se capacity with an associated metabolic syndrome. Mice bearing a genetic deletion of CD38 were protected from diet-induced obesity, hyperglycemia and hyperinsulinemia. Furthermore, CD38 KO mice exhibited a preserved capacity for exercise, a preserved response to exercise and improved metabolic flexibility on HFHSD. 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 PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19725016 Western diet. Results CD38 KO mice are protected against a HFHS-mediated reduction in tissue NAD+ levels We initially compared the effects of normal chow and chronic HFHSD administration on NAD+ tissue levels in WT mice. The mice on chronic HFHSD gained substantial body weight mostly due to fat accumulation with a concomitant reduction in NAD+ levels in white fat and brown fat . No significant changes in NAD+ levels were observed PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19724269 in liver or the gastrocnemius muscle. 2 / 19 CD38 and Exercise Intolerance and Metabolic Inflexibility In contrast, CD38 KO mice on HFHSD exhibited significantly higher tissue NAD+ levels, MK886 including an approximately 2 fold increase in liver, 3-fold increase in the gastrocnemius muscle and brown fat and over 11-fold increase in white fat. Thus mice fed the HFHSD can respond to the loss of the CD38 gene with increased NAD+ levels in multiple tissues, including tissues such as muscle and liver that do not exhibit a diet induced suppression of NAD+. CD38 KO mice are protected from HFHSD- induced obesity HFHSD fed mice develop obesity, hyperleptinemia, hyperglycemia and hyperinsulinemia, compared to normal diet controls. A comparison of WT to CD38 KO mice on regular chow diet shows no obvious differences in fasting insulin, free fatty acid, triglyceride, or cholesterol levels. Body weight and fasting glucose are slightly but significantly lower in KO mice. Wild type mice challenged with HFHSD for 4 months gain over 20 g of body weight, whereas the CD38 KO mice gain only about 13 g. Fat mass accounts for the majority of this difference, as individual fat depots weight 25%-33% less than WT controls. Muscle weights are similar between both genotypes, confirming that the body weight differences between genotypes is primarily due to fat pad mass. Both WT controls and CD38 KO mice are equally active. Surprisingly, CD38 KO mice consume slightly more food per gram body weight compared to WT control, suggesting that activity and food intake were not responsible for the differences observed on HFHSD. The serum chemistry profiles suggest that CD38 KO mice are less susceptible to the metabolic effects induced by HFHSD and exhibited significantly lower fasting glucose, insulin, and leptin levels than the wild type HFHSD fed controls, indicating better glycemic control in CD38 KO mice, although it should be noted that these levels are still significantly elevated compared to a normal-chow comparator. Circulating lipids, including free-fatty acid, triglyceride, or cholesterol levels are not different between genotypes on HFHSD. As shown in Fig 2B, the fat mass of CD38 KO mice remained constantly lower compared with WT controls throughout the HFHSD treatment. We asked whether an alteration in adipose physiology may be responsible for the genotype associated difference in adipose tissue mass. Hormone sensitive lipase is a key regulator of lipolysis and its enzymatic activity is in turn increased by beta-adrenergic signaling. We

The strains were isolated during previous studies

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