ABSTRACT
Objectives
White adipose tissue plays a critical role in obesity, as its dysfunction can impair lipid homeostasis. We previously demonstrated that desaminotyrosine (DAT), a microbial metabolite, prevents high-fat diet (HFD)-induced body weight gain in mice, but the role of DAT on white adipocyte is unknown. Here, we investigated the role of DAT in host metabolic health and its therapeutic potentials in treating obesity.
Methods
In this study, we employed a pharmacological approach by administering DAT to mice. These mice were subjected to HFD feeding to establish overweight model, followed by DAT treatment. The effect of DAT on white adipocytes were studied using both in vivo and in vitro models.
Results
Our data indicated that DAT is a potent weight loss chemical for obesity treatment. This is related to DAT's dual-function in regulating white adipose tissue remodeling. DAT enhances mature white adipocyte-autonomous fat disposal through sustained lipolysis and augmented expression of carnitine palmitoyltransferase I family protein CPT1A, a critical enzyme facilitating fatty acid oxidation (FAO), especially under lipolytic-inducing conditions. In the meantime, it blocks white adipogenesis via FAO-dependent pathway potentiation.
Conclusions
Collectively, these data demonstrate that DAT is a potent antiobesity agent with potential effects on white adipose tissue remodeling. This study provides a novel pharmacological strategy targeting white adipocyte plasticity for treating metabolic disorders.
KEYWORDS: White adipocyte, obesity, desaminotyrosine, lipid metabolism, adipogenesis, energy expenditure
GRAPHICAL ABSTRACT
Introduction
Obesity, a chronic and relapsing disease characterized by an excessive accumulation of body fat, represents a significant risk factor for developing type 2 diabetes (T2D), cardiovascular diseases, and various malignancies.1,2 Recent breakthroughs in the use of glucagon-like peptide−1 (GLP−1) receptor agonists and their integration into multiple-hormone receptor agonists have revolutionized antiobesity pharmacotherapy.3 Nevertheless, the long-term safety profile of these hormone-targeting therapies requires further investigation. Significant demand persists for novel nonincretin-based therapeutic strategies.
The gut microbiota, a critical modulator of host metabolism regulation and energy homeostasis, presents promising potential for developing innovative antiobesity therapeutics.4 Desaminotyrosine (DAT, 3-(4-hydroxyphenyl)propionic acid) is derived from intestinal commensal bacterial degradation of dietary flavonoids or the amino acid tyrosine.5‐8 It exhibits multifaceted biological functions, including enhanced antimicrobial defense,9,10 synergistic effects with cancer immunotherapies,11 and anti-inflammatory and antioxidative properties, as demonstrated in obesity-associated inflammation, colitis, and bacterial endotoxin-induced septic shock models.9,12,13 Given the pivotal role of gut microbiota in regulating host lipid metabolism and the fact that obesity is associated with white adipocyte hypertrophy and reduced lipolysis of white adipose tissues,14‐17 we investigated DAT's capacity in white adipocyte biology. Our findings reveal DAT as a potential dual-function agent that simultaneously enhances white adipocyte lipid disposal function and suppresses white adipogenic differentiation, positioning it as a novel therapeutic candidate for obesity-associated metabolic disorders.
Results
DAT enhances white adipocyte-autonomous fat disposal function
Our previous study demonstrated that supplementing exogenous DAT in drinking water significantly attenuated high-fat diet (HFD)-induced body fat mass accumulation and body weight gain in mice without altering food intake.12 These findings suggest a potential regulatory role of DAT in host lipid storage and disposal homeostasis. To investigate this hypothesis, B6 wild-type (WT) male mice fed either a normal chow diet (ND), a HFD, or a HFD supplemented with 100 mM DAT for 12 weeks were used to examine whether DAT administration modulates lipolysis. Serum free fatty acid (FFA) levels were then measured under both fed and 24-h fasting conditions. While no intergroup differences in serum FFA levels were observed in the fed state, HFD-fed mice exhibited blunted fasting-induced lipolysis compared to ND controls (Figure 1A). Importantly, DAT supplementation reversed this HFD-induced impairment (Figure 1A), indicating that DAT restores attenuated lipolytic responses caused by an obesogenic HFD. Furthermore, ex vivo lipolysis assays demonstrated markedly attenuated lipolytic capacity in the epididymal adipose tissue (eWAT) of HFD-fed mice versus ND controls, while DAT partially restored this HFD-induced impairment (Figure 1B), suggesting that DAT may directly modulate white adipocyte lipid handling function. To test WAT response to cold stress challenge with or without DAT treatment in vivo, the mice were trained to adapt to cold at 4 °C for 4 h each day for a total of three days, followed by cold challenge at 4 °C for 24 h. Immunoblotting analysis revealed that DAT treatment augmented expression levels of CPT1A, a critical enzyme facilitating FAO, in eWAT (Figure 1C). Furthermore, cold-induced beige adipogenesis in WAT,18 evaluated by uncoupling protein 1 (UCP1) expression levels, was inhibited by HFD, but was restored by DAT treatment (Figure 1C).
