Spexin is a Novel Human Peptide That Reduces Adipocyte Uptake of Long Chain Fatty Acids and Causes Weight Loss in Rodents with Diet-induced Obesity

Overview

Journal Obesity (Silver Spring)

Specialties Endocrinology
Nutritional Sciences
Physiology

Date 2014 Feb 20

PMID 24550067

Citations 73

Authors

Jose L Walewski

Fengxia Ge

Harrison Lobdell 4th

Nancy Levin

Gary J Schwartz

Joseph R Vasselli

Afons Pomp

Gregory Dakin

Paul D Berk

Affiliations

Soon will be listed here.

Abstract

Objective: Microarray studies identified Ch12:orf39 (Spexin) as the most down-regulated gene in obese human fat. Therefore, we examined its role in obesity pathogenesis.

Methods: Spexin effects on food intake, meal patterns, body weight, respiratory exchange ratio (RER), and locomotor activity were monitored electronically in C57BL/6J mice or Wistar rats with diet-induced obesity (DIO). Its effects on adipocyte [(3)H]-oleate uptake were determined.

Results: In humans, Spexin gene expression was down-regulated 14.9-fold in obese omental and subcutaneous fat. Circulating Spexin changed in parallel, correlating (r = -0.797) with Leptin. In rats, Spexin (35 µg/kg/day SC) reduced caloric intake ∼32% with corresponding weight loss. Meal patterns were unaffected. In mice, Spexin (25 µg/kg/day IP) significantly reduced the RER at night, and increased locomotion. Spexin incubation in vitro significantly inhibited facilitated fatty acid (FA) uptake into DIO mouse adipocytes. Conditioned taste aversion testing (70 µg/kg/day IP) demonstrated no aversive Spexin effects.

Conclusions: Spexin gene expression is markedly down-regulated in obese human fat. The peptide produces weight loss in DIO rodents. Its effects on appetite and energy regulation are presumably central; those on adipocyte FA uptake appear direct and peripheral. Spexin is a novel hormone involved in weight regulation, with potential for obesity therapy.

Citing Articles

Involvement of central opioid and melanocortin receptors in spexin-induced hypophagia following intracerebroventricular injection in neonatal broiler chicks.

Badri M, Alimohammadi S, Zendehdel M, Hassanpour S BMC Vet Res. 2025; 21(1):110.

PMID: 40011886 PMC: 11863689. DOI: 10.1186/s12917-025-04564-8.

Adiponectin Resistance in Obesity: Adiponectin Leptin/Insulin Interaction.

Engin A Adv Exp Med Biol. 2024; 1460:431-462.

PMID: 39287861 DOI: 10.1007/978-3-031-63657-8_15.

Serum Spexin Level Is Negatively Associated With Peripheral Neuropathy and Sensory Pain in Type 2 Diabetes.

Liu Y, Wu D, Zheng H, Ni Y, Zhu L, Jiang Y J Diabetes Res. 2024; 2024:4538199.

PMID: 38919263 PMC: 11199070. DOI: 10.1155/2024/4538199.

Spexin ameliorated obesity-related metabolic disorders through promoting white adipose browning mediated by JAK2-STAT3 pathway.

Zeng B, Shen Q, Wang B, Tang X, Jiang J, Zheng Y Nutr Metab (Lond). 2024; 21(1):22.

PMID: 38658956 PMC: 11040786. DOI: 10.1186/s12986-024-00790-3.

Role of Spexin in White Adipose Tissue Thermogenesis under Basal and Cold-Stimulated Conditions.

Gambaro S, Zubiria M, Giordano A, Castro P, Garraza C, Harnichar A Int J Mol Sci. 2024; 25(3).

PMID: 38339044 PMC: 10855774. DOI: 10.3390/ijms25031767.

References

Liu Y, Li S, Qi X, Zhou W, Liu X, Lin H . A novel neuropeptide in suppressing luteinizing hormone release in goldfish, Carassius auratus. Mol Cell Endocrinol. 2013; 374(1-2):65-72. DOI: 10.1016/j.mce.2013.04.008. View

Sun H, Malabunga M, Tonra J, DiRenzo R, Carrick F, Zheng H . Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys. Am J Physiol Endocrinol Metab. 2006; 292(3):E964-76. DOI: 10.1152/ajpendo.00089.2006. View

Stump D, Fan X, Berk P . Oleic acid uptake and binding by rat adipocytes define dual pathways for cellular fatty acid uptake. J Lipid Res. 2001; 42(4):509-20. View

