Adropin

Adropin is a protein encoded by the energy homeostasis-associated gene ENHO in humans{{Cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=ENHO|title=ENHO Gene - GeneCards {{pipe}} ENHO Protein {{pipe}} ENHO Antibody|website=www.genecards.org}} and is highly conserved across mammals.{{Cite web |title=ortholog_gene_375704[group] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/?Term=ortholog_gene_375704%5Bgroup%5D |access-date=2022-08-21 |website=www.ncbi.nlm.nih.gov}}

The biological role of adropin was first described in mice by Andrew Butler's team. They identified it as a protein hormone (hepatokine) secreted from the liver, playing a role in obesity and energy homeostasis. The name "Adropin" is derived from the Latin words "aduro" (to set fire to) and "pinguis" (fat).{{cite journal | vauthors = Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW, Mynatt RL, Burris TP, Dong JZ, Halem HA, Culler MD, Heisler LK, Stephens JM, Butler AA | title = Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism | language = English | journal = Cell Metabolism | volume = 8 | issue = 6 | pages = 468–481 | date = December 2008 | pmid = 19041763 | pmc = 2746325 | doi = 10.1016/j.cmet.2008.10.011 }} Adropin is produced in various tissues, including the liver, brain, heart, and gastrointestinal tract.{{cite journal | vauthors = Jasaszwili M, Billert M, Strowski MZ, Nowak KW, Skrzypski M | title = Adropin as A Fat-Burning Hormone with Multiple Functions-Review of a Decade of Research | journal = Molecules | volume = 25 | issue = 3 | pages = 549 | date = January 2020 | pmid = 32012786 | pmc = 7036858 | doi = 10.3390/molecules25030549 | doi-access = free }}

In animals, adropin regulates carbohydrate and lipid metabolism{{cite journal | vauthors = Banerjee S, Ghoshal S, Stevens JR, McCommis KS, Gao S, Castro-Sepulveda M, Mizgier ML, Girardet C, Kumar KG, Galgani JE, Niehoff ML, Farr SA, Zhang J, Butler AA | title = Hepatocyte expression of the micropeptide adropin regulates the liver fasting response and is enhanced by caloric restriction | language = English | journal = The Journal of Biological Chemistry | volume = 295 | issue = 40 | pages = 13753–13768 | date = October 2020 | pmid = 32727846 | pmc = 7535914 | doi = 10.1074/jbc.RA120.014381 | doi-access = free }} and influences endothelial function.{{cite journal | vauthors = Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, Al-Omran M, Teoh H, Verma S | title = Adropin is a novel regulator of endothelial function | journal = Circulation | volume = 122 | issue = 11 Suppl | pages = S185–S192 | date = September 2010 | pmid = 20837912 | doi = 10.1161/CIRCULATIONAHA.109.931782 | s2cid = 798093 | doi-access = free }}{{cite journal | vauthors = Jurrissen TJ, Ramirez-Perez FI, Cabral-Amador FJ, Soares RN, Pettit-Mee RJ, Betancourt-Cortes EE, McMillan NJ, Sharma N, Rocha HN, Fujie S, Morales-Quinones M, Lazo-Fernandez Y, Butler AA, Banerjee S, Sacks HS, Ibdah JA, Parks EJ, Rector RS, Manrique-Acevedo C, Martinez-Lemus LA, Padilla J | title = Role of adropin in arterial stiffening associated with obesity and type 2 diabetes | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 323 | issue = 5 | pages = H879–H891 | date = November 2022 | pmid = 36083795 | pmc = 9602697 | doi = 10.1152/ajpheart.00385.2022 | s2cid = 252160224 | hdl = 10355/94230 }} Its expression in the liver is controlled by feeding status, macronutrient content, as well as by the biological clock.{{cite journal | vauthors = Kolben Y, Weksler-Zangen S, Ilan Y | title = Adropin as a potential mediator of the metabolic system-autonomic nervous system-chronobiology axis: Implementing a personalized signature-based platform for chronotherapy | journal = Obesity Reviews | volume = 22 | issue = 2 | pages = e13108 | date = February 2021 | pmid = 32720402 | doi = 10.1111/obr.13108 | s2cid = 220841405 }} Liver adropin is upregulated by estrogen{{cite journal | vauthors = Stokar J, Gurt I, Cohen-Kfir E, Yakubovsky O, Hallak N, Benyamini H, Lishinsky N, Offir N, Tam J, Dresner-Pollak R | title = Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice | journal = Molecular Metabolism | volume = 60 | pages = 101482 | date = June 2022 | pmid = 35364299 | pmc = 9044006 | doi = 10.1016/j.molmet.2022.101482 }} via the estrogen receptor alpha (ERα).{{cite journal | vauthors = Meda C, Dolce A, Vegeto E, Maggi A, Della Torre S | title = ERα-Dependent Regulation of Adropin Predicts Sex Differences in Liver Homeostasis during High-Fat Diet | journal = Nutrients | volume = 14 | issue = 16 | pages = 3262 | date = August 2022 | pmid = 36014766 | pmc = 9416503 | doi = 10.3390/nu14163262 | doi-access = free }}

