observed that phosphorylation of serine 660 of Hsl in white adipose tissue is reduced in the WAT of mice on a HFHSD.This result indicates that lipolytic Fast Green FCF pathways are inhibited and this in turn is consistent with the observed 3 / 19 CD38 and Exercise Intolerance and Metabolic Inflexibility Fig 1. HFHSD reduces tissue NAD+ levels and CD38 KO 
mice have elevated tissue NAD+ levels. Tissue NAD+ was determined from snap frozen liver, gastrocnemius, brown fat and white fat of WT mice fed a ND or HFHSD for 5 months. PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19725016 Mice were fasted for 6 hrs before tissue collection. n = 5 per group., p value<0.01. See Material and Methods for experimental details. Tissue NAD+ was measured from snap frozen liver, gastrocnemius, brown fat and white fat of WT or CD38 KO mice fed with HFHSD before the study. Interestingly, loss of CD38 preserves this beta-adrenergic receptor signaling in the WAT of mice on the HFHSD, suggesting that loss of CD38 in adipose 4 / 19 CD38 and Exercise Intolerance and Metabolic Inflexibility Fig 2. CD38 KO mice are protected from HFHSD- induced obesity. Body weight was measured for WT and CD38 KO during the 4 months of ND or HFHSD treatment from age of 2months old. n = 1315. , p value<0.01. Fat mass was measured by qNMR for WT and CD38 KO during the 4 months of ND or HFHSD treatment from age of 2months old.Tissue weights were measured PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19723429 for WT and CD38 KO after animals were dissected after 4 months of HFHSD. n = 8 , p value<0.01. doi:10.1371/journal.pone.0134927.g002 tissue can prevent diet-induced catecholamine resistance and therefore facilitate lipolysis and the delivery of fatty acids to tissues for use as fuel. In order to determine whether the reduced fasting glucose, insulin, and leptin levels in CD38 KO mice indicate any physiological impact on whole body insulin sensitivity, oral glucose tolerance and intraperitoneal insulin tolerance tests were conducted. 5 / 19 CD38 and Exercise Intolerance and Metabolic Inflexibility Fig 3. CD38 KO mice are protected from HFHSD- induced hyperglycemia and hyperinsulinemia. Blood glucose was measured for WT and CD38 KO after 6 hrs of fasting. n = 8., p value<0.01; , p value<0.05; , p value<0.01. Serum insulin and leptin were measured for WT and CD38 KO on ND or HFHSD with 6 hrs of fasting.There are no significant differences between genotypes in the oral glucose tolerance test or insulin tolerance test results, in contrast to other reports that did observe such differences. Results similar to ours showing no significant differences were also reported by an independent group. This result implies that the loss of CD38 enzymatic Fig 4. CD38 KO mice retain sensitivity to beta-adrenergic signaling. Lysates from WAT of C57Bl6 mice fed with either ND or HFHSD were immunoblotted with indicated antibodies. Lysates from WAT of WT or CD38 KO mice on HFHSD were immunoblotted with indicated antibodies. CD38 KO mice are protected from western diet-induced exercise intolerance To determine whether the loss of the CD38 gene beneficially impacts the overall physical fitness of the HFHSD fed mouse we performed an exhaustive exercise test. This test measures exercise capacity and thus is a good indicator of overall physical health. Mice challenged with 5 months of ND or HFHSD were compared via a treadmill running test. This test is designed to run animals to exhaustion. Following an acclimation at a 10 incline, mice were run at 10m/min for 5 minutes. After this 5 minute period, speed is increased by 2m/min every