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http://dx.doi.org/10.14348/molcells.2022.2044

Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity  

Sa, Moonsun (KU-KIST Graduate School of Converging Science and Technology, Korea University)
Park, Mingu Gordon (KU-KIST Graduate School of Converging Science and Technology, Korea University)
Lee, C. Justin (KU-KIST Graduate School of Converging Science and Technology, Korea University)
Publication Information
Molecules and Cells / v.45, no.2, 2022 , pp. 65-75 More about this Journal
Abstract
Hypothalamus is a brain region that controls food intake and energy expenditure while sensing signals that convey information about energy status. Within the hypothalamus, molecularly and functionally distinct neurons work in concert under physiological conditions. However, under pathological conditions such as in diet-induced obesity (DIO) model, these neurons show dysfunctional firing patterns and distorted regulation by neurotransmitters and neurohormones. Concurrently, resident glial cells including astrocytes dramatically transform into reactive states. In particular, it has been reported that reactive astrogliosis is observed in the hypothalamus, along with various neuroinflammatory signals. However, how the reactive astrocytes control and modulate DIO by influencing neighboring neurons is not well understood. Recently, new lines of evidence have emerged indicating that these reactive astrocytes directly contribute to the pathology of obesity by synthesizing and tonically releasing the major inhibitory transmitter GABA. The released GABA strongly inhibits the neighboring neurons that control energy expenditure. These surprising findings shed light on the interplay between reactive astrocytes and neighboring neurons in the hypothalamus. This review summarizes recent discoveries related to the functions of hypothalamic reactive astrocytes in obesity and raises new potential therapeutic targets against obesity.
Keywords
gliotransmitter; high-fat diet; hypothalamus; obesity; reactive astrocytes;
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1 Chun, H. and Lee, C.J. (2018). Reactive astrocytes in Alzheimer's disease: a double-edged sword. Neurosci. Res. 126, 44-52.   DOI
2 Verkhratsky, A., Zorec, R., and Parpura, V. (2017). Stratification of astrocytes in healthy and diseased brain. Brain Pathol. 27, 629-644.   DOI
3 Wang, S.W., Wang, M., Grossman, B.M., and Martin, R.J. (1994). Effects of dietary fat on food intake and brain uptake and oxidation of fatty acids. Physiol. Behav. 56, 517-522.   DOI
4 Xu, L., Emery, J.F., Ouyang, Y.B., Voloboueva, L.A., and Giffard, R.G. (2010). Astrocyte targeted overexpression of Hsp72 or SOD2 reduces neuronal vulnerability to forebrain ischemia. Glia 58, 1042-1049.   DOI
5 Yaswen, L., Diehl, N., Brennan, M.B., and Hochgeschwender, U. (1999). Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat. Med. 5, 1066-1070.   DOI
6 Yi, C.X., Gericke, M., Kruger, M., Alkemade, A., Kabra, D.G., Hanske, S., Filosa, J., Pfluger, P., Bingham, N., Woods, S.C., et al. (2012). High calorie diet triggers hypothalamic angiopathy. Mol. Metab. 1, 95-100.   DOI
7 Yoon, B.E. and Lee, C.J. (2014). GABA as a rising gliotransmitter. Front. Neural Circuits 8, 141.   DOI
8 Moraes, J.C., Coope, A., Morari, J., Cintra, D.E., Roman, E.A., Pauli, J.R., Romanatto, T., Carvalheira, J.B., Oliveira, A.L., Saad, M.J., et al. (2009). High-fat diet induces apoptosis of hypothalamic neurons. PLoS One 4, e5045.   DOI
9 Myers, M.G., Jr., Munzberg, H., Leinninger, G.M., and Leshan, R.L. (2009). The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab. 9, 117-123.   DOI
