Abstract
Metformin (MF), a first-line drug in the treatment of diabetes mellitus, has been used in recent years to treat obesity. Its therapeutic effect is due not only to the influence on the peripheral tissues but also on the hypothalamus, which controls food behavior and energy metabolism. The goal was to study the effect of MF therapy (200 mg/kg/day, 8 weeks) in rats with obesity caused by a high-carbohydrate and high-fat diet on metabolic and hormonal parameters and the functional state of the hypothalamic signaling systems. MF treatment of obese rats (the group ObM) normalized food behavior; reduced the body weight and fat weight and the glucose, insulin, and leptin levels; increased sensitivity to glucose and insulin; improved the lipid metabolism; and restored Ser473 phosphorylation of Akt kinase in the liver. In the hypothalamus, the stimulating effects of agonists of type-4 melanocortin receptor and type-1 dopamine receptor on adenylyl cyclase (AC) were partially restored, the inhibitory effect on AC of agonists of subtype-1B serotonin receptor (5-HT1BR) increased (which was associated with an increase in Htr1b gene expression), and the stimulating effect of the 5-HT6R agonist EMD-386088 normalized. At the same time, the differences in the activity of the leptin and insulin systems and the ratio of anorexigenic and orexigenic factors in the hypothalamus of the rat groups Ob and ObM were insignificant. Thus, MF treatment changes the functional activity of the hypothalamic melanocortin, dopamine, and serotonin systems in obese rats, which is one way to decrease their food intake and to restore the metabolic parameters and insulin sensitivity.
Similar content being viewed by others
REFERENCES
Derkach, K.V., Ivantsov A.O., Chistyakova, O.V., Sukhov I.B., Buzanakov D.M., Kulikova A.A., and Shpakov, A.O., Intranasal insulin restores metabolic parameters and insulin sensitivity in rats with metabolic syndrome, Bull. Exp. Biol. Med., 2017, vol. 163, no. 2, pp. 184–189.
Sukhov I.B., Derkach, K.V., Chistyakova, O.V., Bondareva V.M., and Shpakov, A.O., Functional state of hypothalamic signaling systems in rats with type 2 diabetes mellitus treated with intranasal insulin, J. Evol. Biochem. Physiol., 2016, vol. 52, no. 3, pp. 204–216.
Shpakov, A.O., Functional activity of the insulin signaling system of the brain in health and type 2 diabetes mellitus, Neurosci. Behav. Physiol., 2017, vol. 47, no. 2, pp. 190–203.
Shpakov, A.O., The brain leptin signaling system and its functional state in metabolic syndrome and type 2 diabetes mellitus, J. Evol. Biochem. Physiol., 2016, vol. 52, no. 3, pp. 177–195.
Shpakov, A.O. and Derkach, K.V., Molecular mechanisms of influence of metformin on the functional activity of brain neurons, Ross. Fiziol. Zh. im. I.M. Sechenova, 2017, vol. 103, no. 5, pp. 504–517.
Banks, W.A. and Farrell, C.L., Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible, Am. J. Physiol., 2003, vol. 285, no. 1, pp. 10–15.
Cakir, I., Cyr, N.E., Perello, M., et al., Obesity induces hypothalamic endoplasmic reticulum stress and impairs proopiomelanocortin (POMC) post-translational processing, J. Biol. Chem., 2013, vol. 288, no. 24, pp. 17675–17688.
Derkach, K.V., Bogush, I.V., Berstein, L.M., and Shpakov, A.O., The influence of intranasal insulin on hypothalamic-pituitary-thyroid axis in normal and diabetic rats, Horm. Metab. Res., 2015, vol. 47, no. 12, pp. 916–924.
Derkach, K.V., Bondareva, V.M., Chistyakova, O.V., et al., The effect of long-term intranasal serotonin treatment on metabolic parameters and hormonal signaling in rats with high-fat diet/low-dose streptozotocin- induced type 2 diabetes, Int. J. Endocrinol., 2015, vol. 2015, art. ID 245459. doi 10.1155/2015/245459
Doslikova, B., Garfield, A.S., Shaw, J., et al., 5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist co-application: an effect mediated via increased proportion of pro-opiomelanocortin neurons activated, J. Neurosci., 2013, vol. 33, no. 23, pp. 9800–9804.
El-Haschimi, K., Pierroz, D.D., Hileman, S.M., et al., Two defects contribute to hypothalamic leptin resistance in mice with dietinduced obesity, J. Clin. Invest., 2000, vol. 105, pp. 1827–1832.
Foretz, M., Guigas, B., Bertrand, L., et al., Metformin: from mechanisms of action to therapies, Cell Metab., 2014, vol. 20, no. 6, pp. 953–966.
