Skip to main content Accessibility help
×
Home

Hypothalamic dysfunction in obesity

  • Lynda M. Williams (a1)

Abstract

A growing number of studies have shown that a diet high in long chain SFA and/or obesity cause profound changes to the energy balance centres of the hypothalamus which results in the loss of central leptin and insulin sensitivity. Insensitivity to these important anorexigenic messengers of nutritional status perpetuates the development of both obesity and peripheral insulin insensitivity. A high-fat diet induces changes in the hypothalamus that include an increase in markers of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, autophagy defect and changes in the rate of apoptosis and neuronal regeneration. In addition, a number of mechanisms have recently come to light that are important in the hypothalamic control of energy balance, which could play a role in perpetuating the effect of a high-fat diet on hypothalamic dysfunction. These include: reactive oxygen species as an important second messenger, lipid metabolism, autophagy and neuronal and synaptic plasticity. The importance of nutritional activation of the Toll-like receptor 4 and the inhibitor of NF-κB kinase subunit β/NK-κB and c-Jun amino-terminal kinase 1 inflammatory pathways in linking a high-fat diet to obesity and insulin insensitivity via the hypothalamus is now widely recognised. All of the hypothalamic changes induced by a high-fat diet appear to be causally linked and inhibitors of inflammation, ER stress and autophagy defect can prevent or reverse the development of obesity pointing to potential drug targets in the prevention of obesity and metabolic dysfunction.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Hypothalamic dysfunction in obesity
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Hypothalamic dysfunction in obesity
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Hypothalamic dysfunction in obesity
      Available formats
      ×

Copyright

Corresponding author

Corresponding author: Lynda M. Williams, fax +44 1224 438 699, email: L.Williams@abdn.ac.uk

