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

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 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 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.

The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism

“…To date, no thorough studies were performed to assess the contribution of PARPs to beige and brown adipocyte differentiation. These findings are in agreement with the observations that better NAD + availability (Yamaguchi et al 2019) or SIRT1 activation supports brown and beige differentiation (Qiang et al 2012;Khanh et al 2018).…”

NAD+/sirtuin metabolism is enhanced in response to cold‐induced changes in lipid metabolism in mouse liver

“…Studies on the role of sirtuins in thermogenesis were mainly conducted in adipose tissue [13,44–46]. Since sirtuins are a family of NAD + ‐dependent deacetylases, it may be very likely that cold exposure also changed sirtuin metabolism accompanied by enhanced NAD + synthesis.…”

Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity

“…The counts per million (CPM) reads were used to select genes that were significantly (P < 0.005) positively and negatively associated with AT pO 2 using Pearson's correlation. Functional enrichment analyses were performed on genes significantly associated with AT pO 2 using the Database for Annotation, Visualization and Integrated Discovery (DAVID) Bioinformatics Resources 6.8 (http://david.abcc.ncifcrf.gov/) with Gene Ontology biological process (GO BP) Direct category as we previously described (80). GO terms with a false discovery rate less than 0.01 were considered to be significantly enriched, and redundant GO terms were removed using the REVIGO program (http://revigo.irb.…”

“…AT RNA sequencing. Total RNA was isolated from frozen SAAT samples using QIAzol lysis reagent and an RNeasy Mini Kit (QIAGEN) in combination with an RNase-free DNase Set (QIAGEN) as we previously described (80). One SAAT sample from the MHO group was excluded from further analysis because of poor RNA quality attributable to RNA degradation.…”