In humans, lower levels of circulating adropin are linked to several medical conditions, including the metabolic syndrome, obesity, and inflammatory bowel disease.{{cite journal | vauthors = Soltani S, Kolahdouz-Mohammadi R, Aydin S, Yosaee S, Clark CC, Abdollahi S | title = Circulating levels of adropin and overweight/obesity: a systematic review and meta-analysis of observational studies | journal = Hormones | volume = 21 | issue = 1 | pages = 15–22 | date = March 2022 | pmid = 34897581 | doi = 10.1007/s42000-021-00331-0 | s2cid = 245119139 }} and inflammatory bowel disease.{{cite journal | vauthors = Brnić D, Martinovic D, Zivkovic PM, Tokic D, Tadin Hadjina I, Rusic D, Vilovic M, Supe-Domic D, Tonkic A, Bozic J | title = Serum adropin levels are reduced in patients with inflammatory bowel diseases | journal = Scientific Reports | volume = 10 | issue = 1 | pages = 9264 | date = June 2020 | pmid = 32518265 | pmc = 7283308 | doi = 10.1038/s41598-020-66254-9 | bibcode = 2020NatSR..10.9264B }} The brain exhibits the highest levels of adropin expression,{{Cite web |title=Tissue expression of ENHO - Summary - The Human Protein Atlas |url=https://www.proteinatlas.org/ENSG00000168913-ENHO/tissue |access-date=2022-08-21 |website=www.proteinatlas.org}} In the brain, adropin has been shown to have a potential protective role against neurological disease,{{cite journal | vauthors = Gunraj RE, Yang C, Liu L, Larochelle J, Candelario-Jalil E | title = Protective roles of adropin in neurological disease | journal = American Journal of Physiology. Cell Physiology | volume = 324 | issue = 3 | pages = C674–C678 | date = March 2023 | pmid = 36717106 | pmc = 10027081 | doi = 10.1152/ajpcell.00318.2022 }} where it may play a protective role against neurological diseases, brain aging, cognitive decline, and acute ischemia.{{cite journal | vauthors = Banerjee S, Ghoshal S, Girardet C, DeMars KM, Yang C, Niehoff ML, Nguyen AD, Jayanth P, Hoelscher BA, Xu F, Banks WA, Hansen KM, Zhang J, Candelario-Jalil E, Farr SA, Butler AA | title = Adropin correlates with aging-related neuropathology in humans and improves cognitive function in aging mice | journal = npj Aging and Mechanisms of Disease | volume = 7 | issue = 1 | pages = 23 | date = August 2021 | pmid = 34462439 | pmc = 8405681 | doi = 10.1038/s41514-021-00076-5 }}{{cite journal | vauthors = Aggarwal G, Morley JE, Vellas B, Nguyen AD, Butler AA | title = Low circulating adropin concentrations predict increased risk of cognitive decline in community-dwelling older adults | journal = GeroScience | date = May 2023 | volume = 46 | issue = 1 | pages = 897–911 | pmid = 37233882 | doi = 10.1007/s11357-023-00824-3 | doi-access = free | pmc = 10828274 }} as well as following acute ischemia.{{cite journal | vauthors = Yang C, Liu L, Lavayen BP, Larochelle J, Gunraj RE, Butler AA, Candelario-Jalil E | title = Therapeutic Benefits of Adropin in Aged Mice After Transient Ischemic Stroke via Reduction of Blood-Brain Barrier Damage | journal = Stroke | volume = 54 | issue = 1 | pages = 234–244 | date = January 2023 | pmid = 36305313 | pmc = 9780180 | doi = 10.1161/STROKEAHA.122.039628 | s2cid = 253184087 }}

The orphan G protein-coupled receptor GPR19 has been proposed as a receptor for adropin.{{cite journal | vauthors = Stein LM, Yosten GL, Samson WK | title = Adropin acts in brain to inhibit water drinking: potential interaction with the orphan G protein-coupled receptor, GPR19 | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 310 | issue = 6 | pages = R476–R480 | date = March 2016 | pmid = 26739651 | pmc = 4867374 | doi = 10.1152/ajpregu.00511.2015 }}{{Cite journal | vauthors = Devine RN, Butler A, Chrivia J, Vagner J, Arnatt CK |date= June 2023 |title=Probing Adropin-Gpr19 Interactions and Signal Transduction |url=https://jpet.aspetjournals.org/content/385/S3/430 |journal=Journal of Pharmacology and Experimental Therapeutics |language=en |volume=385 |issue=S3 |page=430 |doi=10.1124/jpet.122.550630 |issn=0022-3565|doi-access=free }}

Structure

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Adropin is a small protein composed of 76 amino acids, and it is produced primarily in the liver and the brain. The precursor of adropin is a larger protein called Energy Homeostasis-Associated (ENHO), and adropin is released through the cleavage of ENHO.

