Table 2.
Main findings of articles (in alphabetical order) included and discussed in this systematic review.
| First author | Year | Species | n | Study type | Main findings | Risk of bias |
|---|---|---|---|---|---|---|
| Angelone T (21) | 2013 | Wistar rats | 6 rats/group – in total n = 24 | Experimental intervention study | By using a nesfatin-1 antibody, the presence of nesfatin-1 was identified in the rat heart. Exogenous nesfatin-1 directly showed negative inotropic and lusitropic effects without affecting coronary motility. These effects were mediated by involving pGC-NPR-A, the cGMP/PKG pathway, and ERK1/2. | |
| Ayada C (22) | 2015 | Male Wistar rats | 7 rats/group – in total n = 28 | Experimental intervention study | Nesfatin-1 induced heart failure during clinical treatments by increasing expression of the cardiac L-type Ca2+ channel. | Selection bias |
| Aydin B (23) | 2018 | Male Sprague-Dawley rats | 7 rats/group – in total n = 70 | Experimental intervention study | Nesfatin-1 elevated mean arterial pressure and modulates heart rate in rats via the central cholinergic system. | Selection bias |
| Barutcigil A (24) | 2018 | Male Wistar rats | Not indicated | Experimental intervention study | Nesfatin-1 dose-dependently induced a relaxation on the endothelium-intact thoracic aorta of rats and produced positive inotropic and chronotropic effects on atria. These effects might be beta-1 receptor independent, while involving the NO-cGMP cascade. | Selection bias |
| Brailoiu GC (25) | 2013 | Male and female Sprague-Dawley rats (in vitro), male Sprague-Dawley rats (in vivo), Nucleus ambiguous neurons | 6 rats/group (in vitro), 5 rats/group (in vivo) | Experimental intervention study | Nesfatin-1 increased cytosolic Ca2+ levels via a Gi/o-coupled mechanism in cardiac vagal neurons of nucleus ambiguous by involving P/Q type voltage-activated Ca2+ channels. Moreover, nesfatin-1 led to a dose-dependent depolarization of cardiac vagal neurons via a Gi/o-coupled mechanism. | Selection bias |
| Brailoiu GC (26) | 2007 | Hypothalamic neurons, male and female Sprague-Dawley rats | 170 neurons, different group sizes, number of rats not indicated | Experimental intervention study | In rats nesfatin-1 was present in hypothalamic and brainstem neurons and stimulated Ca2+ influx via GPCR. | |
| Buzcu H (27) | 2019 | Female Sprague-Dawley rats | 8 rats/group – in total n = 56 | Experimental intervention study | In acute pancreatitis nesfatin-1 showed an antioxidant and anti-inflammatory effect via the melanocortin signaling pathway. | Selection bias |
| Chen X (28) | 2015 | Male C57BL/6 mice, male Wistar rats | 6 rats/group – in total n = 12, 10 mice/group – in total n = 30 |
Experimental intervention study | Nesfatin-1 reduced dark-phase food intake in mice by inhibiting excitability of dopaminergic neurons in the VTA and reducing dopamine release in the nucleus acumbens. | Selection bias |
| Chen Z (29) | 2018 | Human neuroblastoma SH-SY5Y cells | 4 cells/group – in total n = 24 | Experimental intervention study | In human neuroblastoma SH-SY5Y cells nesfatin-1 led to an over-expression of synapsin I and phosphorylated ERK1/2 mediated via CRF1. | |
| Dong J (30) | 2013 | Male Kumming SPF mice | Not indicated | Experimental intervention study | Nesfatin-1 normalized free fatty acids and was thus able to improve lipid disorder via activation of AMPK-ACC pathway in T2DM mice. | Selection bias |
| Dore R (31) | 2017 | Male Wistar rats, male, C57BL/6N wild type mice | Different group sizes (5-10/group), 6 groups in total | Experimental intervention study | Nesfatin-1 treatment increased dry heat loss, iBAT and tail temperature through activation of the melanocortin system. | Selection bias |
