Brain Signaling Systems in the Type 2 Diabetes and Metabolic Syndrome: Promising Target to Treat and Prevent These Diseases

References

• Robertson RP , HarmonJ, TranPO, PoitoutV. Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in Type 2 diabetes. Diabetes53(Suppl. 1), S119–S124 (2004).
   PubMed Web of Science ®Google Scholar
• Lencioni C , LupiR, Del PratoS. Beta-cell failure in Type 2 diabetes mellitus. Curr. Diab. Rep.8, 179–184 (2008).
   PubMed Web of Science ®Google Scholar
• Larsen MO . Beta-cell function and mass in Type 2 diabetes. Dan. Med. Bull.56, 153–164 (2009).
   PubMedGoogle Scholar
• Montgomery MK , TurnerN. Mitochondrial dysfunction and insulin resistance: an update. Endocr. Connect.4, R1–R15 (2015).
   PubMed Web of Science ®Google Scholar
• Nowotny K , JungT, HöhnA, WeberD, GruneT. Advanced glycation end products and oxidative stress in Type 2 diabetes mellitus. Biomolecules5, 194–222 (2015).
   PubMed Web of Science ®Google Scholar
• Taskinen MR , BorénJ. New insights into the pathophysiology of dyslipidemia in Type 2 diabetes. Atherosclerosis239, 483–495 (2015).
   PubMed Web of Science ®Google Scholar
• Zhang X , ZhangG, ZhangH, KarinM, BaiH, CaiD. Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell135, 61–73 (2008).
   PubMed Web of Science ®Google Scholar
• Martinez de Morentin PB , VarelaL, Fern⊘J, NogueirasR, DiéguezC, LópezM. Hypothalamic lipotoxicity and the metabolic syndrome. Biochim. Biophys. Acta1801, 350–361 (2010).
   PubMed Web of Science ®Google Scholar
• Purkayastha S , ZhangH, ZhangG, AhmedZ, WangY, CaiD. Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress. Proc. Natl Acad. Sci. USA108, 2939–2944 (2011).
   PubMed Web of Science ®Google Scholar
• Shpakov AO , DerkachKV. The functional state of hormone-sensitive adenylyl cyclase signaling system in diabetes mellitus. J. Signal Transd. 2013, 594213 (2013).
   PubMedGoogle Scholar
• Cole AR , AstellA, GreenC, SutherlandC. Molecular connexions between dementia and diabetes. Neurosci. Biobehav. Rev.31, 1046–1063 (2007).
   PubMed Web of Science ®Google Scholar
• de la Monte SM . Insulin resistance and Alzheimer's disease. BMB Rep.42, 475–481 (2009).
   PubMed Web of Science ®Google Scholar
• de la Monte SM , TongM, NguyenV, SetshediM, LongatoL, WandsJR. Ceramide-mediated insulin resistance and impairment of cognitive-motor functions. J. Alzheimers Dis.21, 967–984 (2010).
   PubMed Web of Science ®Google Scholar
• Shpakov AO . Alterations in hormonal signaling systems in diabetes mellitus: origin, causality and specificity. Endocrinol. Metab. Syndr.1, https://doi.org/10.4172/2161-1017.1000e106 (2012).
   Google Scholar
• Kim B , FeldmanEL. Insulin resistance in the nervous system. Trends Endocrinol. Metab.23, 133–141 (2012).
   PubMed Web of Science ®Google Scholar
• Obici S , ZhangBB, KarkaniasG, RossettiL. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med.8, 1376–1382 (2002).
   PubMed Web of Science ®Google Scholar
• Gelling RW , MortonGJ, MorrisonCDet al. Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metab.3, 67–73 (2006).
   PubMed Web of Science ®Google Scholar
• Morton GJ . Hypothalamic leptin regulation of energy homeostasis and glucose metabolism. J. Physiol.583, 437–443 (2007).
   PubMed Web of Science ®Google Scholar
• Meek TH , MortonGJ. Leptin, diabetes, and the brain. Indian J. Endocrinol. Metab.16(Suppl. 3), 534–542 (2012).
   Google Scholar
• Abraham MA , YueJT, LaPierreMPet al. Hypothalamic glucagon signals through the KATP channels to regulate glucose production. Mol. Metab.3, 202–208 (2013).
   PubMed Web of Science ®Google Scholar
• Vogt MC , BruningJC. CNS insulin signaling in the control of energy homeostasis and glucose metabolism – from embryo to old age. Trends Endocrinol. Metab.24, 76–84 (2013).
   PubMed Web of Science ®Google Scholar
• Williams KW , ElmquistJK. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat. Neurosci.15, 1350–1355 (2012).
   PubMed Web of Science ®Google Scholar
• Amitani M , AsakawaA, AmitaniH, InuiA. The role of leptin in the control of insulin–glucose axis. Front. Neurosci.7, 51 (2013).
   PubMed Web of Science ®Google Scholar
• Zhou Y , RuiL. Leptin signaling and leptin resistance. Front. Med.7, 207–222 (2013).
   PubMed Web of Science ®Google Scholar
• Girardet C , ButlerAA. Neural melanocortin receptors in obesity and related metabolic disorders. Biochim. Biophys. Acta1842, 482–494 (2014).
   PubMed Web of Science ®Google Scholar
• Opland DM , LeinningerGM, MyersMGJr. Modulation of the mesolimbic dopamine system by leptin. Brain Res.1350, 65–70 (2010).
   PubMed Web of Science ®Google Scholar
• van Zessen R , van der PlasseG, AdanRA. Contribution of the mesolimbic dopamine system in mediating the effects of leptin and ghrelin on feeding. Proc. Nutr. Soc.71, 435–445 (2012).
   PubMed Web of Science ®Google Scholar
• Fetissov SO , MeguidMM, ChenC, MiyataG. Synchronized release of dopamine and serotonin in the medial and lateral hypothalamus of rats. Neuroscience101, 657–663 (2002).
   Web of Science ®Google Scholar
• Mendlewicz J . Disruption of the circadian timing systems: molecular mechanisms in mood disorders. CNS Drugs.23(Suppl. 2), 15–26 (2009).
   PubMed Web of Science ®Google Scholar
• Patton DF , MistlbergerRE. Circadian adaptations to meal timing: neuroendocrine mechanisms. Front. Neurosci.7, 185 (2013).
   PubMed Web of Science ®Google Scholar
• Nonogaki K , StrackAM, DallmanMF, TecottLH. Leptin-independent hyperphagia and Type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat. Med.4, 1152–1156 (1998).
   PubMed Web of Science ®Google Scholar
• Kawashima N , ChakiS, OkuyamaS. Electrophysiological effects of melanocortin receptor ligands on neuronal activities of monoaminergic neurons in rats. Neurosci. Lett.353, 119–122 (2003).
   PubMed Web of Science ®Google Scholar
• Balthasar N , DalgaardLT, LeeCEet al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell123, 493–505 (2005).
   PubMed Web of Science ®Google Scholar
• Shpakov AO , DerkachKV, ChistyakovaOV, SukhovIB, ShipilovVN, BondarevaVM. The brain adenylyl cyclase signaling system and cognitive functions in rat with neonatal diabetes under the influence of intranasal serotonin. J. Metabolic Synd.1, https://doi.org/10.4172/jms.1000104 (2012).
   Google Scholar
• Etemad A , RamachandranV, PishvaSRet al. Analysis of Gln223Agr polymorphism of Leptin Receptor Gene in type II diabetic mellitus subjects among Malaysians. Int. J. Mol. Sci.14, 19230–19244 (2013).
   PubMed Web of Science ®Google Scholar
• Kleinridders A , CaiW, CappellucciLet al. Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proc. Natl Acad. Sci. USA112, 3463–3468 (2015).
   PubMed Web of Science ®Google Scholar
• Sargent BJ , MooreNA. New central targets for the treatment of obesity. Br. J. Clin. Pharmacol.68, 852–860 (2009).
   PubMed Web of Science ®Google Scholar
• De Felice FG , FerreiraST. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting Type 2 diabetes to Alzheimer disease. Diabetes63, 2262–2272 (2014).
   PubMed Web of Science ®Google Scholar
• Maekawa F , FujiwaraK, KohnoD, KuramochiM, KuritaH, YadaT. Young adult-specific hyperphagia in diabetic Goto-kakizaki rats is associated with leptin resistance and elevation of neuropeptide Y mRNA in the arcuate nucleus. J. Endocrinol.18, 748–756 (2006).
   Google Scholar
• Zhou L , SuttonGM, RochfordJJet al. Serotonin 2C receptor agonists improve Type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab.6, 398–405 (2007).
   PubMed Web of Science ®Google Scholar
• Gautam D , JeonJ, LiJHet al. Metabolic roles of the M3 muscarinic acetylcholine receptor studied with M3 receptor mutant mice: a review. J. Recept. Signal Transduct. Res.28, 93–108 (2008).
   PubMed Web of Science ®Google Scholar
• Nonogaki K , OhbaY, SumiiM, OkaY. Serotonin systems upregulate the expression of hypothalamic NUCB2 via 5-HT2C receptors and induce anorexia via a leptin-independent pathway in mice. Biochem. Biophys. Res. Commun.372, 186–190 (2008).
   PubMed Web of Science ®Google Scholar
• Bach AG , MühlbauerE, PeschkeE. Adrenoceptor expression and diurnal rhythms of melatonin and its precursors in the pineal gland of Type 2 diabetic goto-kakizaki rats. Endocrinology151, 2483–2493 (2010).
   PubMed Web of Science ®Google Scholar
• Haley AP , GonzalesMM, TarumiT, TanakaH. Subclinical vascular disease and cerebral glutamate elevation in metabolic syndrome. Metab. Brain Dis.27, 513–520 (2012).
   PubMed Web of Science ®Google Scholar
• Shpakov AO . The functional state of biogenic amines- and acetylcholine-regulated signaling systems of the brain in diabetes mellitus. Tsitologiia54, 459–468 (2012).
