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

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

HFHSD reduces tissue NAD⁺ levels and CD38 KO mice have elevated tissue NAD⁺ levels.

<p>(A) Tissue NAD⁺ was determined from snap frozen liver, gastrocnemius, brown fat and white fat of WT mice fed a ND (white) or HFHSD (grey) for 5 months. Mice were fasted for 6 hrs before tissue collection. n = 5 per group. ††, p value<0.01 (ND vs HFHSD). See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134927#sec009" target="_blank">Material and Methods</a> for experimental details. (B) Tissue NAD⁺ was measured from snap frozen liver, gastrocnemius, brown fat and white fat of WT (grey) or CD38 KO (black) mice fed with HFHSD before the study. Mice were fasted for 6 hrs before tissue collection. n = 5 per group. *, p value<0.05 (WT vs KO); **, p value<0.01 (WT vs KO).</p

CD38 KO mice retain sensitivity to beta-adrenergic signaling.

<p>(A) Lysates from WAT of C57Bl6 mice fed with either ND or HFHSD were immunoblotted with indicated antibodies. (B) Lysates from WAT of WT or CD38 KO mice on HFHSD were immunoblotted with indicated antibodies.</p

CD38 KO mice are protected from HFHSD- induced obesity.

<p>(A) Body weight was measured for WT (grey) and CD38 KO (black) during the 4 months of ND (dashed lines) or HFHSD (solid lines) treatment from age of 2months old. n = 13–15. **, p value<0.01 (WT vs KO). (B) Fat mass was measured by qNMR for WT (grey) and CD38 KO (black) during the 4 months of ND (dashed lines) or HFHSD (solid lines) treatment from age of 2months old. n = 13–15. **, p value<0.01 (WT vs KO). (C) Tissue weights were measured for WT (grey) and CD38 KO (black) after animals were dissected after 4 months of HFHSD. n = 8 **, p value<0.01 (WT vs KO).</p

Blood and NAD⁺ measurement.

<p>Blood and NAD⁺ measurement.</p