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  • Review Article
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The pathophysiology of defective proteostasis in the hypothalamus — from obesity to ageing

Nature Reviews Endocrinology volume 12, pages 723–733 (2016)Cite this article

Subjects

Key Points

  • Specialized neurons of the hypothalamus control caloric intake and energy expenditure in response to hormonal, nutritional and neural signals that reflect the energy stores in the body

  • Malfunction of the hypothalamus occurs in obesity and ageing, which leads to an imbalance between caloric intake and energy expenditure resulting in positive energy balance and reduced lifespan

  • The excessive consumption of certain nutrients and ageing affect different aspects of proteostasis in selected neurons of the hypothalamus, contributing to neuronal dysfunction in obesity and ageing

  • Inflammation is one of the most important outcomes of disturbed proteostasis to occur in the hypothalamus during obesity and ageing

  • Several genetic and pharmacological approaches used to correct the defects of proteostasis and reduce inflammation have proven effective in reducing obesity and increasing lifespan in experimental models

Abstract

Hypothalamic dysfunction has emerged as an important mechanism involved in the development of obesity and its comorbidities, as well as in the process of ageing and age-related diseases, such as type 2 diabetes mellitus, hypertension and Alzheimer disease. In both obesity and ageing, inflammatory signalling is thought to coordinate many of the cellular events that lead to hypothalamic neuronal dysfunction. This process is triggered by the activation of signalling via the toll-like receptor 4 pathway and endoplasmic reticulum stress, which in turn results in intracellular inflammatory signalling. However, the process that connects inflammation with neuronal dysfunction is complex and includes several regulatory mechanisms that ultimately control the homeostasis of intracellular proteins and organelles (also known as 'proteostasis'). This Review discusses the evidence for the key role of proteostasis in the control of hypothalamic neurons and the involvement of this process in regulating whole-body energy homeostasis and lifespan.

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Figure 1: Control of energy balance and lifespan by the hypothalamic network.
Figure 2: Features of protein synthesis and folding.
Figure 3: Integration of mechanisms involved in protein and organelle degradation.
Figure 4: Proteostasis and inflammation in the hypothalamus during ageing and obesity.

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References

  1. Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S. & Schwartz, M. W. Central nervous system control of food intake and body weight. Nature 443, 289–295 (2006).

    CAS  PubMed  Google Scholar 

  2. Konner, A. C., Klockener, T. & Bruning, J. C. Control of energy homeostasis by insulin and leptin: targeting the arcuate nucleus and beyond. Physiol. Behav. 97, 632–638 (2009).

    PubMed  Google Scholar 

  3. Velloso, L. A., Folli, F. & Saad, M. J. TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation. Endocr. Rev. 36, 245–271 (2015).

    CAS  PubMed  Google Scholar 

  4. Velloso, L. A. & Schwartz, M. W. Altered hypothalamic function in diet-induced obesity. Int. J. Obes. (Lond.) 35, 1455–1465 (2011).

    CAS  Google Scholar 

  5. Kalin, S. et al. Hypothalamic innate immune reaction in obesity. Nat. Rev. Endocrinol. 11, 339–351 (2015).

    PubMed  Google Scholar 

  6. Goris, A. H. & Westerterp, K. R. Physical activity, fat intake and body fat. Physiol. Behav. 94, 164–168 (2008).

    CAS  PubMed  Google Scholar 

  7. Miller, W. C. Diet composition, energy intake, and nutritional status in relation to obesity in men and women. Med. Sci. Sports Exerc. 23, 280–284 (1991).

    CAS  PubMed  Google Scholar 

  8. De Souza, C. T. et al. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146, 4192–4199 (2005).

    CAS  PubMed  Google Scholar 

  9. Zhang, X. et al. Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61–73 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Moraes, J. C. et al. High-fat diet induces apoptosis of hypothalamic neurons. PLoS ONE 4, e5045 (2009).

    PubMed  PubMed Central  Google Scholar 

  11. Ignacio-Souza, L. M. et al. Defective regulation of the ubiquitin/proteasome system in the hypothalamus of obese male mice. Endocrinology 155, 2831–2844 (2014).

    PubMed  Google Scholar 

  12. van de Sande-Lee, S. et al. Partial reversibility of hypothalamic dysfunction and changes in brain activity after body mass reduction in obese subjects. Diabetes 60, 1699–1704 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).