10 Escartin, C., Galea, E., Lakatos, A., O'Callaghan, J.P., Petzold, G.C., Serrano-Pozo, A., Steinhauser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al. (2021). Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24, 312-325.   DOI
11 Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J., and Cone, R.D. (1997). Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165-168.   DOI
12 Horvath, T.L., Sarman, B., Garcia-Caceres, C., Enriori, P.J., Sotonyi, P., Shanabrough, M., Borok, E., Argente, J., Chowen, J.A., Perez-Tilve, D., et al. (2010). Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc. Natl. Acad. Sci. U. S. A. 107, 14875-14880.   DOI
13 Jo, S., Yarishkin, O., Hwang, Y.J., Chun, Y.E., Park, M., Woo, D.H., Bae, J.Y., Kim, T., Lee, J., Chun, H., et al. (2014). GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease. Nat. Med. 20, 886-896.   DOI
14 Pandit, S., Neupane, C., Woo, J., Sharma, R., Nam, M.H., Lee, G.S., Yi, M.H., Shin, N., Kim, D.W., Cho, H., et al. (2020). Bestrophin1-mediated tonic GABA release from reactive astrocytes prevents the development of seizure-prone network in kainate-injected hippocampi. Glia 68, 1065-1080.   DOI
15 Garcia-Caceres, C., Quarta, C., Varela, L., Gao, Y., Gruber, T., Legutko, B., Jastroch, M., Johansson, P., Ninkovic, J., Yi, C.X., et al. (2016). Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166, 867-880.   DOI
16 Gonzalez-Garcia, I., Ferno, J., Dieguez, C., Nogueiras, R., and Lopez, M. (2017). Hypothalamic lipids: key regulators of whole body energy balance. Neuroendocrinology 104, 398-411.   DOI
17 Guyenet, S.J., Nguyen, H.T., Hwang, B.H., Schwartz, M.W., Baskin, D.G., and Thaler, J.P. (2013). High-fat diet feeding causes rapid, non-apoptotic cleavage of caspase-3 in astrocytes. Brain Res. 1512, 97-105.   DOI
18 Hill, J.W. (2012). PVN pathways controlling energy homeostasis. Indian J. Endocrinol. Metab. 16(Suppl 3), S627-S636.
19 Borg, M.L., Omran, S.F., Weir, J., Meikle, P.J., and Watt, M.J. (2012). Consumption of a high-fat diet, but not regular endurance exercise training, regulates hypothalamic lipid accumulation in mice. J. Physiol. 590, 4377-4389.   DOI
20 Bedner, P., Dupper, A., Huttmann, K., Muller, J., Herde, M.K., Dublin, P., Deshpande, T., Schramm, J., Haussler, U., Haas, C.A., et al. (2015). Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain 138, 1208-1222.   DOI
21 Chun, H., Im, H., Kang, Y.J., Kim, Y., Shin, J.H., Won, W., Lim, J., Ju, Y., Park, Y.M., Kim, S., et al. (2020). Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer's disease via H2O2(-) production. Nat. Neurosci. 23, 1555-1566.   DOI
22 Michetti, F., D'Ambrosi, N., Toesca, A., Puglisi, M.A., Serrano, A., Marchese, E., Corvino, V., and Geloso, M.C. (2019). The S100B story: from biomarker to active factor in neural injury. J. Neurochem. 148, 168-187.   DOI
23 Ju, Y.H., Bhalla, M., Hyeon, S.J., Oh, J.E., Yoo, S., Chae, U., Kwon, J., Koh, W., Lim, J., Park, Y.M., et al. (2021). Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer's disease. BioRxiv, https://doi.org/10.1101/2021.10.15.464517   DOI
24 Gruber, T., Pan, C., Contreras, R.E., Wiedemann, T., Morgan, D.A., Skowronski, A.A., Lefort, S., De Bernardis Murat, C., Le Thuc, O., Legutko, B., et al. (2021). Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension. Cell Metab. 33, 1155-1170.e10.   DOI
25 Gupta, S., Knight, A.G., Gupta, S., Keller, J.N., and Bruce-Keller, A.J. (2012). Saturated long-chain fatty acids activate inflammatory signaling in astrocytes. J. Neurochem. 120, 1060-1071.   DOI
26 Konturek, P.C., Konturek, J.W., Czesnikiewicz-Guzik, M., Brzozowski, T., Sito, E., and Konturek, S.J. (2005). Neuro-hormonal control of food intake: basic mechanisms and clinical implications. J. Physiol. Pharmacol. 56 Suppl 6, 5-25.