Receptors and targets

The specific receptors for adropin are not yet fully elucidated, and this is an area of active research. However, studies suggest that adropin might exert its effects by interacting with certain cell surface receptors.{{cite journal | vauthors = Stein LM, Yosten GL, Samson WK | title = Adropin acts in brain to inhibit water drinking: potential interaction with the orphan G protein-coupled receptor, GPR19 | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 310 | issue = 6 | pages = R476–R480 | date = March 2016 | pmid = 26739651 | pmc = 4867374 | doi = 10.1152/ajpregu.00511.2015 }}

Function

= Metabolic =

One of the primary areas of interest regarding adropin is its role in metabolic regulation. Research indicates that adropin may play a crucial role in glucose and lipid metabolism. It has been associated with insulin sensitivity, suggesting a potential role in the regulation of blood sugar levels.{{cite journal | vauthors = Gao S, McMillan RP, Zhu Q, Lopaschuk GD, Hulver MW, Butler AA | title = Therapeutic effects of adropin on glucose tolerance and substrate utilization in diet-induced obese mice with insulin resistance | journal = Molecular Metabolism | volume = 4 | issue = 4 | pages = 310–324 | date = April 2015 | pmid = 25830094 | pmc = 4354928 | doi = 10.1016/j.molmet.2015.01.005 }}

In animal studies, alterations in adropin levels have been linked to changes in energy expenditure and body weight. For example, some studies have shown that mice with elevated adropin levels tend to be more resistant to diet-induced obesity.{{cite journal | vauthors = Ganesh Kumar K, Zhang J, Gao S, Rossi J, McGuinness OP, Halem HH, Culler MD, Mynatt RL, Butler AA | title = Adropin deficiency is associated with increased adiposity and insulin resistance | journal = Obesity | volume = 20 | issue = 7 | pages = 1394–1402 | date = July 2012 | pmid = 22318315 | pmc = 3905465 | doi = 10.1038/oby.2012.31 }}

A study in humans demonstrated that changes in vascular insulin resistance following short-term adverse lifestyle changes were associated with a decrease in plasma adropin in men but not women,{{Cite journal |date=2023-02-11 |title=Correction to: "Young Women are Protected Against Vascular Insulin Resistance Induced by Adoption of an Obesogenic Lifestyle" |url=https://doi.org/10.1210/endocr/bqad037 |journal=Endocrinology |volume=164 |issue=4 |doi=10.1210/endocr/bqad037 |issn=1945-7170 |pmc=10413422 |pmid=36869675}} perhaps related to adropin's regulation by estrogen.

= Cardiovascular =

Adropin also appears to have cardiovascular effects. It has been implicated in the regulation of endothelial function, which is essential for maintaining blood vessel health. Dysfunction in endothelial cells can contribute to conditions such as atherosclerosis and hypertension. Some studies suggest that adropin may have a protective role in cardiovascular health by promoting the dilation of blood vessels and reducing oxidative stress.{{cite journal | vauthors = Bozic J, Kumric M, Ticinovic Kurir T, Males I, Borovac JA, Martinovic D, Vilovic M | title = Role of Adropin in Cardiometabolic Disorders: From Pathophysiological Mechanisms to Therapeutic Target | journal = Biomedicines | volume = 9 | issue = 10 | pages = 1407 | date = October 2021 | pmid = 34680524 | pmc = 8533182 | doi = 10.3390/biomedicines9101407 | doi-access = free }}

