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

Abstract

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.

Role of Deleted in Breast Cancer 1 (DBC1) Protein in SIRT1 Deacetylase Activation Induced by Protein Kinase A and AMP-activated Protein Kinase

“…S3, the methodology used in this study was sensitive to small variations in NAD ϩ concentration. Furthermore, we have previously detected changes in NAD ϩ and NAD ϩ metabolites in several cells and tissues using the same method (10,11,14,31,(55)(56)(57). Taken together, these results demonstrate that AMPK can activate SIRT1 without detectable changes in cellular NAD ϩ levels.…”

“…Because SIRT1 enzymatic activity is dependent on NAD ϩ (8), changes in the concentration of this nucleotide can lead to changes in SIRT1 activity. Indeed, modification of the two main enzymes responsible for the control of intracellular NAD ϩ levels, namely NamPT (9) and CD38 (10 -12), can lead to changes in SIRT1 activity (11,13,14). However, the specificity of this mechanism seems low as there are several other NAD ϩ -consuming enzymes in the cell.…”

Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure

“…SIRT1 deacetylase activity was determined using the SIRT1 Fluorimetric Kit (Biomol International, LP, Plymouth Meeting, PA, USA), according to the manufacturer's instructions as previously described [32]. Briefly, crude nuclear extract samples prepared from FVB/N mice at postnatal age of 7 d, 2, 18 and 24 months, TG mice or WT littermates on postnatal day 4 (P4) (10 μg protein/well) were incubated in 40 mmol L 1 Tris-HCl (pH 7.4) containing 500 µmol L 1 NAD, and 100 µmol L 1 Fluor de Lys-SIRT1 substrate at 37°C for 1 h. Following incubation, the reaction was terminated by the addition of a solution containing Fluor de Lys Developer and 2 mmol L 1 nicotinamide.…”

Deleted in breast cancer–1 regulates SIRT1 activity and contributes to high-fat diet–induced liver steatosis in mice

“…These measurements were performed as previously described (58). Each mouse was placed in a 30 cm × 10 cm cylindrical chamber for 24 hours prior to the measurement of 24-hour activity and EE.…”