Franco, R., Martínez-Pinilla, E., Lanciego, J.L., and Navarro, G., Basic pharmacological and structural evidence for Class A G-protein-coupled receptor heteromerization, Front. Pharmacol., 2016, vol. 7, p. 76.
Hawley, S.A., Ross, F.A., Chevtzoff, C., et al., Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation, Cell Metab., 2010, vol. 11, no. 6, pp. 554–565.
Heisler, L.K., Jobst, E.E., Sutton, G.M., et al., Serotonin reciprocally regulates melanocortin neurons to modulate food intake, Neuron, 2006, vol. 51, no. 2, pp. 239–249.
Higgs, S., Cooper, A.J., and Barnes, N.M., The 5‑HT2C receptor agonist, lorcaserin, and the 5-HT6 receptor antagonist, SB-742457, promote satiety; a microstructural analysis of feeding behavior, Psychopharmacology (Heidelberg), 2016, vol. 233, no. 3, pp. 417–424.
Hostalek, U., Gwilt, M., and Hildemann, S., Therapeutic use of metformin in prediabetes and diabetes prevention, Drugs, 2015, vol. 75, no. 10, pp. 1071–1094.
Hou, M., Venier, N., Sugar, L., et al., Protective effect of metformin in CD1 mice placed on a high carbohydrate-high fat diet, Biochem. Biophys. Res. Commun., 2010, vol. 397, no. 3, pp. 537–542.
Igel, L.I., Sinha, A., Saunders, K.H., et al., Metformin: an old therapy that deserves a new indication for the treatment of obesity, Curr. Atheroscler. Rep., 2016, vol. 18, no. 4, pp. 16. doi 10.1007/s11883–016–0568–3
López, M., EJE PRIZE 2017: Hypothalamic AMPK: a golden target against obesity?, Eur. J. Endocrinol., 2017, vol. 176, no. 5, pp. 235–246.
López, M., Nogueiras, R., Tena-Sempere, M., and Diéguez, C., Hypothalamic AMPK: a canonical regulator of whole-body energy balance, Nat. Rev. Endocrinol., 2016, vol. 12, no. 7, pp. 421–432.
Lv, W.S., Wen, J.P., Li L., et al., The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats, Brain Res., 2012, vol. 1444, pp. 11–19.
Matsui, Y., Hirasawa, Y., Sugiura, T., et al., Metformin reduces body weight gain and improves glucose intolerance in high-fat diet-fed C57BL/6J mice, Biol. Pharm. Bull., 2010, vol. 33, no. 6, pp. 963–970.
Paolisso, G., Amato, L., Eccellente, R., et al., Effect of metformin on food intake in obese subjects, Eur. J. Clin. Invest., 1998, vol. 28, no. 6, pp. 441–446.
Perreault, M.L., Hasbi, A., O’Dowd, B.F., and George, S.R., Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance, Neuropsychopharmacology, 2014, vol. 39, no. 1, pp. 156–168.
Sakai, G., Inoue, I., Suzuki, T., et al., Effects of the activation of three major hepatic Akt substrates on glucose metabolism in male mice, Endocrinology, 2017, vol. 158, no. 8, pp. 2659–2671.
Seifarth, C., Schehler, B., and Schneider, H.J., Effectiveness of metformin on weight loss in non-diabetic individuals with obesity, Exp. Clin. Endocrinol. Diabetes, 2013, vol. 121, no. 1, pp. 27–31.
Shpakov, A.O., Derkach, K.V., and Berstein, L.M., Brain signaling systems in the type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases, Future Sci. OA, 2015, vol. 1, no. 3, p. FSO25. doi 10.4155/fso.15.23
Stevanovic, D., Janjetovic, K., Misirkic, M., et al., Intracerebroventricular administration of metformin inhibits ghrelin-induced hypothalamic AMP-kinase signaling and food intake, Neuroendocrinology, 2012, vol. 96, no. 1, pp. 24–31.
Yang, X., Xu, Z., Zhang, C., et al., Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells, Biochim. Biophys. Acta, 2017, vol. 1863, no. 8, pp. 1984–1990.
ACKNOWLEDGMENTS
The work was supported by the Russian Science Foundation (project no. 16-15-10388).
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated by E. Sherstyuk
Rights and permissions
About this article
Cite this article
Derkach, K.V., Sukhov, I.B., Bondareva, V.M. et al. Effect of Metformin on Metabolic Parameters and Hypothalamic Signaling Systems in Rats with Obesity Induced by a High-Carbohydrate and High-Fat Diet. Adv Gerontol 8, 228–234 (2018). https://doi.org/10.1134/S2079057018030037
Published:
Issue Date:
DOI: https://doi.org/10.1134/S2079057018030037