| Erfani S (32) | 2018 | Male Wistar rats | 7 rats/group – in total n = 28 | Experimental intervention study | Nesfatin-1 had neuroprotective effects in neuronal cells and neuroinflammatory processes caused by brain ischemia by decreasing activation of caspase-3. | Selection bias |
| Fan XT (33) | 2018 | Male C57BL/6J mice (GHSR+/+) and (GHSR-/-) | 6-8 GHSR+/+ mice/group – in total n = 38, 3-5 GHSR-/-mice/group – in total n = 17 | Experimental intervention study | Nesfatin-1 required GHSR for mediating its effects on food intake and glucose metabolism. | Selection bias |
| Feijóo-Bandín S (34) | 2013 | humans, male Sprague-Dawley rats, HL-1 cardiac muscle cells of mice | 178 men, 90 women, 44 rats, number of muscle cells not indicated, different group sizes | Experimental intervention study | Cardiomyocytes can synthesize and release nesfatin-1 and the peptide stimulated glucose uptake by HL-1 cells and cardiomyocytes and translocation of GLUT4 to the periphery of these cells. | Selection bias |
| Feng H (35) | 2017 | Male Wistar rats | 144 rats, group sizes not indicated | Experimental intervention study | Nesfatin-1-expressing neurons in the hippocampus project to the VMH and there, nesfatin-1 modulated GD-responsive neurons and thus had an impact on the control of gastrointestinal functions. | Selection bias |
| Gao S (36) | 2016 | Sprague-Dawley rats | Not indicated | Experimental intervention study | Nesfatin-1 altered firing rates of GD-responsive VMH neurons, thereby inhibiting food intake, gastric acid production, gastric motility, and gastric emptying. | |
| Ge JF (37) | 2015 | Male Sprague-Dawley rats | 10 rats/group – in total n = 40 | Experimental intervention study | Nesfatin-1 mediated anxiety-like behavior in rats without altering memory. | Selection bias |
| Guo FF (38) | 2015 | Male Wistar rats | Not indicated | Experimental intervention study | Nesfatin-1 acted as an inhibitory neurotransmitter to regulate gastric motility via the LHA-PVN pathway. | Selection bias |
| Heidarza-deh H (39) | 2018 | Male meat-type chicken | 44 chicken/group – in total n = 304 | Experimental intervention study | In neonatal chicks nesfatin-1 used CRF1/CRF2 as well as H1-R and H3-R to mediate its anorexigenic effect. | Selection bias |
| Ishida E (40) | 2012 | mouse neuroblastoma cell line NB41A3, male C57/BL6 (B6) mice | Not indicated | Observational study | Nesfatin-1 bound to cell surface of NB41A3 cells and mouse hypothalamus indicating the presence of a specific nesfatin-1 receptor. Moreover, nesfatin-1 induced phosphorylation of CREB via binding to a Gi/o protein-coupled receptor and by utilizing Ca2+ influx and/or MAPK signaling cascade. | Selection bias |
| Iwasaki Y (41) | 2009 | Male ICR mice | Not indicated | Experimental intervention study | Peripheral nesfatin-1 stimulated Ca2+ influx through voltage-gated N-type channels, thereby directly activating afferent vagal neurons. | Selection bias |
| Jia FY (42) | 2013 | Male Sprague-Dawley rats | 9 rats/group – in total n = 36 | Experimental intervention study | Nesfatin-1 was involved in CRF/CRF1 signaling pathways in the brain, contributing to visceral hypersensitivity in rats. | Selection bias |
| Jiang L (43) | 2020 | human neuroblastoma SH-SY5Y cells, Sprague-Dawley rats | 5 human samples, 15 rats/group – in total n = 45 | Experimental intervention study | Treatment with nesfatin-1 obviated cartilage degeneration in rats which plays a major role in the development of osteoarthritis. | |
| Kan JY (44) | 2016 | humans, male inbred mice (BALB/cByJNarl) | 119 healthy donors, 160 colon cancer patients – in total n = 279 subjects, number of mice not indicated | Experimental intervention study | Nesfatin-1/NUCB2 increased invasion, migration and mesenchymal phenotype in colon cancer via LKB1/AMPK/TORC1/ZEB1 signaling pathways and may be a prospective marker for prediction of metastasis. | Selection bias |
