{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T10:59:57Z","timestamp":1793012397407,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lipedema is a chronic, progressive adipose tissue disorder that affects up to 10% of women and is characterized by disproportionate lower-limb fat accumulation, pain, edema, and resistance to conventional weight-loss approaches. Its pathophysiology involves a complex interplay of adipocyte hypertrophy, chronic inflammation, extracellular matrix fibrosis, mitochondrial dysfunction, and sex steroid imbalance, highlighting the need for disease-modifying therapies. This narrative review synthesizes mechanistic, translational, and clinical evidence linking metabolic, inflammatory, and fibrotic pathways to lipedema and tirzepatide\u2019s potential therapeutic relevance. Tirzepatide, a dual GLP-1 (Glucagon-Like Peptide-1)\/GIP (Glucose-Dependent Insulinotropic Polypeptide) receptor agonist, has demonstrated unprecedented efficacy in obesity and diabetes, alongside pleiotropic actions on inflammation, fibrosis, and adipose remodeling. Mechanistic studies reveal favorable effects on macrophage polarization, cytokine signaling, extracellular matrix turnover, and thermogenesis, suggesting potential relevance to lipedema biology. Translational evidence from related fibro-inflammatory conditions such as steatohepatitis and heart failure further supports its antifibrotic and immunomodulatory plausibility. Although direct clinical evidence in lipedema is lacking, the convergence of mechanistic pathways provides a strong rationale to investigate tirzepatide as a disease-modifying candidate. If future clinical studies confirm these mechanisms, tirzepatide could represent a novel metabolic\u2013hormonal therapy capable of modifying the natural course of lipedema.<\/jats:p>","DOI":"10.3390\/ijms262110741","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T07:58:05Z","timestamp":1762329485000},"page":"10741","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Tirzepatide as a Potential Disease-Modifying Therapy in Lipedema: A Narrative Review on Bridging Metabolism, Inflammation, and Fibrosis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9245-2509","authenticated-orcid":false,"given":"Diogo Pinto da Costa","family":"Viana","sequence":"first","affiliation":[{"name":"Department of Gynecology, Escola Paulista de Medicina, Federal University of Sao Paulo (EPM-UNIFESP), Sao Paulo 04024-002, Brazil"},{"name":"Brazilian Society for Research and Teaching in Medicine (SOBRAPEM), Sao Paulo 01318-901, Brazil"},{"name":"Brazilian Society of Obesity Medicine (SBEMO), Florian\u00f3polis 88070-800, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2392-2887","authenticated-orcid":false,"given":"Adriana Luckow","family":"Invitti","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Escola Paulista de Medicina, Federal University of Sao Paulo (EPM-UNIFESP), Sao Paulo 04024-002, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6141-320X","authenticated-orcid":false,"given":"Eduardo","family":"Schor","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Escola Paulista de Medicina, Federal University of Sao Paulo (EPM-UNIFESP), Sao Paulo 04024-002, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"ref_1","first-page":"184","article-title":"Lipedema of the Legs: A Syndrome Characterized by Fat Legs and Orthostatic Edema","volume":"15","author":"Allen","year":"1940","journal-title":"Proc. Staff Meet Mayo Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.7326\/0003-4819-34-5-1243","article-title":"Lipedema of the Legs: A Syndrome Characterized by Fat Legs and Edema","volume":"34","author":"Wold","year":"1951","journal-title":"Ann. Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1043","DOI":"10.1097\/GOX.0000000000001043","article-title":"Lipedema: A Relatively Common Disease with Extremely Common Misconceptions","volume":"4","author":"Buck","year":"2016","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Katzer, K., Hill, J.L., McIver, K.B., and Foster, M.T. (2021). Lipedema and the Potential Role of Estrogen in Excessive Adipose Tissue Accumulation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111720"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Christoffersen, V., and Tennfjord, M.K. (2023). Younger Women with Lipedema, Their Experiences with Healthcare Providers, and the Importance of Social Support and Belonging: A Qualitative Study. Int. J. Environ. Res. Public Health, 20.","DOI":"10.3390\/ijerph20031925"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.mehy.2014.08.011","article-title":"Pathophysiological Dilemmas of Lipedema","volume":"83","author":"Groma","year":"2014","journal-title":"Med. Hypotheses"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Felmerer, G., Stylianaki, A., Hollm\u00e9n, M., Str\u00f6bel, P., Stepniewski, A., Wang, A., Frueh, F.S., Kim, B.