   PubMedGoogle Scholar
• Ito Y , BannoR, ShibataMet al. GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet. J. Neurosci.33, 17166–17173 (2013).
   PubMed Web of Science ®Google Scholar
• Diané A , PierceWD, RussellJCet al. Down-regulation of hypothalamic pro-opiomelanocortin (POMC) expression after weaning is associated with hyperphagia-induced obesity in JCR rats overexpressing neuropeptide Y. Br. J. Nutr.111, 924–932 (2014).
   PubMed Web of Science ®Google Scholar
• Allas S , AbribatT. Clinical perspectives for ghrelin-derived therapeutic products. Endocr. Dev.25, 157–166 (2013).
   PubMedGoogle Scholar
• Perret J , De VrieseC, DelporteC. Polymorphisms for ghrelin with consequences on satiety and metabolic alterations. Curr. Opin. Clin. Nutr. Metab. Care17, 306–311 (2014).
   PubMed Web of Science ®Google Scholar
• Havrankova J , RothJ, BrownsteinMJ. Insulin receptors are widely distributed in the central nervous system of the rat. Nature272, 827–829 (1978).
   PubMed Web of Science ®Google Scholar
• Havrankova J , RothJ, BrownsteinMJ. Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocin-treated rodents. J. Clin. Invest.64, 636–642 (1979).
   PubMed Web of Science ®Google Scholar
• Bassil F , FernagutPO, BezardE, MeissnerWG. Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification?Prog. Neurobiol.118, 1–18 (2014).
   PubMed Web of Science ®Google Scholar
• Boura-Halfon S , ZickY. Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am. J. Physiol.296, 581–591 (2009).
   PubMed Web of Science ®Google Scholar
• Kleinridders A , FerrisHA, CaiW, KahnCR. Insulin action in brain regulates systemic metabolism and brain function. Diabetes63, 2232–2243 (2014).
   PubMed Web of Science ®Google Scholar
• Derakhshan F , TothC. Insulin and the brain. Curr. Diabetes Rev.9, 102–116 (2013).
   PubMedGoogle Scholar
• Blázquez E , VelázquezE, Hurtado-CarneiroV, Ruiz-AlbusacJM. Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, Type 2 diabetes and Alzheimer's disease. Front. Endocrinol. (Lausanne)5, 161 (2014).
   PubMed Web of Science ®Google Scholar
• Ballard FJ , FrancisGL, RossM, BagleyCJ, MayB, WallaceJC. Natural and synthetic forms of insulin-like growth factor-1 (IGF-1) and the potent derivative, destripeptide IGF-1: biological activities and receptor binding. Biochem. Biophys. Res. Commun.149, 398–404 (1987).
   PubMed Web of Science ®Google Scholar
• Kar S , ChabotJ-G, QuirionR. Quantitative autoradiographic localization of [125I] insulin-like growth factor I, [125I] insulin-like growth factor II, and [125I] insulin receptor binding sites in developing and adult rat brain. J. Comp. Neurol.333, 375–397 (1993).
   PubMed Web of Science ®Google Scholar
• O'Kusky J , YeP. Neurodevelopmental effects of insulin-like growth factor signaling. Front. Neuroendocrinol.33, 230–251 (2012).
   PubMed Web of Science ®Google Scholar
• Du Y , WeiT. Inputs and outputs of insulin receptor. Protein Cell5, 203–213 (2014).
   PubMed Web of Science ®Google Scholar
• Copps KD , WhiteMF. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia55, 2565–2582 (2012).
   PubMed Web of Science ®Google Scholar
• Brummer T , Schmitz-PeifferC, DalyRJ. Docking proteins. FEBS J.277, 4356–4369 (2010).
   PubMed Web of Science ®Google Scholar
• White MF . Insulin signaling in health and disease. Science302, 1710–1711 (2003).
   PubMed Web of Science ®Google Scholar
• Taguchi A , WhiteMF. Insulin-like signaling, nutrient homeostasis, and life span. Annu. Rev. Physiol.70, 191–212 (2008).
   PubMed Web of Science ®Google Scholar
• Lizcano JM , AlessiDR. The insulin signalling pathway. Curr. Biol.12, R236–R238 (2002).
   PubMed Web of Science ®Google Scholar
• Sarbassov DD , GuertinDA, AliSM, SabatiniDM. Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science307, 1098–1101 (2005).
   PubMed Web of Science ®Google Scholar
• McCubrey JA , SteelmanLS, BertrandFEet al. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget5, 2881–2911 (2014).
   PubMed Web of Science ®Google Scholar
• Baskin DG , SteinLJ, IkedaHet al. Genetically obese Zucker rats have abnormally low brain insulin content. Life Sci.36, 627–633 (1985).
   PubMed Web of Science ®Google Scholar
• Banks WA , JaspanJB, KastinAJ. Effect of diabetes mellitus on the permeability of the blood–brain barrier to insulin. Peptides18, 1577–1584 (1997).
   PubMed Web of Science ®Google Scholar
• Banks WA , JaspanJB, HuangW, KastinAJ. Transport of insulin across the blood–brain barrier: saturability at euglycemic doses of insulin. Peptides18, 1423–1429 (1997).
   PubMed Web of Science ®Google Scholar
• Kaiyala KJ , PrigeonRL, KahnSE, WoodsSC, SchwartzMW. Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes49, 1525–1533 (2000).
   PubMed Web of Science ®Google Scholar
• Messier C , TeutenbergK. The role of insulin, insulin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer's disease. Neural Plast.12, 311–328 (2005).
   PubMedGoogle Scholar
• Mielke JG , TaghibiglouC, LiuLet al. A biochemical and functional characterization of diet-induced brain insulin resistance. J. Neurochem.93, 1568–1578 (2005).
   PubMed Web of Science ®Google Scholar
• Neumann KF , RojoL, NavarreteLP, FaríasG, ReyesP, MaccioniRB. Insulin resistance and Alzheimer's disease: molecular links & clinical implications. Curr. Alzheimer Res.5, 438–447 (2008).
   PubMed Web of Science ®Google Scholar
• Clauson PG , BrismarK, HallK, LinnarssonR, GrillV. Insulin-like growth factor-I and insulin-like growth factor binding protein-1 in a representative population of Type 2 diabetic patients in Sweden. Scand. J. Clin. Lab. Invest.58, 353–360 (1998).
   PubMed Web of Science ®Google Scholar
• Varewijck AJ , JanssenJA, VähätaloM, HoflandL, LambertsSW, Yki-JärvinenH. Addition of insulin glargine or NPH insulin to metformin monotherapy in poorly controlled Type 2 diabetic patients decreases IGF-I bioactivity similarly. Diabetologia55, 1186–1194 (2012).
   PubMed Web of Science ®Google Scholar
• Akturk M , ArslanM, AltinovaAet al. Association of serum levels of IGF-I and IGFBP-1 with renal function in patients with Type 2 diabetes mellitus. Growth Horm. IGF Res.17, 186–193 (2007).
   PubMed Web of Science ®Google Scholar
• Frystyk J , SkjaerbaekC, VestboE, FiskerS, OrskovH. Circulating levels of free insulin-like growth factors in obese subjects: the impact of Type 2 diabetes. Diabetes Metab. Res. Rev.15, 314–322 (1999).
   PubMed Web of Science ®Google Scholar
• Cortizo AM , LeePD, CédolaNV, JasperH, GagliardinoJJ. Relationship between non-enzymatic glycosylation and changes in serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 levels in patients with Type 2 diabetes mellitus. Acta Diabetol.35, 85–90 (1998).
   PubMed Web of Science ®Google Scholar
• Lopez-Bermejo A , KhosraviJ, Fernandez-RealJMet al. Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-rP1/MAC25). Diabetes55, 2333–2339 (2006).
   PubMedGoogle Scholar
• Ruan W , LaiM. Insulin-like growth factor binding protein: a possible marker for the metabolic syndrome?Acta Diabetol.47, 5–14 (2010).
   PubMed Web of Science ®Google Scholar
• Zhu X , PerryG, SmithMA. Insulin signaling, diabetes mellitus and risk of Alzheimer disease. J. Alzheimers Dis.7, 81–84 (2005).
   PubMed Web of Science ®Google Scholar
• Bruning JC , GautamD, BurksDJet al. Role of brain insulin receptor in control of body weight and reproduction. Science.289, 2122–2125 (2000).
   PubMed Web of Science ®Google Scholar
• Obici S , FengZ, KarkaniasG, BaskinDG, RossettiL. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat. Neurosci.5, 566–572 (2002).
   PubMed Web of Science ®Google Scholar
• Koch C , AugustineRA, StegerJet al. Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. J. Neurosci.30, 16180–16187 (2010).
   PubMed Web of Science ®Google Scholar
• Spielman LJ , LittleJP, KlegerisA. Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration. J. Neuroimmunol.273, 8–21 (2014).
   PubMed Web of Science ®Google Scholar
• McNay EC , RecknagelAK. Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in Type 2 diabetes. Neurobiol. Learn. Mem.96, 432–442 (2011).
   PubMed Web of Science ®Google Scholar
• Talbot K , WangHY, KaziHet al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest.122, 1316–1338 (2012).
   PubMed Web of Science ®Google Scholar
• Bloemer J , BhattacharyaS, AminR, SuppiramaniamV. Impaired insulin signaling and mechanisms of memory loss. Prog. Mol. Biol. Transl. Sci.121, 413–449 (2014).
   PubMed Web of Science ®Google Scholar
• Kullmann S , HeniM, VeitRet al. Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. Diabetes Care doi:10.2337/dc14-2319 (2015) ( Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Adam CL , FindlayPA, AitkenRP, MilneJS, WallaceJM. In vivo changes in central and peripheral insulin sensitivity in a large animal model of obesity. Endocrinology153, 3147–3157 (2012).
   PubMed Web of Science ®Google Scholar
• Lu M , SarrufDA, LiPet al. Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues. J. Biol. Chem.288, 10722–10735 (2013).
   PubMed Web of Science ®Google Scholar
• Heni M , WagnerR, KullmannSet al. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes63, 4083–4088 (2014).
