{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:03:13Z","timestamp":1785409393230,"version":"3.56.0"},"reference-count":56,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["141924"],"award-info":[{"award-number":["141924"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["142719"],"award-info":[{"award-number":["142719"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"award":["141924"],"award-info":[{"award-number":["141924"]}],"id":[{"id":"https:\/\/ror.org\/05s0g1g46","id-type":"ROR","asserted-by":"publisher"}]},{"award":["142719"],"award-info":[{"award-number":["142719"]}],"id":[{"id":"https:\/\/ror.org\/05s0g1g46","id-type":"ROR","asserted-by":"publisher"}]},{"name":"L\u2019Or\u00e9al-UNESCO for Women in Science Programme","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Technology Innovation Agency","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>While amyloid precursor protein (APP) overexpression in adipose tissue is a recognized consequence of high-fat diet (HFD) feeding, its role in metabolically active organs and the mechanisms linking it to systematic dysfunction remain unclear. In particular, the potential for diet-induced APP dysregulation in the other tissues and the contribution of its \u03b2C-terminal fragment (\u03b2CTF) are poorly characterized. Using a high-fat diet (HFD) mouse model to induce systematic metabolic stress, we assessed APP and \u03b2CTF levels across multiple tissues. HFD triggered a tissue-specific response, with APP levels increasing &gt;2-fold in visceral and subcutaneous white adipose tissue (WAT) and in the kidney but remained unchanged in the liver and brain. \u03b2CTF levels were significantly elevated in the visceral WAT (3-fold) and kidney. In these responsive tissues, APP and \u03b2CTF accumulated within mitochondria, which coincided with significantly reduced complex I and IV activities. Complementary in vitro studies confirmed that APP levels can dictate mitochondrial function. Furthermore, we identified that cytokines\u2013IL-4, IL-13, TNF-\u03b1, and IL-1\u03b2\u2013induced APP transcription, providing a mechanistic link between diet-induced inflammation and APP dysregulation. Collectively, our findings demonstrate that APP is overexpressed in response to HFD in select peripheral tissues, which coincides with reduced mitochondrial complex enzyme activities and increased cytokine levels.<\/jats:p>","DOI":"10.3390\/cells15111033","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T03:37:29Z","timestamp":1780544249000},"page":"1033","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diet-Induced Amyloid Precursor Protein Dysregulation in Kidney and Adipose Tissue Mediates Mitochondrial Dysfunction"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3511-4369","authenticated-orcid":false,"given":"Alexandr\u00e9","family":"Delport","sequence":"first","affiliation":[{"name":"Discipline of Biochemistry, School of Agriculture and Science, University of KwaZulu-Natal, Pietermaritzburg 3201, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebrahim","family":"Ally","sequence":"additional","affiliation":[{"name":"Animal House, School of Agriculture and Science, University of KwaZulu-Natal, Pietermaritzburg 3201, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9380-0028","authenticated-orcid":false,"given":"Shantal","family":"Maharaj","sequence":"additional","affiliation":[{"name":"Discipline of Biochemistry, School of Agriculture and Science, University of KwaZulu-Natal, Pietermaritzburg 3201, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6025-8826","authenticated-orcid":false,"given":"Raymond","family":"Hewer","sequence":"additional","affiliation":[{"name":"Discipline of Biochemistry, School of Agriculture and Science, University of KwaZulu-Natal, Pietermaritzburg 3201, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1006\/exnr.1999.7150","article-title":"Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: An ovine head impact model","volume":"159","author":"Blumbergs","year":"1999","journal-title":"Exp. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1002\/mus.20612","article-title":"Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease","volume":"34","author":"Koistinen","year":"2006","journal-title":"Muscle Nerve"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Garcia, J., Chang, R., Steinberg, R.A., Arce, A., Yang, J., Van Der Eb, P., Abdullah, T., Chandrashekar, D.V., Eck, S.M., and Meza, P. (2022). Modulation of hepatic amyloid precursor protein and lipoprotein receptor-related protein 1 by chronic alcohol intake: Potential link between liver steatosis and amyloid-\u03b2. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.930402"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1038\/oby.2008.267","article-title":"Amyloid precursor protein expression is upregulated in adipocytes in obesity","volume":"16","author":"Lee","year":"2008","journal-title":"Obesity"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1038\/s42255-019-0149-1","article-title":"Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity","volume":"1","author":"An","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"43725","DOI":"10.1038\/srep43725","article-title":"Amyloid precursor protein modulates macrophage phenotype and diet-dependent weight gain","volume":"7","author":"Puig","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Puig, K.L., Floden, A.M., Adhikari, R., Golovko, M.Y., and Combs, C.K. (2012). Amyloid precursor protein and proinflammatory changes are regulated in brain and adipose tissue in a murine model of high fat diet-induced obesity. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030378"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9057","DOI":"10.1523\/JNEUROSCI.1469-06.2006","article-title":"Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer\u2019s Disease Brain Is Associated with Mitochondrial Dysfunction","volume":"26","author":"Devi","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9835","DOI":"10.1038\/s41598-017-10233-0","article-title":"Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta","volume":"7","author":"Waugh","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s00401-020-02234-7","article-title":"Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer\u2019s disease models and human brains","volume":"141","author":"Mary","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.nbd.2011.09.001","article-title":"Mitochondrial dysfunction and accumulation of the \u03b2-secretase-cleaved C-terminal fragment of APP in Alzheimer\u2019s disease transgenic mice","volume":"45","author":"Devi","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1007\/s12035-022-02863-x","article-title":"The amyloid precursor protein: A converging point in Alzheimer\u2019s disease","volume":"59","author":"Delport","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Muller, C.R., Leite, A.P.O., Yokota, R., Pereira, R.O., Americo, A.L.V., Nascimento, N.R.F., Evangelista, F.S., Farah, V., Fonteles, M.C., and Fiorino, P. (2019). Post-weaning exposure to high-fat diet induces kidney lipid accumulation and function impairment in adult rats. Front. Nutr., 6.","DOI":"10.3389\/fnut.2019.00060"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/s41419-020-03122-4","article-title":"High-fat diet promotes renal injury by inducing oxidative stress and mitochondrial dysfunction","volume":"11","author":"Sun","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Prem, P.N., and Kurian, G.A. (2021). High-fat diet increased oxidative stress and mitochondrial dysfunction induced by renal ischemia-reperfusion injury in rat. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.715693"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s12020-009-9224-9","article-title":"Diet-induced obesity is associated with hyperleptinemia, hyperinsulinemia, hepatic steatosis, and glomerulopathy in C57Bl\/6J mice","volume":"36","author":"Hoffler","year":"2009","journal-title":"Endocrine"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cavaliere, G., Trinchese, G., Penna, E., Cimmino, F., Pirozzi, C., Lama, A., Annunziata, C., Catapano, A., Mattace Raso, G., and Meli, R. (2019). High-Fat Diet Induces Neuroinflammation and Mitochondrial Impairment in Mice Cerebral Cortex and Synaptic Fraction. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00509"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e3631","DOI":"10.21769\/BioProtoc.3631","article-title":"Mouse adipose tissue protein extraction","volume":"10","author":"An","year":"2020","journal-title":"Bio-Protocol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"400","DOI":"10.2337\/db20-0687","article-title":"Deletion of the brain-specific \u03b1 and \u03b4 isoforms of adapter protein SH2B1 protects mice from obesity","volume":"70","author":"Cote","year":"2020","journal-title":"Diabetes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e116","DOI":"10.1002\/cpcb.116","article-title":"Measuring mitochondrial respiration in previously frozen biological samples","volume":"89","author":"Osto","year":"2020","journal-title":"Curr. Protoc. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s10930-019-09829-4","article-title":"Determining the protein stability of Alzheimer\u2019s disease protein, amyloid precursor protein","volume":"38","author":"Delport","year":"2019","journal-title":"Protein J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"bpae077","DOI":"10.1093\/biomethods\/bpae077","article-title":"Optimizing Western blotting immunodetection: Streamlining antibody cocktails for reduced protocol time and enhanced multiplexing applications","volume":"9","author":"Yamani","year":"2024","journal-title":"Biol. Methods Protoc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6672","DOI":"10.1038\/s41598-022-10653-7","article-title":"A superior loading control for the cellular thermal shift assay","volume":"12","author":"Delport","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.1007\/s11033-020-05364-z","article-title":"The amyloid precursor protein affects glyceraldehyde 3-phosphate dehydrogenase levels, organelle localisation and thermal stability","volume":"47","author":"Delport","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/nprot.2012.058","article-title":"Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells","volume":"7","author":"Spinazzi","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/cyto.a.10031","article-title":"Comparison of the effect of mitochondrial inhibitors on mitochondrial membrane potential in two different cell lines using flow cytometry and spectrofluorometry","volume":"52A","author":"Drahota","year":"2003","journal-title":"Cytom. Part A"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1365-2818.2006.01706.x","article-title":"A guided tour into subcellular colocalization analysis in light microscopy","volume":"224","author":"Bolte","year":"2006","journal-title":"J. Microsc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1111\/j.1365-2818.1993.tb03313.x","article-title":"Measurement of co-localization of objects in dual-colour confocal images","volume":"169","author":"Manders","year":"1993","journal-title":"J. Microsc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3993","DOI":"10.1529\/biophysj.103.038422","article-title":"Automatic and quantitative measurement of protein-protein colocalization in live cells","volume":"86","author":"Costes","year":"2004","journal-title":"Biophys. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/S2213-8587(14)70034-8","article-title":"Age-related and disease-related muscle loss: The effect of diabetes, obesity, and other diseases","volume":"2","author":"Kalyani","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1093\/clinchem\/44.5.905","article-title":"Low Serum Creatine Kinase Activity","volume":"44","author":"Rosalki","year":"1998","journal-title":"Clin. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"F339","DOI":"10.1152\/ajprenal.2000.278.3.F339","article-title":"Renal physiology of the mouse","volume":"278","author":"Meneton","year":"2000","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1042\/BJ20110162","article-title":"Assessing mitochondrial dysfunction in cells","volume":"435","author":"Brand","year":"2011","journal-title":"Biochem. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"eadx2678","DOI":"10.1126\/science.adx2678","article-title":"A human pan-disease blood atlas of the circulating proteome","volume":"390","author":"Kenrick","year":"2025","journal-title":"Science"},{"key":"ref_36","unstructured":"(2026, April 21). The Human Protein Atlas. Amyloid Precursor Protein. Available online: https:\/\/www.proteinatlas.org\/ENSG00000142192-APP\/cell+line."},{"key":"ref_37","unstructured":"(2026, April 23). The Human Protein Atlas. Huntingtin. Available online: https:\/\/www.proteinatlas.org\/ENSG00000197386-HTT\/cell+line."},{"key":"ref_38","unstructured":"(2026, April 23). The Human Protein Atlas. Synuclein Alpha. Available online: https:\/\/www.proteinatlas.org\/ENSG00000145335-SNCA."},{"key":"ref_39","unstructured":"(2026, April 23). The Human Protein Atlas. Acetylcholinesterase. Available online: https:\/\/www.proteinatlas.org\/ENSG00000087085-ACHE\/cell+line."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7605","DOI":"10.1073\/pnas.131152998","article-title":"Phenserine regulates translation of \u03b2-amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development","volume":"98","author":"Shaw","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"eaal3321","DOI":"10.1126\/science.aal3321","article-title":"A subcellular map of the human proteome","volume":"356","author":"Thul","year":"2017","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1093\/nutrit\/nuab033","article-title":"High-fat diet promotes hypothalamic inflammation in animal models: A systematic review","volume":"80","author":"Santos","year":"2022","journal-title":"Nutr. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12270","DOI":"10.1038\/s41598-019-48800-2","article-title":"Acute exposure to a high-fat diet in juvenile male rats disrupts hippocampal-dependent memory and plasticity through glucocorticoids","volume":"9","author":"Khazen","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/BF02463354","article-title":"Distribution of microglia and astrocytes in different regions of the normal adult rat brain","volume":"29","author":"Savchenko","year":"1997","journal-title":"Neurophysiology"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Recena Aydos, L., Aparecida do Amaral, L., Serafim de Souza, R., Jacobowski, A.C., Freitas dos Santos, E., and Rodrigues Macedo, M.L. (2019). Nonalcoholic fatty liver disease induced by high-fat diet in C57bl\/6 models. Nutrients, 11.","DOI":"10.3390\/nu11123067"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e0286726","DOI":"10.1371\/journal.pone.0286726","article-title":"Ability of high fat diet to induce liver pathology correlates with the level of linoleic acid and Vitamin E in the diet","volume":"18","author":"Graham","year":"2023","journal-title":"PLoS ONE"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1146\/annurev-nutr-072610-145138","article-title":"Inflammation in alcoholic liver disease","volume":"32","author":"Wang","year":"2012","journal-title":"Annu. Rev. Nutr."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Oates, J.R., McKell, M.C., Moreno-Fernandez, M.E., Damen, M.S.M.A., Deepe, G.S., Qualls, J.E., and Divanovic, S. (2019). Macrophage function in the pathogenesis of non-alcoholic fatty liver disease: The mac attack. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02893"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1097\/MPA.0b013e3181744b50","article-title":"Chronic high-fat diets induce oxide injuries and fibrogenesis of pancreatic cells in rats","volume":"37","author":"Zhang","year":"2008","journal-title":"Pancreas"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"24378","DOI":"10.1074\/jbc.M112.371807","article-title":"Short term high fat diet challenge promotes alternative macrophage polarization in adipose tissue via natural killer T-cells and interleukin-4","volume":"287","author":"Ji","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"E47","DOI":"10.1152\/ajpendo.00026.2010","article-title":"Central administration of interleukin-4 exacerbates hypothalamic inflammation and weight gain during high-fat feeding","volume":"299","author":"Thaler","year":"2010","journal-title":"Am. J. Physiol. Endocrinol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1038\/s41366-021-00902-6","article-title":"Non-hematopoietic IL-4R\u03b1 expression contributes to fructose-driven obesity and metabolic sequelae","volume":"45","author":"Damen","year":"2021","journal-title":"Int. J. Obes."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Sato, K., Takayama, K.-I., Hashimoto, M., and Inoue, S. (2021). Transcriptional and post-transcriptional regulations of amyloid-\u03b2 precursor protein (APP) mRNA. Front. Aging, 2.","DOI":"10.3389\/fragi.2021.721579"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1002\/jcb.22382","article-title":"Amyloid precursor protein expression is induced by tumor necrosis factor-\u03b1 in 3T3-L1 adipocytes","volume":"108","author":"Sommer","year":"2009","journal-title":"J. Cell Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Keegan, A.D., Zamorano, J., Keselman, A., and Heller, N.M. (2018). IL-4 and IL-13 receptor signaling from 4PS to insulin receptor substrate 2: There and back again, a historical view. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01037"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Shi, J., Song, X., Traub, B., Luxenhofer, M., and Kornmann, M. (2021). Involvement of IL-4, IL-13 and their receptors in pancreatic cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22062998"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/11\/1033\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T01:56:13Z","timestamp":1780624573000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/11\/1033"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":56,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cells15111033"],"URL":"https:\/\/doi.org\/10.3390\/cells15111033","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]}}}