{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T01:31:32Z","timestamp":1791250292121,"version":"4.1.0"},"reference-count":37,"publisher":"American Diabetes Association","issue":"8","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"content-version":"vor","delay-in-days":3331,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,8,1]]},"abstract":"<jats:sec>\n                  <jats:title\/>\n                  <jats:p>Chronic inflammation in adipose tissue contributes to obesity-related insulin resistance. The 3-phosphoinositide-dependent protein kinase 1 (Pdk1)\/forkhead transcription factor (Foxo1) pathway is important in regulating glucose and energy homeostasis, but little is known about this pathway in adipose tissue macrophages (ATMs). To investigate this, we generated transgenic mice that carried macrophage\/granulocyte-specific mutations, including a Pdk1 knockout (LysMPdk1\u2212\/\u2212), a Pdk1 knockout with transactivation-defective Foxo1 (\u0394256LysMPdk1\u2212\/\u2212), a constitutively active nuclear (CN) Foxo1 (CNFoxo1LysM), or a transactivation-defective Foxo1 (\u0394256Foxo1LysM). We analyzed glucose metabolism and gene expression in ATM populations isolated with fluorescence-activated cell sorting. The LysMPdk1\u2212\/\u2212 mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Overexpression of transactivation-defective Foxo1 rescued these phenotypes. CNFoxo1LysM promoted transcription of the C-C motif chemokine receptor 2 (Ccr2) in ATMs and increased M1 macrophages in adipose tissue. On a high-fat diet, CNFoxo1LysM mice exhibited insulin resistance. Pdk1 deletion or Foxo1 activation in bone marrow\u2013derived macrophages abolished insulin and interleukin-4 induction of genes involved in alternative macrophage activation. Thus, Pdk1 regulated macrophage infiltration by inhibiting Foxo1-induced Ccr2 expression. This shows that the macrophage Pdk1\/Foxo1 pathway is important in regulating insulin sensitivity in vivo.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db11-0770","type":"journal-article","created":{"date-parts":[[2012,5,15]],"date-time":"2012-05-15T06:29:45Z","timestamp":1337063385000},"page":"1935-1948","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":59,"title":["Loss of Pdk1-Foxo1 Signaling in Myeloid Cells Predisposes to Adipose Tissue Inflammation and Insulin Resistance"],"prefix":"10.2337","volume":"61","author":[{"given":"Yoshinaga","family":"Kawano","sequence":"first","affiliation":[{"name":"Frontier Medicine on Metabolic Syndrome, Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Itoh","sequence":"additional","affiliation":[{"name":"Frontier Medicine on Metabolic Syndrome, Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2012,7,17]]},"reference":[{"key":"2022031223073091000_B1","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1101\/gad.1550907","article-title":"Mechanisms of obesity-associated insulin resistance: many choices on the menu","volume":"21","author":"Qatanani","year":"2007","journal-title":"Genes Dev"},{"key":"2022031223073091000_B2","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1146\/annurev-physiol-021909-135846","article-title":"Macrophages, inflammation, and insulin 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