   PubMed Web of Science ®Google Scholar
• Špolcová A , MikuláškováB, KrškováKet al. Deficient hippocampal insulin signaling and augmented Tau phosphorylation is related to obesity- and age-induced peripheral insulin resistance: a study in Zucker rats. BMC Neurosci.15, 111 (2014).
   PubMed Web of Science ®Google Scholar
• Correia SC , SantosRX, PerryG, ZhuX, MoreiraPI, SmithMA. Insulin-resistant brain state: the culprit in sporadic Alzheimer's disease?Ageing Res. Rev.10, 264–273 (2011).
   PubMed Web of Science ®Google Scholar
• Chen Z , ZhongC. Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog. Neurobiol.108, 21–43 (2013).
   PubMed Web of Science ®Google Scholar
• Bhat NR , ThirumangalakudiL. Increased tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet. J. Alzheimers Dis.36, 781–789 (2013).
   PubMed Web of Science ®Google Scholar
• Schubert M , GautamD, SurjoDet al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc. Natl Acad. Sci. USA101, 3100–3105 (2004).
   PubMed Web of Science ®Google Scholar
• Takalo M , HaapasaloA, MartiskainenHet al. High-fat diet increases tau expression in the brain of T2DM and AD mice independently of peripheral metabolic status. J. Nutr. Biochem.25, 634–641 (2014).
   PubMed Web of Science ®Google Scholar
• Lin HV , AcciliD. Reconstitution of insulin action in muscle, white adipose tissue, and brain of insulin receptor knock-out mice fails to rescue diabetes. J. Biol. Chem.286, 9797–9804 (2011).
   PubMed Web of Science ®Google Scholar
• Li ZG , ZhangW, SimaAA. Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes56, 1817–1824 (2007).
   PubMed Web of Science ®Google Scholar
• Lee YH , WhiteMF. Insulin receptor substrate proteins and diabetes. Arch. Pharm. Res.27, 361–370 (2004).
   PubMed Web of Science ®Google Scholar
• Faria JA , KinoteA, Ignacio-SouzaLMet al. Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats. Am. J. Physiol.305, 230–242 (2013).
   Google Scholar
• O'Neill C . PI3-kinase/Akt/mTOR signaling: impaired on/off switches in aging, cognitive decline and Alzheimer's disease. Exp. Gerontol.48, 647–653 (2013).
   PubMed Web of Science ®Google Scholar
• Lin X , TaguchiA, ParkSet al. Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. J. Clin. Invest.114, 908–916 (2004).
   PubMed Web of Science ®Google Scholar
• Anhe GF , CaperutoLC, Pereira-Da-SilvaMet al. In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus. J. Neurochem.90, 559–566 (2004).
   PubMed Web of Science ®Google Scholar
• Srinivasan V , OhtaY, EspinoJet al. Metabolic syndrome, its pathophysiology and the role of melatonin. Recent Pat. Endocr. Metab. Immune Drug Discov.7, 11–25 (2013).
   PubMedGoogle Scholar
• Nogueira TC , Lellis-SantosC, JesusDSet al. Absence of melatonin induces night-time hepatic insulin resistance and increased gluconeogenesis due to stimulation of nocturnal unfolded protein response. Endocrinology152, 1253–1263 (2011).
   PubMed Web of Science ®Google Scholar
• Lucassen EA , RotherKI, CizzaG. Interacting epidemics? Sleep curtailment, insulin resistance, and obesity. Ann. NY Acad. Sci.1264, 110–134 (2012).
   PubMed Web of Science ®Google Scholar
• Born J , LangeT, KernW, McGregorGP, BickelU, FehmHL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat. Neurosci.5, 514–516 (2002).
   PubMed Web of Science ®Google Scholar
• Thorne RG , PronkGJ, PadmanabhanV, FreyWH. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience127, 481–496 (2004).
   PubMed Web of Science ®Google Scholar
• Lochhead JJ , ThorneRG. Intranasal delivery of biologics to the central nervous system. Adv. Drug Deliv. Rev.64, 614–628 (2012).
   PubMed Web of Science ®Google Scholar
• Mittal D , AliA, MdS, BabootaS, SahniJK, AliJ. Insights into direct nose to brain delivery: current status and future perspective. Drug Deliv.21, 75–86 (2014).
   PubMed Web of Science ®Google Scholar
• Subramanian S , JohnM. Intranasal administration of insulin lowers amyloid-beta levels in rat model of diabetes. Indian J. Exp. Biol.50, 41–44 (2012).
   PubMed Web of Science ®Google Scholar
• de la Monte SM . Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art. Expert Opin. Drug Deliv.10, 1699–1709 (2013).
   PubMed Web of Science ®Google Scholar
• Novak V , MilbergW, HaoYet al. Enhancement of vasoreactivity and cognition by intranasal insulin in Type 2 diabetes. Diabetes Care37, 751–759 (2014).
   PubMed Web of Science ®Google Scholar
• Ott V , BenedictC, SchultesB, BornJ, HallschmidM. Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism. Diabetes Obes. Metab.14, 214–221 (2012).
   PubMed Web of Science ®Google Scholar
• Chapman CD , FreyWH, CraftSet al. Intranasal treatment of central nervous system dysfunction in humans. Pharm. Res.30, 2475–2484 (2013).
   PubMed Web of Science ®Google Scholar
• Freiherr J , HallschmidM, FreyWH2ndet al. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs27, 505–514 (2013).
   PubMed Web of Science ®Google Scholar
• Frey WH 2nd . Intranasal insulin to treat and protect against posttraumatic stress disorder. J. Nerv. Ment. Dis.201, 638–639 (2013).
   PubMed Web of Science ®Google Scholar
• Ketterer C , TschritterO, PreisslH, HeniM, HäringHU, FritscheA. Insulin sensitivity of the human brain. Diabetes Res. Clin. Pract.93(Suppl. 1), S47–S51 (2011).
   PubMedGoogle Scholar
• Shpakov AO , ChistyakovaOV, DerkachKV, MoiseyukIV, BondarevaVM. Intranasal insulin affects adenylyl cyclase system in rat tissues in neonatal diabetes. Central Eur. J. Biol.7, 33–47 (2012).
   Google Scholar
• Kuznetsova LA , PlesnevaSA, SharovaTS, PertsevaMN, ShpakovAO. Attenuation of inhibitory influence of hormones on adenylyl cyclase systems in the myocardium and brain of obese and Type 2 diabetic rats as affected by the intranasal insulin treatment. J. Evol. Biochem. Physiol.50, 399–408 (2014).
   Web of Science ®Google Scholar
• Shpakov AO , DerkachKV, ChistyakovaOV, MoiseyukIV, SukhovIB, BondarevaVM. Effect of intranasal insulin and serotonin on functional activity of the adenylyl cyclase system in myocardium, ovary, and uterus of rats with prolonged neonatal model of diabetes mellitus. J. Evol. Biochem. Physiol.49, 153–164 (2013).
   Web of Science ®Google Scholar
• Iwen KA , SchererT, HeniMet al. Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans. J. Clin. Endocrinol. Metab.99, 246–251 (2014).
   Web of Science ®Google Scholar
• Shpakov A , DerkachK, MoyseyukI, ChistyakovaO. Alterations of hormone-sensitive adenylyl cyclase system in the tissues of rats with long-term streptozotocin diabetes and the influence of intranasal insulin. Dataset Papers Pharmacol. 2013, 698435 (2013).
   Google Scholar
• Sukhov IB , ShipilovVN, ChistyakovaOV, TrostAM, ShpakovAO. Long-term intranasal insulin administration improves spatial memory in male rats with prolonged type 1 diabetes mellitus and in healthy rats. Dokl. Biol. Sci.453, 349–352 (2013).
   PubMedGoogle Scholar
• Leissring MA , MalitoE, HedouinSet al. Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. PLoS ONE5, e10504 (2010).
   PubMed Web of Science ®Google Scholar
• Maianti JP , McFedriesA, FodaZHet al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature511, 94–98 (2014).
   PubMed Web of Science ®Google Scholar
• Lupien SB , BluhmEJ, IshiiDN. Systemic insulin-like growth factor-I administration prevents cognitive impairment in diabetic rats, and brain IGF regulates learning/memory in normal adult rats. J. Neurosci. Res.74, 512–523 (2003).
   PubMed Web of Science ®Google Scholar
• Serbedzija P , MadlJE, IshiiDN. Insulin and IGF-I prevent brain atrophy and DNA loss in diabetes. Brain Res.1303, 179–194 (2009).
   PubMed Web of Science ®Google Scholar
• Sebastião I , CandeiasE, SantosMS, de OliveiraCR, MoreiraPI, DuarteAI. Insulin as a bridge between Type 2 diabetes and Alzheimer disease - how anti-diabetics could be a solution for dementia. Front. Endocrinol. (Lausanne)5, 110 (2014).
   PubMed Web of Science ®Google Scholar
• Pernicova I , KorbonitsM. Metformin-mode of action and clinical implications for diabetes and cancer. Nat. Rev. Endocrinol.10, 143–156 (2014).
   PubMed Web of Science ®Google Scholar
• Correia S , CarvalhoC, SantosMSet al. Metformin protects the brain against the oxidative imbalance promoted by Type 2 diabetes. Med. Chem.4, 358–364 (2008).
   PubMed Web of Science ®Google Scholar
• El-Mir MY , DetailleD, R-VillanuevaGet al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J. Mol. Neurosci.34, 77–87 (2008).
   PubMed Web of Science ®Google Scholar
• Ullah I , UllahN, NaseerMI, LeeHY, KimMO. Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons. BMC Neurosci.13, 11 (2012).
   PubMed Web of Science ®Google Scholar
• Kickstein E , KraussS, ThornhillPet al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc. Natl Acad. Sci. USA107, 21830–21835 (2010).
   PubMed Web of Science ®Google Scholar
• Cai Z , YanL-J, LiK, QuaziSH, ZhaoB. Roles of AMP-activated protein kinase in Alzheimer's disease. Neuromolecular Med.14, 1–14 (2012).