In mice, adropin regulates cardiac energy metabolism and improves cardiac function and efficiency.{{cite journal | vauthors = Altamimi TR, Gao S, Karwi QG, Fukushima A, Rawat S, Wagg CS, Zhang L, Lopaschuk GD | title = Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency | journal = Metabolism | volume = 98 | pages = 37–48 | date = September 2019 | pmid = 31202835 | doi = 10.1016/j.metabol.2019.06.005 }} In rats, adropin treatment alleviated diabetes related myocardial fibrosis and diastolic dysfunction,{{cite journal | vauthors = Liu M, Ai J, Shuai Z, Tang K, Li Z, Huang Y | title = Adropin Alleviates Myocardial Fibrosis in Diabetic Cardiomyopathy Rats: A Preliminary Study | language = English | journal = Frontiers in Cardiovascular Medicine | volume = 8 | pages = 688586 | date = 2021-07-12 | pmid = 34322528 | pmc = 8310998 | doi = 10.3389/fcvm.2021.688586 | doi-access = free }} and enhanced the therapeutic potential of mesenchymal stem cells in myocardial infarction.{{cite journal | vauthors = Li H, Hu D, Chen G, Zheng D, Li S, Lin Y, Hong H, Luo Y, Ke Y, Huang Y, Wu L, Lan T, Wang W, Fang J | title = Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction | journal = Cell Death & Disease | volume = 12 | issue = 6 | pages = 505 | date = May 2021 | pmid = 34006853 | pmc = 8131743 | doi = 10.1038/s41419-021-03610-1 }}

= Central nervous system =

Adropin is produced in the brain, particularly in the hypothalamus. The hypothalamus is a crucial region for the regulation of various physiological processes, including metabolism and energy balance. The presence of adropin in the brain suggests that it may have additional roles in the central nervous system, although the specifics are still being explored.

= Circadian rhythm =

There is evidence to suggest that adropin levels exhibit a circadian rhythm, meaning they follow a natural 24-hour cycle.{{cite journal | vauthors = Banerjee S, Ghoshal S, Stevens JR, McCommis KS, Gao S, Castro-Sepulveda M, Mizgier ML, Girardet C, Kumar KG, Galgani JE, Niehoff ML, Farr SA, Zhang J, Butler AA | title = Hepatocyte expression of the micropeptide adropin regulates the liver fasting response and is enhanced by caloric restriction | journal = The Journal of Biological Chemistry | volume = 295 | issue = 40 | pages = 13753–13768 | date = October 2020 | pmid = 32727846 | pmc = 7535914 | doi = 10.1074/jbc.ra120.014381 | doi-access = free }} Circadian rhythms play a vital role in regulating various physiological processes, including sleep-wake cycles, hormone secretion, and metabolism.

= Gonads and sexual development =

In mice, adropin treatment significantly increased sperm count and testicular testosterone by increasing expression of GPR19 and steroidogenic proteins via modulating redox potential.{{cite journal | vauthors = Tripathi S, Maurya S, Singh A | title = Adropin promotes testicular functions by modulating redox homeostasis in adult mouse | journal = Endocrine | date = June 2024 | pmid = 38878191 | doi = 10.1007/s12020-024-03921-1 }} In the mouse ovary, adropin and GPR19 are strongly detected in the granulosa cells of large antral follicles and corpus luteum.{{cite journal | vauthors = Maurya S, Tripathi S, Arora T, Singh A | title = Adropin may regulate corpus luteum formation and its function in adult mouse ovary | journal = Hormones | volume = 22 | issue = 4 | pages = 725–739 | date = December 2023 | pmid = 37597158 | doi = 10.1007/s42000-023-00476-0 | s2cid = 261029605 }} An additional study suggests a role for adropin in the acceleration of pubertal development.{{cite journal | vauthors = Maurya S, Tripathi S, Singh A | title = Ontogeny of adropin and its receptor expression during postnatal development and its pro-gonadal role in the ovary of pre-pubertal mouse | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 234 | pages = 106404 | date = November 2023 | pmid = 37743028 | doi = 10.1016/j.jsbmb.2023.106404 | s2cid = 262133676 | doi-access = free }}

Clinical significance

Given its involvement in metabolic and cardiovascular processes, adropin has sparked interest as a potential biomarker and therapeutic target for conditions such as obesity, diabetes, and cardiovascular disease. However, much more research is needed to understand the precise mechanisms of adropin action and its potential applications in clinical settings.

= Systemic sclerosis =

Adropin is a repressor of fibroblast activation and is dysregulated in patients with Systemic sclerosis. Adropin showed antifibrotic activity in mouse models of skin and lung fibrosis as well as in human skin biopsies. Thus, adropin is a potential therapeutic target in tissue fibrosis.{{cite journal | vauthors = Liang M, Dickel N, Györfi AH, SafakTümerdem B, Li YN, Rigau AR, Liang C, Hong X, Shen L, Matei AE, Trinh-Minh T, Tran-Manh C, Zhou X, Zehender A, Kreuter A, Zou H, Schett G, Kunz M, Distler JH | title = Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis | journal = Science Translational Medicine | volume = 16 | issue = 740 | pages = eadd6570 | date = March 2024 | pmid = 38536934 | doi = 10.1126/scitranslmed.add6570 | doi-access = free }}