Figure 1.
DAT enhances white adipocyte-autonomous lipid disposal function. (A–C) B6 WT mice were fed for 12 weeks with either a normal chow diet (ND), a high-fat diet (HFD), or HFD plus 100 mM DAT in the drinking water (HFD + DAT). (A) Serum FFA levels were determined before and after 24 h of fasting. n = 3 for ND; 8 or 4 for HFD under fed or fasting state, respectively; 8 or 4 for HFD + DAT under fed or fasting state, respectively. (B) Ex vivo lipolysis of eWAT explants from the indicated mice. Glycerol levels in the culture supernatant were determined at the indicated time points. n = 4 for all groups. (C) The mice were trained to adapt to cold at 4 °C for 4 h each day for a total of three days, followed by cold challenge at 4 °C for 24 h. The relative expression levels of CPT1A and UCP1 in the eWAT of the indicated mice were determined by immunoblot (upper panel), and quantified by densitometry analysis (lower panel). n = 3 or 4. (D) The lipolysis activity of 3T3-L1-derived adipocytes that were treated with or without 1 mM DAT was determined at the indicated time points. The ISO-treated group was set as the positive control. n = 4. (E) 3T3-L1-derived mature adipocytes were treated with or without 1 mM DAT in KRHB buffer with 2% FFA-free BSA for 15 or 120 min, the relative expression levels of CPT1A were then determined by immunoblots (upper panel) and quantified by densitometry analysis (lower panel). n = 3. (F and G) 3T3-L1 preadipocytes differentiated into mature white adipocytes. Mature adipocytes were treated with or without DAT (1 mM or 5 mM) for 48 h. (D) Oil Red O staining was performed, and representative images of Oil Red O staining are shown. Scale bar = 200 µm. n = 3. (E) Quantification of Oil Red O content, representing overall lipid droplet accumulation, was performed using a colorimetric assay. n = 3. Data are represented as mean ± SEM. Statistical analysis with one-way ANOVA analysis (A, C, E, and G), two-way ANOVA analysis (B, D). *p < 0.5; **p < 0.01; ***p < 0.001; ****p < 0.0001; ns, no statistical significance.
To confirm that DAT can directly influence white adipocyte lipid disposal function, in vitro lipolysis experiments were conducted in 3T3-L1-derived white adipocytes. The results indicated that under control condition, cellular basal lipolytic activity plateaued at 24 h, and DAT treatment induced sustained lipolytic activity for more than 48 h (Figure 1D), suggesting that DAT may induce a long-term sustainability of lipid disposal in adipocyte. In contrast to the β-adrenergic receptor agonist isoproterenol (ISO), DAT did not trigger instant explosion of lipolysis (Figure 1D). Furthermore, under lipolytic induction conditions (i.e., cells were incubated in KRHB buffer with 2% FFA-free BSA), DAT treatment upregulated CPT1A protein expression levels at 2 h (Figure 1E), which was consistent with our in vivo findings. Notably, Oil Red O staining for neutral lipids revealed that 48 h of DAT treatment significantly depleted 3T3-L1 adipocytes fat store (Figure 1F and G). These findings collectively suggest that DAT enhances white adipocyte-autonomous fat disposal function.