27 Lee, D., Thaler, J.P., Berkseth, K.E., Melhorn, S.J., Schwartz, M.W., and Schur, E.A. (2013). Longer T(2) relaxation time is a marker of hypothalamic gliosis in mice with diet-induced obesity. Am. J. Physiol. Endocrinol. Metab. 304, E1245-E1250.   DOI
28 Moulle, V.S., Picard, A., Le Foll, C., Levin, B.E., and Magnan, C. (2014). Lipid sensing in the brain and regulation of energy balance. Diabetes Metab. 40, 29-33.   DOI
29 Timper, K. and Bruning, J.C. (2017). Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity. Dis. Model. Mech. 10, 679-689.   DOI
30 Wang, Y., Hsuchou, H., He, Y., Kastin, A.J., and Pan, W. (2015). Role of astrocytes in leptin signaling. J. Mol. Neurosci. 56, 829-839.   DOI
31 Heo, J.Y., Nam, M.H., Yoon, H.H., Kim, J., Hwang, Y.J., Won, W., Woo, D.H., Lee, J.A., Park, H.J., Jo, S., et al. (2020). Aberrant tonic inhibition of dopaminergic neuronal activity causes motor symptoms in animal models of Parkinson's disease. Curr. Biol. 30, 276-291.e9.   DOI
32 Ben Haim, L., Carrillo-de Sauvage, M.A., Ceyzeriat, K., and Escartin, C. (2015). Elusive roles for reactive astrocytes in neurodegenerative diseases. Front. Cell. Neurosci. 9, 278.   DOI
33 Escartin, C., Guillemaud, O., and Carrillo-de Sauvage, M.A. (2019). Questions and (some) answers on reactive astrocytes. Glia 67, 2221-2247.   DOI
34 Gantz, I., Konda, Y., Tashiro, T., Shimoto, Y., Miwa, H., Munzert, G., Watson, S.J., DelValle, J., and Yamada, T. (1993). Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 268, 8246-8250.   DOI
35 Argaw, A.T., Asp, L., Zhang, J., Navrazhina, K., Pham, T., Mariani, J.N., Mahase, S., Dutta, D.J., Seto, J., Kramer, E.G., et al. (2012). Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J. Clin. Invest. 122, 2454-2468.   DOI
36 Balland, E. and Cowley, M.A. (2017). Short-term high-fat diet increases the presence of astrocytes in the hypothalamus of C57BL6 mice without altering leptin sensitivity. J. Neuroendocrinol. 29, e12504.   DOI
37 Belanger, M., Allaman, I., and Magistretti, P.J. (2011). Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 14, 724-738.   DOI
38 Chun, H., Lim, J., Park, K.D., and Lee, C.J. (2022). Inhibition of monoamine oxidase B prevents reactive astrogliosis and scar formation in stab wound injury model. Glia 70, 354-367.   DOI
39 Buckman, L.B., Thompson, M.M., Lippert, R.N., Blackwell, T.S., Yull, F.E., and Ellacott, K.L. (2015). Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice. Mol. Metab. 4, 58-63.   DOI
40 Buckman, L.B., Thompson, M.M., Moreno, H.N., and Ellacott, K.L. (2013). Regional astrogliosis in the mouse hypothalamus in response to obesity. J. Comp. Neurol. 521, 1322-1333.   DOI
41 Cai, D. and Liu, T. (2011). Hypothalamic inflammation: a double-edged sword to nutritional diseases. Ann. N. Y. Acad. Sci. 1243, E1-E39.   DOI
42 Cansell, C., Stobbe, K., Sanchez, C., Le Thuc, O., Mosser, C.A., Ben-Fradj, S., Leredde, J., Lebeaupin, C., Debayle, D., Fleuriot, L., et al. (2021). Dietary fat exacerbates postprandial hypothalamic inflammation involving glial fibrillary acidic protein-positive cells and microglia in male mice. Glia 69, 42-60.   DOI
43 de Git, K.C. and Adan, R.A. (2015). Leptin resistance in diet-induced obesity: the role of hypothalamic inflammation. Obes. Rev. 16, 207-224.   DOI
