understanding of liver fibrosis and SAMac, offering potential therapeutic approaches for liver cirrhosis.

Discovery of PPARγ and glucocorticoid receptor dual agonists to promote the adiponectin and leptin biosynthesis in human bone marrow mesenchymal stem cells.

Adiponectin and leptin are major adipocytokines that control crosstalk between adipose tissue and other organ systems. Hypoadiponectinemia and hypoleptinemia are associated with human metabolic diseases. Compounds with adipocytokine biosynthesis-stimulating activities could be developed as therapeutics against diverse metabolic conditions. In phenotypic screening with human bone marrow mesenchymal stem cells (hBM-MSCs), (E)-4-hydroxy-3-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-6-methyl-2H-pyran-2-one (1) was identified to increase adiponectin biosynthesis during adipogenesis and simultaneously to stimulate leptin production. Using the compound 1 structure, the structure-activity relationship study was performed to discover more potent compounds stimulating both adiponectin and leptin production. (E)-3-(3-(2-fluoropyridin-4-yl)acryloyl)-4-hydroxy-6-methyl-2H-pyran-2-one (11) exhibited the most potent adiponectin (EC50, 2.87 µM) and leptin (EC50, 2.82 µM) biosynthesis-stimulating activities in hBM-MSCs. In a target identification study, compound 11 was characterized as a dual modulator binding to both peroxisome proliferator-activated receptor (PPAR) γ and glucocorticoid receptor (GR). This study provides a novel pharmacophore for PPARγ/GR dual modulators with therapeutic potential against human metabolic diseases.

Macakurzin C Derivatives as a Novel Pharmacophore for Pan-Peroxisome Proliferator-Activated Receptor Modulator.

The natural flavonoid macakurzin C (1) exhibited adiponectin biosynthesis-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells and its molecular mechanism was directly associated with a pan-peroxisome proliferator-activated receptor (PPAR) modulator affecting all three PPAR subtypes α, γ, and δ. In this study, increases in adiponectin biosynthesis-inducing activity by macakurzin C derivatives (2-7) were studied. The most potent adiponectin biosynthesis-inducing compound 6, macakurzin C 3,5-dimethylether, was elucidated as a dual PPARα/γ modulator. Compound 6 may exhibit the most potent activity because of the antagonistic relationship between PPARδ and PPARγ. Docking studies revealed that the O-methylation of macakurzin C to generate compound 6 significantly disrupted PPARδ binding. Compound 6 has therapeutic potential in hypoadiponectinemia-related metabolic diseases.

Discovery of Pan-peroxisome Proliferator-Activated Receptor Modulators from an Endolichenic Fungus, Daldinia childiae.

Adiponectin-synthesis-promoting compounds possess therapeutic potential to treat diverse metabolic diseases, including obesity and diabetes. Phenotypic screening to find adiponectin-synthesis-promoting compounds was performed using the adipogenesis model of human bone marrow mesenchymal stem cells. The extract of the endolichenic fungus Daldinia childiae 047215 significantly promoted adiponectin production. Bioactivity-guided isolation led to 13 active polyketides (1-13), which include naphthol monomers, dimers, and trimers. To the best of our knowledge, trimers of naphthol (1-4) have not been previously isolated as either natural or synthetic products. The novel naphthol trimer 3,1',3',3″-ternaphthalene-5,5',5″-trimethoxy-4,4',4″-triol (2) and a dimer, nodulisporin A (12), exhibited concentration-dependent adiponectin-synthesis-promoting activity (EC50 30.8 and 15.2 µM, respectively). Compounds 2 and 12 bound to all three peroxisome proliferator-activated receptor (PPAR) subtypes, PPARα, PPARγ, and PPARδ. In addition, compound 2 transactivated retinoid X receptor α, whereas 12 did not. Naphthol oligomers 2 and 12 represent novel pan-PPAR modulators and are potential pharmacophores for designing new therapeutic agents against hypoadiponectinemia-associated metabolic diseases.