DAT inhibits white adipogenesis through CPT1A-dependent fatty acid oxidation (FAO) potentiation
Obesity is also associated not only with adipocyte hypertrophy but also with abnormal adipogenesis. We next investigated the regulatory effects of DAT on white- adipogenic differentiation. 3T3-L1 preadipocytes were exposed to DAT (1 or 5 mM) throughout both the differentiation induction (days 0−4) and maintenance phases (days 4−9). Subsequent Oil Red O staining revealed dose-dependent attenuation of intracellular lipid accumulation in the DAT-treated groups (Figure 2A and B). Molecular analysis further demonstrated coordinated suppression of adipogenic markers, such as adipocyte-specific genes (Adipoq) and key transcriptional regulators (Pparg and Cebpa), in the DAT-treated groups (Figure 2C). These results demonstrate DAT's inhibitory role in adipocyte terminal differentiation.
Figure 2.
DAT inhibits white adipogenesis through CPT1A-dependent FAO potentiation (A-C) 3T3-L1 preadipocytes were exposed to DAT (1 or 5 mM) throughout both the differentiation induction (days 0−4) and maintenance phases (days 4−9). 3T3-L1, nondifferentiated; Ctrl, differentiated without DAT; 1 mM DAT, differentiated with 1 mM DAT; 5 mM DAT, differentiated with 5 mM DAT. (A) Representative images of Oil Red O-stained 3T3-L1-derived adipocytes 9 days after differentiation under the indicated conditions. (B) Quantification of the Oil Red O-positive area per view field via ImageJ. n = 3. (C) The relative mRNA expression levels of Acc, Adipoq, Pparg, and Cebpa 9 days after differentiation. n = 3. (D and E) 3T3-L1 preadipocytes were cotreated with DAT (1 mM) and etomoxir (ETO, 5 µM) during the differentiation maintenance phase (days 4−9). Ctrl, no ETO and no DAT; DAT, 1 mM DAT but no ETO; ETO, 5 µM ETO but no DAT; ETO + DAT, 5 µM ETO and 1 mM DAT. (E) Representative images of Oil Red O-stained 3T3-L1-derived adipocytes 9 days after differentiation under the indicated conditions. (F) Quantification of the Oil Red O-positive area per view field by Image J. n = 3. Data are represented as mean ± SEM. Statistical analysis with one-way ANOVA analysis (B–E). *p < 0.5; **p < 0.01; ***p < 0.001; ****p < 0.0001; ns, no statistical significance.
Since DAT treatment enhanced CPT1A expression and depleted fat store in mature 3T3-L1 adipocytes (Figure 1F and G), we posited that the antiadipogenic function may also be related to FAO pathway. To verify FAO's involvement in DAT-mediated antiadipogenic effect, we cotreated 3T3-L1 preadipocytes with DAT (1 mM) and etomoxir (ETO, 5 µM), an irreversible inhibitor of CPT1A, during the differentiation maintenance phase (days 4−9). ETO alone exhibited no effects on lipid-laden adipocyte biogenesis, and cotreatment with ETO reversed DAT's inhibitory effect on adipogenesis (Figure 2D and E), suggesting DAT's anti-adipogenic mechanism through CPT1A-dependent FAO potentiation.
DAT is a potent weight loss chemical for obesity treatment
Given our findings that DAT enhances adipocyte-autonomous lipid disposal capacity while suppressing adipogenesis, we propose that DAT may be able to manage weight gain in obese individuals. To investigate this hypothesis, B6 WT male mice were fed a HFD for 4 weeks to establish an overweight model and then treated with 100 mM DAT (Figure 3A). Compared with those in the HFD group, the circulating DAT levels in DAT-supplemented mice fed on a HFD were significantly increased and similar with that of mice fed on a normal chow diet (Supplementary Figure S1). Compared to vehicle-treated HFD overweight controls, DAT intervention induced more than 10% body weight loss within 2~4 weeks of treatment (Figure 3B), without greatly influence ad libitum daily water and food intake (Figure 3C and D). Intraperitoneal glucose tolerance tests indicated no significant improvement in HFD-induced insulin resistance (Figure 3E and F, and supplementary Figure S2). The primary therapeutic effect of DAT treatment manifested through reduced white adipose tissue mass (Figure 3G and H) and decreased white adipocyte size (Figure 3I). HFD-induced obesity is normally accompanied by hepatic steatosis. DAT effectively alleviated HFD-induced hepatic steatosis (Supplementary Figure S3A–F). We further measured serum levels of the ketone body β-hydroxybutyrate, a biomarker for excess FAO, under fasting condition. DAT-treated mice had increased β-hydroxybutyrate levels compared to HFD-fed controls (Supplementary Figure S3G), further supporting a role of DAT in promoting FAO. These findings collectively identified DAT as a potential antiobesity agent with specific effects on adipose tissue remodeling.