44 Choi, H.B., Gordon, G.R., Zhou, N., Tai, C., Rungta, R.L., Martinez, J., Milner, T.A., Ryu, J.K., McLarnon, J.G., Tresguerres, M., et al. (2012). Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase. Neuron 75, 1094-1104.   DOI
45 Cohen, P.P. (1981). The ornithine-urea cycle: biosynthesis and regulation of carbamyl phosphate synthetase I and ornithine transcarbamylase. Curr. Top. Cell. Regul. 18, 1-19.   DOI
46 de Almeida, I.T., Cortez-Pinto, H., Fidalgo, G., Rodrigues, D., and Camilo, M.E. (2002). Plasma total and free fatty acids composition in human nonalcoholic steatohepatitis. Clin. Nutr. 21, 219-223.   DOI
47 Eng, L.F. and Ghirnikar, R.S. (1994). GFAP and astrogliosis. Brain Pathol. 4, 229-237.   DOI
48 Lee, N., Sa, M., Hong, Y.R., Lee, C.J., and Koo, J. (2018). Fatty acid increases cAMP-dependent lactate and MAO-B-dependent GABA production in mouse astrocytes by activating a Galphas protein-coupled receptor. Exp. Neurobiol. 27, 365-376.   DOI
49 Lemus, M.B., Bayliss, J.A., Lockie, S.H., Santos, V.V., Reichenbach, A., Stark, R., and Andrews, Z.B. (2015). A stereological analysis of NPY, POMC, Orexin, GFAP astrocyte, and Iba1 microglia cell number and volume in diet-induced obese male mice. Endocrinology 156, 1701-1713.   DOI
50 Liao, G.Y., Kinney, C.E., An, J.J., and Xu, B. (2019). TrkB-expressing neurons in the dorsomedial hypothalamus are necessary and sufficient to suppress homeostatic feeding. Proc. Natl. Acad. Sci. U. S. A. 116, 3256-3261.   DOI
51 Miyata, S. (2015). New aspects in fenestrated capillary and tissue dynamics in the sensory circumventricular organs of adult brains. Front. Neurosci. 9, 390.   DOI
52 Liu, T.W., Heden, T.D., Matthew Morris, E., Fritsche, K.L., Vieira-Potter, V.J., and Thyfault, J.P. (2015). High-fat diet alters serum fatty acid profiles in obesity prone rats: implications for in vitro studies. Lipids 50, 997-1008.   DOI
53 Liu, X. and Zheng, H. (2019). Leptin-mediated sympathoexcitation in obese rats: role for neuron-astrocyte crosstalk in the arcuate nucleus. Front. Neurosci. 13, 1217.   DOI
54 Meijer, A.J., Lamers, W.H., and Chamuleau, R.A. (1990). Nitrogen metabolism and ornithine cycle function. Physiol. Rev. 70, 701-748.   DOI
55 Montgomery, M.K., Hallahan, N.L., Brown, S.H., Liu, M., Mitchell, T.W., Cooney, G.J., and Turner, N. (2013). Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding. Diabetologia 56, 1129-1139.   DOI
56 Morris, S.M., Jr. (2002). Regulation of enzymes of the urea cycle and arginine metabolism. Annu. Rev. Nutr. 22, 87-105.   DOI
57 Nillni, E.A. (2010). Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs. Front. Neuroendocrinol. 31, 134-156.   DOI
58 Garcia-Caceres, C., Balland, E., Prevot, V., Luquet, S., Woods, S.C., Koch, M., Horvath, T.L., Yi, C.X., Chowen, J.A., Verkhratsky, A., et al. (2019). Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat. Neurosci. 22, 7-14.   DOI
59 Giles, C., Takechi, R., Mellett, N.A., Meikle, P.J., Dhaliwal, S., and Mamo, J.C. (2016). The effects of long-term saturated fat enriched diets on the brain lipidome. PLoS One 11, e0166964.   DOI
60 Nam, M.H., Cho, J., Kwon, D.H., Park, J.Y., Woo, J., Lee, J.M., Lee, S., Ko, H.Y., Won, W., Kim, R.G., et al. (2020). Excessive astrocytic GABA causes cortical hypometabolism and impedes functional recovery after subcortical stroke. Cell Rep. 32, 107861.   DOI