    CAS  PubMed  Google Scholar 

  14. Ramachandrappa, S. & Farooqi, I. S. Genetic approaches to understanding human obesity. J. Clin. Invest. 121, 2080–2086 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Valette, M. et al. Eating behaviour in obese patients with melanocortin-4 receptor mutations: a literature review. Int. J. Obes. (Lond.) 37, 1027–1035 (2013).

    CAS  Google Scholar 

  16. Everitt, A. V. & Cavanagh, L. M. The ageing process in the hypophysectiomised rat. Gerontologia 11, 198–207 (1965).

    CAS  PubMed  Google Scholar 

  17. Brown-Borg, H. M. The somatotropic axis and longevity in mice. Am. J. Physiol. Endocrinol. Metab. 309, E503–E510 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Satoh, A. et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab. 18, 416–430 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, G. et al. Hypothalamic programming of systemic ageing involving IKKβ, NF-κB and GnRH. Nature 497, 211–216 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Satoh, A., Brace, C. S., Rensing, N. & Imai, S. Deficiency of Prdm13, a dorsomedial hypothalamus-enriched gene, mimics age-associated changes in sleep quality and adiposity. Aging Cell 14, 209–218 (2015).

    CAS  PubMed  Google Scholar 

  21. Benayoun, B. A., Pollina, E. A. & Brunet, A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat. Rev. Mol. Cell Biol. 16, 593–610 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Dilman, V. M. & Anisimov, V. N. Hypothalmic mechanisms of ageing and of specific age pathology — I. Sensitivity threshold of hypothalamo-pituitary complex to homeostatic stimuli in the reproductive system. Exp. Gerontol. 14, 161–174 (1979).

    CAS  PubMed  Google Scholar 

  24. Yan, J. et al. Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response. Nat. Med. 20, 1001–1008 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Schneeberger, M. et al. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155, 172–187 (2013).

    CAS  PubMed  Google Scholar 

  26. Dietrich, M. O., Liu, Z. W. & Horvath, T. L. Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155, 188–199 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Portovedo, M. et al. Saturated fatty acids modulate autophagy's proteins in the hypothalamus. PLoS ONE 10, e0119850 (2015).

    PubMed  PubMed Central  Google Scholar 

  28. Roberts, E., Sethi, A., Montoya, J., Woese, C. R. & Luthey-Schulten, Z. Molecular signatures of ribosomal evolution. Proc. Natl Acad. Sci. USA 105, 13953–13958 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Klinge, S., Voigts-Hoffmann, F., Leibundgut, M., Arpagaus, S. & Ban, N. Crystal structure of the eukaryotic 60S ribosomal subunit in complex with initiation factor 6. Science 334, 941–948 (2011).

    CAS  PubMed  Google Scholar 

  30. Sherman, M. Y. & Qian, S. B. Less is more: improving proteostasis by translation slow down. Trends Biochem. Sci. 38, 585–591 (2013).

    CAS  PubMed  Google Scholar 

  31. Clark, P. L. & King, J. A newly synthesized, ribosome-bound polypeptide chain adopts conformations dissimilar from early in vitro refolding intermediates. J. Biol. Chem. 276, 25411–25420 (2001).

    CAS  PubMed  Google Scholar 

  32. Horwich, A. L., Fenton, W. A., Chapman, E. & Farr, G. W. Two families of chaperonin: physiology and mechanism. Annu. Rev. Cell Dev. Biol. 23, 115–145 (2007).

    CAS  PubMed  Google Scholar 

  33. Hartl, F. U., Bracher, A. & Hayer-Hartl, M. Molecular chaperones in protein folding and proteostasis. Nature 475, 324–332 (2011).

    CAS  PubMed  Google Scholar 

  34. Powers, E. T., Morimoto, R. I., Dillin, A., Kelly, J. W. & Balch, W. E. Biological and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem. 78, 959–991 (2009).

    CAS  PubMed  Google Scholar 

  35. Lindquist, S. Protein folding sculpting evolutionary change. Cold Spring Harb. Symp. Quant. Biol. 74, 103–108 (2009).

