The Circadian Protein Nocturnin Regulates Metabolic Adaptation in Brown Adipose Tissue

Onder, Yasemin; Laothamatas, Isara; Berto, Stefano; Sewart, Katharina; Kilaru, Gokhul; Bordieanu, Bogdan; Stubblefield, Jeremy J.; Konopka, Genevieve; Mishra, Prashant; Green, Carla B.

doi:10.2139/ssrn.3334980

Cited by 5 publications

(8 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By forcing translation initiation to Met1 in the mNoc-M65A-mCherry mutant, the long isoform was confirmed as the mitochondria-localized NOC (Fig. 3C), supporting our recently published work (17,18). In contrast, the short isoform (M1A) was present in the cytoplasm in a highly reticular pattern resembling membranes with much of it colocalized with the YFP-KDEL endoplasmic reticulum (ER) marker (Fig.…”

Section: Significancesupporting

confidence: 86%

“…One of the interesting but understudied aspects of nicotinamide dinucleotides is the variation in local subcellular concentrations and their specific contributions to physiology (16). We have previously reported the existence of two isoforms of NOC that are generated by two in-frame translation initiation sites (17,18). Initiation at Met1 produces a long isoform that encodes a mitochondrial-targeting signal (MTS) resulting in mitochondrial localization (followed by cleavage of the MTS), whereas initiation at Met65 produces a cytoplasmic short isoform (Fig.…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Spatiotemporal regulation of NADP(H) phosphatase Nocturnin and its role in oxidative stress response

Laothamatas

Gao

Wickramaratne

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

An intimate link exists between circadian clocks and metabolism with nearly every metabolic pathway in the mammalian liver under circadian control. Circadian regulation of metabolism is largely driven by rhythmic transcriptional activation of clock-controlled genes. Among these output genes, Nocturnin (Noct) has one of the highest amplitude rhythms at the mRNA level. The Noct gene encodes a protein (NOC) that is highly conserved with the endonuclease/exonuclease/phosphatase (EEP) domain-containing CCR4 family of deadenylases, but highly purified NOC possesses little or no ribonuclease activity. Here, we show that NOC utilizes the dinucleotide NADP(H) as a substrate, removing the 2′ phosphate to generate NAD(H), and is a direct regulator of oxidative stress response through its NADPH 2′ phosphatase activity. Furthermore, we describe two isoforms of NOC in the mouse liver. The cytoplasmic form of NOC is constitutively expressed and associates externally with membranes of other organelles, including the endoplasmic reticulum, via N-terminal glycine myristoylation. In contrast, the mitochondrial form of NOC possesses high-amplitude circadian rhythmicity with peak expression level during the early dark phase. These findings suggest that NOC regulates local intracellular concentrations of NADP(H) in a manner that changes over the course of the day.

show abstract

Section: Significancesupporting

confidence: 86%

Section: Significancementioning

confidence: 99%

Spatiotemporal regulation of NADP(H) phosphatase Nocturnin and its role in oxidative stress response

Laothamatas

Gao

Wickramaratne

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…This, in turn, may affect the central circadian pacemaker of the suprachiasmatic nuclei (SCN) in the brain, which uses GABA as a principal neurotransmitter [33]. Although further experiments are warranted to substantiate this assumption, it is worth to mention that Noct regulates metabolic adaptation in brown adipose tissue [34] and that it may maintain a proper metabolic balance in the face of metabolic challenges [35]. Hence, the downregulation of Noct in obese diabetic may further dysregulate metabolism in BTBR ob/ob mice.…”

