NEUROADIPOCRINOLOGY OF DIABESITY
Abstract
Today’s achievements in systems biology and -omics sciences have facilitated a move from studying individual molecule and tissue to characterizing molecules and cells holistically. Here we make an attempt to discuss the status of a much-needed coherent view that integrates studies on neurobiology and adipobiology as well as those on diabetes and obesity. Globally, cardiometabolic diseases (atherosclerosis, hypertension, type 2 diabetes mellitus, obesity, diabesity, and metabolic syndrome) are most prevalent pathologies at present. In 2000 Astrup and Finer (Obes Rev 1: 57-59) wrote: “Since type 2 diabetes is obesity dependent, and obesity is the main aetiogical cause of type 2 diabetes, we propose the term 'diabesity' should be adopted” Arguably, the research field of adipobiology has witnessed three major paradigm shifts since the discovery of leptin, an adipose-derived hormone, in 1994. Various neuroendocrine and neurotrophic factors were also included in the increasing list of endocrine and paracrine adipose-secreted signaling proteins collectively designated adipokines. These findings open a novel field of research, neuroadipocrinology, a component of neuroendocrinology. Adipokines, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), mediate multiple biological processes such as food intake, immunity, inflammation, memory, mood, and metabolism. The effects on metabolism involve the maintenance of glucose, lipid and energy homeostasis, also cardioprotection, neuroprotection, and ageing. Here we highlight the role of metabotrophic factors (MTF), adipose- and nonadipose-derived biomolecules which mediate these effects. Recent results demonstrate that the circulating and/or tissue levels of some MTF, e.g. adiponectin, NGF, BDNF, glucagon-like protein-1, sirtuin-1, interleukin-10, aquaporin-7, are altered in cardiometabolic diseases, including diabesity. Overall, this may cultivate a novel thinking for diabesity, herein also referred to as Homo diabesus.
Key words: adipobiology, adipokines, diabetes, obesity, neurobiology, NGF, BDNF, metabotrophins
References
Williams G, Frühbeck G. Obesity: Science to Practice. 2009 John Wiley & Sons, Ltd, UK.
Chaldakov GN, Fiore M, Tonchev AB, Dimitrov D, Pancheva R, Rančič G, Aloe L. Homo obesus: a metabotrophin-deficient species. Pharmacology and nutrition insight. Curr Pharm Des 2007; 13: 2176-2179.
Farag YM, Gaballa MR. Diabesity: an overview of a rising epidemic. Mephrol Dial Transplant 2011;26:28-35. doi: 10.1093/ndt/gfq576
Aloe L, Tonchev AB, Fiore M, Chaldakov GN. Homo diabesus: involvement of metabotrophic factors. Adipobiology 2013; 5: 45-49.
Louise TE, Saeed N, Hajnal JV, Brynes A,Goldstone AP, FrostG, et al. Magnetic resonance imaging of total body fat. J Appl Physiol 1998; 85: 1778-1785.
Jin C, Flavell RA. Innate sensors of pathogen and stress: linking inflammation to obesity. J Allergy Clin Immunol 2013; 132:287-294. doi:10.1016/j.jaci.2013. 06.022
Sacks H, Symonds ME. Anatomical locations of human brown adipose tissue functional relevance and implications in obesity and type 2 diabetes. Diabetes 2013; 62:1783-1790.
Giralt M, Villarrova F. White, brown, beige/brite: different adipose cells for different functions? Endocrinology 2013; 154:2992-3000. doi: 10.1210/en.2013-1403.
Chaldakov GN, Stankulov IS, Hristova M, Ghenev PI. Adipobiology of disease: adipokines and adipokine-targeted pharmacology. Curr Pharm Des 2003; 9: 1023-1031.
Chaldakov GN. Cardiovascular adipobiology: a novel. Heart-associated adipose tissue in cardiovascular disease. Ser J Exp Clin Res 2008; 9:81-88.
Renes J, Mariman E. Application of proteomics technology in adipocyte biology. Mol Biosyst 2013; 9:1076-1091.
Chaldakov GN, Tonchev AB, Fiore M, Hristova MG, Pancheva R, Rancic G, Aloe L.
Sornelli F, Fiore M, Chaldakov GN, Aloe L. Adipose tissue-derived nerve growth factor and brain-derived neurotrophic factor: results from experimental stress and diabetes. Gen Physiol Biophys 2009; 28:179-183.
