American Diabetes Association
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Loss of cAMP signaling in CD11c immune cells protects against diet-induced obesity

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posted on 2023-05-31, 18:42 authored by Liping Zeng, D. Scott Herdman, Sung Min Lee, Ailin Tao, Manasi Das, Samuel Bertin, Lars Eckmann, Sushil Mahata, Panyisha Wu, Miki Hara, Ji-Won Byun, Shwetha Devulapalli, Hemal H. Patel, Anthony J.A. Molina, Olivia Osborn, Maripat Corr, Eyal Raz, Nicholas J.G. Webster

In obesity, CD11c+ innate immune cells are recruited to adipose tissue and create an inflammatory state that causes both insulin and catecholamine resistance. We found that ablation of Gnas, the gene that encodes Gas, 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-derived 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 WAT, modulating catecholamine-induced lipolysis, and increasing thermogenesis, which together created a lean phenotype.


This work was funded primarily by NIH grants R01HL141999, U01AI125860 and R01CA196853 to ER and NJGW, and in part by a VA Merit Review Award I01BX004848 and Senior Research Career Scientist Award IBX005224 to NJGW. The research was also supported by the NIH Cancer Center Support Grant P30CA023100, the Diabetes Research Center Grant P30DK063491, and the San Diego Digestive Disease Center Grant P30DK120515. We would like to acknowledge the assistance of Dr. Valeria Estrada and the Biorepository and Tissue Technology Shared Resource at the Moores Cancer Center. The ANCOVA analysis of calorimetric data done for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (MMPC, using their Energy Expenditure Analysis page ( and supported by grants DK076169 and DK115255.


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