Transcriptional Response of White Adipose Tissue to Withdrawal of Vitamin B3

Abstract

Scope Distinct markers for mild vitamin B3 deficiency are lacking. To identify these, the molecular responses of white adipose tissue (WAT) to vitamin B3 withdrawal are examined. Methods and results A dietary intervention is performed in male C57BL/6JRccHsd mice, in which a diet without nicotinamide riboside (NR) is compared to a diet with NR at the recommended vitamin B3 level. Both diets contain low but adequate level of tryptophan. Metabolic flexibility and systemic glucose tolerance are analyzed and global transcriptomics, qRT‐PCR, and histology of epididymal WAT (eWAT) are performed. A decreased insulin sensitivity and a shift from carbohydrate to fatty acid oxidation in response to vitamin B3 withdrawal are observed. This is consistent with molecular changes in eWAT, including an activated MEK/ERK signaling, a lowering of glucose utilization markers, and an increase in makers of fatty acid catabolism, possibly related to the consistent lower expression of mitochondrial electron transport complexes. The synthesis pathway of tetrahydropteridine (BH4), an essential cofactor for neurotransmitter synthesis, is transcriptionally activated. Genes marking these processes are technically validated. Conclusion The downregulation of Anp32a , Tnk2 and the upregulation of Mapk1 , Map2k1 , Qdpr , Mthfs , and Mthfsl are proposed as a WAT transcriptional signature marker for mild vitamin B3 deficiency.

The female mouse is resistant to mild vitamin B3 deficiency

“…Also, glucose tolerance was completely rescued by NMN administration in diabetic female mice, while in male mice this rescue effect was partial. These results are in line with our results, where male mice on the vitamin B 3 deficient diet showed insulin resistance, a mildly impaired metabolic flexibility and differential expression in white adipose tissue of seven vitamin B 3 responsive genes [17], while females fed the same period the same 0NR diet did not display these adverse health signs; their insulin sensitivity (Fig. 5), metabolic flexibility (Fig.…”

“…Similar to the females in this study, the male mice in our previous study did not have decreased liver or white adipose tissue NAD + levels after 18 weeks on a diet with 0.115% tryptophan and without vitamin B 3 [17]. In the male mice a lower level of NMN in the liver was observed in 0NR, compared to 30NR [17], while hepatic NMN levels were indistinguishable between 30 and 0NR in the female mice of this study (Fig. 4).…”

“…This might be explained by an adaptation effect, since it has been previously reported for rats on a diet with either 0.09% or 0.11% tryptophan that NAD + levels were decreased after 3 weeks, but no longer after 5 weeks [29]. Similar to the females in this study, the male mice in our previous study did not have decreased liver or white adipose tissue NAD + levels after 18 weeks on a diet with 0.115% tryptophan and without vitamin B 3 [17]. In the male mice a lower level of NMN in the liver was observed in 0NR, compared to 30NR [17], while hepatic NMN levels were indistinguishable between 30 and 0NR in the female mice of this study (Fig.…”

“…In a recent study in male C57BL/6JRccHsd mice, we found that mild vitamin B 3 deficiency emerged after 18 weeks on a diet without vitamin B 3 . In particular, in the male mice on the deficient diet insulin sensitivity was decreased, liver nicotinamide mononucleotide (NMN) levels were lower and in white adipose tissue seven genes were differentially expressed, compared to male mice on the same diet with vitamin B 3 [ 17 ]. In this study, NR was used as vitamin B 3 in the control diet at the AIN93 recommended level (30 mg/kg diet) [ 18 ], which we recently confirmed as optimal dose to support health in mice [ 13 ].…”

Nicotinamide Riboside Neutralizes Hypothalamic Inflammation and Increases Weight Loss Without Altering Muscle Mass in Obese Rats Under Calorie Restriction: A Preliminary Investigation

“…However, although NR modulates BW, adiposity, and, according to this study, SMT, we have no clear evidence that this is the result of a change in food intake. For example, recent evidence shows that NR supplementation does not alter food intake in rodents (29)(30)(31).…”