References

Hide All
1. Brown, WV, Fujioka, K, Wilson, PW et al. (2009) Obesity: why be concerned? Am J Med 122, S4–S11.
2. Luchsinger, JA & Gustafson, DR (2009) Adiposity, type 2 diabetes, and Alzheimer's disease. J Alzheimers Dis 16, 693704.
3. Butland, B, Jebb, S, Kopelman, P et al. (2007) Tackling Obesities: Future Choices – Foresight Project Report, 2nd edition. Government Office for Science.
4. Hex, N, Bartlett, C, Wright, D et al. (2012) Estimating the current and future costs of type 1 and type 2 diabetes in the United Kingdom, including direct health costs and indirect societal and productivity costs. Diabetes Medicine 29, 855862.
5. Galgani, J & Ravussin, E (2008) Energy metabolism, fuel selection and body weight regulation. Int J Obes 32, S109S119.
6. Farooqi, IS & O'Rahilly, S (2007) Genetic factors in human obesity. Obes Rev 8 3740.
7. Velloso, LA & Schwartz, MW (2011) Altered hypothalamic function in diet-induced obesity. Int J Obes 35, 14551465.
8. Wynne, K, Stanley, S, McGowan, B et al. (2005) Appetite control. J Endocrinol 184, 291318.
9. Berthoud, HR (2002) Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev 26, 393428.
10. Lopez, M, Tovar, S, Vazquez, MJ et al. (2007) Peripheral tissue-brain interactions in the regulation of food intake. Proc Nutr Soc 66, 131155.
11. Lam, TK, Schwartz, GJ & Rossetti, L (2005) Hypothalamic sensing of fatty acids. Nat Neurosci 8, 579584.
12. Blouet, C & Schwartz, GJ (2010) Hypothalamic nutrient sensing in the control of energy homeostasis. Behav Brain Res 209, 112.
13. Dieguez, C, Vazquez, MJ, Romero, A et al. (2011) Hypothalamic control of lipid metabolism: focus on leptin, ghrelin and melanocortins. Neuroendocrinology 94, 111.
14. Koch, C, Augustine, RA, Steger, J et al. (2010) Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. J Neurosci 30, 1618016187.
15. Nogueiras, R, Wiedmer, P, Perez-Tilve, D et al. (2007) The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 117, 34753488.
16. Perez-Tilve, D, Hofmann, SM, Basford, J et al. (2010) Melanocortin signaling in the CNS directly regulates circulating cholesterol. Nat Neurosci 13, 877882.
17. Bruinstroop, E, Pei, L, Ackermans, MT et al. (2012) Hypothalamic neuropeptide Y (NPY) controls hepatic VLDL-triglyceride secretion in rats via the sympathetic nervous system. Diabetes 61, 10431050.
18. Koch, L, Wunderlich, FT, Seibler, J et al. (2008) Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Invest 118, 21322147.
19. Obici, S, Feng, Z, Arduini, A et al. (2003) Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 9, 756761.
20. Lam, TK, Gutierrez-Juarez, R, Pocai, A et al. (2005) Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309, 943947.
21. Farooqi, IS & O'Rahilly, S (2009) Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr 89, 980S984S.
22. Berglund, ED, Vianna, CR, Donato, J Jr. et al. (2012) Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Invest 122, 10001009.
23. Nogueiras, R, Williams, LM & Dieguez, C (2010) Ghrelin: new molecular pathways modulating appetite and adiposity. Obes Facts 3, 285292.
24. Cummings, DE (2006) Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav 89, 7184.
25. Briggs, DI, Enriori, PJ, Lemus, MB et al. (2010) Diet-induced obesity causes ghrelin resistance in arcuate AgRP/NPY neurons. Endocrinol 151, 47454755.
26. Jeffery, RW & Harnack, LJ (2007) Evidence implicating eating as a primary driver for the obesity epidemic. Diabetes 56, 26732676.
27. Calder, PC, Ahluwalia, N, Brouns, F et al. (2011) Dietary factors and low-grade inflammation in relation to overweight and obesity. Br J Nutr 106, S5S78.
28. Kolb, H & Mandrup-Poulsen, T (2010) The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation. Diabetologia 53, 1020.
29. Hotamisligil, GS (2006) Inflammation and metabolic disorders. Nature 44, 860867.
30. Mathis, D & Shoelson, SE (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11, 81.
31. Fessler, MB, Rudel, LL & Brown, JM (2009) Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome. Curr Opin Lipidol 20, 379385.
32. de Souza, CT, Araujo, EP, Bordin, S et al. (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinol 146, 41924199.
33. Zhang, X, Zhang, G, Zhang, H et al. (2008) Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 6173.
34. Posey, KA, Clegg, DJ, Printz, RL et al. (2009) Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol 296, E1003E1012.
35. Thaler, JP, Yi, CX, Schur, EA et al. (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122, 153162.