Levi-Montalcini R. The nerve growth factor 35 years later. Science 1987; 237:1154–1162. doi:10.1126/science.3306916
Yanev S, Aloe L, Fiore F, Chaldakov GN. Neurotrophic and metabotrophic potential of nerve growth factor and brain-derived neurotrophic factor: Linking cardiometabolic and neuropsychiatric diseases. World J Pharmacol 2013; 2: 92-99.
Chaldakov GN. The metabotrophic NGF and BDNF: an emerging concept. Arch Ital Biol 2011;149: 257-263.
Gomez-Pinilla F, Vaynman S, Ying Z. Brain-derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition. Eur J Neurosci 2008; 28: 2278-2287. doi: 10.1111/j.1460-9568.2008.06524.x
Hiriart-Urdanivia M, Tableros VN, Velasco M, Larqué C, Cabrera-Vásquez S, Soto CS, et al. Insulin regulation in development and obesity. In: M. Hiriart-Urdanivia and J. Mas-Oliva, editrors. Advances in Obesity-diabetes Research at UNAM (Universidad Nacional Autónoma de México). Manual Moderno, México D.F., Bogotá, DC. 2010; pp 69-79.
Chaldakov GN, Fiore M, Stankulov IS, Manni L, Hristova MG, Antonelli A, et al. Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardiovascular disease? Prog Brain Res 2004; 146: 279-289. doi: 10.1016/S0079-6123(03)46018-4
Yamanaka M, Itakura Y, Ono-Kishino M, Tsuchida A, Nakagawa T, Taiji M. Intermittent administration of brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism and prevents pancreatic exhaustion in diabetic mice. J Biosci Bioeng 2008; 105: 395-402. doi: 10.1263/jbb.105.395
de la Monte S, Wands JR. Alzheimer’s disease is type 3 diabetes – evidence reviewed. J Diabetes Sci Technol 2008; 2: 1101-1113.
Chaldakov GN, Tunçel N, Beltowski J, Fiore M, Ranćić G, Tonchev A, et al Adipoparacrinology: an emerging field in biomedical research. Balkan Med J 2012; 29: 2-9. doi: 10.5152/balkanmedj.2012.022
Chaldakov GN, Fiore M, Ghenev PI, Beltowski J, Rancic G, Tunçel N, Aloe L. Triactome: neuro-immune-adipose interactions. Implication in vascular biology. Front Immunol 2014; 5:130. doi: 10.3389/fimmu.2014.00130
Chaldakov GN, Fiore M, Tonchev AB, Aloe L..Neuroadipology: a novel component of neuroendocrinology. Cell Biol. Int 2010; 34: 1051–1053.
Manni L, Nikolova V, Vyagova D, Chaldakov GN, Aloe L. Reduced plasma levels of NGF and BDNF in patients with acute coronary syndromes. Int J Cardiol 2005; 102:169-171.
Ejiri J, Inoue N, Kobayashi S, Shiraki R, Otsui K, Honjo T, et al. Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease. Circulation 2005; 112: 2114-2120.
Sposato V, Manni L, Chaldakov GN, Aloe L. Streptozotocin-induced diabetes is associated with changes in NGF levels in pancreas and brain. Arch Ital Biol 145: 87-97, 2007.
Larrieta ME, Vital P, Mendoza-Rodriguez A, Cerbón M, Hiriart M. Nerve growth factor increases in pancreatic beta cells after streptozotocin-induced damage in rats. Exp Biol Med (Maywood) 2006; 231: 396-402.
Hoang PT, Park P, Cobb LJ, Paharkova-Vatchkova V, Hakimi M, Cohen P, et al. The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice. Metabolism 2010; 59:343-349. doi: 10.1016/j.metabol.2009.08.001.
Mahboobi H, Golmirzaei J, Gan SH, Jalalian M, Jalalian M. Humanin: a possible linkage between Alzheimer's disease and type 2 diabetes. CNS Neurol Disord Drug Targets 2013 Dec 22. [Epub ahead of print].
Novelle MG, Contreras C, Romero-Picó A, López M, Diéguez C. Irisin, two years later. Int J Endocrinol 2013; 2013:746281.