Macrophage-Specific Connexin 43 Knockout Protects Mice from Obesity-Induced Inflammation and Metabolic Dysfunction.

Adipose tissue macrophages are a major immune cell type contributing to homeostatic maintenance and pathological adipose tissue remodeling. However, the mechanisms underlying macrophage recruitment and polarization in adipose tissue during obesity remain poorly understood. Previous studies have suggested that the gap junctional protein, connexin 43 (Cx43), plays a critical role in macrophage activation and phagocytosis. Herein, we investigated the macrophage-specific roles of Cx43 in high fat diet (HFD)-induced pathological remodeling of adipose tissue. Expression levels of Cx43 were upregulated in macrophages co-cultured with dying adipocytes in vitro, as well as in macrophages associated with dying adipocytes in the adipose tissue of HFD-fed mice. Cx43 knockdown reduced lipopolysaccharide (LPS)-induced ATP release from macrophages and decreased inflammatory responses of macrophages co-cultured with dying adipocytes. Based on global gene expression profiling, macrophage-specific Cx43-knockout (Cx43-MKO) mice were resistant to HFD-induced inflammatory responses in adipose tissue, potentially via P2X7-mediated signaling pathways. Cx43-MKO mice exhibited reduced HFD-induced macrophage recruitment in adipose tissue. Moreover, Cx43-MKO mice showed reduced inflammasome activation in adipose tissues and improved glucose tolerance. Collectively, these findings demonstrate that Cx43 expression in macrophages facilitates inflammasome activation, which, in turn, contributes to HFD-induced metabolic dysfunction.

Design, Synthesis, and Biological Activity of l-1'-Homologated Adenosine Derivatives.

On the basis of the previously reported polypharmacological profile of truncated d-1'-homologated adenosine derivatives [J. Med. Chem.2020, 63, 16012], the l-nucleoside analogues were synthesized using computer-aided design and evaluated for biological activity. The target molecules were synthesized from d-ribose via the key intramolecular cyclization of the monotosylate and Mitsunobu condensation. The peroxisome proliferator-activated receptor (PPAR) binding activities of l-nucleoside analogue 2d (K i = 4.3 µM for PPARγ and 1.0 µM for PPARδ) were significantly improved in comparison with those of the d-nucleoside compound 1 (11.9 and 2.7 µM, respectively). In addition, the l-nucleosides showed more potent adiponectin-secretion-promoting activity than the d-nucleoside analogues.

Abiraterone Acetate Attenuates SARS-CoV-2 Replication by Interfering with the Structural Nucleocapsid Protein.

The drug repurposing strategy has been applied to the development of emergency COVID-19 therapeutic medicines. Current drug repurposing approaches have been directed against RNA polymerases and viral proteases. Recently, we found that the inhibition of the interaction between the SARS-CoV-2 structural nucleocapsid (N) and spike (S) proteins decreased viral replication. In this study, drug repurposing candidates were screened by in silico molecular docking simulation with the SARS-CoV-2 structural N protein. In the ChEMBL database, 1994 FDA-approved drugs were selected for the in silico virtual screening against the N terminal domain (NTD) of the SARS-CoV-2 N protein. The tyrosine 109 residue in the NTD of the N protein was used as the center of the ligand binding grid for the docking simulation. In plaque forming assays performed with SARS-CoV-2 infected Vero E6 cells, atovaquone, abiraterone acetate, and digoxin exhibited a tendency to reduce the size of the viral plagues without affecting the plaque numbers. Abiraterone acetate significantly decreased the accumulation of viral particles in the cell culture supernatants in a concentration-dependent manner. In addition, abiraterone acetate significantly decreased the production of N protein and S protein in the SARS-CoV-2-infected Vero E6 cells. In conclusion, abiraterone acetate has therapeutic potential to inhibit the viral replication of SARS-CoV-2.

3,4,5-Trimethoxycinnamate thymol ester inhibits melanogenesis in normal human melanocytes and 3D human epidermal equivalents via the PGC-1α-independent PPARγ partial agonism.

