The Role of AMPK in the Regulation of Appetite and Energy Homeostasis: Role of AMPK in Appetite

Year 2020, Volume: 4 Issue: 1, 25 - 31, 15.07.2020

Ismail Belli Mustafa Yaman

Abstract

Today, excessive nutrition and sedentary life have brought along many chron-ic diseases such as obesity and diabetes. As is known, obesity is a disorder of both energy metabolism and appetite regulation. In re-cent studies, it has been reported that AMPK regu-lates the metabolic energy balance as well as governs appetite control. When AMPK is activated, anabol-ic reactions are inhibited, while catabolic reactions are activated to produce energy. In addition to many pharmacological drugs and nutritional supplements, exercise activates AMPK and enhances the translo-cation of the glucose trans-porter (GLUT4) protein, which provides insulin-independent cellular glu-cose uptake. AMPK is an essential intracellular sensor against obesity because when AMP and LKB1 acti-vate AMPK, the use of body fat stores will be en-couraged to produce energy. Appetite-stimulating and suppressing agents act on AMPK to regulate both food intake and body weight control. When appe-tite suppressors such as leptin, insulin, metformin, inhibit AMPK leucine, and berberine, the expression of orexigenic neuropeptides are decreased while the expression of anorexigenic neuropeptides is increased. Understanding the mecha-nisms controlled by the hypothalamic AMPK is crucial for developing ef-fective nutritional strategies for the treatment of nutri-tional intake disorders such as obesity, diabetes mellitus, cardiovascular disease, hypertension and cancer.