Figure 3.
DAT is a potent weight loss chemical for obesity treatment in mice. (A) Schematic of experimental design. B6 WT male mice were divided into three groups: (1) ND group, fed with a normal chow diet for 12 weeks, n = 5; (2) HFD group, fed with a HFD for 12 weeks, n = 10; (3) HFD + DAT group, initially fed with HFD for 4 weeks, followed by HFD feeding plus 100 mM DAT supplemented in drinking water for the next 8 weeks, n = 10. (B–D) Weekly body weight changes (B), daily water intake (C), and daily food intake (D) were recorded. (E and F) Intraperitoneal glucose tolerance test at 12 weeks after HFD feeding (E), and the area under the curve (AUC) (F) was calculated accordingly. (G–I) Adipose tissue weight (G) and representative images of inguinal (iWAT) and epididymal (eWAT) white adipose tissue (H) at 12 weeks after HFD feeding. BAT, brown adipose tissue. (I) Representative images of H&HampE-stained sections of eWAT. The average size of adipocytes was quantified using ImageJ. Data are represented as mean ± SEM. Statistical analysis with one-way ANOVA analysis (C, D, F, G, and I), two-way ANOVA analysis (B and E). **p < 0.01; ***p < 0.001; ****p < 0.0001; ns, no statistical significance.
We subsequently measured energy expenditure to assess the impact of DAT on caloric utilization efficiency under both cold (4 °C) and room temperature (24 °C) conditions with standard day‒night cycles. At 24°C room temperature, compared to HFD overweight controls, DAT intervention group showed elevated hourly oxygen consumption (VO₂), carbon dioxide production (VCO₂), and heat generation exclusively during nocturnal periods (Figure 4). Under cold challenge conditions, DAT administration consistently increased VO₂, VCO₂, and thermal output throughout the entire experimental period regardless of day or night (Figure 4). These findings demonstrate DAT's capability to improve host energy expenditure under both a high-calorie fat diet intake and cold stress conditions.
Figure 4.
DAT promotes energy expenditure. (A-D) B6 WT male mice were divided into three groups: (1) ND group, fed with a normal chow diet for 12 weeks; (2) HFD group, fed with a HFD for 12 weeks; (3) HFD + DAT group, initially fed with HFD for 4 weeks, followed by HFD feeding plus 100 mM DAT supplemented in drinking water for the next 8 weeks. The mice were then trained to adapt to cold at 4 °C for 4 h each day for a total of three days, followed by cold challenge at 4 °C for 24 h. The oxygen consumption rate (VO2) (A) and CO2 production (VCO2) (B) were recorded. The heat production (C) and respiratory exchange rate (RER) (D) were calculated accordingly. n = 4. Data are represented as mean ± SEM. Statistical analysis with one-way ANOVA analysis. **p < 0.01; ****p < 0.0001; ns, no statistical significance.
Discussion
In this study, we identified DAT, a bacterium-derived metabolite, as a therapeutic agent with potent antiobesity effects. Unlike GLP-1-based therapies, DAT exerts its metabolic benefits independent of appetite regulation and demonstrates efficacy in attenuating adipocyte dysplasia and hypertrophy even under sustained high-caloric dietary intake. These findings position the DAT as a novel pharmaceutical class targeting metabolic dysfunction, with significant potential for translational development.
Mechanistically, DAT enhances mature white adipocyte-autonomous fat disposal function through inducing a long-term sustainability of lipolysis and augmented expression of CPT1A, a critical enzyme facilitating FAO, especially under lipolytic-inducing conditions. In the meantime, it blocks white adipogenesis via FAO-dependent pathway potentiation. Therefore, DAT achieves dual regulation of white adipose tissue remodeling. In addition, our previous study demonstrate that DAT has anti-inflammatory and antioxidation functions,9,12,19 which can potentially inhibit obesity-associated adipocyte damage and chronic inflammation. These multifaceted biological functions of DAT are all beneficial for the management of obesity.