Sorrentino D, Robinson R, Kiang C, Berk P . At physiologic albumin/oleate concentrations oleate uptake by isolated hepatocytes, cardiac myocytes, and adipocytes is a saturable function of the unbound oleate concentration. Uptake kinetics are consistent with the conventional theory. J Clin Invest. 1989; 84(4):1325-33. PMC: 329794. DOI: 10.1172/JCI114301. View

Lago F, Gomez R, Gomez-Reino J, Dieguez C, Gualillo O . Adipokines as novel modulators of lipid metabolism. Trends Biochem Sci. 2009; 34(10):500-10. DOI: 10.1016/j.tibs.2009.06.008. View

Liang N, Bello N, Moran T . Experience with activity based anorexia enhances conditioned taste aversion learning in rats. Physiol Behav. 2010; 102(1):51-7. PMC: 2997125. DOI: 10.1016/j.physbeh.2010.10.004. View

Wang Y, Beydoun M . The obesity epidemic in the United States--gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev. 2007; 29:6-28. DOI: 10.1093/epirev/mxm007. View

Tolppanen A, Pulkkinen L, Kolehmainen M, Schwab U, Lindstrom J, Tuomilehto J . Tenomodulin is associated with obesity and diabetes risk: the Finnish diabetes prevention study. Obesity (Silver Spring). 2007; 15(5):1082-8. DOI: 10.1038/oby.2007.613. View

Spector A, Fletcher J, Ashbrook J . Analysis of long-chain free fatty acid binding to bovine serum albumin by determination of stepwise equilibrium constants. Biochemistry. 1971; 10(17):3229-32. DOI: 10.1021/bi00793a011. View

10.

Ma L, Wang D, Zhang T, Yu H, Wang Y, Huang S . Region-specific involvement of BDNF secretion and synthesis in conditioned taste aversion memory formation. J Neurosci. 2011; 31(6):2079-90. PMC: 3044502. DOI: 10.1523/JNEUROSCI.5348-10.2011. View

11.

Berk P . Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome. Hepatology. 2008; 48(5):1362-76. PMC: 2956590. DOI: 10.1002/hep.22632. View

12.

Berk P, Zhou S, Kiang C, Stump D, Fan X, Bradbury M . Selective up-regulation of fatty acid uptake by adipocytes characterizes both genetic and diet-induced obesity in rodents. J Biol Chem. 1999; 274(40):28626-31. DOI: 10.1074/jbc.274.40.28626. View

13.

Allison D, Fontaine K, Manson J, Stevens J, VANITALLIE T . Annual deaths attributable to obesity in the United States. JAMA. 1999; 282(16):1530-8. DOI: 10.1001/jama.282.16.1530. View

14.

Bachman K . Obesity, weight management, and health care costs: a primer. Dis Manag. 2007; 10(3):129-37. DOI: 10.1089/dis.2007.103643. View

15.

Mirabeau O, Perlas E, Severini C, Audero E, Gascuel O, Possenti R . Identification of novel peptide hormones in the human proteome by hidden Markov model screening. Genome Res. 2007; 17(3):320-7. PMC: 1800923. DOI: 10.1101/gr.5755407. View

16.

Vijayakumar A, Wu Y, Sun H, Li X, Jeddy Z, Liu C . Targeted loss of GHR signaling in mouse skeletal muscle protects against high-fat diet-induced metabolic deterioration. Diabetes. 2011; 61(1):94-103. PMC: 3237669. DOI: 10.2337/db11-0814. View

17.

Toll L, Khroyan T, Sonmez K, Ozawa A, Lindberg I, McLaughlin J . Peptides derived from the prohormone proNPQ/spexin are potent central modulators of cardiovascular and renal function and nociception. FASEB J. 2011; 26(2):947-54. PMC: 3290442. DOI: 10.1096/fj.11-192831. View

18.

Porzionato A, Rucinski M, Macchi V, Stecco C, Malendowicz L, De Caro R . Spexin expression in normal rat tissues. J Histochem Cytochem. 2010; 58(9):825-37. PMC: 2924798. DOI: 10.1369/jhc.2010.956300. View

19.

Bray G . Medical consequences of obesity. J Clin Endocrinol Metab. 2004; 89(6):2583-9. DOI: 10.1210/jc.2004-0535. View

20.

Li X, Wu X, Camacho R, Schwartz G, LeRoith D . Intracerebroventricular leptin infusion improves glucose homeostasis in lean type 2 diabetic MKR mice via hepatic vagal and non-vagal mechanisms. PLoS One. 2011; 6(2):e17058. PMC: 3040739. DOI: 10.1371/journal.pone.0017058. View