| Kerbel B (45) | 2012 | goldfish Carassius auratus | n = 36 | Experimental intervention study | There is a possible relationship between nesfatin-1 and ghrelin, CCK and orexin A in goldfish to regulate food intake. | |
| Levata L (46) | 2019 | Male C57BL/6J mice | Not indicated | Experimental intervention study | Nesfatin-1 increased peripheral sympathetic outflow, resulting in iBAT thermogenesis and body weight loss. | Selection bias |
| Li C (47) | 2014 | Wistar rats | Not indicated | Experimental intervention study | In the substantia nigra nesfatin-1 post-synaptically hyperpolarized dopaminergic neurons, thus leading to a direct inhibition of these neurons. | |
| Li T (48) | 2021 | human HTR-8/trophoblasts | Not indicated | Experimental intervention study | Overexpression of nesfatin-1 increased human trophoblast proliferation, migration, invasion, and epithelial-mesenchymal transition and simultaneously suppressed oxidative stress. | |
| Li ZL (49) | 2013 | Male Wistar rats | n = 348 in different experiments | Experimental intervention study | Nesfatin-1 modulated gastrointestinal motility by affecting ghrelin-responsive GD neurons in the arcuate nucleus in rats. | Selection bias |
| Li Z (14) | 2013 | Male C57BL/6J mice, HFD- induced obese mice, Sprague-Dawley rats | Approximately n = 44 mice, number of rats not indicated | Experimental intervention study | Peripheral nesfatin-1 administration altered glucose metabolism in mice via increasing insulin secretion and insulin sensitivity by altering AKT phosphorylation and GLUT 4 membrane translocation in the adipose tissue, liver and skeletal muscle. | |
| Lu QB (50) | 2018 | Wistar-Kyoto rats, spontaneous hypertensive rats (SHR), human VSMCs, rat VSMCs | 6 Wistar-Kyoto rats/group – in total n = 84, 6 SHR/group – in total n = 68 | Experimental intervention study | Nesfatin-1 promoted VSMC differentiation and proliferation, leading to hypertension and vascular remodeling. | |
| Maejima Y (51) | 2017 | Male C57BL/6J mice, HEK239 cells | 16 mice/group – in total n = 35 | Experimental intervention study | Nesfatin-1/NUCB2 expression was found in pancreatic beta-cells in mice. Here, nesfatin-1 was found to inhibit Kv-channels in a direct manner. | Selection bias |
| Maejima Y (52) | 2009 | Male Wistar rats, Zucker-lean rats, Zucker-fatty rats | Not indicated | Experimental intervention study | Nesfatin-1 induced anorexia in a leptin-independent, but melanocortin-dependent manner via oxytocin neurons in the PVN. | |
| Mazza R (53) | 2015 | goldfish Carassius auratus | 4 goldfish/group – in total n = 44 | Experimental intervention study | Exposure of the isolated and perfused working heart to nesfatin-1 resulted in positive inotropism. | |
| Mori Y (54) | 2019 | Male C57BL/6J mice, transgene nucleobindin-2 mice, human VECs and VSMCs | n = 25 C57BL/6J mice, n = 13 transgene mice, different group sizes | Experimental intervention study | Nesfatin-1 administration dose-dependently suppressed peripheral artery remodeling in vascular endothelial cells and decreased neointimal hyperplasia. | Selection bias |
| Nair N (55) | 2016 | Male and female zebrafish (Danio rerio | 8 zebrafish/group – in total n = 64 | Experimental intervention study | NUCB2/nesfatin-1 may be localized in cardiomyocytes in zebrafish and administration of nesfatin-1 led to inhibition of end diastolic and end systolic volumes, decreasing heart rate and cardiac output. | |
| Nakata M (56) | 2011 | Male ICR mice | Not indicated | Experimental intervention study | Nesfatin-1 dose-dependently stimulated both insulin secretion in islets and intracellular Ca2+ levels in beta-cells under elevated plasma glucose concentration. | Selection bias |
