CD38 downregulation modulates NAD⁺ and NADP(H) levels in thermogenic adipose tissues

Different strategies to boost NAD⁺ levels are considered promising means to promote healthy aging and ameliorate dysfunctional metabolism. CD38 is a NAD⁺-dependent enzyme involved in the regulation of different cell functions. In the context of systemic energy metabolism, it has been demonstrated that brown adipocytes, the parenchymal cells of brown adipose tissue (BAT) as well as beige adipocytes that emerge in white adipose tissue (WAT) depots in response to catabolic conditions, are important to maintain metabolic homeostasis. In this study we aim to understand the functional relevance of CD38 for NAD⁺ and energy metabolism in BAT and WAT, also using a CD38^-/- mouse model. During cold exposure, an increase in NAD⁺ levels occurred in BAT of wild type mice, together with a marked downregulation of CD38, as detected at the mRNA and protein level. CD38 downregulation was observed also in WAT of cold-exposed mice, where it was accompanied by a strong increase in NADP(H) levels. Accordingly, NAD kinase and glucose-6-phosphate dehydrogenase activities were enhanced in WAT (but not in BAT). Increased NAD⁺ levels were observed in BAT/WAT from CD38^-/- compared with wild type mice, in line with CD38 being a major NAD⁺-consumer in AT. CD38^-/- mice kept at 6 °C had higher levels of Ucp1 and Pgc-1α in BAT and WAT, and increased levels of phosphorylated hormone-sensitive lipase in BAT, compared with wild type mice. These results demonstrate that CD38, by modulating cellular NAD(P)⁺ levels, is involved in the regulation of thermogenic responses in cold-activated BAT and WAT.