61 Qin, C., Li, J., and Tang, K. (2018). The paraventricular nucleus of the hypothalamus: development, function, and human diseases. Endocrinology 159, 3458-3472.   DOI
62 Hidalgo, J., Florit, S., Giralt, M., Ferrer, B., Keller, C., and Pilegaard, H. (2010). Transgenic mice with astrocyte-targeted production of interleukin-6 are resistant to high-fat diet-induced increases in body weight and body fat. Brain Behav. Immun. 24, 119-126.   DOI
63 Gold, R.M. (1973). Hypothalamic obesity: the myth of the ventromedial nucleus. Science 182, 488-490.   DOI
64 Gonzalez-Garcia, I. and Garcia-Caceres, C. (2021). Hypothalamic astrocytes as a specialized and responsive cell population in obesity. Int. J. Mol. Sci. 22, 6176.   DOI
65 Gooley, J.J., Schomer, A., and Saper, C.B. (2006). The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms. Nat. Neurosci. 9, 398-407.   DOI
66 Hong, J., Stubbins, R.E., Smith, R.R., Harvey, A.E., and Nunez, N.P. (2009). Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutr. J. 8, 11.   DOI
67 Horvath, T.L., Diano, S., and Tschop, M. (2004). Brain circuits regulating energy homeostasis. Neuroscientist 10, 235-246.   DOI
68 Tatemoto, K., Carlquist, M., and Mutt, V. (1982). Neuropeptide Y--a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature 296, 659-660.   DOI
69 Santamarina, A.B., Jamar, G., Mennitti, L.V., de Rosso, V.V., Cesar, H.C., Oyama, L.M., and Pisani, L.P. (2018). The use of jucara (Euterpe edulis Mart.) supplementation for suppression of NF-kappaB pathway in the hypothalamus after high-fat diet in Wistar rats. Molecules 23, 1814.   DOI
70 Schneeberger, M., Gomis, R., and Claret, M. (2014). Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. J. Endocrinol. 220, T25-T46.   DOI
71 Thaler, J.P., Yi, C.X., Schur, E.A., Guyenet, S.J., Hwang, B.H., Dietrich, M.O., Zhao, X., Sarruf, D.A., Izgur, V., Maravilla, K.R., et al. (2012). Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153-162.   DOI
72 Timper, K., Del Rio-Martin, A., Cremer, A.L., Bremser, S., Alber, J., Giavalisco, P., Varela, L., Heilinger, C., Nolte, H., Trifunovic, A., et al. (2020). GLP-1 receptor signaling in astrocytes regulates fatty acid oxidation, mitochondrial integrity, and function. Cell Metab. 31, 1189-1205.e13.   DOI
73 Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., and Cai, D. (2008). Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61-73.   DOI
74 Shim, H.S., Park, H.J., Woo, J., Lee, C.J., and Shim, I. (2019). Role of astrocytic GABAergic system on inflammatory cytokine-induced anxiety-like behavior. Neuropharmacology 160, 107776.   DOI
75 Posey, K.A., Clegg, D.J., Printz, R.L., Byun, J., Morton, G.J., Vivekanandan-Giri, A., Pennathur, S., Baskin, D.G., Heinecke, J.W., Woods, S.C., et al. (2009). Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 296, E1003-E1012.   DOI
76 Quadt, L., Critchley, H.D., and Garfinkel, S.N. (2018). The neurobiology of interoception in health and disease. Ann. N. Y. Acad. Sci. 1428, 112-128.   DOI
77 Tupone, D., Madden, C.J., Cano, G., and Morrison, S.F. (2011). An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J. Neurosci. 31, 15944-15955.   DOI