Spiegelman BM. Banting Lecture 2012: Regulation of adipogenesis: toward new therapeutics for metabolic disease. Diabetes 2013; 62:1774-1782. doi: 10.2337/db12-1665.
Perry T, Lahiri DK, Chen D, Zhou J, Shaw KT, Egan JM, et al. A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther 2002; 300:958-966.
Li L. Is glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer’s disease? Neurosci Bull 2007; 23: 58-65. doi: 10.1007/s12264-007-0009-y
Prior M, Dargusch R, Ehren JL, Chiruta C, Schubert D. The neurotrophic compound J147 reverses cognitive impairment aged Alzheimer's disease mice. Alzheimers Res Ther 2013; 5: 25. doi: 10.1186/alzrt179
Ferenz KB, Rose K, König S, Krieglstein J. ATP-NGF-complex, but not NGF, is the neuroprotective ligand. Neurochem Int 2011; 59: 989-995. doi: 10.1016/j.neuint.2011.08.020
Liu J, Li JD, Lu J, Xing J, Li J. Contribution of nerve growth factor to upregulation of P2X₃ expression in DRG neurons of rats with femoral artery occlusion. Am J Physiol Heart Circ Physiol 2011; 301: H1070-H1079 doi: 10.1152/ajpheart.00188.2011
Yoo DY, Kim W, Nam SM, Yoo KY, Lee CH, Choi JH, Won MH, Hwang IK, Yoon YS. Reduced cell proliferation and neuroblast differentiation in the dentate gyrus of high fat diet-fed mice are ameliorated by metformin and glimepiride treatment. Neurochem Res 2011; 36: 2401-2408. doi: 10.1007/s11064-011-0566-3
Hernández-Pedro N, Granados-Soto V, Ordoñez G, Pineda B, Rangel-López E, Salazar-Ramiro A, et al. Vitamin A increases nerve growth factor and retinoic acid receptor beta and improves diabetic neuropathy in rats. Trans Res 2014; S1931-5244(14). doi: 10.1016/j.trsl.2014.04.002
Rabe T, Shamsi F, Mansouri A. The roles of microRNAs in pancreas development and regeneration. Biomed Rev 2013; 24: 57-65.
Mortuza R, Feng B, Chakrabarti S. miR-195 regulates SIRT1-mediated changes in diabetic retinopathy. Diabetologia 2014; 57:1037-1046. doi: 10.1007/s00125-014-3197-9.
Cyr NE, Steger JS, Toorie AM, Yang JZ, Stuart R, Nillni EA. Central Sirt1 regulates body weight and energy expenditure along with the POMC-derived peptide α-MSH and the processing enzyme CPE production in diet-induced obesity male rats. Endocrinology 2014 Apr 28: en20131998.
Iacobellis G, Di Gioia C, Petramala L, Chiappetta C, Serra V, Zinnamosca L, et al. Brown fat expresses adiponectin in humans. Int J Endocrinol 2013; 2013:126751. doi: 10.1155/2013/126751.
Tan BK, Adya R, Randeva HS. Omentin: a novel link between inflammation, diabesity, and cardiovascular disease. Trends Cardiovasc Med 2010; 20:143-148. doi: 10.1016/j.tcm.2010.12.002.
Castan-Laurell I, Dray C, Attané C, Duparc T, Knauf C, Valet P. Apelin, diabetes, and obesity. Endocrine 2011; 40:1-9. doi: 10.1007/s12020-011-9507-9.
Wang GX, Cho KW, Uhm M, Hu CR, Li S, Cozacov Z, et al. Otopetrin 1 protects mice from obesity-associated metabolic dysfunction through attenuating adipose tissue inflammation. . Diabetes 2013 Dec 30. [Epub ahead of print]
Karatzas A, Katsanos K, Lilis I, Papadaki H, Kitrou P, Lecht S, et al. NGF promotes hemodynamic recovery in a rabbit hindlimb ischemic model through trkA- and VEGFR2-dependent pathways. J Cardiovasc Pharmacol 2013; 62:270-277. doi: 10.1097/FJC.0b013e3182982de7.
Aloe L, Tirassa P, Lambiase A. The topical application of nerve growth factor as a
Schäffler A, Schölmerich J, Buechler C. The role of ”adipotrophins” and the clinical importance of a potential hypothalamic-pituitary-adipose axis. Nat Clin Pract Endocrinol Metab 2006; 2:374-383.