Keywords

AMPK, Food intake, Ghrelin, Leptin, Obesity, Neuropeptides

References

• Bhurosy T, Jeewon R. Overweight and obesity epidemic in developing countries: a problem with diet, physical activity, or socioeconomic status? TheScientificWorldJournal (2014) 2014:964236. doi:10.1155/2014/964236.
• Suzuki K, Jayasena CN, Bloom SR. Obesity and appetite control. Experimental Diabetes Research (2012) 2012:824305. doi:10.1155/2012/824305.
• Lenard NR, Berthoud H-R. Central and peripheral regulation of food intake and physical activity: pathways and genes. Obesity (Silver Spring, Md.) (2008) 16 Suppl 3:S11-22. doi:10.1038/oby.2008.511.
• Kola B, Farkas I, Christ-Crain M, Wittmann G, Lolli F, Amin F, et al. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PloS one (2008) 3(3):e1797. doi:10.1371/journal.pone.0001797.
• Jørgensen SB, Viollet B, Andreelli F, Frøsig C, Birk JB, Schjerling P, et al. Knockout of the α 2 but Not α 1 5′-AMP-activated Protein Kinase Isoform Abolishes 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranosidebut Not Contraction-induced Glucose Uptake in Skeletal Muscle. Journal of Biological Chemistry (2004) 279(2):1070–1079. doi:10.1074/jbc.M306205200.
• Ross FA, Jensen TE, Hardie DG. Differential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms. The Biochemical journal (2016) 473(2):189–199. doi:10.1042/BJ20150910.
• Hardie DG, Hawley SA. AMP-activated protein kinase: the energy charge hypothesis revisited. BioEssays news and reviews in molecular, cellular and developmental biology (2001) 23(12):1112–1119. doi:10.1002/bies.10009.
• Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature reviews. Molecular cell biology (2012) 13(4):251–262. doi:10.1038/nrm3311.
• Hardie DG. AMPK--sensing energy while talking to other signaling pathways. Cell metabolism (2014) 20(6):939–952. doi:10.1016/j.cmet.2014.09.013.
• Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, et al. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell metabolism (2005) 2(1):9–19. doi:10.1016/j.cmet.2005.05.009.
• Moore F, Weekes J, Hardie DG. Evidence that AMP triggers phosphorylation as well as direct allosteric activation of rat liver AMP-activated protein kinase. A sensitive mechanism to protect the cell against ATP depletion. European journal of biochemistry (1991) 199(3):691–697. doi:10.1111/j.1432-1033.1991.tb16172.x.
• Gowans GJ, Hawley SA, Ross FA, Hardie DG. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell metabolism (2013) 18(4):556–566. doi:10.1016/j.cmet.2013.08.019.
• Cordero MD, Viollet B, editors. AMP-Activated Protein Kinase. Berlin/Heidelberg: Springer-Verlag (2011).
• Cheung PCF, Salt IP, Davies SP, Hardie DG, Carling D. Characterization of AMP-activated protein kinase γ-subunit isoforms and their role in AMP binding. Biochemical Journal (2000) 346(3):659. doi:10.1042/0264-6021:3460659.
• Hardie DG, Hawley SA, Scott JW. AMP-activated protein kinase--development of the energy sensor concept. The Journal of physiology (2006) 574(Pt 1):7–15. doi:10.1113/jphysiol.2006.108944.
• Kişmiroğlu C, Cengiz S, Yaman M. AMPK'nin Biyokimyası: Etki Mekanizmaları ve Diyabetin Tedavisindeki Önemi. European Journal of Science and Technology (2020):162–170. doi:10.31590/ejosat.676335.
• O'neill HM. AMPK and exercise: glucose uptake and insulin sensitivity. Diabetes & Metabolism Journal (2013) 37(1):1–21.
• Świderska E, Strycharz J, Wróblewski A, Szemraj J, Drzewoski J, Śliwińska A. Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake. In: Szablewski L, editor. Blood Glucose Levels: IntechOpen (2020).
• Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Current biology CB (2000) 10(20):1247–1255. doi:10.1016/s0960-9822(00)00742-9.
• Halse R, Fryer LGD, McCormack JG, Carling D, Yeaman SJ. Regulation of glycogen synthase by glucose and glycogen: A possible role for AMP-activated protein kinase. Diabetes (2003) 52(1):9–15. doi:10.2337/diabetes.52.1.9.
• Hunter RW, Treebak JT, Wojtaszewski JFP, Sakamoto K. Molecular mechanism by which AMP-activated protein kinase activation promotes glycogen accumulation in muscle. Diabetes (2011) 60(3):766–774. doi:10.2337/db10-1148.
• Koonen DPY, Glatz JFC, Bonen A, Luiken JJFP. Long-chain fatty acid uptake and FAT/CD36 translocation in heart and skeletal muscle. Biochimica et biophysica acta (2005) 1736(3):163–180. doi:10.1016/j.bbalip.2005.08.018.
• Eberlé D, Hegarty B, Bossard P, Ferré P, Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie (2004) 86(11):839–848. doi:10.1016/j.biochi.2004.09.018.