   PubMed Web of Science ®Google Scholar
• Li J , DengJ, ShengW, ZuoZ. Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacol. Biochem. Behav.101, 564–574 (2012).
   PubMed Web of Science ®Google Scholar
• Chen Y , ZhouK, WangRet al. Antidiabetic drug metformin (glucophage R) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc. Natl Acad. Sci. USA106, 3907–3912 (2009).
   PubMed Web of Science ®Google Scholar
• Tiganis T . PTP1B and TCPTP – nonredundant phosphatases in insulin signaling and glucose homeostasis. FEBS J.280, 445–458 (2013).
   PubMed Web of Science ®Google Scholar
• Lantz KA , HartSG, PlaneySLet al. Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. Obesity (Silver Spring)18, 1516–1523 (2010).
   PubMed Web of Science ®Google Scholar
• Pandey NR , ZhouX, ZamanTet al. LMO4 is required to maintain hypothalamic insulin signaling. Biochem. Biophys. Res. Commun.450, 666–672 (2014).
   PubMed Web of Science ®Google Scholar
• Qin Z , PandeyNR, ZhouXet al. Functional properties of Claramine: a novel PTP1B inhibitor and insulin-mimetic compound. Biochem. Biophys. Res. Commun.458(1), 21–27 (2015).
   PubMed Web of Science ®Google Scholar
• Pandey NR , ZhouX, QinZet al. The LIM domain only 4 protein is a metabolic responsive inhibitor of protein tyrosine phosphatase 1B that controls hypothalamic leptin signaling. J. Neurosci.33, 12647–12655 (2013).
   PubMed Web of Science ®Google Scholar
• Park HK , AhimaRS. Leptin signaling. F1000Prime Rep.6, 73 (2014).
   PubMedGoogle Scholar
• Mutze J , RothJ, GersbergM, MatsumuraK, HubschleT. Immunohistocemical evidence of functional leptin receptor expression in neuronal and endothelial cells of the brain. Neurosci. Lett.394, 105–110 (2006).
   PubMed Web of Science ®Google Scholar
• Marino JS , XuY, HillJW. Central insulin and leptin-mediated autonomic control of glucose homeostasis. Trends Endocrinol. Metab.22, 275–285 (2011).
   PubMed Web of Science ®Google Scholar
• van Swieten MM , PanditR, AdanRA, van der PlasseG. The neuroanatomical function of leptin in the hypothalamus. J. Chem. Neuroanat.61–62, 207–220 (2014).
   Web of Science ®Google Scholar
• Mutze J , RothJ, GerstbergerR, HubschleT. Nuclear translocation of the transcription factor STAT5 in the rat brain after systemic leptin administration. Neurosci. Lett.417, 286–291 (2007).
   PubMed Web of Science ®Google Scholar
• Rahmouni K , SigmundCD, HaynesWG, MarkAL. Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes58, 536–542 (2009).
   PubMed Web of Science ®Google Scholar
• Hegyi K , FulopK, KovacsK, TothS, FalusA. Leptin-induced signal transduction pathways. Cell. Biol. Int.28, 159–169 (2004).
   PubMed Web of Science ®Google Scholar
• Duan C , LiM, RuiL. SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin. J. Biol. Chem.279, 43684–43691 (2004).
   PubMed Web of Science ®Google Scholar
• Schwartz MW , WoodsSC, PorteD, SeeleyRJ, BaskinDG. Central nervous system control of food intake. Nature404, 661–671 (2000).
   PubMed Web of Science ®Google Scholar
• Morton GJ , GellingRW, NiswenderKD, MorrisonCD, RhodesCJ, SchwartzMW. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab.2, 411–420 (2005).
   PubMed Web of Science ®Google Scholar
• Signore AP , ZhangF, WengZ, GaoYQ, ChenJ. Leptin neuroprotection in the central nervous system: mechanisms and therapeutic potentials. J. Neurochem.106, 1977–1990 (2008).
   PubMed Web of Science ®Google Scholar
• Huo L , GamberK, GreeleySet al. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab.9, 537–547 (2009).
   PubMed Web of Science ®Google Scholar
• Williams KW , ScottMM, ElmquistJK. Modulation of the central melanocortin system by leptin, insulin, and serotonin: co-ordinated actions in a dispersed neuronal network. Eur. J. Pharmacol.660, 2–12 (2011).
   PubMed Web of Science ®Google Scholar
• Iepsen EW , LundgrenJ, DirksenCet al. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss. Int. J. Obes. (Lond).39(5), 834–841 (2014).
   PubMed Web of Science ®Google Scholar
• Trevaskis JL , SunC, AthanacioJet al. Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents. Diabetes Obes. Metab.17, 61–73 (2015).
   PubMed Web of Science ®Google Scholar
• Harvey J . Leptin regulation of neuronal excitability and cognitive function. Curr. Opin. Pharmacol.7, 643–647 (2007).
   PubMed Web of Science ®Google Scholar
• Arnoldussen IA , KiliaanAJ, GustafsonDR. Obesity and dementia: adipokines interact with the brain. Eur. Neuropsychopharmacol.24, 1982–1999 (2014).
   PubMed Web of Science ®Google Scholar
• Weng Z , SignoreAP, GaoYet al. Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. J. Biol. Chem.282, 34479–34491 (2007).
   PubMed Web of Science ®Google Scholar
• Khanh DV , ChoiYH, MohSH, KinyuaAW, KimKW. Leptin and insulin signaling in dopaminergic neurons: relationship between energy balance and reward system. Front. Psychol.5, 846 (2014).
   PubMed Web of Science ®Google Scholar
• Wang B , ChandrasekeraPC, PippinJJ. Leptin-and leptin receptor-deficient rodent models: relevance for human Type 2 diabetes. Curr. Diabetes Rev.10, 131–145 (2014).
   PubMedGoogle Scholar
• Wang MY , ChenL, ClarkGOet al. Leptin therapy in insulin-deficient type I diabetes. Proc. Natl Acad. Sci. USA107, 4813–4819 (2010).
   PubMed Web of Science ®Google Scholar
• Kalra SP . Should leptin replace insulin as a lifetime monotherapy for diabetes type 1 and 2?Indian J. Endocrinol. Metab.17(Suppl. 1), 23–24 (2013).
   Google Scholar
• Toda C , ShiuchiT, LeeSet al. Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues. Diabetes58, 2757–2765 (2009).
   PubMed Web of Science ®Google Scholar
• Kojima S , AsakawaA, AmitaniHet al. Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice. Peptides30, 962–966 (2009).
   PubMed Web of Science ®Google Scholar
• Li XL , AouS, OomuraY, HoriN, FukunagaK, HoriT. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience113, 607–615 (2002).
   PubMed Web of Science ®Google Scholar
• Ramos-Rodriguez JJ , Molina-GilS, Ortiz-BarajasOet al. Central proliferation and neurogenesis is impaired in Type 2 diabetes and prediabetes animal models. PLoS ONE9, e89229 (2014).
   PubMed Web of Science ®Google Scholar
• Stieg MR , SieversC, FarrO, StallaGK, MantzorosCS. Leptin: a hormone linking activation of neuroendocrine axes with neuropathology. Psychoneuroendocrinology51, 47–57 (2015).
   PubMed Web of Science ®Google Scholar
• Labad J , PriceJF, StrachanMWet al. Serum leptin and cognitive function in people with Type 2 diabetes. Neurobiol. Aging33, 2938–2941 (2012).
   PubMed Web of Science ®Google Scholar
• Ramos-Rodriguez JJ , OrtizO, Jimenez-PalomaresMet al. Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice. Psychoneuroendocrinology38, 2462–2475 (2013).
   PubMed Web of Science ®Google Scholar
• Nazarians-Armavil A , MenchellaJA, BelshamDD. Cellular insulin resistance disrupts leptin-mediated control of neuronal signaling and transcription. Mol. Endocrinol.27, 990–1003 (2013).
   PubMed Web of Science ®Google Scholar
• Demirel C , BalcıSO, KorkmazH, AkarsuE. Relationship between the level of hippocampal leptin receptor gene expression and learning performance in diabetic rats. Exp. Clin. Endocrinol. Diabetes122, 615–619 (2014).
   PubMed Web of Science ®Google Scholar
• Chen J , LiangL, ZhanLet al. ZiBuPiYin recipe protects db/db mice from diabetes-associated cognitive decline through improving multiple pathological changes. PLoS ONE9, e91680 (2014).
   PubMed Web of Science ®Google Scholar
• Yang C , ZhuB, HuaF. Leptin deficiency is involved in the cognitive impairment of streptozocin-induced diabetic rats undergoing cardiopulmonary bypass. Int. J. Clin. Exp. Med.7, 2571–2577 (2014).
   PubMed Web of Science ®Google Scholar
• Heymsfield SB , GreenbergAS, FujiokaKet al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA282, 1568–1575 (1999).
   PubMed Web of Science ®Google Scholar
• Farooqi IS , MatareseG, LordGMet al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest.110, 1093–1103 (2002).
   PubMed Web of Science ®Google Scholar
• Oral EA , SimhaV, RuizEet al. Leptin-replacement therapy for lipodystrophy. N. Engl. J. Med.346, 570–578 (2002).
   PubMed Web of Science ®Google Scholar
• Javor ED , GhanyMG, CochranEKet al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology41, 753–760 (2005).
   PubMed Web of Science ®Google Scholar
• Moon HS , DalamagaM, KimSYet al. Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocr. Rev.34, 377–412 (2013).
   PubMed Web of Science ®Google Scholar
• Lecoultre V , RavussinE, RedmanLM. The fall in leptin concentration is a major determinant of the metabolic adaptation induced by caloric restriction independently of the changes in leptin circadian rhythms. J. Clin. Endocrinol. Metab.96, E1512–E1516 (2011).
   PubMed Web of Science ®Google Scholar
• Roujeau C , JockersR, DamJ. New pharmacological perspectives for the leptin receptor in the treatment of obesity. Front. Endocrinol (Lausanne)5, 167 (2014).