-S., Giovanoli, P., and Lindenblatt, N. (2020). Increased Levels of VEGF-C and Macrophage Infiltration in Lipedema Patients without Changes in Lymphatic Vascular Morphology. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-67987-3"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.jss.2020.03.055","article-title":"Adipose Tissue Hypertrophy, An Aberrant Biochemical Profile and Distinct Gene Expression in Lipedema","volume":"253","author":"Felmerer","year":"2020","journal-title":"J. Surg. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Clarke, A.D.A., Copas, C., Hannon, O., Padgett, C., Knight, J.M., Falkenberg, A., Varto, H., Mason, K., Wellington, C.L., and Van Donkelaar, P. (2024). Detecting a Hidden Pandemic: The Current State and Future Direction of Screening and Assessment Tools for Intimate Partner Violence-Related Brain Injury. Neurosci. Biobehav. Rev., 167.","DOI":"10.1016\/j.neubiorev.2024.105912"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.17219\/acem\/181146","article-title":"Disability and Emotional Symptoms in Women with Lipedema: A Comparison with Overweight\/Obese Women","volume":"33","author":"Chachaj","year":"2024","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tomada, I. (2025). Lipedema: From Women\u2019s Hormonal Changes to Nutritional Intervention. Endocrines, 6.","DOI":"10.3390\/endocrines6020024"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1210\/jcem.83.2.4561","article-title":"Identification of Progesterone Receptor in Human Subcutaneous Adipose Tissue","volume":"83","author":"Welter","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"175","DOI":"10.9734\/jammr\/2025\/v37i25731","article-title":"Hormonal Links between Lipedema and Gynecological Disorders: Therapeutic Roles of Gestrinone and Drospirenone","volume":"37","author":"Viana","year":"2025","journal-title":"J. Adv. Med. Med. Res."},{"key":"ref_14","first-page":"Doc11","article-title":"Lipedema in a Male Patient: Report of a Rare Case\u2014Management and Review of the Literature","volume":"10","author":"Bertlich","year":"2021","journal-title":"GMS Interdiscip. Plast. Reconstr. Surg. DGPW"},{"key":"ref_15","first-page":"170","article-title":"Microlymphatic Aneurysms in Patients with Lipedema","volume":"34","author":"Franzeck","year":"2001","journal-title":"Lymphology"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Poojari, A., Dev, K., and Rabiee, A. (2022). Lipedema: Insights into Morphology, Pathophysiology, and Challenges. Biomedicines, 10.","DOI":"10.3390\/biomedicines10123081"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.soard.2021.12.027","article-title":"Persistent Lipedema Pain in Patients after Bariatric Surgery: A Case Series of 13 Patients","volume":"18","author":"Cornely","year":"2022","journal-title":"Surg. Obes. Relat. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/cob.12239","article-title":"Lipoedema in Patients after Bariatric Surgery: Report of Two Cases and Review of Literature","volume":"8","author":"Pouwels","year":"2018","journal-title":"Clin. Obes."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1186\/s13063-021-05727-2","article-title":"A Randomised Controlled Multicentre Investigator-Blinded Clinical Trial Comparing Efficacy and Safety of Surgery versus Complex Physical Decongestive Therapy for Lipedema (LIPLEG)","volume":"22","author":"Podda","year":"2021","journal-title":"Trials"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Patton, L., Ricolfi, L., Bortolon, M., Gabriele, G., Zolesio, P., Cione, E., and Cannataro, R. (2024). Observational Study on a Large Italian Population with Lipedema: Biochemical and Hormonal Profile, Anatomical and Clinical Evaluation, Self-Reported History. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031599"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"113499","DOI":"10.1016\/j.intimp.2024.113499","article-title":"Tirzepatide\u2019s Role in Targeting Adipose Tissue Macrophages to Reduce Obesity-Related Inflammation and Improve Insulin Resistance","volume":"143","author":"Xia","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0140-6736(21)01324-6","article-title":"Efficacy and Safety of a Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide in Patients with Type 2 Diabetes (SURPASS-1): A Double-Blind, Randomised, Phase 3 Trial","volume":"398","author":"Rosenstock","year":"2021","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1056\/NEJMoa2206038","article-title":"Tirzepatide Once Weekly for the Treatment of Obesity","volume":"387","author":"Jastreboff","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101550","DOI":"10.1016\/j.molmet.2022.101550","article-title":"Tirzepatide Induces a Thermogenic-like Amino Acid Signature in Brown Adipose Tissue","volume":"64","author":"Samms","year":"2022","journal-title":"Mol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1007\/s11695-009-9917-4","article-title":"YKL-40 Is Elevated in Morbidly Obese Patients and Declines After Weight Loss","volume":"19","author":"Hempen","year":"2009","journal-title":"Obes. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E169","DOI":"10.1152\/ajpendo.00558.2020","article-title":"Fight against Fibrosis in Adipose Tissue Remodeling","volume":"321","author":"Li","year":"2021","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"113937","DOI":"10.1016\/j.intimp.2024.113937","article-title":"Dual GIP and GLP-1 Receptor Agonist Tirzepatide Alleviates Hepatic Steatosis and Modulates Gut Microbiota and Bile Acid Metabolism in Diabetic Mice","volume":"147","author":"Hu","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1056\/NEJMoa2410027","article-title":"Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity","volume":"392","author":"Packer","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Pinto Da Costa Viana, D., Caseri C\u00e2mara, L., and Borges Palau, R. (2025). Menopause as a Critical Turning Point in Lipedema: The Estrogen Receptor Imbalance, Intracrine Estrogen, and Adipose Tissue Dysfunction Model. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202506.1813.v1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1055\/a-2334-9260","article-title":"Safety and Effectiveness of Liposuction Modalities in Managing Lipedema: Systematic Review and Meta-Analysis","volume":"51","author":"Mortada","year":"2024","journal-title":"Arch. Plast. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1146\/annurev-immunol-032414-112220","article-title":"Macrophages: Development and Tissue Specialization","volume":"33","author":"Varol","year":"2015","journal-title":"Annu. Rev. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, Q.K. (2024). Mechanisms of Action and Therapeutic Applications of GLP-1 and Dual GIP\/GLP-1 Receptor Agonists. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1431292"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.fertnstert.2023.03.006","article-title":"Endometriosis and Adenomyosis: Shared Pathophysiology","volume":"119","author":"Bulun","year":"2023","journal-title":"Fertil. Steril."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wolf, S., Rannikko, J.H., Virtakoivu, R., Cinelli, P., Felmerer, G., Burger, A., Giovanoli, P., Detmar, M., Lindenblatt, N., and Hollm\u00e9n, M. (2022). A Distinct M2 Macrophage Infiltrate and Transcriptomic Profile Decisively Influence Adipocyte Differentiation in Lipedema. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1004609"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Grewal, T., Kempa, S., and Buechler, C. (2025). Lipedema: A Disease Triggered by M2 Polarized Macrophages?. Biomedicines, 13.","DOI":"10.3390\/biomedicines13030561"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/ijo.2013.73","article-title":"Glucose-Dependent Insulinotropic Polypeptide Has Impaired Effect on Abdominal, Subcutaneous Adipose Tissue Metabolism in Obese Subjects","volume":"38","author":"Asmar","year":"2014","journal-title":"Int. J. Obes."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.molmed.2016.03.005","article-title":"Reappraisal of GIP Pharmacology for Metabolic Diseases","volume":"22","author":"Finan","year":"2016","journal-title":"Trends Mol. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10741\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T08:04:11Z","timestamp":1762329851000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10741"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,5]]},"references-count":37,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110741"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110741","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,5]]}}}