36. Wisse, BE, Ogimoto, K, Tang, J et al. (2007) Evidence that lipopolysaccharide-induced anorexia depends upon central, rather than peripheral, inflammatory signals. Endocrinology 148, 52305237.
37. Thaler, JP, Choi, SJ, Schwartz, MW et al. (2010) Hypothalamic inflammation and energy homeostasis: resolving the paradox. Front Neuroendocrinol 31, 7984.
38. Cai, D & Liu, T (2012) Inflammatory cause of metabolic syndrome via brain stress and NF-kappaB. Aging 4, 98–115.
39. Diano, S, Liu, ZW, Jeong, JK et al. (2011) Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat Med 17, 11211127.
40. Andrews, ZB, Liu, ZW, Walllingford, N et al. (2008) UCP2 mediates ghrelin's action on AgRP/NPY neurons by lowering free radicals. Nature 454, 846851.
41. Yang, L & Hotamisligil, GS (2008) Stressing the brain, fattening the body. Cell 135, 2022.
42. Pinto, S, Roseberry, AG, Liu, H et al. (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110115.
43. McNay, DE, Briancon, N, Kokoeva, MV et al. (2012) Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice. J Clin Invest 122, 142152.
44. Yang, Y, Atasoy, D, Su, HH et al. (2011) Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992–1003.
45. Thaler, JP, Yi, C-X, Hwang, BH et al. (2010) Rapid onset of hypothalamic inflammation reactive gliosis and microglial accumulation during high-fat diet-induced obesity. Endocrine Rev 32, OR33-1.
46. Solinas, G & Karin, M (2010) JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J 24, 25962611.
47. Chen, CY, Gherzi, R, Andersen, JS et al. (2000) Nucleolin and YB-1 are required for JNK-mediated interleukin-2 mRNA stabilization during T-cell activation. Genes Dev 14, 12361248.
48. Chen, CY, Del Gatto-Konczak, F, Wu, Z et al. (1998) Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. Science 280, 19451949.
49. Hayden, MS & Ghosh, S (2008) Shared principles in NF-kappaB signaling. Cell 132, 344362.
50. Chiolero, R, Revelly, JP & Tappy, L (1997) Energy metabolism in sepsis and injury. Nutrition 13, 45S51S.
51. Williamson, RT (1901) On the treatment of glycosuria and diabetes mellitus with sodium Salicylate. Br Med J 1, 760762.
52. Reid, J, MacDougall, AI & Andrews, MM (1957) Aspirin and diabetes mellitus. Br Med J 2, 10711074.
53. Kim, JK, Kim, YJ, Fillmore, JJ et al. (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108, 437446.
54. Hotamisligil, GS (2006) Inflammation and metabolic disorders. Nature 444, 860867.
55. Lee, DF, Kuo, HP, Chen, CT et al. (2007) IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130, 440455.
56. Cota, D, Proulx, K, Smith, KA et al. (2006) Hypothalamic mTOR signaling regulates food intake. Science 312, 927930.
57. Ozcan, U, Ozcan, L, Yilmaz, E et al. (2008) Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 29, 541551.
58. Unger, EK, Piper, ML, Olofsson, LE et al. (2010) Functional role of c-Jun-N-terminal kinase in feeding regulation. Endocrinol 151, 671682.
59. Cai, D, Yuan, M, Frantz, DF et al. (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11, 183190.
60. Serhan, CN, Brain, SD, Buckley, CD et al. (2007) Resolution of inflammation: state of the art, definitions and terms. FASEB J 21, 325332.
61. Xu, H, Barnes, GT, Yang, Q et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112, 18211830.
62. Apovian, CM, Bigornia, S, Mott, M et al. (2008) Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects. Arterioscler Thromb Vasc Biol 28, 16541659.
63. Wood, IS, de Heredia, FP, Wang, B et al. (2009) Cellular hypoxia and adipose tissue dysfunction in obesity. Proc Nutr Soc 68, 370377.
64. Sanyal, AJ, Campbell-Sargent, C, Mirshahi, F et al. (2001) Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 11831192.
65. Kosteli, A, Sugaru, E, Haemmerle, G et al. (2010) Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest 120, 34663479.
66. Uysal, KT, Wiesbrock, SM, Marino, MW et al. (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610614.
67. Hotamisligil, GS, Shargill, NS & Spiegelman, BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 8791.
68. Bernstein, LE, Berry, J, Kim, S et al. (2006) Effects of etanercept in patients with the metabolic syndrome. Arch Intern Med 166, 902908.
69. Nappo, F, Esposito, K, Cioffi, M et al. (2002) Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol 39, 11451150.
70. van Oostrom, AJ, Rabelink, TJ, Verseyden, C et al. (2004) Activation of leukocytes by postprandial lipemia in healthy volunteers. Atherosclerosis 177, 175182.
71. Blanco-Colio, LM, Valderrama, M, varez-Sala, LA et al. (2000) Red wine intake prevents nuclear factor-kappaB activation in peripheral blood mononuclear cells of healthy volunteers during postprandial lipemia. Circulation 102, 10201026.