   PubMed Web of Science ®Google Scholar
• Trevaskis JL , TurekVF, GriffinPS, WittmerC, ParkesDG, RothJD. Multi-hormonal weight loss combinations in diet-induced obese rats: therapeutic potential of cholecystokinin?Physiol. Behav.100, 187–195 (2010).
   PubMed Web of Science ®Google Scholar
• Müller TD , SullivanLM, HabeggerKet al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J. Pept. Sci.18, 383–393 (2012).
   PubMed Web of Science ®Google Scholar
• Clemmensen C , ChabenneJ, FinanBet al. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet. Diabetes63, 1422–1427 (2014).
   PubMed Web of Science ®Google Scholar
• Roth JD , RolandBL, ColeRLet al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl Acad. Sci. USA105, 7257–7262 (2008).
   PubMed Web of Science ®Google Scholar
• Trevaskis JL , ParkesDG, RothJD. Insights into amylin-leptin synergy. Trends Endocrinol. Metab.21, 473–479 (2010).
   PubMed Web of Science ®Google Scholar
• Trevaskis JL , CoffeyT, ColeRet al. Amylin-mediated restoration of leptin responsiveness in diet-induced obesity: magnitude and mechanisms. Endocrinology149, 5679–5687 (2008).
   PubMed Web of Science ®Google Scholar
• Williams DL , BaskinDG, SchwartzMW. Leptin regulation of the anorexic response to glucagon-like peptide-1 receptor stimulation. Diabetes55, 3387–3393 (2006).
   PubMed Web of Science ®Google Scholar
• Zhao S , KanoskiSE, YanJ, GrillHJ, HayesMR. Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive manner. Int. J. Obes. (Lond).36, 1522–1528 (2012).
   PubMed Web of Science ®Google Scholar
• Byun K , GilSY, NamkoongCet al. Clusterin/ApoJ enhances central leptin signaling through Lrp2-mediated endocytosis. EMBO Rep.15, 801–810 (2014).
   PubMed Web of Science ®Google Scholar
• Bates SH , StearnsWH, DundonTAet al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature421, 856–859 (2003).
   PubMed Web of Science ®Google Scholar
• Jiang L , YouJ, YuX, GonzalezLet al. Tyrosine-dependent and -independent actions of leptin receptor in control of energy balance and glucose homeostasis. Proc. Natl Acad. Sci. USA105, 18619–18624 (2008).
   PubMed Web of Science ®Google Scholar
• Piper ML , UngerEK, MyersMGJr, XuAW. Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons. Mol. Endocrinol.22, 751–759 (2008).
   PubMedGoogle Scholar
• Grasso P , Rozhavskaya-ArenaM, LeinungMC, LeeDW. [d-LEU-4]-OB3, a synthetic leptin agonist, improves hyperglycemic control in C57BL/6J ob/ob mice. Regul. Pept.101, 123–129 (2001).
   PubMed Web of Science ®Google Scholar
• Novakovic ZM , LeinungMC, LeeDW, GrassoP. Oral delivery of mouse [d-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, in male C57BL/6J wild-type and ob/ob mice: effects on energy balance, glycaemic control and serum osteocalcin levels. Diabetes Obes. Metab.12, 532–539 (2010).
   PubMed Web of Science ®Google Scholar
• Waldrop MA , LeinungMC, LeeDW, GrassoP. Intranasal delivery of mouse [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, improves energy balance, glycaemic control, insulin sensitivity and bone formation in leptin-resistant C57BLK/6-m db/db mice. Diabetes Obes. Metab.12, 871–875 (2010).
   PubMed Web of Science ®Google Scholar
• Kaszubska W , FallsHD, SchaeferVGet al. Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line. Mol. Cell. Endocrinol.195, 109–118 (2002).
   PubMed Web of Science ®Google Scholar
• Bhattarai BR , KafleB, HwangJ-Set al. Novel thiazolidinedione derivatives with anti-obesity effects: dual action as PTP1B inhibitors and PPAR-γ activators. Bioorg. Med. Chem. Lett.20, 6758–6763 (2010).
   PubMed Web of Science ®Google Scholar
• Reed AS , UngerEK, OlofssonLE, PiperML, MyersMG, XuAW. Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes.59, 894–906 (2010).
   PubMed Web of Science ®Google Scholar
• Ito M , FukudaS, SakataS, MorinagaH, OhtaT. Pharmacological effects of JTT-551, a novel protein tyrosine phosphatase 1B inhibitor, in diet-induced obesity mice. J. Diabetes Res. 2014, 680348 (2014).
   PubMed Web of Science ®Google Scholar
• Vauthier V , SwartzTD, ChenPet al. Endospanin 1 silencing in the hypothalamic arcuate nucleus contributes to sustained weight loss of high fat diet obese mice. Gene Ther.21, 638–644 (2014).
   PubMed Web of Science ®Google Scholar
• Zhang C , SuZ, ZhaoBet al. Tat-modified leptin is more accessible to hypothalamus through brain-blood barrier with a significant inhibition of body-weight gain in high-fat-diet fed mice. Exp. Clin. Endocrinol. Diabetes.118, 31–37 (2010).
   PubMed Web of Science ®Google Scholar
• Yi X , YuanD, FarrS, BanksW, PoonC-D, KabanovAV. Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity. J. Control. Release191, 34–46 (2014).
   PubMed Web of Science ®Google Scholar
• Undieh AS . Pharmacology of signaling induced by dopamine D1-like receptor activation. Pharmacol. Ther.128, 37–60 (2010).
   PubMed Web of Science ®Google Scholar
• Pijl H , EdoAM. Modulation of monoaminergic neural circuits: potential for the treatment of Type 2 diabetes mellitus. Treat. Endocrinol.1, 71–78 (2002).
   PubMedGoogle Scholar
• Grunberger G . Novel therapies for the management of Type 2 diabetes mellitus: part 1. pramlintide and bromocriptine-QR. J. Diabetes5, 110–117 (2013).
   PubMed Web of Science ®Google Scholar
• Scranton RE , GazianoJM, RuttyD, EzrokhiM, CincottaA. A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of Type 2 diabetes with usual diabetes therapy and either Cycloset or placebo. BMC Endocr. Disord.7, 3 (2007).
   PubMedGoogle Scholar
• Scranton R , CincottaA. Bromocriptine – unique formulation of a dopamine agonist for the treatment of Type 2 diabetes. Expert. Opin. Pharmacother.11, 269–279 (2010).
   PubMed Web of Science ®Google Scholar
• Shivaprasad C , KalraS. Bromocriptine in Type 2 diabetes mellitus. Indian J. Endocrinol. Metab.15(Suppl. 1), 17–24 (2011).
   Google Scholar
• Weiland CM , HilaireML. Bromocriptine mesylate (Cycloset) for Type 2 diabetes mellitus. Am. Fam. Physician87, 718–720 (2013).
   PubMedGoogle Scholar
• Cincotta AH , MeierAH, CincottaMJr. Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert Opin. Investig. Drugs8, 1683–1707 (1999).
   PubMedGoogle Scholar
• Pijl H , OhashiS, MatsudaMet al. Bromocriptine: a novel approach to the treatment of Type 2 diabetes. Diabetes Care23, 1154–1161 (2000).
   PubMed Web of Science ®Google Scholar
• Aminorroaya A , JanghorbaniM, RamezaniM, HaghighiS, AminiM. Does bromocriptine improve glycemic control of obese type-2 diabetics?Horm. Res.62, 55–59 (2004).
   PubMed Web of Science ®Google Scholar
• Mahajan R . Bromocriptinemesylate: FDA-approved novel treatment for type-2 diabetes. Indian J. Pharmacol.41, 197–198 (2009).
   PubMed Web of Science ®Google Scholar
• Holt RI , BarnettAH, BaileyCJ. Bromocriptine: old drug, new formulation and new indication. Diabetes Obes Metab.12, 1048–1057 (2010).
   PubMed Web of Science ®Google Scholar
• Kerr JL , TimpeEM, PetkewiczKA. Bromocriptine mesylate for glycemic management in Type 2 diabetes mellitus. Ann. Pharmacother.44, 1777–1785 (2010).
   PubMed Web of Science ®Google Scholar
• Mikhail N . Quick-release bromocriptine for treatment of Type 2 diabetes. Curr. Drug Deliv.8, 511–516 (2011).
   PubMed Web of Science ®Google Scholar
• Vinik AI , CincottaAH, ScrantonRE, BohannonN, EzrokhiM, GazianoJM. Effect of bromocriptine-QR on glycemic control in subjects with uncontrolled hyperglycemia on one or two oral anti-diabetes agents. Endocr. Pract.18, 931–943 (2012).
   PubMed Web of Science ®Google Scholar
• Garber AJ , BlondeL, BloomgardenZT, HandelsmanY, Dagogo-JackS. The role of bromocriptine-QR in the management of Type 2 diabetes expert panel recommendations. Endocr. Pract.19, 100–106 (2013).
   PubMed Web of Science ®Google Scholar
• Nade VS , KawaleLA, TodmalUB, TajanpureAB. Effect of bromocriptine on cardiovascular complications associated with metabolic syndrome in fructose fed rats. Indian J. Pharmacol.44, 688–693 (2012).
   PubMed Web of Science ®Google Scholar
• Kumar VSH , VinuthaMB, AithalS, BaleedSR, PatilUN. Bromocriptine, a dopamine (d2) receptor agonist, used alone and in combination with glipizide in sub-therapeutic doses to ameliorate hyperglycaemia. J. Clin. Diagn. Res.7, 1904–1907 (2013).
   PubMedGoogle Scholar
• Shpakov AO , DerkachKV, ChistyakovaOV, BondarevaVM. The influence of bromocryptine treatment on activity of the adenylyl cyclase system in the brain of rats with Type 2 diabetes mellitus induced by high-fat diet. Dokl. Biochem. Biophys.459, 186–189 (2014).
   PubMed Web of Science ®Google Scholar
• Ramteke KB , RamanandSJ, RamanandJBet al. Evaluation of the efficacy and safety of bromocriptine QR in Type 2 diabetes. Indian J. Endocrinol. Metab.15(Suppl. 1), 33–39 (2011).
   PubMedGoogle Scholar
• Ghosh A , SenguptaN, SahanaP, GiriD, SenguptaP, DasN. Efficacy and safety of add on therapy of bromocriptine with metformin in Indian patients with Type 2 diabetes mellitus: a randomized open labelled phase IV clinical trial. Indian J. Pharmacol.46, 24–28 (2014).
   PubMed Web of Science ®Google Scholar
• Kok P , RoelfsemaF, FrölichMet al. Activation of dopamine D2 receptors simultaneously ameliorates various metabolic features of obese women. Am. J. Physiol.291, 1038–1043 (2006).
   Google Scholar
• Liang Y , CincottaAH. Increased responsiveness to the hyperglycemic, hyperglucagonemic and hyperinsulinemic effects of circulating norepinephrine in ob/ob mice. Int. J. Obes. Relat. Metab. Disord.25, 698–704 (2001).
   PubMed Web of Science ®Google Scholar
• Cincotta AH . Hypothalamic role in insulin resistance and insulin resistance syndrome. In: Frontiers in Animal Diabetes Research. HansenB, ShafrirE ( Eds). Taylor & Francis, London, UK, 271–312 (2002).
   Google Scholar
• Gaziano JM , CincottaAH, VinikA, BlondeL, BohannonN, ScrantonR. Effect of bromocriptine-QR (a quick-release formulation of bromocriptine mesylate) on major adverse cardiovascular events in Type 2 diabetes subjects. J. Am. Heart Assoc.1, e002279 (2012).
   PubMed Web of Science ®Google Scholar
• Cusi K . The role of adipose tissue and lipotoxicity in the pathogenesis of Type 2 diabetes. Curr. Diab. Rep.10, 306–315 (2010).
   PubMed Web of Science ®Google Scholar
• Nielsen MF , CaumoA, ChandramouliVet al. Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects. Am. J. Physiol.286, 102–110 (2004).
   Google Scholar
• Dicostanzo CA , DardevetDP, NealDWet al. Role of the hepatic sympathetic nerves in the regulation of net hepatic glucose uptake and the mediation of the portal glucose signal. Am. J. Physiol.290, 9–16 (2006).
   PubMed Web of Science ®Google Scholar
• Luo S , LuoJ, CincottaAH. Association of the antidiabetic effects of bromocriptine with a shift in the daily rhythm of monoamine metabolism within the suprachiasmatic nuclei of the Syrian hamster. Chronobiol. Int.17, 155–172 (2000).
   PubMed Web of Science ®Google Scholar
• Schulz E , GoriT, MunzelT. Oxidative stress and endothelial dysfunction in hypertension. Hypertens. Res.34, 665–673 (2011).
   PubMed Web of Science ®Google Scholar
• Gaziano JM , CincottaAH, O'ConnorCMet al. Randomized clinical trial of quick-release bromocriptine among patients with Type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care33, 1503–1508 (2010).
   PubMed Web of Science ®Google Scholar
• Mejía-Rodríguez O , Herrera-AbarcaJE, Ceballos-ReyesGet al. Cardiovascular and renal effects of bromocriptine in diabetic patients with stage 4 chronic kidney disease. Biomed. Res. Int. 2013, 104059 (2013).
   PubMed Web of Science ®Google Scholar
• Derkach KV , ShpakovaEA, ZharovaOA, BondarevaVM, ShpakovAO. The influence of immunization of rats with BSA-conjugated peptide 269–280 of type 3 melanocotrtin receptors on the metabolic parameters and the function of thyroid gland. Tsitologiia56, 850–857 (2014).
   PubMedGoogle Scholar
• Derkach KV , BondarevaVM, MoyseyukIV, ShpakovAO. The influence of two-month bromocryptine treatment on activity of the adenylyl cyclase signaling system in the myocardium and testes of rats with type diabetes mellitus. Tsitologiia56, 907–918 (2014).
   PubMedGoogle Scholar
• Kumar TP , AntonyS, GireeshG, GeorgeN, PauloseCS. Curcumin modulates dopaminergic receptor, CREB and phospholipase C gene expression in the cerebral cortex and cerebellum of streptozotocin induced diabetic rats. J. Biomed. Sci.17, 43 (2010).
   PubMed Web of Science ®Google Scholar
• Bina KG , CincottaAH. Dopaminergic agonists normalize elevated hypothalamic neuropeptide Y and corticotropin-releasing hormone, body weight gain, and hyperglycemia in ob/ob mice. Neuroendocrinology71, 68–78 (2000).
   PubMed Web of Science ®Google Scholar
• Kuo DY . Hypothalamic neuropeptide Y (NPY) and the attenuation of hyperphagia in streptozotocin diabetic rats treated with dopamine D1/D2 agonists. Br. J. Pharmacol.148, 640–647 (2006).
   PubMed Web of Science ®Google Scholar
• Barnes NM , SharpT. A review of central 5-HT receptors and their function. Neuropharmacology38, 1083–1152 (1999).
   PubMed Web of Science ®Google Scholar
• Pucadyil TJ , KalipatnapuS, ChattopadhyayA. Membrane organization and dynamics of the G-protein-coupled serotonin1A receptor monitored using fluorescence-based approaches. J. Fluoresc.15, 785–796 (2005).
   PubMed Web of Science ®Google Scholar
• Raymond JR , MukhinYV, GelascoAet al. Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol. Ther.92, 179–212 (2001).
   PubMed Web of Science ®Google Scholar
• Pytliak M , VargováV, MechírováV, FelšöciM. Serotonin receptors – from molecular biology to clinical applications. Physiol. Res.60, 15–25 (2011).
   PubMed Web of Science ®Google Scholar
• del Olmo E , Lopez-GimenezJF, VilaroMT, MengodG, PalaciosJM, PazosA. Early localization of mRNA coding for 5-HT1A receptors in human brain during development. Mol. Brain Res.60, 123–126 (1998).
   PubMedGoogle Scholar
• Gaspar P , CasesO, MaroteauxL. The developmental role of serotonin: news from mouse molecular genetics. Nat. Rev. Neurosci.4, 1002–1012 (2003).
   PubMed Web of Science ®Google Scholar
• Gingrich JA , HenR. Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice. Psychopharmacology155, 1–10 (2001).
   PubMed Web of Science ®Google Scholar
• Muldoon MF , MackeyRH, WilliamsKV, KorytkowskiMT, FloryJD, ManuckSB. Low central nervous system serotonergic responsivity is associated with the metabolic syndrome and physical inactivity. J. Clin. Endocrinol. Metab.89, 266–271 (2004).
   PubMed Web of Science ®Google Scholar
• Manjarrez G , VazquezF, DelgadoM, HerreraR, HernandezJ. A functional disturbance in the auditory cortex related to a low serotonergic neurotransmission in women with Type 2 diabetes. Neuroendocrinology86, 289–294 (2007).
   PubMed Web of Science ®Google Scholar
• Kloiber S , KohliMA, BruecklTet al. Variations in tryptophan hydroxylase 2 linked to decreased serotonergic activity are associated with elevated risk for metabolic syndrome in depression. Mol. Psychiatry15, 736–747 (2010).
   PubMed Web of Science ®Google Scholar
• Herrera-Marquez R , Hernandez-RodriguezJ, Medina-SerranoJ, Boyzo-Montes de OcaA, Manjarrez-GutierrezG. Association of metabolic syndrome with reduced central serotonergic activity. Metab. Brain Dis.26, 29–35 (2011).
   PubMed Web of Science ®Google Scholar
• Park S , HarroldJA, WiddowsonPS, WilliamsG. Increased binding at 5-HT1A, 5-HT1B, and 5-HT2A receptors and 5-HT transporters in diet-induced obese rats. Brain Res.847, 90–97 (1999).
   PubMed Web of Science ®Google Scholar
• Collin M , Håkansson-OvesjöML, MisaneI, OgrenSO, MeisterB. Decreased 5-HT transporter mRNA in neurons of the dorsal raphe nucleus and behavioral depression in the obese leptin-deficient ob/ob mouse. Brain Res. Mol. Brain Res.81, 51–61 (2000).
   PubMedGoogle Scholar
• Goodnick PJ . Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy. Annu. Clin. Psychiatry13, 31–41 (2001).
   PubMedGoogle Scholar
• Lustman PJ , ClouseRE. Depression in diabetic patients: the relationship between mood and glycemic control. J. Diabetes Complications19, 113–122 (2005).
   PubMed Web of Science ®Google Scholar
• Deuschle M . Effects of antidepressants on glucose metabolism and diabetes mellitus Type 2 in adults. Curr. Opin. Psychiatry26, 60–65 (2013).
   PubMed Web of Science ®Google Scholar
• Lustman PJ , AndersonRJ, FreedlandKE, de GrootM, CarneyRM, ClouseRE. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care23, 934–942 (2000).
   PubMed Web of Science ®Google Scholar
• Van Tilburg MA , McCaskillCC, LaneJDet al. Depressed mood is a factor in glycemic control in type 1 diabetes. Psychosom. Med.63, 551–555 (2001).
   PubMed Web of Science ®Google Scholar
• Heisler LK , CowleyMA, TecottLHet al. Activation of central melanocortin pathways by fenfluramine. Science297, 609–611 (2002).
   PubMed Web of Science ®Google Scholar
• Lee MD , AloyoVJ, FluhartySJ, SimanskyKJ. Infusion of the serotonin1B (5-HT1B) agonist CP-93,129 into the parabrachial nucleus potently and selectively reduces food intake in rats. Psychopharmacology (Berl).136, 304–307 (1998).
   PubMed Web of Science ®Google Scholar
• Simansky KJ , NicklousDM. Parabrachial infusion of D-fenfluramine reduces food intake. Blockade by the 5-HT1B antagonist SB-216641. Pharmacol. Biochem. Behav.71, 681–690 (2002).
