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We found that ablation of Gnas, the gene that encodes G\u03b1s, in CD11c expressing cells protects mice from obesity, glucose intolerance, and insulin resistance. Transplantation studies showed that the lean phenotype was conferred by bone marrow\u2013derived cells and did not require adaptive immunity. Loss of cAMP signaling was associated with increased adipose tissue norepinephrine and cAMP signaling, and prevention of catecholamine resistance. The adipose tissue had reduced expression of catecholamine transport and degradation enzymes, suggesting that the elevated norepinephrine resulted from decreased catabolism. Collectively, our results identified an important role for cAMP signaling in CD11c+ innate immune cells in whole-body metabolism by controlling norepinephrine levels in white adipose tissue, modulating catecholamine-induced lipolysis and increasing thermogenesis, which, together, created a lean phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>We undertook this study to understand how immune cells communicate with adipocytes, specifically, whether cAMP signaling in the immune cell and the adipocyte are connected. We identified a reciprocal interaction between CD11c+ innate immune cells and adipocytes in which high cAMP signaling in the immune cell compartment induces low cAMP signaling in adipocytes and vice versa. This interaction regulates lipolysis in adipocytes and inflammation in immune cells, resulting in either a lean, obesity-resistant, and insulin-sensitive phenotype, or an obese, insulin-resistant phenotype.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db22-1035","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T14:50:37Z","timestamp":1685544637000},"page":"1235-1250","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":9,"title":["Loss of cAMP Signaling in CD11c Immune Cells Protects Against Diet-Induced Obesity"],"prefix":"10.2337","volume":"72","author":[{"given":"Liping","family":"Zeng","sequence":"first","affiliation":[{"name":"1The Second Affiliated Hospital of Guangzhou Medical University, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, China"},{"name":"2Department of Medicine, University of California San Diego, La Jolla, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. 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