    CAS  PubMed  Google Scholar 

  36. Hutt, D. M. & Balch, W. E. Expanding proteostasis by membrane trafficking networks. Cold Spring Harb. Perspect. Med. 3, 1–21 (2013).

    Google Scholar 

  37. Wolff, S., Weissman, J. S. & Dillin, A. Differential scales of protein quality control. Cell 157, 52–64 (2014).

    CAS  PubMed  Google Scholar 

  38. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).

    CAS  PubMed  Google Scholar 

  39. Hollien, J. Evolution of the unfolded protein response. Biochim. Biophys. Acta 1833, 2458–2463 (2013).

    CAS  PubMed  Google Scholar 

  40. Hotamisligil, G. S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900–917 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Hotamisligil, G. S. Inflammation and endoplasmic reticulum stress in obesity and diabetes. Int. J. Obes. (Lond.) 32, S52–S54 (2008).

    CAS  Google Scholar 

  42. Araujo, E. P., de Souza, C. T. & Velloso, L. A. Atypical transforming growth factor-β signaling in the hypothalamus is linked to diabetes. Nat. Med. 20, 985–987 (2014).

    CAS  PubMed  Google Scholar 

  43. Anderson, P. & Kedersha, N. Stress granules: the Tao of RNA triage. Trends Biochem. Sci. 33, 141–150 (2008).

    CAS  PubMed  Google Scholar 

  44. Moeller, B. J., Cao, Y., Li, C. Y. & Dewhirst, M. W. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5, 429–441 (2004).

    CAS  PubMed  Google Scholar 

  45. Milanski, M. et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J. Neurosci. 29, 359–370 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ozcan, L. et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 9, 35–51 (2009).

    CAS  PubMed  Google Scholar 

  47. Williams, K. W. et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab. 20, 471–482 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Clarke, J. R. et al. Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation. EMBO Mol. Med. 7, 190–210 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Christianson, J. C. & Ye, Y. Cleaning up in the endoplasmic reticulum: ubiquitin in charge. Nat. Struct. Mol. Biol. 21, 325–335 (2014).

    CAS  PubMed  Google Scholar 

  50. Ristic, G. The 2nd International Conference on Radiation and Dosimetry in Various Fields of Research and the 2nd East European Radon Symposium (SEERAS). Preface. Radiat. Prot. Dosimetry 162, 1 (2014).

    PubMed  Google Scholar 

  51. Pickart, C. M. & Fushman, D. Polyubiquitin chains: polymeric protein signals. Curr. Opin. Chem. Biol. 8, 610–616 (2004).

    CAS  PubMed  Google Scholar 

  52. Nath, D. & Shadan, S. The ubiquitin system. Nature 458, 421 (2009).

    CAS  PubMed  Google Scholar 

  53. Komatsu, M. et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163 (2007).

    CAS  PubMed  Google Scholar 

  54. Swaab, D. F. et al. Tau and ubiquitin in the human hypothalamus in aging and Alzheimer's disease. Brain Res. 590, 239–249 (1992).

    CAS  PubMed  Google Scholar 

  55. Ferreira, S. T., Vieira, M. N. & De Felice, F. G. Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases. IUBMB Life 59, 332–345 (2007).

    CAS  PubMed  Google Scholar 

  56. Wang, Q. M. et al. Proteomic analysis of rat hypothalamus revealed the role of ubiquitin-proteasome system in the genesis of DR or DIO. Neurochem. Res. 36, 939–946 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Susaki, E. et al. Increased E4 activity in mice leads to ubiquitin-containing aggregates and degeneration of hypothalamic neurons resulting in obesity. J. Biol. Chem. 285, 15538–15547 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Wu, H. et al. UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53. Nat. Med. 17, 347–355 (2011).

    CAS  PubMed  Google Scholar 

  59. Nordquist, K. A. et al. Structural and functional characterization of the monomeric U-box domain from E4B. Biochemistry 49, 347–355 (2010).

    CAS  PubMed  Google Scholar 

  60. Kundu, M. & Thompson, C. B. Autophagy: basic principles and relevance to disease. Annu. Rev. Pathol. 3, 427–455 (2008).

    CAS  PubMed  Google Scholar 

  61. Nakatogawa, H., Suzuki, K., Kamada, Y. & Ohsumi, Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol. 10, 458–467 (2009).