BACKGROUND: 3,4,5-Trimethoxycinnamate thymol ester (TCTE), an anti-melanogenic cosmetic agent prescribed currently, promotes adiponectin synthesis during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Adiponectin inhibits melanin biosynthesis and its biosynthesis is directly regulated by peroxisome proliferator-activated receptor (PPAR) γ. In this regard, TCTE may potentially affect PPARγ activity. However, contradicting effects of PPARγ agonists with different chemical structures on human melanogenesis have been reported. OBJECTIVE: A molecular target of TCTE was investigated to elucidate the association of both adiponectin and PPARγ with anti-melanogenic activity. METHODS: The adiponectin secretion-promoting activity of TCTE was tested in an adipogenesis model of hBM-MSCs. A molecular target of TCTE for adiponectin secretion was evaluated via time-resolved fluorescence resonance energy transfer-based receptor binding and transactivation of PPARs. RESULTS: TCTE significantly promoted adiponectin secretion (EC50, 27.9 µM) during adipogenesis in hBM-MSCs and directly bound to PPARγ (Ki, 13.2 µM). The TCTE-bound PPARγ increased the recruitment of SRC-1, SRC-3, and TRAP220/DRIP-1 coactivator peptides without affecting PGC-1α coactivation. In the docking analysis, the optimal ligand binding mode of TCTE exhibited typical ligand-receptor interactions of PPARγ partial agonists. The PPARγ partial agonism of TCTE was established experimentally and the anti-melanogenic activity of TCTE was decreased by treatment with a PPARγ antagonist in cultured normal human melanocytes and a 3D model of human epidermis. CONCLUSION: The anti-melanogenic activity of TCTE was associated with a PGC-1α-independent PPARγ partial agonism.

Adiponectin-Secretion-Promoting Cyclic Peptide-Polyketide Hybrids from a Halophyte-Associated Fungus, Colletotrichum gloeosporioides JS0417.

Three new cyclic peptide-polyketide hybrids (1-3) and two new chaetiacandin-type polyketides (4 and 5) along with nine known compounds were isolated from cultures of a halophyte-associated fungus, Colletotrichum gloeosporioides JS0417. Spectroscopic analysis revealed that 1-3 were cyclic depsipeptides where 3,5,11-trihydroxy-2,6-dimethyldodecanoic acid was linked to two amino acids through amide and ester bonds to form a 12-membered ring. Relative and absolute configurations for the peptides were determined with spectroscopic analysis and chemical reactions. The cyclic depsipeptides 2 and 6 were determined to act as strong adiponectin-secretion-promoting modulators with potential to treat metabolic diseases associated with hypoadiponectinemia. Notably, a known compound, tryptophol, significantly inhibited PGE2 synthesis and also promoted adiponectin secretion, exhibiting a similar biological activity profile to aspirin, but with greater potency. The presence of an isoleucine moiety and non-glycosylation may be important for biological activity of the cyclic peptide-polyketide hybrids, and non-methoxylation of the side chain may influence activity of the indole derivatives.

Sunscreen filter octocrylene is a potential obesogen by acting as a PPARγ partial agonist.

Octocrylene (OC) is an extensively prescribed organic ultraviolet B filter used in sunscreen products. Due to its extensive use, a significant level of OC is detected in marine and freshwater environments. Notably, the bioaccumulation of OC in aquatic biota may affect human health. In this study, the effect of OC on metabolism was investigated using the adipogenesis model of human bone marrow mesenchymal stem cells (hBM-MSCs). OC promoted adiponectin production during adipogenesis in hBM-MSCs compared to the vehicle-treated control (EC50, 29.6 µM). In target identification, OC directly bound to peroxisome proliferator-activated receptor (PPAR) γ (Ki, 37.8 µM). OC-bound PPARγ also significantly recruited nuclear receptor coactivator proteins SRC-1 (EC50, 54.1 µM) and SRC-2 (EC50, 58.6 µM). In the molecular docking simulation study, the optimal ligand-binding mode of OC suggested that OC is a PPARγ partial agonist. A competitive analysis with a PPARγ full agonist pioglitazone revealed that OC acted as a PPARγ partial agonist. OC altered the gene transcription profile of lipid-metabolism associated enzymes in normal human keratinocytes, primarily exposed human cells after the application of sunscreens. In conclusion, OC is a potential metabolic disrupting obesogen.