• Madsen A, Bozickovic O, Bjune J-I, Mellgren G, Sagen JV. Metformin inhibits hepatocellular glucose, lipid and cholesterol biosynthetic pathways by transcriptionally suppressing steroid receptor coactivator 2 (SRC-2). Scientific reports (2015) 5:16430. doi:10.1038/srep16430.
• Takeuchi K, Reue K. Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. American Journal of Physiology-Endocrinology And Metabolism (2009) 296(6):E1195-E1209.
• Bruce CR, Hoy AJ, Turner N, Watt MJ, Allen TL, Carpenter K, et al. Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance. Diabetes (2009) 58(3):550–558. doi:10.2337/db08-1078.
• Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD. High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5'-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. The Journal of biological chemistry (1995) 270(29):17513–17520. doi:10.1074/jbc.270.29.17513.
• Ronnebaum SM, Patterson C. The FoxO family in cardiac function and dysfunction. Annual review of physiology (2010) 72:81–94. doi:10.1146/annurev-physiol-021909-135931.
• Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Molecular cell (2008) 30(2):214–226. doi:10.1016/j.molcel.2008.03.003.
• Thupari JN, Landree LE, Ronnett GV, Kuhajda FP. C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity. Proceedings of the National Academy of Sciences of the United States of America (2002) 99(14):9498–9502. doi:10.1073/pnas.132128899.
• Kim CJ, Cho YG, Park JY, Kim TY, Lee JH, Kim HS, et al. Genetic analysis of the LKB1/STK11 gene in hepatocellular carcinomas. European journal of cancer (Oxford, England 1990) (2004) 40(1):136–141. doi:10.1016/s0959-8049(03)00659-2.
• Pocai A, Lam TKT, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. The Journal of clinical investigation (2006) 116(4):1081–1091. doi:10.1172/JCI26640.
• Yamauchi M, Kambe F, Cao X, Lu X, Kozaki Y, Oiso Y, et al. Thyroid Hormone Activates Adenosine 5'-monophosphate-activated Protein Kinase via Intracellular Calcium Mobilization and Activation of calcium/calmodulin-dependent Protein Kinase Kinase-Beta. Molecular Endocrinology (2008) 22:893–903.
• Schwartz MW. Progress in the search for neuronal mechanisms coupling type 2 diabetes to obesity. The Journal of clinical investigation (2001) 108(7):963–964. doi:10.1172/JCI14127.
• Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature (2006) 443(7109):289–295. doi:10.1038/nature05026.
• Ropelle ER, Pauli JR, Zecchin KG, Ueno M, Souza CT de, Morari J, et al. A central role for neuronal adenosine 5'-monophosphate-activated protein kinase in cancer-induced anorexia. Endocrinology (2007) 148(11):5220–5229. doi:10.1210/en.2007-0381.
• Minokoshi Y, Alquier T, Furukawa N, Kim Y-B, Lee A, Xue B, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature (2004) 428(6982):569–574. doi:10.1038/nature02440.
• Lage R, Diéguez C, Vidal-Puig A, López M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends in molecular medicine (2008) 14(12):539–549. doi:10.1016/j.molmed.2008.09.007.
• Cohen Jr MM. Role of leptin in regulating appetite, neuroendocrine function, and bone remodeling. American Journal of Medical Genetics Part A (2006) 140(5):515–524.
• Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature (1998) 395(6704):763–770. doi:10.1038/27376.
• Muoio DM, Dohm GL, Fiedorek FT, Tapscott EB, Coleman RA, Dohn GL. Leptin directly alters lipid partitioning in skeletal muscle. Diabetes (1997) 46(8):1360–1363. doi:10.2337/diab.46.8.1360.
• Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature (1997) 389(6649):374–377.
• Unger RH, Zhou YT, Orci L. Regulation of fatty acid homeostasis in cells: novel role of leptin. In: Proceedings of the National Academy of Sciences (1996). p. 2327–2332.
• Minokoshi Y, Kim Y-B, Peroni OD, Fryer LGD, Müller C, Carling D, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature (2002) 415(6869):339–343. doi:10.1038/415339a.
• Hussain Z, Khan JA. Food intake regulation by leptin: Mechanisms mediating gluconeogenesis and energy expenditure. Asian Pacific journal of tropical medicine (2017) 10(10):940–944. doi:10.1016/j.apjtm.2017.09.003.
• Mountjoy PD, Bailey SJ, Rutter GA. Inhibition by glucose or leptin of hypothalamic neurons expressing neuropeptide Y requires changes in AMP-activated protein kinase activity. Diabetologia (2006) 50(1):168–177. doi:10.1007/s00125-006-0473-3.
• Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, et al. AMP-activated protein kinase plays a role in the control of food intake. The Journal of biological chemistry (2004) 279(13):12005–12008. doi:10.1074/jbc.C300557200.
• Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. Journal of Biological Chemistry (2005) 280(26):25196–25201.
• Kohno D, Sone H, Minokoshi Y, Yada T. Ghrelin raises Ca2+i via AMPK in hypothalamic arcuate nucleus NPY neurons. Biochemical and biophysical research communications (2008) 366(2):388–392. doi:10.1016/j.bbrc.2007.11.166.
• Woods A, Dickerson K, Heath R, Hong S-P, Momcilovic M, Johnstone SR, et al. Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell metabolism (2005) 2(1):21–33. doi:10.1016/j.cmet.2005.06.005.
• Williams CM, Kirkham TC. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology (1999) 143(3):315–317. doi:10.1007/s002130050953.
• Christ-Crain M, Kola B, Lolli F, Fekete C, Seboek D, Wittmann G, et al. AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing's syndrome. FASEB journal official publication of the Federation of American Societies for Experimental Biology (2008) 22(6):1672–1683. doi:10.1096/fj.07-094144.
• Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell metabolism (2007) 6(1):55–68. doi:10.1016/j.cmet.2007.06.003.
• Cavaliere G, Viggiano E, Trinchese G, Filippo C de, Messina A, Monda V, et al. Long Feeding High-Fat Diet Induces Hypothalamic Oxidative Stress and Inflammation, and Prolonged Hypothalamic AMPK Activation in Rat Animal Model. Frontiers in physiology (2018) 9:818. doi:10.3389/fphys.2018.00818.
• Cavadas C, Aveleira CA, Souza GFP, Velloso LA. The pathophysiology of defective proteostasis in the hypothalamus - from obesity to ageing. Nature reviews. Endocrinology (2016) 12(12):723–733. doi:10.1038/nrendo.2016.107.
• Pimentel GD, Lira FS, Rosa JC, Oliveira JL, Losinskas-Hachul AC, Souza GIH, et al. Intake of trans fatty acids during gestation and lactation leads to hypothalamic inflammation via TLR4/NFκBp65 signaling in adult offspring. The Journal of nutritional biochemistry (2012) 23(3):265–271. doi:10.1016/j.jnutbio.2010.12.003.
• Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes/metabolism research and reviews (2010) 26(7):540–549. doi:10.1002/dmrr.1114.
• Gizlici MN. Diabetes Mellitus ve Çinko İlişkisi. Turkish Journal of Diabetes and Obesity (2019) 3(2):107–113. doi:10.25048/tjdo.2019.48.
• Ewart M-A, Kennedy S. AMPK and vasculoprotection. Pharmacology & Therapeutics (2011) 131(2):242–253. doi:10.1016/j.pharmthera.2010.11.002.
• Zang M, Zuccollo A, Hou X, Nagata D, Walsh K, Herscovitz H, et al. AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. The Journal of biological chemistry (2004) 279(46):47898–47905. doi:10.1074/jbc.M408149200.
• Shaw RJ, Lamia KA, Vasquez D, Koo S-H, Bardeesy N, Depinho RA, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science (New York, N.Y.) (2005) 310(5754):1642–1646. doi:10.1126/science.1120781.
• Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA (2005) 293(1):43–53. doi:10.1001/jama.293.1.43.
• Ropelle ER, Pauli JR, Fernandes MFA, Rocco SA, Marin RM, Morari J, et al. A central role for neuronal AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in high-protein diet-induced weight loss. Diabetes (2008) 57(3):594–605. doi:10.2337/db07-0573.
• Catania C, Binder E, Cota D. mTORC1 signaling in energy balance and metabolic disease. International journal of obesity (2005) (2011) 35(6):751–761. doi:10.1038/ijo.2010.208.
• Cota D, Matter EK, Woods SC, Seeley RJ. The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. The Journal of neuroscience the official journal of the Society for Neuroscience (2008) 28(28):7202–7208. doi:10.1523/JNEUROSCI.1389-08.2008.
• Xu G, Kwon G, Cruz WS, Marshall CA, McDaniel ML. Metabolic Regulation by Leucine of Translation Initiation Through the mTOR-Signaling Pathway by Pancreatic -Cells. Diabetes (2001) 50(2):353–360. doi:10.2337/diabetes.50.2.353.
• Cao Z-P, Wang F, Xiang X-S, Cao R, Zhang W-B, Gao S-B. Intracerebroventricular administration of conjugated linoleic acid (CLA) inhibits food intake by decreasing gene expression of NPY and AgRP. Neuroscience letters (2007) 418(3):217–221. doi:10.1016/j.neulet.2007.03.010.
• Liu J. The Effects and Mechanisms of Mitochondrial Nutrient α-Lipoic Acid on Improving Age-Associated Mitochondrial and Cognitive Dysfunction: An Overview. Neurochemical Research (2008) 33(1):194–203. doi:10.1007/s11064-007-9403-0.
• Kim WS, Lee YS, Cha SH, Jeong HW, Choe SS, Lee M-R, et al. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. American journal of physiology. Endocrinology and metabolism (2009) 296(4):E812-9. doi:10.1152/ajpendo.90710.2008.