# Decoding Adipose Tissue Phenotypic Switching: From Mechanisms to Computational Drug Discovery

**Authors:** Yuqing Ye, Ruxin Yin, Junjie Sun, Yuwei Dai, Di Zhao, Xiaoling Zou

PMC · DOI: 10.1007/s13679-026-00701-y · Current Obesity Reports · 2026-03-23

## TL;DR

This paper reviews how brown fat can turn into white fat and uses computational methods to find potential drugs to prevent this process.

## Contribution

The paper introduces a computational screening approach to identify candidate molecules like 4-hydroxybenzoic acid for combating BAT whitening.

## Key findings

- BAT whitening is linked to mitochondrial dysfunction, which may connect various triggers to metabolic decline.
- 4-hydroxybenzoic acid is proposed as a promising candidate for further experimental validation.
- Bioinformatic tools are highlighted as valuable for preliminary screening of intervention molecules.

## Abstract

This review aims to explore the therapeutic potential of brown adipose tissue (BAT) to combat obesity and associated metabolic disorders by synthesizing the multifactorial influences and underlying mechanisms of BAT whitening and employing computational screening to identify promising candidate molecules for further investigation.

BAT whitening is characterized by the loss of thermogenic capacity, representing a critical aspect of adipose plasticity. Although diverse physiological and environmental triggers have been identified, the mechanistic interconnections underlying this process remain poorly understood. Emerging evidence supports an integrated view of these factors, and bioinformatic approaches now provide a valuable tool for the preliminary screening of potential intervention candidates.

This review synthesizes current understanding on BAT whitening, from influencing factors to mechanistic pathways. Mitochondrial dysfunction appears to be a critical hub that could link diverse triggers to downstream metabolic and functional decline. Through bioinformatic screening, 4-hydroxybenzoic acid (4-HBA) is proposed as a candidate worthy of further study. Future work should prioritize experimental validation to clarify its mechanism and assess its translational potential.

## Linked entities

- **Chemicals:** 4-hydroxybenzoic acid (PubChem CID 135)
- **Diseases:** obesity (MONDO:0011122)

