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Publication
Adipose tissue NAD+ biosynthesis is required for regulating adaptive
thermogenesis and whole-body energy homeostasis in mice.
Authors Yamaguchi S, Franczyk MP, Chondronikola M, Qi N, Gunawardana SC, Stromsdorfer
KL, Porter LC, Wozniak DF, Sasaki Y, Rensing N, Wong M, Piston DW, Klein S,
Yoshino J
Submitted By Submitted Externally on 3/26/2020
Status Published
Journal Proceedings of the National Academy of Sciences of the United States of America
Year 2019
Date Published 11/1/2019
Volume : Pages 116 : 23822 - 23828
PubMed Reference 31694884
Abstract Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for cellular
energy metabolism. The aim of the present study was to determine the importance
of brown and white adipose tissue (BAT and WAT) NAD+ metabolism in regulating
whole-body thermogenesis and energy metabolism. Accordingly, we generated and
analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt)
knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because
NAMPT is the rate-limiting NAD+ biosynthetic enzyme. We found ANKO mice, which
lack NAMPT in both BAT and WAT, had impaired gene programs involved in
thermogenesis and mitochondrial function in BAT and a blunted thermogenic
(rectal temperature, BAT temperature, and whole-body oxygen consumption)
response to acute cold exposure, prolonged fasting, and administration of
ß-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence
of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely
through inactivation of the NAD+-SIRT1-caveolin-1 axis, which limits an
important fuel source fatty acid for BAT thermogenesis. These metabolic
abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN),
which bypasses the block in NAD+ synthesis induced by NAMPT deficiency. Although
BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar
to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We
also found NAMPT expression in supraclavicular adipose tissue (where human BAT
is localized) obtained from human subjects increased during cold exposure,
suggesting our finding in rodents could apply to people. These results
demonstrate that adipose NAMPT-mediated NAD+ biosynthesis is essential for
regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.




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