A Transcriptomic and Proteomic Atlas of Obesity and Type 2 Diabetes in 1 Cynomolgus Monkeys 2 3

17 18 Obesity and type 2 diabetes (T2D) remain major global healthcare challenges and developing 19 therapeutics necessitate using nonhuman primate models. Here, we present transcriptomic and 20 proteomic analyses of all the major organs of cynomolgus monkeys with spontaneous obesity or 21 T2D in comparison to healthy controls. Molecular changes occur predominantly in the adipose 22 tissues of individuals with obesity, while extensive expression perturbations among T2D 23 individuals are observed in many tissues, such as the liver, kidney, brain, and heart. Immune 24 response-related pathways are upregulated in obesity and T2D, whereas metabolism and 25 mitochondrial pathways are downregulated. Incorporating human single-cell RNA sequencing 26 findings corroborates the role of macrophages and monocytes in obesity. Moreover, we highlight 27 some potential therapeutic targets including SLC2A1 and PCSK1 in obesity as well as SLC30A8 28 and SLC2A2 in T2D. Our findings provide insights into tissue-specific molecular foundations of 29 obesity and T2D and reveal the mechanistic links between these two metabolic disorders. 30 31