## Full-text entities

- **Genes:** TFAM (transcription factor A, mitochondrial) [NCBI Gene 7019] {aka MTDPS15, MTTF1, MTTFA, TCF6, TCF6L1, TCF6L2}, TFEB (transcription factor EB) [NCBI Gene 7942] {aka ALPHATFEB, BHLHE35, TCFEB}, Dapk2 (death-associated protein kinase 2) [NCBI Gene 13143], Ucp1 (uncoupling protein 1) [NCBI Gene 24860] {aka Ucp, Ucpa, Uncp}, Cyp1a1 (cytochrome P450, family 1, subfamily a, polypeptide 1) [NCBI Gene 13076] {aka AHH, AHRR, CP11, CYPIA1, P450-1}, Elovl3 (ELOVL fatty acid elongase 3) [NCBI Gene 12686] {aka CIN-2, Cig30}, Fabp4 (fatty acid binding protein 4, adipocyte) [NCBI Gene 11770] {aka 422/aP2, AFABP, ALBP, ALBP/Ap2, Ap2, Lbpl}, Fasn (fatty acid synthase) [NCBI Gene 14104] {aka A630082H08Rik, FAS}, Adipoq (adiponectin, C1Q and collagen domain containing) [NCBI Gene 11450] {aka 30kDa, APN, Acdc, Acrp30, Ad, Adid}, DNM1L (dynamin 1 like) [NCBI Gene 10059] {aka DLP1, DRP1, DVLP, DYMPLE, EMPF, EMPF1}, Ppara (peroxisome proliferator activated receptor alpha) [NCBI Gene 25747] {aka PPAR}, Fabp3 (fatty acid binding protein 3, muscle and heart) [NCBI Gene 14077] {aka Fabph-1, Fabph-4, Fabph1, Fabph4, H-FABP, Mdgi}, Ddit3 (DNA-damage inducible transcript 3) [NCBI Gene 13198] {aka AltDDIT3, CHOP-10, CHOP10, chop, gadd153}, APOO (apolipoprotein O) [NCBI Gene 79135] {aka FAM121B, MIC26, MICOS26, Mic23, My025}, RBMS3 (RNA binding motif single stranded interacting protein 3) [NCBI Gene 27303], Mir215 (microRNA 215) [NCBI Gene 387211] {aka Mirn215, mir-215, mmu-mir-215}, Baat (bile acid-Coenzyme A: amino acid N-acyltransferase) [NCBI Gene 12012] {aka BAT}, Pnpla2 (patatin-like phospholipase domain containing 2) [NCBI Gene 66853] {aka 0610039C21Rik, 1110001C14Rik, Atgl, TTS-2.2}, NOG (noggin) [NCBI Gene 9241] {aka SYM1, SYNS1, SYNS1A}, PNPLA2 (patatin like domain 2, triacylglycerol lipase) [NCBI Gene 57104] {aka 1110001C14Rik, ATGL, FP17548, PEDF-R, TTS-2.2, TTS2}, Plin1 (perilipin 1) [NCBI Gene 103968] {aka 6030432J05Rik, Peri, Plin}, MCRIP2 (MAPK regulated corepressor interacting protein 2) [NCBI Gene 84331] {aka C16orf14, FAM195A, c349E10.1}, Apoo (apolipoprotein O) [NCBI Gene 68316] {aka 0610008C08Rik, 1110019O03Rik, Micos26}, Hcar1 (hydrocarboxylic acid receptor 1) [NCBI Gene 243270] {aka Gpr81}, ADRB3 (adrenoceptor beta 3) [NCBI Gene 155] {aka BETA3AR}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 22339] {aka L-VEGF, Vegf, Vpf}, Tlr4 (toll-like receptor 4) [NCBI Gene 21898] {aka Lps, Ly87, Ran/M1, Rasl2-8}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, Tfeb (transcription factor EB) [NCBI Gene 21425] {aka Tcfeb, bHLHe35}, KDM5A (lysine demethylase 5A) [NCBI Gene 5927] {aka NEDEHC, RBBP-2, RBBP2, RBP2}, DICER1 (dicer 1, ribonuclease III) [NCBI Gene 23405] {aka DCR1, Dicer, Dicer1e, GLOW, HERNA, K12H4.8-LIKE}, Nr3c1 (nuclear receptor subfamily 3, group C, member 1) [NCBI Gene 14815] {aka GR, Grl-1, Grl1}, H3c7 (H3 clustered histone 7) [NCBI Gene 260423] {aka H3.2-221, H3c13, H3c14, H3c15, H3c2, H3c3}, PRKAB1 (protein kinase AMP-activated non-catalytic subunit beta 1) [NCBI Gene 5564] {aka AMPK, HAMPKb}, Ucp1 (uncoupling protein 1 (mitochondrial, proton carrier)) [NCBI Gene 22227] {aka Slc25a7, Ucp}, MLXIPL (MLX interacting protein like) [NCBI Gene 51085] {aka CHREBP, MIO, MONDOB, WBSCR14, WS-bHLH, bHLHd14}, CTBP1 (C-terminal binding protein 1) [NCBI Gene 1487] {aka BARS, HADDTS}, Lep (leptin) [NCBI Gene 16846] {aka ob, obese}, Mcrip2 (MAPK regulated corepressor interacting protein 2) [NCBI Gene 68241] {aka 9530058B02Rik, Fam195a}, Fgf21 (fibroblast growth factor 21) [NCBI Gene 56636] {aka Fgf8c}, Th (tyrosine hydroxylase) [NCBI Gene 21823], Esrrg (estrogen-related receptor gamma) [NCBI Gene 26381] {aka ERR3, Errg, NR3B3, mKIAA0832}, Ppara (peroxisome proliferator activated receptor alpha) [NCBI Gene 19013] {aka 4933429D07Rik, Nr1c1, PPAR-alpha, PPARalpha, Ppar}, ESRRG (estrogen related receptor gamma) [NCBI Gene 2104] {aka ERR-gamma, ERR3, ERRg, ERRgamma, NR3B3}, UCP1 (uncoupling protein 1) [NCBI Gene 7350] {aka SLC25A7, UCP}, Btg1 (BTG anti-proliferation factor 1) [NCBI Gene 12226]
- **Diseases:** toxicity (MESH:D064420), Hyperprolactinemia (MESH:D006966), Mitochondrial dysfunction (MESH:D028361), diabetes (MESH:D003920), Obesity (MESH:D009765), hypoxic (MESH:D002534), metabolic disturbances (MESH:D024821), adipose tissue dysfunction (MESH:D018205), inflammation (MESH:D007249), metabolic diseases (MESH:D008659), tumor (MESH:D009369)
- **Chemicals:** nicotine (MESH:D009538), alpha-lipoic acid (MESH:D008063), salbutamol (MESH:D000420), mirabegron (MESH:C520025), coenzyme Q10 (MESH:C024989), triglyceride (MESH:D014280), norepinephrine (MESH:D009638), lipid (MESH:D008055), fat (MESH:D005223), PTC (MESH:C550005), vanillic acid (MESH:D014641), hydrogen (MESH:D006859), purine (MESH:C030985), Cr (MESH:D002857), 12,13-dihydroxy-9Z-octadecenoic acid (-), gallic acid (MESH:D005707), Creatine (MESH:D003401), 4-HBA (MESH:C038193), fatty acid (MESH:D005227), 18F-FDG (MESH:D019788), lactate (MESH:D019344), polystyrene (MESH:D011137), ozone (MESH:D010126), oxygen (MESH:D010100), imeglimin (MESH:C575881), ellagic acid (MESH:D004610), D-2HG (MESH:C019417), sucrose (MESH:D013395), tamoxifen (MESH:D013629), polyphenols (MESH:D059808), BPS (MESH:C543008), ATP (MESH:D000255), palm oil (MESH:D000073878), Prl (MESH:D011388), nicotinamide riboside (MESH:C018613), nitrogen (MESH:D009584), glucose (MESH:D005947), tyrosine (MESH:D014443), benzoic acid (MESH:D019817), PO (MESH:D011059), quercetin (MESH:D011794), ceramide (MESH:D002518), salicylic acid (MESH:D020156), dasatinib (MESH:D000069439), ROS (MESH:D017382), NAD+ (MESH:D009243), urate (MESH:D014527), endocannabinoid (MESH:D063388), omega-3 fatty acids (MESH:D015525), fructose (MESH:D005632), dotinurad (MESH:C000706811), dechlorane (MESH:D008917)
- **Species:** Homo sapiens (human, species) [taxon 9606], Ovis aries (domestic sheep, species) [taxon 9940], Mus musculus (house mouse, species) [taxon 10090], Roseburia hominis (species) [taxon 301301], Oryctolagus cuniculus (domestic rabbit, species) [taxon 9986], Rattus norvegicus (brown rat, species) [taxon 10116]

## Full text

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## Figures

4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13006473/full.md

## References

6 references — full list in the complete paper: https://tomesphere.com/paper/PMC13006473/full.md

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Source: https://tomesphere.com/paper/PMC13006473