Hausman GJ, Barb CR, Dean RG. Patterns of gene expression in pig adipose tissue: insulin-like growth factor system proteins, neuropeptide Y (NPY), NPY receptors, neurotrophic factors and other secreted factors. Domest Anim Endocrinol 2008;35:24–34.
Rao AA. Views and opinion on BDNF as a target for diabetic cognitive dysfunction.
Meek TH, Wisse BE, Thaler JP, Guyenet SJ, Matsen ME, Fischer JD, et al. BDNF action in the brain attenuates diabetic hyperglycemia via insulin-independent inhibition of hepatic glucose production. Diabetes 2013; 62: 1512-1518. doi: 10.2337/db12-0837
Byerly MS, Swanson RD, Semsarzadeh NN, McCulloh PS, Kwon K, Aja S, et al. Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite. Am J Physiol Regul Integr Comp Physiol 2013; 304: R1085-R1095. doi: 10.1152/ajpregu.00368.2012
Kostopoulos CG, Spiroglou SG, Varakis JN, Apostolakis E, Papadaki HH. Adiponectin/T-cadherin and apelin/APJ expression in human arteries and periadventitial fat: implication of local adipokine signaling in atherosclerosis? Cardiovasc Pathol 2014; doi:
Bouckenooghe T, Sisino G, Aurientis S, Chinetti-Gbaguidi G, Kerr-Conte J, Staels B, , et al. Adipose tissue macrophages (ATM) of obese patients are releasing increased levels of prolactin during an inflammatory challenge: a role for prolactin in diabesity? Biochim Biophys Acta 2014; 1842:584-593. doi: 10.1016/j.bbadis.2013.12.005.
Benga G, Popescu O, Pop VI, Holmes RP. p-(Chloromercuri)benzenesulfonate binding by membrane proteins and the inhibition of water transport in human erythrocytes. Biochemistry 1986; 25: 1535–1538. doi:10.1021/bi00355a011
Benga G. Aquaporin-7 and adipose tissue. Biomed Rev 2006; 17: 102-108.
Frühbeck G, Catalan V, Gomes-Ambrosi J, Rodriguez A. Aquaporin-7 and glycerol permeability as novel obesity drug-traget pathwas. Trends Pharmacol Sci 2006; 27: 345-347.
Jackson HM, Soto I, Graham LC, Carter GW, Howell GR. Clustering of transcriptional profiles identifies changes to insulin signaling as an early event in a mouse model of Alzheimer’s disease. BMC Genomics 2013 14:831. doi:10.1186/1471-2164-14-831
Luchsinger JA, Mayeux R. Adiposity and Alzheimer’s disease. Curr Alzheimer Res 2007; 4: 127-134. doi: 10.2174/156720507780362100
Naderali EK, Ratcliffe SH, Dale MC. Review: obesity and Alzheimer's disease: a link between body weight and cognitive function in old age. Am J Alzheimers Dis Other Demen 2009; 24:445-449.
Frisardi V, Solfrizzi V, Seripa D, Capurso C, Santamato A, Sancarlo D, et al. Metabolic-cognitive syndrome: A cross-talk between metabolic syndrome and Alzheimer’s disease. Ageing Res Rev 2010; 9:399-417.
O'Neill C, Kiely AP, Coakley MF, Manning S, Long-Smith CM. Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease. Biochem Soc Trans 2012; 40:721-727.
de la Monte SM. Brain insulin resistance and deficiency as therapeutic targets in Alzheimer's disease. Curr Alzheimer Res 2012; 9:35-66.
Hildreth KL, Van Pelt RE, Schwartz RS. Obesity, insulin resistance, and Alzheimer's disease. Obesity 2012; 20:1549-1557.
Passaro A, Dalla Nora E, Morieri ML, Soavi C, Sanz JM, Zurlo A, et al. Brain-derived neurotrophic factor plasma levels: Relationship with dementia and diabetes in the elderly population. J Gerontol A Biol Sci Med Sci 2014 Mar 12. [Epub ahead of print]
Li Z, Zhang C, Fan J, Yuan C, Huang J, Chen J, et al. Brain-derived neurotrophic factor levels and bipolar disorder in patients in their first depressive episode: 3-year prospective longitudinal study. Br J Psychiatry 2014; doi:10.1192/bjp.bp.113.134064