Section: Discussionmentioning

confidence: 99%

Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBROb/Ob mice

et al. 2020

View full text Add to dashboard Cite

Objective To assess the influence of serum carnosinase (CN1) on the course of diabetic kidney disease (DKD). Methods hCN1 transgenic (TG) mice were generated in a BTBR Ob/Ob genetic background to allow the spontaneous development of DKD in the presence of serum carnosinase. The influence of serum CN1 expression on obesity, hyperglycemia, and renal impairment was assessed. We also studied if aggravation of renal impairment in hCN1 TG BTBR Ob/Ob mice leads to changes in the renal transcriptome as compared with wild-type BTBR Ob/Ob mice. Results hCN1 was detected in the serum and urine of mice from two different hCN1 TG lines. The transgene was expressed in the liver but not in the kidney. High CN1 expression was associated with low plasma and renal carnosine concentrations, even after oral carnosine supplementation. Obese hCN1 transgenic BTBR Ob/Ob mice displayed significantly higher levels of glycated hemoglobin, glycosuria, proteinuria, and increased albumincreatinine ratios (1104 ± 696 vs 492.1 ± 282.2 μg/mg) accompanied by an increased glomerular tuft area and renal corpuscle size. Gene-expression profiling of renal tissue disclosed hierarchical clustering between BTBR Ob/Wt , BTBR Ob/Ob, and hCN1 BTBR Ob/Ob mice. Along with aggravation of the DKD phenotype, 26 altered genes have been found in obese hCN1 transgenic mice; among them claudin-1, thrombospondin-1, nephronectin, and peroxisome proliferator-activated receptor-alpha have been reported to play essential roles in DKD. Conclusions Our data support a role for serum carnosinase 1 in the progression of DKD. Whether this is mainly attributed to the changes in renal carnosine concentrations warrants further studies. Jiedong Qiu, Thomas Albrecht and Shiqi Zhang contributed equally to this work. An abstract of this work has been awarded a poster prize on the congress of the German Diabetes Association (DDG) 2018 and on the International Congress on Carnosine and Anserine (ICCA) 2017 and has been presented on the congress of the European Association for the Study of Diabetes (EASD) 2018.

show abstract

“…While the impact of mitochondrial NOCT on mitochondrial RNAs remains to be fully explored, we did not detect altered cellular bioenergetics as assessed by measuring ATP levels, when either mitochondrial or cytoplasmic NOCT was over-expressed, indicating that mitochondrial gene expression was not altered significantly. Moreover, a recent report analyzed the effect of knockout of NOCT in mouse brown adipose, and observed little to no effect on mitochondrial gene expression, though a subset of mitochondrial encoded mRNAs showed a modest decrease in expression during cold adaptation (18).…”

Section: Discussionmentioning

confidence: 99%

“…Characterization of Drosophila and mammalian NOCT protein complexes indicated that they associate with components of the CCR4-NOT deadenylase complex, which initiates the major mRNA decay pathway (13,14). Further evidence in support of NOCT-mediated mRNA regulation comes from studies that employed NOCT knockout mice or RNAi-mediated depletion of NOCT in mouse cells; loss of NOCT expression resulted in changes in gene expression at the transcript level, and therefore may reflect action of NOCT on mRNA substrates (15)(16)(17)(18). In one instance, NOCT was reported to physically associate with a target mRNA (i.e.…”

Section: Introductionmentioning

confidence: 99%

Differential processing and localization of human Nocturnin controls metabolism of mRNA and nicotinamide dinucleotide metabolites

Abshire

Hughes

Diao

et al. 2020

Preprint

View full text Add to dashboard Cite

Nocturnin (NOCT) is a eukaryotic enzyme that belongs to a superfamily of exoribonucleases, endonucleases, and phosphatases. In this study, we analyze the expression, processing, localization, and cellular functions of human NOCT. We demonstrate that the NOCT protein is differentially expressed and processed in a cell and tissue type specific manner as a means to control its localization to the cytoplasm or mitochondria. Our studies also show that the N-terminus of NOCT is necessary and sufficient to confer mitochondrial localization. We then measured the impact of cytoplasmic NOCT on the transcriptome and report that it regulates the levels of hundreds of mRNAs that are enriched for components of signaling pathways, neurological functions, and regulators of osteoblast differentiation. Recent biochemical data indicate that NOCT dephosphorylates nicotinamide adenine dinucleotide (NAD) metabolites, and thus we measured the effect of NOCT on these cofactors in cells. We find that NOCT increases NAD(H) and decreases NADP(H) levels in a manner dependent on its intracellular localization. Collectively, our data indicate that NOCT can regulate levels of both mRNAs and NADP(H) cofactors in manner specified by its intracellular localization.

show abstract

The Circadian Protein Nocturnin Regulates Metabolic Adaptation in Brown Adipose Tissue

Cited by 5 publications

References 45 publications

Spatiotemporal regulation of NADP(H) phosphatase Nocturnin and its role in oxidative stress response

Spatiotemporal regulation of NADP(H) phosphatase Nocturnin and its role in oxidative stress response

Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBROb/Ob mice

Differential processing and localization of human Nocturnin controls metabolism of mRNA and nicotinamide dinucleotide metabolites

Contact Info

Product

Resources

About