   PubMed Web of Science ®Google Scholar
• Lopez-Alonso VE , Mancilla-DiazJM, Rito-DomingoM, Gonzalez-HernandezB, Escartin-PerezRE. The effects of 5-HT1A and 5-HT2C receptor agonists on behavioral satiety sequence in rats. Neurosci. Lett.416, 285–288 (2007).
   PubMed Web of Science ®Google Scholar
• Clissold KA , ChoiE, PrattWE. Serotonin 1A, 1B, and 7 receptors of the rat medial nucleus accumbens differentially regulate feeding, water intake, and locomotor activity. Pharmacol. Biochem. Behav.112, 96–103 (2013).
   PubMed Web of Science ®Google Scholar
• Khoza S , BarnerJC, BohmanTM, RascatiK, LawsonK, WilsonJP. Use of antidepressant agents and the risk of Type 2 diabetes. Eur. J. Clin. Pharmacol.68, 1295–1302 (2012).
   PubMed Web of Science ®Google Scholar
• Yoon JM , ChoEG, LeeHK, ParkSM. Antidepressant use and diabetes mellitus risk: a meta-analysis. Korean J. Fam. Med.34, 228–240 (2013).
   PubMedGoogle Scholar
• Pytliak M , VargováV, MechírováV, FelšöciM. Serotonin receptors – from molecular biology to clinical applications. Physiol. Res.60, 15–25 (2011).
   PubMed Web of Science ®Google Scholar
• Pratt WE , SchallMA, ChoiE. Selective serotonin receptor stimulation of the medial nucleus accumbens differentially affects appetitive motivation for food on a progressive ratio schedule of reinforcement. Neurosci. Lett.511, 84–88 (2012).
   PubMed Web of Science ®Google Scholar
• Pratt WE , BlackstoneK, ConnollyME, SkellyMJ. Selective serotonin receptor stimulation of the medial nucleus accumbens causes differential effects on food intake and locomotion. Behav. Neurosci.123, 1046–1057 (2009).
   PubMed Web of Science ®Google Scholar
• Sandrini M , VitaleG, VergoniAV, OttaniA, BertoliniA. Streptozotocin-induced diabetes provokes changes in serotonin concentration and on 5-HT1A and 5-HT2A receptor in rat brain. Life Sci.60, 1393–1397 (1997).
   PubMed Web of Science ®Google Scholar
• Jackson J , PauloseCS. Enhancement of [m-methoxy 3H]MDL100907 binding to 5HT2A receptors in cerebral cortex and brain stem of streptozotocin induced diabetic rats. Mol. Cell. Biochem.199, 81–85 (1999).
   PubMed Web of Science ®Google Scholar
• Jeong JK , KimJG, LeeBJ. Participation of the central melanocortin system in metabolic regulation and energy homeostasis. Cell. Mol. Life Sci.71, 3799–3809 (2014).
   PubMed Web of Science ®Google Scholar
• Cone RD , LuD, KoppulaSet al. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog. Horm. Res.51, 287–317 (1996).
   PubMedGoogle Scholar
• Shinyama H , MasuzakiH, FangH, FlierJS. Regulation of melanocortin-4 receptor signaling: agonist-mediated desensitization and internalization. Endocrinology144, 1301–1314 (2003).
   PubMed Web of Science ®Google Scholar
• Newman EA , ChaiBX, ZhangW, LiJY, AmmoriJB, MulhollandMW. Activation of the melanocortin-4 receptor mobilizes intracellular free calcium in immortalized hypothalamic neurons. J. Surg. Res.32, 201–207 (2006).
   Google Scholar
• Chai B , LiJY, ZhangW, AmmoriJB, MulhollandMW. Melanocortin-3 receptor activates MAP kinase via PI3 kinase. Regul. Pept.139, 115–121 (2007).
   PubMedGoogle Scholar
• Bäckberg M , MadjidN, OgrenSO, MeisterB. Down-regulated expression of agouti-related protein (AGRP) mRNA in the hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice. Brain Res. Mol. Brain Res.125, 129–139 (2004).
   PubMedGoogle Scholar
• Breit A , WolffK, KalwaH, JarryH, BüchT, GudermannT. The natural inverse agonist agouti-related protein induces arrestin-mediated endocytosis of melanocortin-3 and -4 receptors. J. Biol. Chem.281, 37447–37456 (2006).
   PubMed Web of Science ®Google Scholar
• Fan W , DinulescuDM, ButlerAA, ZhouJ, MarksDL, ConeRD. The central melanocortin system can directly regulate serum insulin levels. Endocrinology141, 3072–3079 (2000).
   PubMed Web of Science ®Google Scholar
• Obici S , FengZ, TanJ, LiuL, KarkaniasG, RossettiL. Central melanocortin receptors regulate insulin action. J. Clin. Invest.108, 1079–1085 (2001).
   PubMed Web of Science ®Google Scholar
• Nogueiras R , WiedmerP, Perez-TilveDet al. The central melanocortin system directly controls peripheral lipid metabolism. J. Clin. Invest.117, 3475–3488 (2007).
   PubMed Web of Science ®Google Scholar
• Haskell-Luevano C , SchaubJW, AndreasenAet al. Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse. FASEB J.23, 642–655 (2009).
   PubMed Web of Science ®Google Scholar
• Fong TM , MaoC, MacNeilTet al. ART (protein product of agouti-related transcript) as an antagonist of MC3 and MC4 receptors. Biochem. Biophys. Res. Commun.237, 629–631 (1997).
   PubMed Web of Science ®Google Scholar
• Huszar D , LynchCA, Fair-HuntressVet al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell88, 131–141 (1997).
   PubMed Web of Science ®Google Scholar
• Farooqi IS , KeoghJM, YeoGS, LankEJ, CheethamT, O'RahillyS. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. New Engl. J. Med.348, 1085–1095 (2003).
   PubMed Web of Science ®Google Scholar
• Tao YX . Mutations in melanocortin-4 receptor and human obesity. Prog. Mol. Biol. Transl. Sci.88, 173–204 (2009).
   PubMed Web of Science ®Google Scholar
• Thearle MS , MullerYL, HansonRLet al. Greater impact of melanocortin-4 receptor deficiency on rates of growth and risk of Type 2 diabetes during childhood compared with adulthood in Pima Indians. Diabetes61, 250–257 (2012).
   PubMed Web of Science ®Google Scholar
• Pan Q , DelahantyLM, JablonskiKAet al. Variation at the melanocortin 4 receptor gene and response to weight-loss interventions in the diabetes prevention program. Obesity (Silver Spring)21, 520–526 (2013).
   Web of Science ®Google Scholar
• Bazzi MD , NasrFA, AlanaziMSet al. Association between FTO, MC4R, SLC30A8, and KCNQ1 gene variants and Type 2 diabetes in Saudi population. Genet. Mol. Res.13, 10194–10203 (2014).
   PubMed Web of Science ®Google Scholar
• Costa JL , HochgeschwenderU, BrennanM. The role of melanocyte-stimulating hormone in insulin resistance and Type 2 diabetes mellitus. Treat. Endocrinol.5, 7–13 (2006).
   PubMedGoogle Scholar
• Havel PJ , HahnTM, SindelarDKet al. Effects of STZ-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. Diabetes49, 44–52 (2000).
   Web of Science ®Google Scholar
• Gout J , SarafianD, TirardJet al. Leptin infusion and obesity in mouse cause alterations in the hypothalamic melanocortin system. Obesity (Silver Spring)16, 1763–1769 (2008).
   PubMed Web of Science ®Google Scholar
• da Silva AA , do CarmoJM, FreemanJN, TallamLS, HallJE. A functional melanocortin system may be required for chronic CNS-mediated antidiabetic and cardiovascular actions of leptin. Diabetes58, 1749–1756 (2009).
   PubMed Web of Science ®Google Scholar
• Meek TH , MatsenME, DamianV, CubeloA, ChuaSC, MortonGJ. Role of melanocortin signaling in neuroendocrine and metabolic actions of leptin in male rats with uncontrolled diabetes. Endocrinology155, 4157–4167 (2014).
   PubMed Web of Science ®Google Scholar
• Giuliani D , MioniC, AltavillaDet al. Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia. Endocrinology147, 1126–1135 (2006).
   PubMed Web of Science ®Google Scholar
• Nargund RP , StrackAM, FongTM. Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. J. Biol. Chem.49, 4035–4043 (2006).
   Google Scholar
• Giuliani D , BittoA, GalantucciMet al. Melanocortins protect against progression of Alzheimer's disease in triple-transgenic mice by targeting multiple pathophysiological pathways. Neurobiol. Aging35, 537–547 (2014).
   PubMed Web of Science ®Google Scholar
• Tatro JB . Melanocortins defend their territory: multifaceted neuroprotection in cerebral ischemia. Endocrinology147, 1122–1125 (2006).
   PubMed Web of Science ®Google Scholar
• Machado I , GonzálezP, SchiöthHB, LasagaM, ScimonelliTN. α-Melanocyte-stimulating hormone (α-MSH) reverses impairment of memory reconsolidation induced by interleukin-1 beta (IL-1β) hippocampal infusions. Peptides31, 2141–2144 (2010).
   PubMed Web of Science ®Google Scholar
• Machado I , GonzalezPV, VilcaesAet al. Interleukin-1β-induced memory reconsolidation impairment is mediated by a reduction in glutamate release and zif268 expression and α-melanocyte-stimulating hormone prevented these effects. Brain Behav. Immun.46, 137–146 (2015).
   PubMed Web of Science ®Google Scholar
• Giuliani D , GalantucciM, NeriLet al. Melanocortins protect against brain damage and counteract cognitive decline in a transgenic mouse model of moderate Alzheimer's disease. Eur. J. Pharmacol.740, 144–150 (2014).
   PubMed Web of Science ®Google Scholar
• Hofbauer KG , LecourtAC, PeterJC. Antibodies as pharmacologic tools for studies on the regulation of energy balance. Nutrition24, 791–797 (2008).