Galangin 3-benzyl-5-methylether derivatives function as an adiponectin synthesis-promoting peroxisome proliferator-activated receptor γ partial agonist.

The upregulation of adiponectin production has been suggested as a novel strategy for the treatment of metabolic diseases. Galangin, a natural flavonoid, exhibited adiponectin synthesis-promoting activity during adipogenesis in human bone marrow mesenchymal stem cells. In target identification, galangin bound both peroxisome proliferator-activated receptor (PPAR) γ and estrogen receptor (ER) ß. Novel galangin derivatives were synthesized to improve adiponectin synthesis-promoting compounds by increasing the PPARγ activity of galangin and reducing its ERß activity, because PPARγ functions can be inhibited by ERß. Three galangin 3-benzyl-5-methylether derivatives significantly promoted adiponectin production by 2.88-, 4.47-, and 2.76-fold, respectively, compared to the effect of galangin. The most potent compound, galangin 3-benzyl-5,7-dimethylether, selectively bound to PPARγ (Ki, 1.7 µM), whereas it did not bind to ERß. Galangin 3-benzyl-5,7-dimethylether was identified as a PPARγ partial agonist in docking and pharmacological competition studies, suggesting that it may have diverse therapeutic potential in a variety of metabolic diseases.

Discovery of a Novel Template, 7-Substituted 7-Deaza-4'-Thioadenosine Derivatives as Multi-Kinase Inhibitors.

The development of anticancer drugs remains challenging owing to the potential for drug resistance. The simultaneous inhibition of multiple targets involved in cancer could overcome resistance, and these agents would exhibit higher potency than single-target inhibitors. Protein kinases represent a promising target for the development of anticancer agents. As most multi-kinase inhibitors are heterocycles occupying only the hinge and hydrophobic region in the ATP binding site, we aimed to design multi-kinase inhibitors that would occupy the ribose pocket, along with the hinge and hydrophobic region, based on ATP-kinase interactions. Herein, we report the discovery of a novel 4'-thionucleoside template as a multi-kinase inhibitor with potent anticancer activity. The in vitro evaluation revealed a lead 1g (7-acetylene-7-deaza-4'-thioadenosine) with potent anticancer activity, and marked inhibition of TRKA, CK1δ, and DYRK1A/1B kinases in the kinome scan assay. We believe that these findings will pave the way for developing anticancer drugs.

Olig2 regulates p53-mediated apoptosis, migration and invasion of melanoma cells.

Melanoma is a disease with a high recurrence rate and poor prognosis; therefore, the need for targeted therapeutics is steadily increasing. Oligodendrocyte transcription factor2 (Olig2) is a basic helix-loop-helix transcription factor that is expressed in the central nervous system during embryonic development. Olig2 is overexpressed in various malignant cell lines such as lung carcinoma, glioma and melanoma. Olig2 is known as a key transcription factor that promotes tumor growth in malignant glioma. However, the role of Olig2 in melanoma is not well characterized. We analyzed the role of Olig2 in apoptosis, migration, and invasion of melanoma cells. We confirmed that Olig2 was overexpressed in melanoma cells and tissues. Reduction of Olig2 increased apoptosis in melanoma cells by increasing p53 level and caspase-3/-7 enzyme activity. In addition, downregulation of Olig2 suppressed migration and invasion of melanoma cells by inhibiting EMT. Reduction of Olig2 inhibited expression of MMP-1 and the enzyme activity of MMP-2/-9 induced by TGF-ß. Moreover, Olig2 was involved in the downstream stages of MEK/ERK and PI3K/AKT, which are major signaling pathways in metastatic progression of melanoma. In conclusion, this study demonstrated the crucial roles of Olig2 in apoptosis, migration, and invasion of melanoma and may help to further our understanding of the relationship between Olig2 and melanoma progression.

