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

Maria Thereza P. Barbosa^*, Sandra M. Soares^*, Colleen M. Novak, David Sinclair, James A. Levine, Pinar Aksoy^* and Eduardo Nunes Chini^*,1

Departments of
^* Anesthesiology and

Endocrinology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and

Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, Massachusetts, USA

¹Correspondence: Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN, 55905 USA. E-mail: chini.eduardo{at}mayo.edu

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-PGC1 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.—Barbosa, M. T. P., Soares, S. M., Novak, C. M., Sinclair, D., Levine, J. A., Aksoy, P., Chini, E. N. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity.

Key Words: sirtuins • SIRT1 • PGC1 • nicotinamide adenine dinucleotide • knockout mice • liver

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