N^G,N^G‐Dimethylarginine Dimethylaminohydrolase 1 Expression Is Dispensable for Cold‐ or Diet‐Induced Thermogenesis

Abstract

The strategy to activate thermogenic adipocytes has therapeutic potential to overcome obesity as they dissipate surplus energy as heat through various mechanisms. NG,NG‐dimethylarginine dimethylaminohydrolases (DDAHs) are enzymes involved in the nitric oxide‐protein kinase G signaling axis which increases thermogenic gene expression. However, the role of DDAHs in thermogenic adipocytes has not been elucidated. The adipocyte‐specific Ddah1 knockout mice are generated by crossing Ddah1fl/fl mice with adiponectin Cre recombinase mice. Adipocyte‐specific DDAH1 overexpressing mice are generated using adeno‐associated virus‐double‐floxed inverse open reading frame (AAV‐DIO) system. These mice are analyzed under basal, cold exposure, or high‐fat diet (HFD) conditions. Primary inguinal white adipose tissue cells from adipocyte‐specific Ddah1 knockout mice expressed comparable amounts of Ucp1 mRNA. Adipocyte‐specific DDAH1 overexpressing mice do not exhibit enhanced activation of thermogenic adipocytes. In addition, when these mice are exposed to cold environment or fed an HFD, their body temperature/weight and thermogenesis‐related gene and protein expressions are unchanged. These findings indicate that DDAH1 does not play a role in either cold‐ or diet‐induced thermogenesis. Therefore, adipocyte targeting DDAH1 gene therapy for the treatment of obesity is unlikely to be effective.