Adipose tissue NAD ⁺ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice

Nov 8, 2019Proceedings of the National Academy of Sciences of the United States of America

Fat tissue production of NAD+ is needed to control body heat generation and overall energy balance in mice

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Abstract

Adipose tissue NAD metabolism is essential for regulating thermogenesis and energy metabolism.

Mice lacking the enzyme NAMPT in both brown and white fat showed reduced gene programs related to thermogenesis and mitochondrial function.
These mice exhibited a weakened thermogenic response during cold exposure, fasting, and stimulation with β-adrenergic agonists.
The absence of NAMPT in white fat significantly diminished lipolytic activity, likely by disrupting the NAD-SIRT1-caveolin-1 pathway.
Treatment with nicotinamide mononucleotide (NMN) restored metabolic functions by circumventing the NAD synthesis block caused by NAMPT deficiency.
Mice lacking NAMPT specifically in brown fat showed similar cellular changes but retained normal thermogenic and lipolytic responses.
Increased NAMPT expression was observed in human supraclavicular adipose tissue during cold exposure, indicating potential relevance to human metabolism.

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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) NADmetabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase () knockout (ANKO) and brown adipocyte-specificknockout (BANKO) mice because NAMPT is the rate-limiting NADbiosynthetic 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 β-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 NADsynthesis 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 foundexpression 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 NADbiosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism. + + + + + + Nampt Nampt NAMPT

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Adipose tissue NAD ⁺ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice

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