Notably, DAT has a modest effect in ameliorating HFD-induced glucose intolerance. The reason behind this phenomenon requires further investigation. Given the complexity of metabolic disorders, combinatorial approaches with adjuvant therapies would be essential. While the therapeutic potential and pharmacologic properties of DAT remains to be further explored, DAT pioneers a novel pharmacological strategy targeting white adipocyte plasticity.
Materials and methods
Animals and treatment
All of the animal studies were approved by the Institutional Animal Care and Treatment Committee of Xuzhou Medical University (SCXK (Su) 2020−0048). All animals were in the B6 background and maintained at Xuzhou Medical University without specific pathogens. All mice used were housed at 20−22 °C with a 12 h light–dark cycle and given free access to food and water. Six to eight-week-old male mice were used to establish an obesity model using a commercial HFD consisting of 60% calories from fat (D12492; Research Diets, Beijing, China). For desaminotyrosine (DAT) (Bide Pharmatech Ltd. China) treatment, the mice were given 100 mM DAT in the drinking water. The DAT-containing water was refreshed every three days.
Intraperitoneal glucose tolerance test
Mice were fasted for 16 h, followed by intraperitoneal injection of 2 g/kg glucose. The blood glucose levels were monitored at the indicated time points using Accu-Check blood glucose meter (Roche, USA).
Indirect calorimetry measurement
The mice were individually placed in metabolic cages to monitor energy expenditure. Food and water were available freely to the mice. The mice were initially trained to adapt to cold at 4 °C for 4 h daily for a total of three days, followed by a 24-h cold challenge. The oxygen consumption and carbon dioxide production rates were monitored using a comprehensive laboratory animal monitoring system (Comprehensive Laboratory Animal Monitoring System, CLAMS, USA).
Histological analysis
The white adipose tissues were fixed in a 4% paraformaldehyde solution for more than 24 h at 4 °C until further processing. After gradual dehydration, the fixed tissues were embedded in paraffin, sectioned at 4 µm, and stained with hematoxylin and eosin (H&Mamp E). An optical microscope was used to collect images for analysis. The size of white adipocytes was determined using ImageJ software.
Cell culture
3T3-L1 preadipocytes were grown and differentiated based on a previously published method with minor modifications.20 Briefly, 3T3-L1 cells were grown to full confluence in full growth media containing DMEM (Keygen Biotech, Nanjing, China), 10% FBS (Gibco) and antibiotic-antimycotic. Then the cells were incubated in differentiation induction media [i.e., full growth media plus 2 µg/ml dexamethasone (MedChemExpress, Shanghai, China), 500 µM IBMX (Sigma), and 5 µg/ml insulin (Sigma)]. The media was refreshed every other day for a total of four days. After that, the cells were kept in maintenance medium (full growth media supplemented with 10 µg/ml insulin) for five more days.
Lipolysis assays
Lipolysis experiments were performed according to a previous report with minor modifications.20 To induce lipolysis in vitro, mature adipocytes derived from 3T3-L1 cells were washed with PBS and placed in KRBH buffer containing 30 mM HEPES, 120 mM NaCl, 4 mM KH2PO4, 1 mM MgSO4, 0.75 mM CaCl2, and 10 mM NaHCO3, 2% fatty-acid-free BSA, and 5 mM glucose, with or without 1 mM DAT. Isoproterenol (ISO, 3 µM) was used as a positive control. Glycerol released in the media were determined using a commercial kit (Nanjing Jiancheng Bioengineering Institute, China) and normalized to cellular protein concentration. For ex vivo lipolysis, approximately 0.1 g of eWAT were collected from nonfasted mice. Tissues were cut into small pieces and incubated in same KRBH buffer as described above at indicated time points. Glycerol released in the media was then determined and normalized by the explant weights.
Oil red O staining
Cells were fixed with 4% paraformaldehyde for 15 min at ambient temperature. The fixed cells were subsequently stained with Oil Red O dye (Solarbio, Beijing, China) for 30 min and then washed three times with water and 60% (v/v) isopropanol to remove excess dye. For quantification of Oil Red O content, stained lipid droplets were eluted with 100% (v/v) isopropanol, and the absorbance of the resulting solution was measured at 490 nm using a microplate reader.
