The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity.

Obesity is one of the major health problems of our times. Elucidating the signaling mechanisms by which high-fat caloric diet induces obesity is critical for the understanding of this condition and for the development of therapeutic strategies for its treatment. Here, we demonstrate a novel role for protein CD38 as a regulator of body weight during a high-fat diet. CD38 is a ubiquitous enzyme that catalyzes the synthesis of second messengers and has been implicated in the regulation of a wide variety of signaling pathways. We report that CD38-deficient mice are protected against high-fat diet-induced obesity owing to enhanced energy expenditure. In fact, calorimetric studies indicate that CD38-deficient animals have a higher metabolic rate compared to control mice. Analysis of the mechanism revealed that this resistance to diet-induced obesity is mediated at least in part via a NAD-dependent activation of SIRT-PGC1alpha axis, a well-established cascade, involved in the regulation of mitochondrial biogenesis and energy homeostasis. Thus, together these results identify a novel pathway regulating body weight and clearly show that CD38 is a nearly obligatory component of the cellular cascade that led to diet-induced obesity.

Reducing Door-to-Reperfusion Time for Mechanical Thrombectomy With a Multitiered Notification System for Acute Ischemic Stroke.

OBJECTIVE: To reduce door-to-angiographic reperfusion (DTR) time to 120 minutes for patients presenting with acute ischemic stroke attributed to anterior circulation large-vessel occlusion amenable to endovascular mechanical thrombectomy. PATIENTS AND METHODS: Patients treated with mechanical thrombectomy before (April 10, 2015, through April 11, 2016) and after (April 12, 2016, through May 10, 2017) implementation of a multitiered notification system were studied. Lean process mapping was used to assess inefficiencies with multidisciplinary triage. A 3-tiered paging platform, which rapidly alerts essential personnel of the acute ischemic stroke team at advancing decision points, was introduced. RESULTS: Sixty-two patients were analyzed before and after implementation (34 vs 28, respectively). Following intervention, DTR time was reduced by 43 minutes (mean DTR, 170 minutes vs 127 minutes; P=.02). At 90-day follow up, 5 of the 28 patients in the postintervention cohort (19%) had excellent neurologic outcomes, defined as a modified Rankin Scale score of 0, compared to 0 of 34 (0%) in the preintervention cohort (P=.89). Reductions were also seen in the length of stay on the neurocritical care service (mean, 6 vs 3 days; P=.006), and total hospital charges for combined groups (mean, $100,083 vs $161,458; P<.001). CONCLUSION: The multitiered notification system was a feasible solution for improving DTR within our institution, resulting in reductions of overall DTR time, neurocritical care service length of stay, and total hospital charges.

Targeting of NAD metabolism in pancreatic cancer cells: potential novel therapy for pancreatic tumors.

PURPOSE: Here, we describe a novel interplay between NAD synthesis and degradation involved in pancreatic tumor growth. EXPERIMENTAL DESIGN: We used human pancreatic cancer cells, both in vitro (cell culture experiments) and in vivo (xenograft experiments), to demonstrate the role of NAD synthesis and degradation in tumor cell metabolism and growth. RESULTS: We demonstrated that pharmacologic and genetic targeting of Nampt, the key enzyme in the NAD salvage synthesis pathway, inhibits cell growth and survival of pancreatic cancer cells. These changes were accompanied by a reduction of NAD levels, glycolytic flux, lactate production, mitochondrial function, and levels of ATP. The massive reduction in overall metabolic activity induced by Nampt inhibition was accompanied by a dramatic decrease in pancreatic tumor growth. The results of the mechanistic experiments showed that neither the NAD-dependent enzymes PARP-1 nor SIRT1 play a significant role on the effect of Nampt inhibition on pancreatic cancer cells. However, we identified a role for the NAD degradation pathway mediated by the NADase CD38 on the sensitivity to Nampt inhibition. The responsiveness to Nampt inhibition is modulated by the expression of CD38; low levels of this enzyme decrease the sensitivity to Nampt inhibition. In contrast, its overexpression decreased cell growth in vitro and in vivo, and further increased the sensitivity to Nampt inhibition. CONCLUSIONS: Our study demonstrates that NAD metabolism is essential for pancreatic cancer cell survival and proliferation and that targeting NAD synthesis via the Nampt pathway could lead to novel therapeutic treatments for pancreatic cancer.

Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome.

Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD(+) metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD(+) levels has beneficial effects, likely because of the activation of sirtuins. Previously, we reported that CD38 is the primary NAD(+)ase in mammals. Moreover, CD38 knockout mice have higher NAD(+) levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD(+) levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD(+) levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD(+) levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD(+)-dependent pathways.

Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD+ oscillation.

The Intracellular levels of nicotinamide adenine dinucleotide (NAD(+)) are rhythmic and controlled by the circadian clock. However, whether NAD(+) oscillation in turn contributes to circadian physiology is not fully understood. To address this question we analyzed mice mutated for the NAD(+) hydrolase CD38. We found that rhythmicity of NAD(+) was altered in the CD38-deficient mice. The high, chronic levels of NAD(+) results in several anomalies in circadian behavior and metabolism. CD38-null mice display a shortened period length of locomotor activity and alteration in the rest-activity rhythm. Several clock genes and, interestingly, genes involved in amino acid metabolism were deregulated in CD38-null livers. Metabolomic analysis identified alterations in the circadian levels of several amino acids, specifically tryptophan levels were reduced in the CD38-null mice at a circadian time paralleling with elevated NAD(+) levels. Thus, CD38 contributes to behavioral and metabolic circadian rhythms and altered NAD(+) levels influence the circadian clock.