# The role of PYY in improving insulin resistance **Authors:** Chunyan Liu, Na Ren, Haixin Zhang, Jian Ma PMC · DOI: 10.3389/fendo.2026.1784709 · Frontiers in Endocrinology · 2026-02-18 ## TL;DR This paper reviews how the hormone PYY helps improve insulin resistance and could be a potential treatment for diabetes and metabolic disorders. ## Contribution The paper clarifies the distinct roles of PYY(1-36) and PYY(3-36) in improving insulin sensitivity and offers new treatment possibilities for insulin resistance. ## Key findings - PYY(3-36) improves insulin sensitivity by acting on Y2 receptors in peripheral tissues and suppressing appetite. - PYY(1-36) protects pancreatic β-cells and fine-tunes insulin secretion via the Y1 receptor. - PYY(3-36) promotes weight loss by delaying gastric emptying and suppressing appetite, which helps reduce insulin resistance. ## Abstract Insulin resistance (IR) is closely related to type 2 diabetes (T2DM) and metabolic syndrome, which poses a serious challenge globally. In terms of IR treatment, peptide YY holds broad therapeutic potential. The study found that the lack of peptide YY (PYY) is closely related to the occurrence of IR. Therefore, PYY plays an important role in glucose homeostasis and improving insulin sensitivity. Specifically, the two primary circulating forms, PYY(1-36) and PYY(3-36), mediate distinct effects through different neuropeptide Y receptors (YRs). PYY(3-36) predominantly acts through the Y2 receptor (Y2R) in the hypothalamus to suppress appetite and in peripheral tissues (adipose, skeletal muscle, liver) to enhance insulin sensitivity. In contrast, PYY(1-36) acts as a broader agonist, with significant effects on pancreatic β-cell protection and insulin secretion fine-tuning via the Y1 receptor. In addition, PYY(3-36) promotes weight loss by suppressing appetite and delaying gastric emptying, thus improving insulin resistance. This review aims to clarify the biological characteristics and signaling mechanism of PYY, and explore its potential applications in improving insulin resistance. Finally, it will explore the new treatment possibilities of PYY for IR and metabolic diseases based on current research progress. ## Linked entities - **Proteins:** PYY (peptide YY) - **Diseases:** type 2 diabetes (MONDO:0005148), metabolic syndrome (MONDO:0000816) ## Full-text entities - **Genes:** ZHX2 (zinc fingers and homeoboxes 2) [NCBI Gene 22882] {aka AFR1, RAF}, Npy2r (neuropeptide Y receptor Y2) [NCBI Gene 18167] {aka NPY2-R}, SREBF1 (sterol regulatory element binding transcription factor 1) [NCBI Gene 6720] {aka HMD, IFAP2, SREBP1, bHLHd1}, Gcg (glucagon) [NCBI Gene 14526] {aka GLP-1, Glu, PPG}, Lep (leptin) [NCBI Gene 16846] {aka ob, obese}, PDE3B (phosphodiesterase 3B) [NCBI Gene 5140] {aka HcGIP1, cGIPDE1}, BCL2A1 (BCL2 related protein A1) [NCBI Gene 597] {aka ACC-1, ACC-2, ACC1, ACC2, BCL2L5, BFL1}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, INSR (insulin receptor) [NCBI Gene 3643] {aka CD220, HHF5}, SHC1 (SHC adaptor protein 1) [NCBI Gene 6464] {aka SHC, SHCA}, TBC1D4 (TBC1 domain family member 4) [NCBI Gene 9882] {aka AS160, NIDDM5}, Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, IRS1 (insulin receptor substrate 1) [NCBI Gene 3667] {aka HIRS-1}, PYY3 (peptide YY 3 (pseudogene)) [NCBI Gene 644059] {aka PYY-III}, Slc2a4 (solute carrier family 2 (facilitated glucose transporter), member 4) [NCBI Gene 20528] {aka GT2, Glut-4, Glut4, twgy}, ADIPOQ (adiponectin, C1Q and collagen domain containing) [NCBI Gene 9370] {aka ACDC, ACRP30, ADIPQTL1, ADPN, APM-1, APM1}, GIP (gastric inhibitory polypeptide) [NCBI Gene 2695], AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, JUN (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 3725] {aka AP-1, AP1, c-Jun, cJUN, p39}, PDK1 (pyruvate dehydrogenase kinase 1) [NCBI Gene 5163], PCK2 (phosphoenolpyruvate carboxykinase 2, mitochondrial) [NCBI Gene 5106] {aka PEPCK, PEPCK-M, PEPCK2, mtPCK2}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, AGRP (agouti related neuropeptide) [NCBI Gene 181] {aka AGRT, ART, ASIP2}, Stambp (STAM binding protein) [NCBI Gene 70527] {aka 5330424L14Rik, 5730422L11Rik, Amsh, mKIAA4198}, IARS1 (isoleucyl-tRNA synthetase 1) [NCBI Gene 3376] {aka GRIDHH, IARS, ILERS, ILRS, IRS, PRO0785}, IRS2 (insulin receptor substrate 2) [NCBI Gene 8660] {aka IRS-2}, Pyy (peptide YY) [NCBI Gene 217212], Nfkb1 (nuclear factor kappa B subunit 1) [NCBI Gene 81736] {aka EBP-1, NF-kB, NFKB-p50, p50}, GPR166P (G protein-coupled receptor 166, pseudogene) [NCBI Gene 442206] {aka GPCR, PGR9}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, KCNJ12 (potassium inwardly rectifying channel subfamily J member 12) [NCBI Gene 3768] {aka IRK-2, IRK2, KCNJN1, Kir2.2, hIRK, hIRK1}, GLP1R (glucagon like peptide 1 receptor) [NCBI Gene 2740] {aka GLP-1, GLP-1-R, GLP-1R}, Npy (neuropeptide Y) [NCBI Gene 109648] {aka 0710005A05Rik}, Gcg (glucagon) [NCBI Gene 24952] {aka GLP-1, Glp1, Glp2}, GCG (glucagon) [NCBI Gene 2641] {aka GLP-1, GLP1, GLP2, GRPP}, Cartpt (CART prepropeptide) [NCBI Gene 27220] {aka Cart}, Gpbar1 (G protein-coupled bile acid receptor 1) [NCBI Gene 227289] {aka BG37, GPCR, GPR131, M-BAR, TGR5}, Mc4r (melanocortin 4 receptor) [NCBI Gene 17202] {aka Mc4-r, Pkcp}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, Lepr (leptin receptor) [NCBI Gene 16847] {aka B219, LEP-R, LEPROT, Leprb, Modb1, OB-RGRP}, PPARG (peroxisome proliferator activated receptor gamma) [NCBI Gene 5468] {aka CIMT1, FPLD3, GLM1, NR1C3, PPARG1, PPARG2}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, XYLT2 (xylosyltransferase 2) [NCBI Gene 64132] {aka PXYLT2, SOS, XT-II, XT2, xylT-II}, PNPLA2 (patatin like domain 2, triacylglycerol lipase) [NCBI Gene 57104] {aka 1110001C14Rik, ATGL, FP17548, PEDF-R, TTS-2.2, TTS2}, PDK2 (pyruvate dehydrogenase kinase 2) [NCBI Gene 5164] {aka PDHK2, PDKII}, GRB2 (growth factor receptor bound protein 2) [NCBI Gene 2885] {aka ASH, EGFRBP-GRB2, Grb3-3, MST084, MSTP084, NCKAP2}, LIPE (lipase E, hormone sensitive type) [NCBI Gene 3991] {aka AOMS4, FPLD6, HSL, LHS, REH}, Bcl2 (BCL2, apoptosis regulator) [NCBI Gene 24224] {aka Bcl-2}, POMC (proopiomelanocortin) [NCBI Gene 5443] {aka ACTH, CLIP, LPH, MSH, NPP, OBAIRH}, TAC1 (tachykinin precursor 1) [NCBI Gene 6863] {aka Hs.2563, NK2, NKNA, NPK, TAC2}, Pomc (pro-opiomelanocortin-alpha) [NCBI Gene 18976] {aka ACTH, BE, Beta-LPH, Clip, Gamma-LPH, Npp}, GH1 (growth hormone 1) [NCBI Gene 2688] {aka GH, GH-N, GHB5, GHN, IGHD1A, IGHD1B}, YARS1 (tyrosyl-tRNA synthetase 1) [NCBI Gene 8565] {aka CMTDIC, IMNEPD2, TYRRS, YARS, YRS, YTS}, IKBKB (inhibitor of nuclear factor kappa B kinase subunit beta) [NCBI Gene 3551] {aka IKK-2, IKK-beta, IKK2, IKKB, IMD15, IMD15A}, PYY (peptide YY) [NCBI Gene 5697] {aka PYY-I, PYY1}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, Npy5r (neuropeptide Y receptor Y5) [NCBI Gene 18168] {aka NPY5-R, NPYY5-R, Y5R} - **Diseases:** DIO (MESH:D009765), beta (MESH:D017086), hyperphagia (MESH:D006963), energy deficit (MESH:D009461), metabolic abnormalities (MESH:D008659), metabolic syndrome (MESH:D024821), Chronic inflammation (MESH:D007249), mitochondrial dysfunction (MESH:D028361), Zucker diabetic (MESH:D003920), NAFLD (MESH:D065626), anorexia (MESH:D000855), overnutrition (MESH:D044343), inflammatory bowel disease (MESH:D015212), adipose tissue (MESH:D018205), type 2 diabetes (MESH:D003924), nausea and vomiting (MESH:D020250), anorexia nervosa (MESH:D000856), appetite (MESH:D001068), hepatic (MESH:D056486), glucose (MESH:D018149), chronic (MESH:D002908), endotoxemia (MESH:D019446), CL (MESH:D002971), PCOS (MESH:D011085), hyperinsulinemia (MESH:D006946), Hyperinsulinemic (MESH:D044903), PYY deficiency (MESH:C535317), gastrointestinal adverse reactions (MESH:D005767), hypoglycemia (MESH:D007003), IR (MESH:D007333), Weight loss (MESH:D015431), toxicity (MESH:D064420) - **Chemicals:** Glycerol-3-phosphate (MESH:C029620), metformin (MESH:D008687), tyrosine (MESH:D014443), STZ (MESH:D013311), peptide (MESH:D010455), FFA (MESH:D005230), glycogen (MESH:D006003), norepinephrine (MESH:D009638), blood glucose (MESH:D001786), cAMP (MESH:D000242), Polyethylene (MESH:D020959), fat (MESH:D005223), polyethylene glycol (MESH:D011092), PIP2 (MESH:D019269), fructosamine (MESH:D019270), streptomycin (MESH:D013307), triglyceride (MESH:D014280), fructooligosaccharides (MESH:C116580), ATP (MESH:D000255), lipid (MESH:D008055), SCFA (MESH:D005232), calcium (MESH:D002118), 5-HT (MESH:D012701), glucose (MESH:D005947), bile acids (MESH:D001647), CIN-110 (-), unsaturated fatty acids (MESH:D005231), carbohydrates (MESH:D002241), fatty acid (MESH:D005227), Phosphatidylinositol-3,4,5-trisphosphate (MESH:C060974), serine (MESH:D012694) - **Species:** Sus scrofa (pig, species) [taxon 9823], Mus musculus (house mouse, species) [taxon 10090], Oryctolagus cuniculus (domestic rabbit, species) [taxon 9986], Rattus norvegicus (brown rat, species) [taxon 10116], Bifidobacterium (genus) [taxon 1678], Homo sapiens (human, species) [taxon 9606] ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12956794/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12956794/full.md ## References 171 references — full 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