| Oh I (1) | 2006 | Zucker obese rats, male Wistar rats | n = 4-10 rats/group, exact number of rats not indicated | Experimental intervention study | Nesfatin-1-induced satiety was associated with leptin-independent melanocortin signaling in the hypothalamus. | Selection bias |
| Osaki A (57) | 2014 | Male ICR mice | 3 mice/group – in total n = 18 | Experimental intervention study | Nesfatin-1 plays a physiological role in regulating blood pressure in mice by altering vascular contractility. | Selection bias |
| Ozcan M (58) | 2016 | Wistar rats | Not indicated | Experimental intervention study | Nesfatin-1 interacted with a GPCR and used a PKC-dependent mechanism to induce calcium influx in neonatal rat dorsal root ganglion neurons. | |
| Ozturk CC (59) | 2015 | Male Sprague-Dawley rats | n = 48 rats, group sizes not indicated | Experimental intervention study | The anti-inflammatory effects of nesfatin-1 in colitis were mediated via oxytocin and ghrelin receptors. | Selection bias |
| Price CJ (60) | 2008 | Male Sprague-Dawley rats | Number of rats not indicated, 85 neurons | Experimental intervention study | In the PVN nesfatin-1 regulated the membrane potential of different subtypes of neurons. | Selection bias |
| Price CJ (61) | 2008 | Male Sprague-Dawley rats | Number of rats not indicated, 102 neurons | Experimental intervention study | Nesfatin-1 exposure led to hyperpolarization in NPY-expressing neurons in the arcuate nucleus. These effects might be mediated via KATP channels. | Selection bias |
| Prinz P (62) | 2016 | Male Sprague-Dawley rats | n = 6 rats | Observational study | Bound nesfatin-1 radiolabel was detected in various peripheral organs and several brain nuclei. | |
| Ramanja-neya M (63) | 2015 | Female Wistar rats, human H295R adrenal cortex cells, mouse Y1 tumor cells | Not indicated | Experimental intervention study | Nesfatin-1 administration suppressed adrenocortical cell growth while increasing apoptosis. | Selection bias |
| Ranjan A (64) | 2019 | Male Parks strain mice | n = 21 mice | Experimental intervention study | Nesfatin-1 in mouse testes led to an increase in testosterone production, which was accompanied by higher expression of steroidogenic enzymes and insulin receptor protein. | |
| Ranjan A (65) | 2019 | Male Parks strain mice | n = 27 mice | Experimental intervention study | Nesfatin-1 played a role in spermatogenesis and steroidogenesis of prepubertal mice by direct action on the testis in association with the progression to puberty. | |
| Ranjan A (66) | 2020 | Male Parks strain mice | 10-20 mice/group – in total n = 50 | Experimental intervention study | Nesfatin-1 played a crucial role in ameliorating the testicular functions of T2DM mice by altering the circulating lipid profile. | |
| Shen XL (67) | 2017 | Male C57BL/6J mice, MES23.5 cells | 6 mice/group – in total n = 30 | Experimental intervention study | Nesfatin-1 showed a neuroprotective effect in dopaminergic neurons by protecting against MPP+/MPTP-induced neurotoxicity. These effects might be mediated via activation of the C-Raf-ERK1/2 signaling cascade. | Selection bias |
| Shimizu H (9) | 2009 | Male ICR mice, db/db mice | Not indicated | Experimental intervention study | The middle segment of nesfatin-1 caused anorexia via a leptin-independent mechanism. | |
| Stengel A (18) | 2009 | Male Sprague-Dawley rats | Not indicated | Experimental intervention study | Nesfatin-1 in rats led to a delayed inhibition of food intake in the dark phase, involving CRF2 receptor-dependent pathways. | Selection bias |
| Tan J (68) | 2016 | HGSMC cells | 20,000 cells/group – in total n = 60,000 | Experimental intervention study | Nesfatin-1 inhibited HGSMC viability and adhesion. | |
