Neuronatin Regulates Whole-body Metabolism: is Thermogenesis Involved?

Overview

Journal FASEB Bioadv

Specialty Biology

Date 2020 Oct 22

PMID 33089074

Citations 10

Authors

Jessica L Braun

Mia S Geromella

Sophie I Hamstra

Val A Fajardo

Affiliations

Soon will be listed here.

Abstract

Neuronatin (NNAT) was originally discovered in 1995 and labeled as a brain developmental gene due to its abundant expression in developing brains. Over the past 25 years, researchers have uncovered NNAT in other tissues; notably, the hypothalamus, pancreatic β-cells, and adipocytes. Recent evidence in these tissues indicates that NNAT plays a significant role in metabolism whereby it regulates food intake, insulin secretion, and adipocyte differentiation. Furthermore, genetic deletion of in mice lowers whole-body energy expenditure and increases susceptibility to diet-induced obesity and glucose intolerance; however, the underlying cellular mechanisms remain unknown. Based on its sequence homology with phospholamban, NNAT has a purported role in regulating the sarco(endo)plasmic reticulum Ca ATPase (SERCA) pump. However, NNAT also shares sequence homology with sarcolipin, which has the unique property of uncoupling the SERCA pump, increasing whole-body energy expenditure and thus promoting adaptive thermogenesis in states of caloric excess or cold exposure. Thus, in this article, we discuss the accumulating evidence suggestive of NNAT's role in whole-body metabolic regulation, while highlighting its potential to mediate adaptive thermogenesis via SERCA uncoupling.

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References

Fajardo V, Watson C, Bott K, Moradi F, Maddalena L, Bellissimo C . Neurogranin is expressed in mammalian skeletal muscle and inhibits calcineurin signaling and myoblast fusion. Am J Physiol Cell Physiol. 2019; 317(5):C1025-C1033. DOI: 10.1152/ajpcell.00345.2018. View

Tung Y, Ma M, Piper S, Coll A, ORahilly S, Yeo G . Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus. J Neurosci. 2008; 28(47):12419-26. PMC: 2650686. DOI: 10.1523/JNEUROSCI.3412-08.2008. View

Periasamy M, Maurya S, Singh S, Sahoo S, Reis F, Bal N . Role of SERCA Pump in Muscle Thermogenesis and Metabolism. Compr Physiol. 2017; 7(3):879-890. DOI: 10.1002/cphy.c160030. View

Giri B, Dey S, Das T, Sarkar M, Banerjee J, Dash S . Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed Pharmacother. 2018; 107:306-328. DOI: 10.1016/j.biopha.2018.07.157. View

Fajardo V, Bombardier E, Vigna C, Devji T, Bloemberg D, Gamu D . Co-expression of SERCA isoforms, phospholamban and sarcolipin in human skeletal muscle fibers. PLoS One. 2013; 8(12):e84304. PMC: 3865254. DOI: 10.1371/journal.pone.0084304. View

Lombardi L, Blanchet C, Poirier K, Lebrun N, Ramoz N, Moro M . Anorexia nervosa is associated with Neuronatin variants. Psychiatr Genet. 2019; 29(4):103-110. DOI: 10.1097/YPG.0000000000000224. View

Lin H, Bell E, Uwanogho D, Perfect L, Noristani H, Bates T . Neuronatin promotes neural lineage in ESCs via Ca(2+) signaling. Stem Cells. 2010; 28(11):1950-60. PMC: 3003906. DOI: 10.1002/stem.530. View

Li X, Thomason P, Withers D, Scott J . Bio-informatics analysis of a gene co-expression module in adipose tissue containing the diet-responsive gene Nnat. BMC Syst Biol. 2010; 4:175. PMC: 3022651. DOI: 10.1186/1752-0509-4-175. View

Joseph R, Dou D, Tsang W . Molecular cloning of a novel mRNA (neuronatin) that is highly expressed in neonatal mammalian brain. Biochem Biophys Res Commun. 1994; 201(3):1227-34. DOI: 10.1006/bbrc.1994.1836. View

10.

Rosell M, Kaforou M, Frontini A, Okolo A, Chan Y, Nikolopoulou E . Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice. Am J Physiol Endocrinol Metab. 2014; 306(8):E945-64. PMC: 3989735. DOI: 10.1152/ajpendo.00473.2013. View

11.

Augustine G, Santamaria F, Tanaka K . Local calcium signaling in neurons. Neuron. 2003; 40(2):331-46. DOI: 10.1016/s0896-6273(03)00639-1. View

12.

Bombardier E, Smith I, Vigna C, Fajardo V, Tupling A . Ablation of sarcolipin decreases the energy requirements for Ca2+ transport by sarco(endo)plasmic reticulum Ca2+-ATPases in resting skeletal muscle. FEBS Lett. 2013; 587(11):1687-92. DOI: 10.1016/j.febslet.2013.04.019. View

13.

Suh Y, Kim W, Moon C, Hong Y, Eun S, Lim J . Ectopic expression of Neuronatin potentiates adipogenesis through enhanced phosphorylation of cAMP-response element-binding protein in 3T3-L1 cells. Biochem Biophys Res Commun. 2005; 337(2):481-9. DOI: 10.1016/j.bbrc.2005.09.078. View

14.

Zheng Y, Ley S, Hu F . Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2017; 14(2):88-98. DOI: 10.1038/nrendo.2017.151. View

15.

Bombardier E, Smith I, Gamu D, Fajardo V, Vigna C, Sayer R . Sarcolipin trumps β-adrenergic receptor signaling as the favored mechanism for muscle-based diet-induced thermogenesis. FASEB J. 2013; 27(9):3871-8. PMC: 3752531. DOI: 10.1096/fj.13-230631. View

16.

Gburcik V, Cleasby M, Timmons J . Loss of neuronatin promotes "browning" of primary mouse adipocytes while reducing Glut1-mediated glucose disposal. Am J Physiol Endocrinol Metab. 2013; 304(8):E885-94. PMC: 3625784. DOI: 10.1152/ajpendo.00463.2012. View

17.

Chouchani E, Kazak L, Spiegelman B . New Advances in Adaptive Thermogenesis: UCP1 and Beyond. Cell Metab. 2018; 29(1):27-37. DOI: 10.1016/j.cmet.2018.11.002. View

18.

John R, Aparicio S, Ainscough J, Arney K, Khosla S, Hawker K . Imprinted expression of neuronatin from modified BAC transgenes reveals regulation by distinct and distant enhancers. Dev Biol. 2001; 236(2):387-99. DOI: 10.1006/dbio.2001.0327. View

19.

Makarewich C, Munir A, Schiattarella G, Bezprozvannaya S, Raguimova O, Cho E . The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy. Elife. 2018; 7. PMC: 6202051. DOI: 10.7554/eLife.38319. View

20.

Gamu D, Bombardier E, Smith I, Fajardo V, Tupling A . Sarcolipin provides a novel muscle-based mechanism for adaptive thermogenesis. Exerc Sport Sci Rev. 2014; 42(3):136-42. DOI: 10.1249/JES.0000000000000016. View