72. Erridge, C (2011) The capacity of foodstuffs to induce innate immune activation of human monocytes in vitro is dependent on food content of stimulants of Toll-like receptors 2 and 4. Br J Nutr 105, 1523.
73. Cani, PD, Amar, J, Iglesias, MA et al. (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 17611772.
74. Erridge, C, Attina, T, Spickett, CM et al. (2007) A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 86, 12861292.
75. Lee, JY, Ye, J, Gao, Z et al. (2003) Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem 278, 3704137051.
76. Lee, JY, Zhao, L, Youn, HS et al. (2004) Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem 279, 1697116979.
77. Lee, JY, Plakidas, A, Lee, WH et al. (2003) Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res 44, 479486.
78. Shi, H, Kokoeva, MV, Inouye, K et al. (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116, 30153025.
79. Saberi, M, Woods, NB, de, LC, Schenk, S et al. (2009) Hematopoietic cell-specific deletion of Toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab 10, 419429.
80. Tsukumo, DM, Carvalho-Filho, MA, Carvalheira, JB et al. (2007) Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56, 19861998.
81. Poggi, M, Bastelica, D, Gual, P et al. (2007) C3H/HeJ mice carrying a Toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50, 12671276.
82. Schwartz, EA, Zhang, WY, Karnik, SK et al. (2010) Nutrient modification of the innate immune response: a novel mechanism by which saturated fatty acids greatly amplify monocyte inflammation. Arterioscler Thromb Vasc Biol 30, 802808.
83. Erridge, C & Samani, NJ (2009) Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler Thromb Vasc Biol 29, 19441949.
84. Chavez, JA & Summers, SA (2003) Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch Biochem Biophys 419, 101109.
85. Arkan, MC, Hevener, AL, Greten, FR et al. (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11, 191198.
86. Hirosumi, J, Tuncman, G, Chang, L et al. (2002) A central role for JNK in obesity and insulin resistance. Nature 420, 333336.
87. Kim, F, Pham, M, Maloney, E et al. (2008) Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance. Arterioscler Thromb Vasc Biol 28, 19821988.
88. Summers, SA (2006) Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 45, 4272.
89. Zigman, JM & Elmquist, JK (2003) Minireview: From anorexia to obesity – the Yin and Yang of body weight control. Endocrinology 144, 37493756.
90. Tao, YX (2009) Mutations in melanocortin-4 receptor and human obesity. Prog Mol Biol Transl Sci 88, 173204.
91. Cone, RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8, 571578.
92. Horvath, TL, Bechmann, I, Naftolin, F et al. (1997) Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations. Brain Res 756, 283286.
93. Theodosis, DT, Poulain, DA & Oliet, SH (2008) Activity-dependent structural and functional plasticity of astrocyte-neuron interactions. Physiol Rev 88, 983–1008.
94. Horvath, TL, Sarman, B, Garcia-Caceres, C et al. (2010) Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci USA 107, 1487514880.
95. Badoer, E (2010) Microglia: activation in acute and chronic inflammatory states and in response to cardiovascular dysfunction. Int J Biochem Cell Biol 42, 15801585.
96. Gloaguen, I, Costa, P, Demartis, A et al. (1997) Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance. Proc Natl Acad Sci USA 94, 64566461.
97. Kokoeva, MV, Yin, H & Flier, JS (2005) Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310, 679683.
98. Ettinger, MP, Littlejohn, TW, Schwartz, SL et al. (2003) Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA 289, 18261832.
99. Lambert, PD, Anderson, KD, Sleeman, MW et al. (2001) Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Proc Natl Acad Sci USA 98, 46524657.
100. Sleeman, MW, Garcia, K, Liu, R et al. (2003) Ciliary neurotrophic factor improves diabetic parameters and hepatic steatosis and increases basal metabolic rate in db/db mice. Proc Natl Acad Sci USA 100, 1429714302.
101. Sleeman, MW, Anderson, KD, Lambert, PD et al. (2000) The ciliary neurotrophic factor and its receptor, CNTFR alpha. Pharm Acta Helv 74, 265272.
102. Pencea, V, Bingaman, KD, Wiegand, SJ et al. (2001) Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21, 67066717.
103. Xu, Y, Tamamaki, N, Noda, T et al. (2005) Neurogenesis in the ependymal layer of the adult rat 3rd ventricle. Exp Neurol 192, 251264.
104. Kokoeva, MV, Yin, H & Flier, JS (2007) Evidence for constitutive neural cell proliferation in the adult murine hypothalamus. J Comp Neurol 505, 209220.