    CAS  PubMed  Google Scholar 

  62. Hayashi-Nishino, M. et al. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11, 1433–1437 (2009).

    CAS  PubMed  Google Scholar 

  63. Klionsky, D. J. et al. A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5, 539–545 (2003).

    CAS  PubMed  Google Scholar 

  64. Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595 (2004).

    CAS  PubMed  Google Scholar 

  65. Yamamoto, A., Cremona, M. L. & Rothman, J. E. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J. Cell Biol. 172, 719–731 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kirkwood, T. B. Understanding the odd science of aging. Cell 120, 437–447 (2005).

    CAS  PubMed  Google Scholar 

  67. Cuervo, A. M. Autophagy and aging: keeping that old broom working. Trends Genet. 24, 604–612 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Carrascosa, J. M., Ros, M., Andres, A., Fernandez-Agullo, T. & Arribas, C. Changes in the neuroendocrine control of energy homeostasis by adiposity signals during aging. Exp. Gerontol. 44, 20–25 (2009).

    CAS  PubMed  Google Scholar 

  69. Smith, R. G., Betancourt, L. & Sun, Y. Molecular endocrinology and physiology of the aging central nervous system. Endocr. Rev. 26, 203–250 (2005).

    CAS  PubMed  Google Scholar 

  70. Coupe, B. et al. Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation. Cell Metab. 15, 247–255 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Kaushik, S. et al. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab. 14, 173–183 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Meng, Q. & Cai, D. Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IκB kinase β (IKKβ)/NF-κB pathway. J. Biol. Chem. 286, 32324–32332 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kaushik, S. et al. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep. 13, 258–265 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Malhotra, N. & Chande, N. Venous thromboprophylaxis in gastrointestinal bleeding. Can. J. Gastroenterol. Hepatol. 29, 145–148 (2015).

    PubMed  PubMed Central  Google Scholar 

  75. Morselli, E. et al. Caloric restriction and resveratrol promote longevity through the sirtuin-1-dependent induction of autophagy. Cell Death Dis. 1, e10 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Bi, S., Robinson, B. M. & Moran, T. H. Acute food deprivation and chronic food restriction differentially affect hypothalamic NPY mRNA expression. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R1030–R1036 (2003).

    CAS  PubMed  Google Scholar 

  77. Aveleira, C. A. et al. Neuropeptide Y stimulates autophagy in hypothalamic neurons. Proc. Natl Acad. Sci. USA 112, E1642–E1651 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Chiba, T. et al. A key role for neuropeptide Y in lifespan extension and cancer suppression via dietary restriction. Sci. Rep. 4, 4517 (2014).

    PubMed  PubMed Central  Google Scholar 

  79. Michalkiewicz, M., Knestaut, K. M., Bytchkova, E. Y. & Michalkiewicz, T. Hypotension and reduced catecholamines in neuropeptide Y transgenic rats. Hypertension 41, 1056–1062 (2003).

    CAS  PubMed  Google Scholar 

  80. Morselli, E. et al. The life span-prolonging effect of sirtuin-1 is mediated by autophagy. Autophagy 6, 186–188 (2010).

    PubMed  Google Scholar 

  81. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).

    CAS  PubMed  Google Scholar 

  82. Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001).

    CAS  PubMed  Google Scholar 

  83. Salminen, A. & Kaarniranta, K. SIRT1: regulation of longevity via autophagy. Cell. Signal. 21, 1356–1360 (2009).

    CAS  PubMed  Google Scholar 

  84. Chang, H. C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109–1112 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Baker, M. J., Tatsuta, T. & Langer, T. Quality control of mitochondrial proteostasis. Cold Spring Harb. Perspect. Biol. 3, a007559 (2011).

    PubMed  PubMed Central  Google Scholar 

  87. Taylor, E. B. & Rutter, J. Mitochondrial quality control by the ubiquitin-proteasome system. Biochem. Soc. Trans. 39, 1509–1513 (2011).

    CAS  PubMed  Google Scholar 

  88. Quiros, P. M., Langer, T. & Lopez-Otin, C. New roles for mitochondrial proteases in health, ageing and disease. Nat. Rev. Mol. Cell Biol. 16, 345–359 (2015).

