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The brainstem is involved in glucose and metabolic homeostasis by integrating peripheral signals such as insulin and leptin. Here, we evaluated the brainstem response to intracerebroventricular administration of insulin or leptin and the relationship with physiological levels of key molecules implicated in their signal transduction pathway and inflammation in 3-, 6-, and 12-month-old mice which progressively increase adiposity and develop signs of insulin resistance. The initial steps of insulin and leptin signaling pathways decline with age, as well as the protein kinase B (Akt) phosphorylation response. Both hormones decrease the phosphorylation of AMP-activated protein kinase (AMPK) but, while the response to insulin increases with age, the response to leptin decreases in older animals. This insulin and leptin resistance is accompanied by changes in basal protein expression or phosphorylation of insulin and leptin receptors and insulin receptor substrates-1 (IRS-1), as well as the imbalance between basal levels of Akt-phosphorylated and non-phosphorylated protein, without changes in other serine kinases and\/or inflammatory pathways such as glycogen-synthase-kinase-3 (GSK3), mammalian targets of rapamycin (mTOR), kinase-p70S6 (p70), protein kinase-C-\u03b5 (PKC\u03b5), p38 mitogen-activated protein kinase (p38), or c-Janus N-terminal kinase (JNK). High levels of proinflammatory cytokines and glial cell activation suggest the development of neuroinflammation in the brainstem with age, which could mediate the age-associated insulin and leptin resistance and the impairment in glucose and metabolic homeostasis commonly observed in the aging process.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s12035-025-05392-5","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T06:22:14Z","timestamp":1768544534000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development of Insulin and Leptin Resistance in the Mouse Brainstem with Age"],"prefix":"10.1007","volume":"63","author":[{"given":"Elvira","family":"De Frutos Gonz\u00e1lez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Lauzurica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Joaqu\u00edn","family":"Ochoa Navarro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Garc\u00eda San Frutos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Aguado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Fern\u00e1ndez-Agull\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"5392_CR1","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Ot\u00edn C, Blasco MA, Partridge L, Serrano M, Kroemer G (2023) Hallmarks of aging: an expanding universe. 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