Western blot analysis
White adipose tissues or cells were collected and directly lysed in RIPA buffer containing proteinase inhibitors, PMSF, and phosphatase inhibitor (Beyotime, China). Protein concentrations in the lysate supernatants were determined using a bicinchoninic acid (BCA) protein assay kit (Beyotime, China). Next, the protein samples were separated by 10% sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS‒PAGE) and then electrotransferred to a polyvinylidene fluoride (PVDF) membrane. The membrane was blocked with 5% nonfat milk for 2 h at room temperature and then incubated with antibodies against CPT1A (Cell Signaling Technology, USA) or UCP1 (Wanleibio, China) at 4 °C overnight. Then, the membranes were washed three times and subsequently incubated with a horseradish peroxidase-conjugated secondary antibody for 1 h at room temperature, and the protein signals were visualized using ECL Western blotting reagents.
RNA extraction and quantitative real-time PCR (qRT‒PCR)
Total RNA was extracted from adipocytes, followed by reverse transcription to cDNA using a high-capacity cDNA reverse transcription kit (Takara, Japan). The qPCR reaction was performed with the FastStart Universal SYBR Green Master (Roche). The mRNA levels for specific genes were calculated using 2−ΔΔCT method and normalized by 𝛽-actin mRNA levels. The primers used were: Adipoq (F: 5′-CTCTTCACCTACGACCAGTATCAG−3′, R: 5′-TGGTAGAGAAGAAAGCCAGTAAATG−3′); Cebpa (F: 5′-GACAAGAACAGCAACGAGTA−3′, R: 5′- GCAGTTGCCATGGCCTTGA−3′); Pparg (F: 5′-TTCAAGGGTGCCAGTTTCG−3′, R: 5′-CCATCTTTATTCATCAGGGAGG−3′); and β-actin (F: 5′-CGTTGACATCCGTAAAGACC−3′, R: 5′-AACAGTCCGCCTAGAAGCA−3′).
Statistical analysis
Data were presented as mean ± SEM and analyzed using Prism (GraphPad Software, La Jolla, CA, USA). Statistical significance was established at p < 0.05.
Supplementary Material
The microbial metabolite desaminotyrosine is a potent antiobesity agent with potential effects on white adipose tissue remodeling in mice.
Acknowledgments
The experiments in this article were partly completed in Public Experimental Research Center of Xuzhou Medical University. We sincerely thank Dr. Fuxing Dong for his enthusiastic help in the experiment of laser scanning confocal microscopy.
Supplementary material
Supplemental data for this article can be accessed at https://doi.org/10.1080/19490976.2025.2587400.
Ethics approval statement
The animal study was reviewed and approved by the Ethics Committee of Xuzhou Medical University.
Author contributions
H.H.H., Writing – review & editing, methodology, investigation, formal analysis, data curation. H.M.B, Writing – original draft, Investigation. L.X.L., Formal analysis, Data curation. Y.Y.X., Formal analysis, Investigation. Q.C.C., Formal analysis, Data curation. G.L.F., Methodology, Investigation. W.P.C., Investigation, Software, Formal analysis. Y.B.K., Formal analysis, Data curation. Z.Z.L., Methodology, Data curation. K.Y.Z., Resources, Funding acquisition, Investigation. Y.G.W., Writing-review & editing, validation, supervision, resources, funding acquisition, formal analysis, data curation, conceptualization. Y.X.W., Writing – review & editing, Methodology, Investigation, Supervision, Formal analysis, Data curation, Resources, Project administration, Funding acquisition, Conceptualization.
Disclosure statement
The authors declare no conflict of interest.
Funding
This work was supported by the National Natural Science Foundation of China (Grant No. 81970730, 82571010, 82471850), the Natural Science Foundation of Jiangsu Province, China (Grant No. BK20221390), the Foundation for Key Program of Universities of Jiangsu Province (24KJA310010), the Open Competition Grant of Xuzhou Medical University (JBGS202202) and the Jiangsu TCM Science and Technology Development Plan (Grant No. MS2022153) and the Science and Technology Foundation of Xuzhou (KC22122).
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
The microbial metabolite desaminotyrosine is a potent antiobesity agent with potential effects on white adipose tissue remodeling in mice.
Data Availability Statement
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.