   PubMed Web of Science ®Google Scholar
• Peter JC , ZipfelG, LecourtAC, BekelA, HofbauerKG. Antibodies raised against different extracellular loops of the melanocortin-3 receptor affect energy balance and autonomic function in rats. J. Recept. Signal Transduct. Res.30, 444–453 (2010).
   PubMed Web of Science ®Google Scholar
• Derkach KV , ShpakovaEA, ZharovaOA, ShpakovAO. The metabolic changes in rats immunized with BSA conjugate of peptide derived from the N-terminal region of type 4 melanocortin receptor. Dokl. Biochem. Biophys.458, 163–166 (2014).
   PubMed Web of Science ®Google Scholar
• Shpakov AO , DerkachKV, ZharovaOA, ShpakovaEA. The functional activity of the adenylyl cyclase system in the brain of rats with metabolic syndrome that induced by immunization with the 11–25 peptide of the melanocortin receptor of the fourth type. Neurochem. J.9, 29–38 (2015).
   Google Scholar
• Li G , ZhangY, WilseyJT, ScarpacePJ. Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression. J. Endocrinol.182, 123–132 (2004).
   PubMed Web of Science ®Google Scholar
• Emmerson PJ , FisherMJ, YanLZ, MayerJP. Melanocortin-4 receptor agonists for the treatment of obesity. Curr. Top. Med. Chem.7, 1121–1130 (2007).
   PubMed Web of Science ®Google Scholar
• Masuzaki H , TanakaT, EbiharaK, HosodaK, NakaoK. Hypothalamic melanocortin signaling and leptin resistance – perspective of therapeutic application for obesity-diabetes syndrome. Peptides30, 1383–1386 (2009).
   PubMed Web of Science ®Google Scholar
• Fosgerau K , RaunK, NilssonC, DahlK, WulffBS. Novel α-MSH analog causes weight loss in obese rats and minipigs and improves insulin sensitivity. J. Endocrinol.220, 97–107 (2014).
   PubMed Web of Science ®Google Scholar
• Wikberg JE , MutulisF. Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. Nat. Rev. Drug Discov.7, 307–323 (2008).
   PubMed Web of Science ®Google Scholar
• Conde-Frieboes K , Th⊘gersenH, LauJFet al. Identification and in vivo and in vitro characterization of long acting and melanocortin 4 receptor (MC4-R) selective α-melanocyte-stimulating hormone (α-MSH) analogues. J. Med. Chem.55, 1969–1977 (2012).
   PubMed Web of Science ®Google Scholar
• Kumar KG , SuttonGM, DongJZet al. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides30, 1892–1900 (2009).
   PubMed Web of Science ®Google Scholar
• Kievit P , HalemH, MarksDLet al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes62, 490–497 (2013).
   PubMed Web of Science ®Google Scholar
• Skowronski AA , MorabitoMV, MuellerBRet al. Effects of a novel MC4R agonist on maintenance of reduced body weight in diet-induced obese mice. Obesity (Silver Spring)22, 1287–1295 (2014).
   PubMed Web of Science ®Google Scholar
• Drucker DJ , NauckMA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in Type 2 diabetes. Lancet368, 1696–1705 (2006).
   PubMed Web of Science ®Google Scholar
• Clemmensen C , FinanB, FischerKet al. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice. EMBO Mol. Med.7, 288–298 (2015).
   PubMed Web of Science ®Google Scholar
• Hamilton A , HolscherC. Receptors for the insulin-like peptide GLP-1 are expressed on neurons in the CNS. Neuroreport20, 1161–1166 (2009).
   PubMed Web of Science ®Google Scholar
• Doyle ME , EganJM. Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol. Ther.113, 546–593 (2007).
   PubMed Web of Science ®Google Scholar
• Chiniwala N , JabbourS. Management of diabetes mellitus in the elderly. Curr. Opin. Endocrinol. Diabetes Obes.18, 148–152 (2011).
   PubMedGoogle Scholar
• Adamska E , OstrowskaL, GórskaM, KrętowskiA. The role of gastrointestinal hormones in the pathogenesis of obesity and Type 2 diabetes. Prz. Gastroenterol.9, 69–76 (2014).
   PubMedGoogle Scholar
• Ravassa S , BeaumontJ, HuertaAet al. Association of low GLP-1 with oxidative stress is related to cardiac disease and outcome in patients with Type 2 diabetes mellitus: a pilot study. Free Radic. Biol. Med.81, 1–12 (2015).
   PubMed Web of Science ®Google Scholar
• Hayes MR . Neuronal and intracellular signaling pathways mediating GLP-1 energy balance and glycemic effects. Physiol. Behav.106, 413–416 (2012).
   PubMed Web of Science ®Google Scholar
• Hamilton A , PattersonS, PorterD, GaultVA, HolscherC. Novel GLP-1 mimetics developed to treat Type 2 diabetes promote progenitor cell proliferation in the brain. J. Neurosci. Res.89, 481–489 (2011).
   PubMed Web of Science ®Google Scholar
• Salcedo I , TweedieD, LiY, GreigNH. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br. J. Pharmacol.166, 1586–1599 (2012).
   PubMed Web of Science ®Google Scholar
• Darsalia V , HuaS, LarssonMet al. Exendin-4 reduces ischemic brain injury in normal and aged Type 2 diabetic mice and promotes microglial M2 polarization. PLoS ONE9, e103114 (2014).
   PubMed Web of Science ®Google Scholar
• Gilman CP , PerryT, FurukawaK, GriegNH, EganJM, MattsonMP. Glucagon-like peptide 1 modulates calcium responses to glutamate and membrane depolarization in hippocampal neurons. J. Neurochem.87, 1137–1144 (2003).
   PubMed Web of Science ®Google Scholar
• Toft-Nielsen MB , DamholtMB, MadsbadSet al. Determinants of the impaired secretion of glucagon-like peptide-1 in Type 2 diabetic patients. J. Clin. Endocrinol. Metab.86, 3717–3723 (2001).
   PubMed Web of Science ®Google Scholar
• Vilsb⊘ll T , KrarupT, DeaconCF, MadsbadS, HolstJJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in Type 2 diabetic patients. Diabetes50, 609–613 (2001).
   PubMed Web of Science ®Google Scholar
• Perry T , HaugheyNJ, MattsonMP, EganJM, GreigNH. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J. Pharmacol. Exp. Ther.302, 881–888 (2002).
   PubMed Web of Science ®Google Scholar
• George RE , JosephS. A review of newer treatment approaches for type-2 diabetes: Focusing safety and efficacy of incretin based therapy. Saudi Pharm. J.22, 403–410 (2014).
   PubMed Web of Science ®Google Scholar
• Stonehouse AH , DarsowT, MaggsDG. Incretin-based therapies. J. Diabetes4, 55–67 (2012).
   PubMed Web of Science ®Google Scholar
• Holst JJ . Treatment of Type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors. Expert Opin. Emerg. Drugs9, 155–166 (2004).
   PubMedGoogle Scholar
• Bron M , WilsonC, FleckP. A Post Hoc analysis of HbA1c, hypoglycemia, and weight change outcomes with alogliptin vs glipizide in older patients with Type 2 diabetes. Diabetes Ther.5, 521–534 (2014).
   PubMed Web of Science ®Google Scholar
• Choe EY , ChoY, ChoiYet al. The effect of DPP-4 inhibitors on metabolic parameters in patients with Type 2 diabetes. Diabetes Metab. J.38, 211–219 (2014).
   PubMedGoogle Scholar
• Gault VA , LennoxR, FlattPR. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline. Diabetes Obes. Metab.17, 403–413 (2015).
   PubMed Web of Science ®Google Scholar
• Kosaraju J , GaliCC, KhatwalRBet al. Saxagliptin: a dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced Alzheimer's disease. Neuropharmacology72, 291–300 (2013).
   PubMed Web of Science ®Google Scholar
• Pintana H , ApaijaiN, ChattipakornN, ChattipakornSC. DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats. J. Endocrinol.218, 1–11 (2013).
   PubMed Web of Science ®Google Scholar
• Darsalia V , OlverlingA, LarssonMet al. Linagliptin enhances neural stem cell proliferation after stroke in Type 2 diabetic mice. Regul. Pept.190–191, 25–31 (2014).
   Google Scholar
• Lovshin JA , DruckerDJ. Incretin-based therapies for Type 2 diabetes mellitus. Nat. Rev. Endocrinol.5, 262–269 (2009).
   PubMed Web of Science ®Google Scholar
• Holst JJ , BurcelinR, NathansonE. Neuroprotective properties of GLP-1: theoretical and practical applications. Curr. Med. Res. Opin.27, 547–558 (2001).
   Google Scholar
• McClean PL , GaultVA, HarriottP, HölscherC. Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: a link between diabetes and Alzheimer's disease. Eur. J. Pharmacol.630, 158–162 (2010).
   PubMed Web of Science ®Google Scholar
• Gengler S , McCleanPL, McCurtinR, GaultVA, HölscherC. Val8GLP-1 rescues synaptic plasticity and reduces dense core plaques in APP/PS1 mice. Neurobiol. Aging33, 265–276 (2012).
   PubMed Web of Science ®Google Scholar
• Li L , ZhangZF, HolscherC, GaoC, JiangYH, LiuYZ. (Val8)glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains. Eur. J. Pharmacol.674, 280–286 (2012).
   PubMed Web of Science ®Google Scholar
• Yamamoto H , KishiT, LeeCEet al. Glucagon-like peptide-1–responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites. J. Neurosci.23, 2939–2946 (2003).
   PubMed Web of Science ®Google Scholar
• Harkavyi A , AbuirmeilehA, LeverR, KingsburyAE, BiggsCS, WhittonPS. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease. J. Neuroinflammation5, 19 (2008).
   PubMed Web of Science ®Google Scholar
• Li Y , PerryT, KindyMSet al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc. Natl Acad. Sci. USA106, 1285–1290 (2009).
   PubMed Web of Science ®Google Scholar