    CAS  PubMed  Google Scholar 

  89. Haynes, C. M. & Ron, D. The mitochondrial UPR — protecting organelle protein homeostasis. J. Cell Sci. 123, 3849–3855 (2010).

    CAS  PubMed  Google Scholar 

  90. Pellegrino, M. W., Nargund, A. M. & Haynes, C. M. Signaling the mitochondrial unfolded protein response. Biochim. Biophys. Acta 1833, 410–416 (2013).

    CAS  PubMed  Google Scholar 

  91. Ashrafi, G. & Schwarz, T. L. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 20, 31–42 (2013).

    CAS  PubMed  Google Scholar 

  92. Liesa, M. & Shirihai, O. S. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 17, 491–506 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Westermann, B. Bioenergetic role of mitochondrial fusion and fission. Biochim. Biophys. Acta 1817, 1833–1838 (2012).

    CAS  PubMed  Google Scholar 

  94. Anderson, R. M. & Weindruch, R. The caloric restriction paradigm: implications for healthy human aging. Am. J. Hum. Biol. 24, 101–106 (2012).

    PubMed  PubMed Central  Google Scholar 

  95. Obici, S., Feng, Z., Arduini, A., Conti, R. & Rossetti, L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat. Med. 9, 756–761 (2003).

    CAS  PubMed  Google Scholar 

  96. Koch, M. et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519, 45–50 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Andrews, Z. B. et al. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846–851 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Lopez, M. et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab. 7, 389–399 (2008).

    CAS  PubMed  Google Scholar 

  99. Coppola, A. et al. A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Cell Metab. 5, 21–33 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Degasperi, G. R. et al. UCP2 protects hypothalamic cells from TNF-α-induced damage. FEBS Lett. 582, 3103–3110 (2008).

    CAS  PubMed  Google Scholar 

  101. Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).

    CAS  PubMed  Google Scholar 

  102. Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature 456, 264–268 (2008).

    CAS  PubMed  Google Scholar 

  103. Coope, A. et al. Chaperone insufficiency links TLR4 protein signaling to endoplasmic reticulum stress. J. Biol. Chem. 287, 15580–15589 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Visintin, A. et al. Regulation of Toll-like receptors in human monocytes and dendritic cells. J. Immunol. 166, 249–255 (2001).

    CAS  PubMed  Google Scholar 

  105. Razolli, D. S. et al. TLR4 expression in bone marrow-derived cells is both necessary and sufficient to produce the insulin resistance phenotype in diet-induced obesity. Endocrinology 156, 103–113 (2015).

    PubMed  Google Scholar 

  106. Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Arruda, A. P. et al. Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat. Med. 20, 1427–1435 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Kelley, D. E., He, J., Menshikova, E. V. & Ritov, V. B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002).

    CAS  PubMed  Google Scholar 

  109. Petersen, K. F. et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 1140–1142 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Vianna, C. R. et al. Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance. Cell Metab. 4, 453–464 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Barzilai, N., Huffman, D. M., Muzumdar, R. H. & Bartke, A. The critical role of metabolic pathways in aging. Diabetes 61, 1315–1322 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span — from yeast to humans. Science 328, 321–326 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Vidal, R. L., Matus, S., Bargsted, L. & Hetz, C. Targeting autophagy in neurodegenerative diseases. Trends Pharmacol. Sci. 35, 583–591 (2014).

    CAS  PubMed  Google Scholar 

  114. O'Neill, C., Kiely, A. P., Coakley, M. F., Manning, S. & Long-Smith, C. M. Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease. Biochem. Soc. Trans. 40, 721–727 (2012).

    CAS  PubMed  Google Scholar 

  115. Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).

    CAS  PubMed  Google Scholar 

  116. Orosco, M., Rouch, C. & Nicolaidis, S. Resistance of the obese Zucker rat to insulin-induced feeding and to satiety induced by coinfusion of insulin and glucose. Appetite 23, 209–218 (1994).

    CAS  PubMed  Google Scholar 

  117. Carvalheira, J. B. et al. Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats. Diabetologia 46, 1629–1640 (2003).

    CAS  PubMed  Google Scholar 

  118. Lin, X. et al. Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes. J. Clin. Invest. 114, 908–916 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Cota, D., Matter, E. K., Woods, S. C. & Seeley, R. J. The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. J. Neurosci. 28, 7202–7208 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Mori, H. et al. Critical role for hypothalamic mTOR activity in energy balance. Cell Metab. 9, 362–374 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Lee, J. H. et al. Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron 85, 303–315 (2015).