105. Muppidi, JR, Tschopp, J & Siegel, RM (2004) Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction. Immunity 21, 461465.
106. Mkaddem, SB, Bens, M & Vandewalle, A (2010) Differential activation of Toll-like receptor-mediated apoptosis induced by hypoxia. Oncotarget 1, 741750.
107. Moraes, JC, Coope, A, Morari, J et al. (2009) High-fat diet induces apoptosis of hypothalamic neurons. PLoS One 4, e5045.
108. Lee, DA, Bedont, JL, Pak, T et al. (2012) Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat Neurosci 15, 700702.
109. Frayn, KN & Coppack, SW (1992) Insulin resistance, adipose tissue and coronary heart disease. Clin Sci 82, 18.
110. Frayn, KN, Williams, CM & Arner, P (1996) Are increased plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases? Clin Sci 90, 243253.
111. Karpe, F, Dickmann, JR & Frayn, KN (2011) Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 60, 24412449.
112. Erion, DM & Shulman, GI (2010) Diacylglycerol-mediated insulin resistance. Nat Med 16, 400402.
113. Unger, RH, Clark, GO, Scherer, PE et al. (2010) Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 1801, 209214.
114. Karmi, A, Iozzo, P, Viljanen, A et al. (2010) Increased brain fatty acid uptake in metabolic syndrome. Diabetes 59, 21712177.
115. Chang, GQ, Karatayev, O, Davydova, Z et al. (2004) Circulating triglycerides impact on orexigenic peptides and neuronal activity in hypothalamus. Endocrinology 145, 39043912.
116. Obici, S, Feng, Z, Morgan, K et al. (2002) Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51, 271275.
117. Loftus, TM, Jaworsky, DE, Frehywot, GL et al. (2000) Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 23792381.
118. Kim, EK, Miller, I, Landree, LE et al. (2002) Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment. Am J Physiol 283, E867E879.
119. Lopez, M, Lelliott, CJ, Tovar, S et al. (2006) Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes 55, 13271336.
120. Kaushik, S, Rodriguez-Navarro, JA, Arias, E et al. (2011) Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab 14, 173183.
121. Lopez, M, Varela, L, Vazquez, MJ et al. (2010) Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 6, 10011008.
122. Lopez, M, Lage, R, Saha, AK et al. (2008) Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab 7, 389399.
123. Mizuno, TM & Mobbs, CV (1999) Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 140, 814817.
124. Liu, T, Kong, D, Shah, BP et al. (2012) Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73, 511522.
125. Cowley, MA, Smith, RG, Diano, S et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649661.
126. Kamegai, J, Tamura, H, Shimizu, T et al. (2000) Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. Endocrinology 141, 47974800.
127. Quan, W, Kim, HK, Moon, EY et al. (2012) Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response. Endocrinology 153, 18171826.
128. Meng, Q & Cai, D (2011) Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IkappaB kinase beta (IKKbeta)/NF-kappaB pathway. J Biol Chem 286, 3232432332.
129. Yi, CX, Habegger, KM, Chowen, JA et al. (2011) A role for astrocytes in the central control of metabolism. Neuroendocrinology 93, 143149.
130. Holland, WL, Bikman, BT, Wang, LP et al. (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 121, 18581870.
131. Martinez de Morentin, PB, Varela, L, Ferno, J et al. (2010) Hypothalamic lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 1801, 350361.
132. Cintra, DE, Ropelle, ER, Moraes, JC et al. (2012) Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS One 7, e30571.
133. Yorimitsu, T & Klionsky, DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12, 15421552.
134. Butler, D & Bahr, BA (2006) Oxidative stress and lysosomes: CNS-related consequences and implications for lysosomal enhancement strategies and induction of autophagy. Antioxid Redox Signal 8, 185196.
135. Yorimitsu, T, Nair, U, Yang, Z et al. (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281, 3029930304.
136. Fujishima, Y, Nishiumi, S, Masuda, A et al. (2011) Autophagy in the intestinal epithelium reduces endotoxin-induced inflammatory responses by inhibiting NF-kappaB activation. Arch Biochem Biophys 506, 223235.
137. Raichle, ME & Gusnard, DA (2002) Appraising the brain's energy budget. Proc Natl Acad Sci USA 99, 1023710239.
138. Melov, S (2004) Modeling mitochondrial function in aging neurons. Trends Neurosci 27, 601606.
139. Lin, MT & Beal, MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787795.
140. Matsuzawa-Nagata, N, Takamura, T, Ando, H et al. (2008) Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism 57, 10711077.
