Genetic Ablation of CD38 Protects against Western Diet-Induced Exercise Intolerance and Metabolic Inflexibility

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a key cofactor required for essential metabolic oxidation-reduction reactions. It also regulates various cellular activities, including gene expression, signaling, DNA repair and calcium homeostasis. Intracellular NAD+ levels are tightly regulated and often respond rapidly to nutritional and environmental changes. Numerous studies indicate that elevating NAD+ may be therapeutically beneficial in the context of numerous diseases. However, the role of NAD+ on skeletal muscle exercise performance is poorly understood. CD38, a multi-functional membrane receptor and enzyme, consumes NAD+ to generate products such as cyclic-ADP-ribose. CD38 knockout mice show elevated tissue and blood NAD+ level. Chronic feeding of high-fat, high-sucrose diet to wild type mice leads to exercise intolerance and reduced metabolic flexibility. Loss of CD38 by genetic mutation protects mice from diet-induced metabolic deficit. These animal model results suggest that elevation of tissue NAD+ through genetic ablation of CD38 can profoundly alter energy homeostasis in animals that are maintained on a calorically-excessive Western diet.

NAD and the aging process: Role in life, death and everything in between

“…Thus, CD38 and BST-1 may have an important impact on the regulation of cellular metabolism and signaling, including regulation of the activity of SIRTUINS (Aksoy et al, 2006b; Barbosa et al, 2007). In fact, we and others have previously shown that CD38 regulates the organismal response to high caloric feeding and that genetic or pharmacological ablation of CD38 protects against high fat diet-induced metabolic dysfunction via modulation of SIRT1 activity (Barbosa et al, 2007; Chiang et al, 2015). …”

“…In addition, NADase activity was almost absent in CD38 knockout mice (Aksoy et al, 2006a; Young et al, 2006), suggesting that CD38 is the main NADase in mammalian tissues. We and others have previously shown that CD38 knockout mice have higher NAD levels and are protected against obesity and metabolic syndrome (Barbosa et al, 2007; Chiang et al, 2015). In addition, treatment of obese mice with CD38 inhibitors increased intracellular NAD levels and improved several aspects of glucose and lipid homeostasis (Escande et al, 2013; Haffner et al, 2015).…”

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

“…For example, cells overexpressing CD38 showed decreased [NAD ϩ ] together with decreased expression of antioxidant proteins, likely due to reduced sirtuin activity (391). As an effect of this metabolism, CD38 knockout mice showed improved resistance to glucose intolerance and diet-induced obesity (392,393). This correlated with increased [NAD ϩ ] in multiple tissues and increased sirtuin activity (392,394).…”

NAD+: A key metabolic regulator with great therapeutic potential

“…Similar to PARPs, alterations in the content of CD38 tightly correlate with changes in NAD + levels, with CD38 deletion leading to marked increases in NAD + and CD38 overexpression and causing reduced NAD + concentrations . Deletion of CD38 raises NAD + levels substantially in mice and protects from diet‐induced obesity, metabolic inflexibility, fatty liver and glucose intolerance . Similarly the flavonoid apigenin was recently described as a CD38 inhibitor, and administration in obese mice increased NAD + levels and improved glucose and lipid homeostasis .…”

“…[49][50][51] Deletion of CD38 raises NAD + levels substantially in mice and protects from diet-induced obesity, metabolic inflexibility, fatty liver and glucose intolerance. 50,52 Similarly the flavonoid apigenin was recently described as a CD38 inhibitor, and administration in obese mice increased NAD + levels and improved glucose and lipid homeostasis. 53 More potent inhibitors of CD38 have recently been described and, although they produce marked increases in tissue NAD + levels, their effect on metabolic parameters has not yet been determined.…”