| Tanida M (69) | 2015 | Male Wistar rats, Zucker fatty rats, HFD rats | 7 Wistar rats/group – in total n = 28, 5-6 Zucker fatty rats/group – in total n = 20-22, 5-6 HFD rats/group – in total n = 20-22 | Experimental intervention study | Hypothalamic ERK signaling underlain the sympathoexcitatory effect of nesfatin-1 on energy intake and lipid metabolism. | |
| Tanida M (70) | 2011 | Male Wistar rats | 4-10 rats/group – in total n = 28 | Experimental intervention study | Nesfatin-1 modulated central sympathetic outflow, thereby stimulating renal sympathetic outflow and increasing blood pressure. | Selection bias |
| Tasatargil A (71) | 2017 | Male Wistar rats | 8 rats/group – in total n = 32 | Experimental intervention study | Nesfatin-1 showed cardioprotective effects in rats by decreasing myocardial apoptosis and inflammation which in turn reduces myocardial infarct size. | Selection bias |
| Vélez EJ (72) | 2020 | rat GH3 cells, RC-4B/C cells | Not indicated | Experimental intervention study | Nesfatin-1 and NLP showed a direct effect on somatotrophs by downregulating the synthesis of GH via a GPCR through the AC/PKA/CREB signaling pathway, most likely including a G-α-inhibitory subunit. | |
| Wang Q (73) | 2014 | Male Wistar rats | 65-65 rats/experiment – in total n = 246 | Experimental intervention study | In the central nucleus of the amygdala nesfatin-1 modulated the activity of GD-sensitive neurons and gastric motility. | Selection bias |
| Wu D (74) | 2014 | Male Sprague-Dawley rats | 51 rats/group – in total n = 102 | Experimental intervention study | Hypothalamic nesfatin-1 was involved in the regulation of glucose homeostasis and hepatic insulin sensitivity, associated with the activation of the mTOR-STAT3 signaling pathway. | Selection bias |
| Xia ZF (75) | 2012 | Male Sprague-Dawley rats, vagal neurons of Sprague-Dawley rats | Not indicated | Experimental intervention study | Nesfatin-1 inhibited gastric acid secretion stimulated by a central vagal mechanism in rats involving T-Typ Ca2+ channels. | Selection bias |
| Xu L (76) | 2017 | Male Wistar rats | 46-120 rats/experiment – in total approximately 439 | Experimental intervention study | Nesfatin-1 signaling in the lateral hypothalamic area modulated the activation of GD-responsive neurons, gastric motility and gastric secretion also involving melanin-concentrating hormone signaling. | Selection bias |
| Xu L (77) | 2015 | Male Wistar rats | 6-58 rats/experiment – in total n = 262 | Experimental intervention study | Nesfatin-1 administration into the BMA increased firing rate of GD-excitatory neurons, while decreasing firing rates of GD-inhibitory neurons. Nesfatin-1 in the BMA is involved in decreasing gastric motility and the Arc may also play a role in this regulating process. | Selection bias |
| Yamawa-ki H (16) | 2012 | Male Wistar rats | 8-23 rats/experiment – in total n = 58 | Experimental intervention study | Nesfatin-1 modulated peripheral arteria contractility by impairing cGMP release, thus inhibiting the SNP-induced smooth muscle relaxation. | Selection bias |
| Yang M (78) | 2012 | Male Sprague-Dawley rats | 8-40 rats/experiment – in total n = 68 | Experimental intervention study | Icv injection of nesfatin-1 increased peripheral and hepatic insulin sensitivity by decreasing gluconeogenesis and promoting peripheral glucose uptake through AMPK/AKT/TORC2 pathway. | Selection bias |
| Yin Y (79) | 2015 | C57BL/6J mice | 24-30 mice/experiment, exact number of mice not indicated | Experimental intervention study | Nesfatin-1 modulated lipid accumulation in hepatocytes via an AMPK-dependent mechanism. | |