141. Benani, A, Troy, S, Carmona, MC et al. (2007) Role for mitochondrial reactive oxygen species in brain lipid sensing: redox regulation of food intake. Diabetes 56, 152160.
142. Leloup, C, Magnan, C, Benani, A et al. (2006) Mitochondrial reactive oxygen species are required for hypothalamic glucose sensing. Diabetes 55, 20842090.
143. Colombani, AL, Carneiro, L, Benani, A et al. (2009) Enhanced hypothalamic glucose sensing in obesity: alteration of redox signaling. Diabetes 58, 21892197.
144. Schrader, M & Fahimi, HD (2006) Peroxisomes and oxidative stress. Biochim Biophys Acta 1763, 17551766.
145. Du, X, Edelstein, D, Obici, S et al. (2006) Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest 116, 10711080.
146. Yamagishi, SI, Edelstein, D, Du, XL et al. (2001) Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem 276, 2509625100.
147. Walter, P & Ron, D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 10811086.
148. Fonseca, SG, Gromada, J & Urano, F (2011) Endoplasmic reticulum stress and pancreatic beta-cell death. Trends Endocrinol Metab 22, 266274.
149. Ozcan, U, Cao, Q, Yilmaz, E et al. (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457461.
150. Ozcan, U, Yilmaz, E, Ozcan, L et al. (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 11371140.
151. Ron, D & Walter, P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8, 519529.
152. Hosoi, T, Sasaki, M, Miyahara, T et al. (2008) Endoplasmic reticulum stress induces leptin resistance. Mol Pharmacol 74, 16101619.
153. Woods, SC, D'Alessio, DA, Tso, P et al. (2004) Consumption of a high-fat diet alters the homeostatic regulation of energy balance. Physiol Behav 83, 573578.
154. Wang, J, Obici, S, Morgan, K et al. (2001) Overfeeding rapidly induces leptin and insulin resistance. Diabetes 50, 27862791.
155. Xu, AW, Kaelin, CB, Takeda, K et al. (2005) PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115, 951958.
156. Morton, GJ, Gelling, RW, Niswender, KD et al. (2005) Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2, 411420.
157. Kim, MS, Pak, YK, Jang, PG et al. (2006) Role of hypothalamic FoxO1 in the regulation of food intake and energy homeostasis. Nat Neurosci 9, 901906.
158. Kitamura, T, Feng, Y, Kitamura, YI et al. (2006) Forkhead protein FoxO1 mediates AgRP-dependent effects of leptin on food intake. Nat Med 12, 534540.
159. Howard, JK & Flier, JS (2006) Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab 17, 365371.
160. Kievit, P, Howard, JK, Badman, MK et al. (2006) Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab 4, 123132.
161. Bence, KK, Delibegovic, M, Xue, B et al. (2006) Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 12, 917924.
162. Prada, PO, Zecchin, HG, Gasparetti, AL et al. (2005) Western diet modulates insulin signaling, c-Jun N-terminal kinase activity, and insulin receptor substrate-1ser307 phosphorylation in a tissue-specific fashion. Endocrinology 146, 15761587.
163. Romanatto, T, Cesquini, M, Amaral, ME et al. (2007) TNF-alpha acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient – effects on leptin and insulin signaling pathways. Peptides 28, 10501058.
164. Zabolotny, JM, ce-Hanulec, KK, Stricker-Krongrad, A et al. (2002) PTP1B regulates leptin signal transduction in vivo . Dev Cell 2, 489495.
165. Zabolotny, JM, Kim, YB, Welsh, LA et al. (2008) Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. J Biol Chem 283, 1423014241.
166. Ito, Y, Banno, R, Hagimoto, S et al. (2012) TNFalpha increases hypothalamic PTP1B activity via the NFkappaB pathway in rat hypothalamic organotypic cultures. Regul Pept 174, 5864.
167. Ozcan, L, Ergin, AS, Lu, A et al. (2009) Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9, 3551.
168. Kleinridders, A, Schenten, D, Konner, AC et al. (2009) MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10, 249259.
169. Lehnardt, S, Massillon, L, Follett, P et al. (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA 100, 85148519.
170. Choi, SJ, Kim, F, Schwartz, MW et al. (2010) Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids. Am J Physiol 298, E1122E1130.
171. Mayer, CM & Belsham, DD (2010) Palmitate attenuates insulin signaling and induces endoplasmic reticulum stress and apoptosis in hypothalamic neurons: rescue of resistance and apoptosis through adenosine 5′ monophosphate-activated protein kinase activation. Endocrinology 151, 576585.

Keywords

Hypothalamic dysfunction in obesity

  • Lynda M. Williams (a1)

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed