# Interplay between obesity-associated insulin resistance and immune system through the lens of evolutionary medicine **Authors:** Maryam Moazzam-Jazi, Saeideh Jafarinejad-Farsangi, Leila Najd-Hassan-Bonab, Maryam Daneshpour, Zhaoli Liu, Manoj Kumar Gupta, Ramakrishna Vadde PMC · DOI: 10.1016/j.molmet.2026.102335 · Molecular Metabolism · 2026-02-13 ## TL;DR This paper explores how insulin resistance linked to obesity may have evolved to benefit survival but now contributes to immune and metabolic diseases. ## Contribution The study provides a novel evolutionary perspective on insulin resistance and its connection to immune system function and disease. ## Key findings - Insulin resistance may have evolved to support immune function during food scarcity. - Persistent insulin resistance in modern times causes low-grade inflammation and metabolic disorders. - Genomic regions near PTEN, IL27, and NUPR1 genes are implicated in immune-metabolic interactions. ## Abstract Insulin resistance (IR), commonly associated with obesity, is linked to a range of metabolic and immune-related disorders in the contemporary human population. Nevertheless, it is evolutionary well-conserved, suggesting its potential survival advantages to our ancestors. This review aims to explore the intricate interplay between IR and the immune system as well as its implications for the development of immune-metabolic and allergic diseases in the modern era. From an evolutionary medicine perspective, the longevity of ancient humans relied on energy storage to endure food shortages and effectively activate the immune system against various diseases. Under normal conditions, insulin induces glycogen and triglyceride synthesis in the liver and adipose tissues. However, IR directs more glucose to insulin-independent tissues, such as the immune system, which are critical for survival in adverse conditions. The persistent IR in our current lifestyle promotes low-grade inflammation, accompanied by various metabolic and allergic disorders. Critically, this evolutionary mismatch not only explains disease susceptibility but also informs therapeutic design to target immune-metabolic crosstalk. Moreover, our evolutionary analysis demonstrates that the genomic regions near the PTEN, IL27, and NUPR1 genes could play an important role in this interaction across diverse populations. ## Linked entities - **Genes:** PTEN (phosphatase and tensin homolog) [NCBI Gene 5728], IL27 (interleukin 27) [NCBI Gene 246778], NUPR1 (nuclear protein 1, transcriptional regulator) [NCBI Gene 26471] ## Full-text entities - **Genes:** IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, NUPR1 (nuclear protein 1, transcriptional regulator) [NCBI Gene 26471] {aka COM1, P8}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, PTK2 (protein tyrosine kinase 2) [NCBI Gene 5747] {aka FADK, FADK 1, FAK, FAK1, FRNK, PPP1R71}, IRF3 (interferon regulatory factor 3) [NCBI Gene 3661] {aka IIAE7}, PPARA (peroxisome proliferator activated receptor alpha) [NCBI Gene 5465] {aka NR1C1, PPAR, PPAR-alpha, PPARalpha, hPPAR}, VHL (von Hippel-Lindau tumor suppressor) [NCBI Gene 7428] {aka HRCA1, RCA1, VHL1, pVHL}, INPPL1 (inositol polyphosphate phosphatase like 1) [NCBI Gene 3636] {aka OPSMD, SHIP2}, SLC2A3 (solute carrier family 2 member 3) [NCBI Gene 6515] {aka GLUT3}, CD14 (CD14 molecule) [NCBI Gene 929], SLC2A4RG (SLC2A4 regulator) [NCBI Gene 56731] {aka GEF, GLUT4EF, HDBP-1, HDBP1, Si-1-2, Si-1-2-19}, FOXO1 (forkhead box O1) [NCBI Gene 2308] {aka FKH1, FKHR, FOXO1A}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, SLC2A4 (solute carrier family 2 member 4) [NCBI Gene 6517] {aka GLUT4}, AVP (arginine vasopressin) [NCBI Gene 551] {aka ADH, ARVP, AVP-NPII, AVRP, VP}, Slc2a2 (solute carrier family 2 (facilitated glucose transporter), member 2) [NCBI Gene 20526] {aka Glut-2, Glut2}, IFIT3 (interferon induced protein with tetratricopeptide repeats 3) [NCBI Gene 3437] {aka CIG-49, GARG-49, IFI60, IFIT4, IRG2, ISG60}, SOS1 (SOS Ras/Rac guanine nucleotide exchange factor 1) [NCBI Gene 6654] {aka GF1, GGF1, GINGF, HGF, NS4, SOS-1}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, IL13 (interleukin 13) [NCBI Gene 3596] {aka IL-13, P600}, SLC2A1 (solute carrier family 2 member 1) [NCBI Gene 6513] {aka CSE, DYT17, DYT18, DYT9, EIG12, GLUT}, PNPLA2 (patatin like domain 2, triacylglycerol lipase) [NCBI Gene 57104] {aka 1110001C14Rik, ATGL, FP17548, PEDF-R, TTS-2.2, TTS2}, XYLT2 (xylosyltransferase 2) [NCBI Gene 64132] {aka PXYLT2, SOS, XT-II, XT2, xylT-II}, kar [NCBI Gene 8083], MYD88 (MYD88 innate immune signal transduction adaptor) [NCBI Gene 4615] {aka IMD68, MYD88D, WM1}, FCER1A (Fc epsilon receptor Ia) [NCBI Gene 2205] {aka FCE1A, FCERIA, FcERI}, MMRN2 (multimerin 2) [NCBI Gene 79812] {aka EMILIN-3, EMILIN3, ENDOGLYX-1}, CCL4 (C-C motif chemokine ligand 4) [NCBI Gene 6351] {aka ACT2, AT744.1, G-26, HC21, LAG-1, LAG1}, IFNA1 (interferon alpha 1) [NCBI Gene 3439] {aka IFL, IFN, IFN-ALPHA, IFN-alphaD, IFNA13, IFNA@}, IL4 (interleukin 4) [NCBI Gene 3565] {aka BCGF-1, BCGF1, BSF-1, BSF1, IL-4}, DNMT1 (DNA methyltransferase 1) [NCBI Gene 1786] {aka ADCADN, AIM, CXXC9, DNMT, HSN1E, MCMT}, 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}, TLR2 (toll like receptor 2) [NCBI Gene 7097] {aka CD282, TIL4}, MED6P1 (mediator complex subunit 6 pseudogene 1) [NCBI Gene 100128990], TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, PDK1 (pyruvate dehydrogenase kinase 1) [NCBI Gene 5163], IARS1 (isoleucyl-tRNA synthetase 1) [NCBI Gene 3376] {aka GRIDHH, IARS, ILERS, ILRS, IRS, PRO0785}, IGHE (immunoglobulin heavy constant epsilon) [NCBI Gene 3497] {aka IgE}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347] {aka GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1}, GLP1R (glucagon like peptide 1 receptor) [NCBI Gene 2740] {aka GLP-1, GLP-1-R, GLP-1R}, GCG (glucagon) [NCBI Gene 2641] {aka GLP-1, GLP1, GLP2, GRPP}, ZHX2 (zinc fingers and homeoboxes 2) [NCBI Gene 22882] {aka AFR1, RAF}, IL12B (interleukin 12B) [NCBI Gene 3593] {aka CLMF, CLMF2, IL-12B, IMD28, IMD29, NKSF}, Lep (leptin) [NCBI Gene 16846] {aka ob, obese}, IL27 (interleukin 27) [NCBI Gene 246778] {aka IL-27, IL-27A, IL27A, IL27p28, IL30, p28}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, INSR (insulin receptor) [NCBI Gene 3643] {aka CD220, HHF5}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, LIPN (lipase family member N) [NCBI Gene 643418] {aka ARCI8, LI4, LIPL4, bA186O14.3}, SHC1 (SHC adaptor protein 1) [NCBI Gene 6464] {aka SHC, SHCA}, RNLS (renalase, FAD dependent amine oxidase) [NCBI Gene 55328] {aka C10orf59, RENALASE}, ACTA2 (actin alpha 2, smooth muscle) [NCBI Gene 59] {aka ACTSA, SMDYS}, PTEN (phosphatase and tensin homolog) [NCBI Gene 5728] {aka 10q23del, BZS, CWS1, DEC, GLM2, MHAM}, CCL3 (C-C motif chemokine ligand 3) [NCBI Gene 6348] {aka G0S19-1, LD78, LD78ALPHA, MIP-1-alpha, MIP1A, SCI}, DNMT3A (DNA methyltransferase 3 alpha) [NCBI Gene 1788] {aka DNMT3A2, HESJAS, M.HsaIIIA, TBRS}, CCL5 (C-C motif chemokine ligand 5) [NCBI Gene 6352] {aka D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228} - **Diseases:** RA (MESH:D001172), endotoxemia (MESH:D019446), hyperinsulinemia (MESH:D006946), immune dysfunction (MESH:D007154), COVID-19 (MESH:D000086382), Crohn's disease (MESH:D003424), infection (MESH:D007239), cardiovascular disease (MESH:D002318), IR (MESH:D007333), cytotoxic (MESH:D064420), weight (MESH:D015431), IBD (MESH:D015212), T2D (MESH:D003924), underweight (MESH:D013851), T1D. (MESH:D003922), systemic (MESH:D015619), allergic disease (MESH:D004342), tuberculosis (MESH:D014376), smallpox (MESH:D012899), malaria (MESH:D008288), multiple sclerosis (MESH:D009103), chronic (MESH:D002908), Infectious (MESH:D003141), hyperglycemia (MESH:D006943), cardiometabolic disease (MESH:D024821), trauma (MESH:D014947), adipose tissue inflammation (MESH:D007249), dyslipidemia (MESH:D050171), diabetic (MESH:D003920), Dysbiosis (MESH:D064806), cancer (MESH:D009369), allergic symptoms (MESH:D063926), asthma (MESH:D001249), dengue (MESH:D003715), autoimmune and allergic diseases (MESH:D001327), Obesity (MESH:D009765), type I hypersensitivity reactions (MESH:D006969), overeating (MESH:D006963), fat (MESH:D004620), metabolic (MESH:D008659) - **Chemicals:** Cori (-), Na + (MESH:D012964), NADPH (MESH:D009249), butyrate (MESH:D002087), Fatty acids (MESH:D005227), fructose (MESH:D005632), ATP (MESH:D000255), LPS (MESH:D008070), lipid (MESH:D008055), NADH (MESH:D009243), PI (3,4,5) P3 (MESH:C118303), SCFA (MESH:D005232), FADH2 (MESH:C058805), Omalizumab (MESH:D000069444), Glucose (MESH:D005947), pyruvate (MESH:D019289), GTP (MESH:D006160), oxygen (MESH:D010100), uric acid (MESH:D014527), choline (MESH:D002794), lactate (MESH:D019344), polyol (MESH:C024617), TCA (MESH:D014233), pentose phosphate (MESH:D010428), TAG (MESH:D014280), metformin (MESH:D008687), glycerol 3-phosphate (MESH:C029620), tyrosine (MESH:D014443), free fatty acids (MESH:D005230), Acetyl-CoA (MESH:D000105), glycogen (MESH:D006003), blood glucose (MESH:D001786), ketone bodies (MESH:D007657), cholesterol (MESH:D002784) - **Species:** Danio rerio (leopard danio, species) [taxon 7955], Homo sapiens (human, species) [taxon 9606], Drosophila melanogaster (fruit fly, species) [taxon 7227], gut metagenome (species) [taxon 749906], Mus musculus (house mouse, species) [taxon 10090], Pseudomonadota (proteobacteria, phylum) [taxon 1224] - **Mutations:** rs4788084, rs8192675, D in 26, rs111770298, Arg457Gln ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12954304/full.md ## Figures 5 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12954304/full.md ## References 159 references — full list in the complete paper: https://tomesphere.com/paper/PMC12954304/full.md --- Source: https://tomesphere.com/paper/PMC12954304