| Ying J (80) | 2015 | Male Wistar rats | Not indicated | Experimental intervention study | Nesfatin-1 inhibited L-type Ca2+ channels via the MC4-R and involved the Gβγ subunit of Gi/o-protein and the downstream PKCθ pathway. | Selection bias |
| Yosten GL (81) | 2014 | Male Sprague-Dawley rats | 5-13 rats/group – in total n = 248 | Experimental intervention study | The hypertensive effect of nesfatin-1 may require both activation of oxytocinergic neurons and recruitment of CRF neurons. | Selection bias |
| Yuan JH (82) | 2017 | Male Wistar rats | 24-56 rats/experiment, exact number of rats not indicated | Experimental intervention study | Nesfatin-1 played a role in inhibition of food intake, alteration of the excitability of glucose sensitive neurons in the LPBN and an increase of UCP expression in brown adipose tissue by involving the melanocortin system. | Selection bias |
| Zhang JR (83) | 2018 | Male Sprague-Dawley rats | 6 rats/group, exact number of rats not indicated | Experimental intervention study | Nesfatin-1 stimulated VSMC proliferation, migration, and phenotype switch from a contractile to a synthetic state. | Selection bias |
| Zhang T (84) | 2019 | Male Sprague-Dawley rats | 6 rats/group – in total n = 54 | Experimental intervention study | Hypothalamic nesfatin-1 regulated feeding behavior through the MC3/4R-ERK signaling pathway. | |
| Zhang X (85) | 2018 | Siberian sturgeons | 6-8 sturgeons/group – in total n = 45 | Experimental intervention study | Nesfatin-1 reduced food intake in Siberia sturgeon predominantly via the CCK-CCK1R signaling pathway. | |
| Zhou XP (86) | 2016 | Male Sprague-Dawley rats | 15-18 rats/group, exact number of rats not indicated | Experimental intervention study | Nesfatin-1/NUCB2 in the amygdala was involved in the pathophysiology of IBS-like visceral hypersensitivity, likely by involving glucocorticoid and mineral corticoid receptor pathways. | Selection bias |
AC, adenylyl cyclase; AMPK, 5’ AMP-activated protein kinase; BMA, basomedial amygdala; CCK, cholecystokinin; CCK1-R, cholecystokinin1 receptor; cGMP, cyclic guanosine monophosphate; CREB, cAMP response element-binding protein; CRF, corticotropin-releasing factor; CRF1, corticotropin-releasing factor receptor 1; EGF, Epidermal growth factor; ERK, extracellular signal-regulated kinases; GD, gastric distension; GHSR, growth hormone secretagogue receptor; GLUT4, glucose transporter type 4; GPCR, G protein-coupled receptor; H1-R, histamine receptor 1; H3-R, histamine receptor 3; HFD, high-fat diet; HGSMC, human gastrointestinal smooth muscle cells; iBAT, interscapular brown adipose tissue; IBS, irritable bowel syndrome; icv, intracerebroventricular; KATP channel, ATP-sensitive potassium channel; Kv, voltage-gated potassium; LHA, lateral hypothalamic area; LKB1, liver kinase B1; LPBN, lateral parabrachial nucleus; MAP, mean arterial pressure; MAPK, mitogen-activated protein kinase; MC3-R, melanocortin 3 receptor; MC4-R, melanocortin 4 receptor; MEK, MAPK kinase/ERK kinase; mTOR, mammalian target of rapamycin; NLP, nesfatin-1-like peptide; NO, nitric oxide; NPR-A, natriuretic peptide receptor A; NPY, neuropeptide Y; NUCB2, nucleobindin-2; pGC, particulate guanylate cyclase; PKA, protein kinase A; PKC, protein kinase C; PKCθ, protein kinase C theta; PKG, protein kinase G; PVN, paraventricular nucleus; RCC, renal cell carcinoma; SNP, sodium nitroprusside; SPF, Specific-pathogen-free; STAT, signal transducers and activators of transcription; TORC1, target of Rapamycin complex 1; TORC2, target of Rapamycin complex 2; TRH, thyrotropin-releasing hormone; T2DM, type 2 diabetes mellitus; UCP, uncoupling protein; VEC, Vascular endothelial cells; VMH, ventromedial hypothalamus; VSMC, vascular smooth muscle cells; ZEB1, zinc finger E-box-binding homeobox 1.