Discovery and Structure-Activity Relationships of Novel Template, Truncated 1'-Homologated Adenosine Derivatives as Pure Dual PPARγ/δ Modulators.

Following our report that A3 adenosine receptor (AR) antagonist 1 exhibited a polypharmacological profile as a dual modulator of peroxisome proliferator-activated receptor (PPAR)γ/δ, we discovered a new template, 1'-homologated adenosine analogues 4a-4t, as dual PPARγ/δ modulators without AR binding. Removal of binding affinity to A3AR was achieved by 1'-homologation, and PPARγ/δ dual modulation was derived from the structural similarity between the target nucleosides and PPAR modulator drug, rosiglitazone. All the final nucleosides were devoid of AR-binding affinity and exhibited high binding affinities to PPARγ/δ but lacked PPARα binding. 2-Cl derivatives exhibited dual receptor-binding affinity to PPARγ/δ, which was absent for the corresponding 2-H derivatives. 2-Propynyl substitution prevented PPARδ-binding affinity but preserved PPARγ affinity, indicating that the C2 position defines a pharmacophore for selective PPARγ ligand designs. PPARγ/δ dual modulators functioning as both PPARγ partial agonists and PPARδ antagonists promoted adiponectin production, suggesting their therapeutic potential against hypoadiponectinemia-associated cancer and metabolic diseases.

Diallyl Biphenyl-Type Neolignans Have a Pharmacophore of PPARα/γ Dual Modulators.

Adiponectin secretion-promoting compounds have therapeutic potentials in human metabolic diseases. Diallyl biphenyl-type neolignan compounds, magnolol, honokiol, and 4-O-methylhonokiol, from a Magnolia officinalis extract were screened as adiponectin- secretion promoting compounds in the adipogenic differentiation model of human bone marrow mesenchymal stem cells (hBM-MSCs). In a target identification study, magnolol, honokiol, and 4-O-methylhonokiol were elucidated as PPARα and PPARγ dual modulators. Diallyl biphenyl-type neolignans affected the transcription of lipid metabolism-associated genes in a different way compared to those of specific PPAR ligands. The diallyl biphenyl-type neolignan structure provides a novel pharmacophore of PPARα/γ dual modulators, which may have unique therapeutic potentials in diverse metabolic diseases.

Benzophenone-3 and benzophenone-8 exhibit obesogenic activity via peroxisome proliferator-activated receptor γ pathway.

Benzophenone-3 (BP-3) and benzopenone-8 (BP-8) are commonly used ultraviolet (UV) filter ingredients in diverse sunscreen products. Recently, the obesogenic activity of avobenzone, a long wave UV A filter, was elucidated in the adipogenesis model of human bone marrow mesenchymal stem cells (hBM-MSCs). In this study, the obesogenic potentials of BP-3 and BP-8 were investigated because of their chemical similarity to avobenzone. During the adipogenesis in hBM-MSCs, BP-3 and BP-8 (EC50, 25.05 and 43.20 µM, respectively) potently promoted adiponectin secretion than avobenzone (EC50, 72.69 µM). In target identification, both BP-3 and BP-8 directly bound to peroxisome proliferator-activated receptor γ (PPARγ), which was associated with the recruitment of steroid receptor coactivator-2 (SRC-2). BP-3 functioned as a PPARγ full agonist whereas BP-8 was a PPARγ partial agonist. In addition, BP-3 and BP-8 significantly increased the gene transcription of PPARα, PPARγ, and major lipid metabolism-associated enzymes in human epidermal keratinocytes, a major target site of UV filters in human skin. This study suggests that BP-3 and BP-8 are obesogenic environmental chemicals similar to phthalates, bisphenols, and organotins.