    CAS  PubMed  Google Scholar 

  122. Takei, N. & Nawa, H. mTOR signaling and its roles in normal and abnormal brain development. Front. Mol. Neurosci. 7, 28 (2014).

    PubMed  PubMed Central  Google Scholar 

  123. Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1–Atg13–FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Conn, C. S. & Qian, S. B. mTOR signaling in protein homeostasis: less is more? Cell Cycle 10, 1940–1947 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Sun, J., Conn, C. S., Han, Y., Yeung, V. & Qian, S. B. PI3K–mTORC1 attenuates stress response by inhibiting cap-independent Hsp70 translation. J. Biol. Chem. 286, 6791–6800 (2011).

    CAS  PubMed  Google Scholar 

  126. Li, H., Tsang, C. K., Watkins, M., Bertram, P. G. & Zheng, X. F. Nutrient regulates Tor1 nuclear localization and association with rDNA promoter. Nature 442, 1058–1061 (2006).

    CAS  PubMed  Google Scholar 

  127. Wang, X. et al. Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase. EMBO J. 20, 4370–4379 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Namkoong, C. et al. Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. Diabetes 54, 63–68 (2005).

    CAS  PubMed  Google Scholar 

  129. Kim, M. S. et al. Anti-obesity effects of α-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat. Med. 10, 727–733 (2004).

    CAS  PubMed  Google Scholar 

  130. Meley, D. et al. AMP-activated protein kinase and the regulation of autophagic proteolysis. J. Biol. Chem. 281, 34870–34879 (2006).

    CAS  PubMed  Google Scholar 

  131. Dai, S. et al. Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK. EMBO J. 34, 275–293 (2015).

    CAS  PubMed  Google Scholar 

  132. Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).

    CAS  PubMed  Google Scholar 

  133. Goldfine, A. B. et al. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann. Intern. Med. 159, 1–12 (2013).

    PubMed  PubMed Central  Google Scholar 

  134. Nicolazzo, J. A. & Mehta, D. C. Transport of drugs across the blood–brain barrier in Alzheimer's disease. Ther. Deliv. 1, 595–611 (2010).

    CAS  PubMed  Google Scholar 

  135. de Lange, E. C. & Hammarlund-Udenaes, M. Translational aspects of blood–brain barrier transport and central nervous system effects of drugs: from discovery to patients. Clin. Pharmacol. Ther. 97, 380–394 (2015).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The work of C.C. and C.A.A. is supported by the European Fund for Economic and Regional Development, with financial resources provided through the Operational Programme Competitiveness Factors and Foundation for Science and Technology (strategic project UID/NEU/04539/2013), the Projeto Mais Centro (CENTRO-07-ST24-FEDER-002006) and FCT/CAPES (340/13). The work of G.F.P.S and L.A.V. is supported by the Sao Paulo Research Foundation and the National Council for Scientific and Technological Development.

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Authors and Affiliations

  1. Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3004–504, Portugal

    Cláudia Cavadas & Célia A. Aveleira

  2. Faculty of Pharmacy, University of Coimbra, Coimbra, 3004–504, Portugal

    Cláudia Cavadas

  3. Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, 1308–970, Brazil

    Gabriela F. P. Souza & Lício A. Velloso

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  1. Cláudia Cavadas
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  2. Célia A. Aveleira
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  3. Gabriela F. P. Souza
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  4. Lício A. Velloso
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Contributions

C.C., C.A.A., G.F.P.S. and L.A.V. researched the data for the article. C.C., C.A.A., G.F.P.S. and L.A.V. provided substantial contribution to discussions of the content. C.C., C.A.A., G.F.P.S. and L.A.V. contributed equally to writing the article. C.A.A., G.F.P.S. and L.A.V. contributed to reviewing and/or editing of the manuscript before submission.

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Correspondence to Lício A. Velloso.

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Cavadas, C., Aveleira, C., Souza, G. et al. The pathophysiology of defective proteostasis in the hypothalamus — from obesity to ageing. Nat Rev Endocrinol 12, 723–733 (2016). https://doi.org/10.1038/nrendo.2016.107

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