78 Rossi, M.A., Basiri, M.L., McHenry, J.A., Kosyk, O., Otis, J.M., van den Munkhof, H.E., Bryois, J., Hubel, C., Breen, G., Guo, W., et al. (2019). Obesity remodels activity and transcriptional state of a lateral hypothalamic brake on feeding. Science 364, 1271-1274.   DOI
79 Yoon, B.E., Woo, J., Chun, Y.E., Chun, H., Jo, S., Bae, J.Y., An, H., Min, J.O., Oh, S.J., Han, K.S., et al. (2014). Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition. J. Physiol. 592, 4951-4968.   DOI
80 Zhang, J., Chen, D., Sweeney, P., and Yang, Y. (2020). An excitatory ventromedial hypothalamus to paraventricular thalamus circuit that suppresses food intake. Nat. Commun. 11, 6326.   DOI
81 Zhang, Y., Reichel, J.M., Han, C., Zuniga-Hertz, J.P., and Cai, D. (2017). Astrocytic process plasticity and IKKbeta/NF-kappaB in central control of blood glucose, blood pressure, and body weight. Cell Metab. 25, 1091-1102.e4.   DOI
82 Lau, J., Farzi, A., Qi, Y., Heilbronn, R., Mietzsch, M., Shi, Y.C., and Herzog, H. (2018). CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis. Mol. Metab. 7, 102-118.   DOI
83 King, B.M. (2006). The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight. Physiol. Behav. 87, 221-244.   DOI
84 Kingsbury, K.J., Paul, S., Crossley, A., and Morgan, D.M. (1961). The fatty acid composition of human depot fat. Biochem. J. 78, 541-550.   DOI
85 Kristensen, P., Judge, M.E., Thim, L., Ribel, U., Christjansen, K.N., Wulff, B.S., Clausen, J.T., Jensen, P.B., Madsen, O.D., Vrang, N., et al. (1998). Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393, 72-76.   DOI
86 Baltatzi, M., Hatzitolios, A., Tziomalos, K., Iliadis, F., and Zamboulis, C. (2008). Neuropeptide Y and alpha-melanocyte-stimulating hormone: interaction in obesity and possible role in the development of hypertension. Int. J. Clin. Pract. 62, 1432-1440.   DOI
87 Miltenberger, R.J., Mynatt, R.L., Wilkinson, J.E., and Woychik, R.P. (1997). The role of the agouti gene in the yellow obese syndrome. J. Nutr. 127, 1902S-1907S.   DOI
88 Arcones, A.C., Cruces-Sande, M., Ramos, P., Mayor, F., Jr., and Murga, C. (2019). Sex differences in high fat diet-induced metabolic alterations correlate with changes in the modulation of GRK2 levels. Cells 8, 1464.   DOI
89 Arruda, A.P., Milanski, M., Coope, A., Torsoni, A.S., Ropelle, E., Carvalho, D.P., Carvalheira, J.B., and Velloso, L.A. (2011). Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. Endocrinology 152, 1314-1326.   DOI
90 Baird, J.P., Choe, A., Loveland, J.L., Beck, J., Mahoney, C.E., Lord, J.S., and Grigg, L.A. (2009). Orexin-A hyperphagia: hindbrain participation in consummatory feeding responses. Endocrinology 150, 1202-1216.   DOI
91 Barson, J.R., Morganstern, I., and Leibowitz, S.F. (2013). Complementary roles of orexin and melanin-concentrating hormone in feeding behavior. Int. J. Endocrinol. 2013, 983964.   DOI
92 Beck, B. (2006). Neuropeptide Y in normal eating and in genetic and dietary-induced obesity. Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1159-1185.   DOI
93 Beutler, L.R., Corpuz, T.V., Ahn, J.S., Kosar, S., Song, W., Chen, Y., and Knight, Z.A. (2020). Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat. Elife 9, e55909.   DOI
94 Hsuchou, H., He, Y., Kastin, A.J., Tu, H., Markadakis, E.N., Rogers, R.C., Fossier, P.B., and Pan, W. (2009). Obesity induces functional astrocytic leptin receptors in hypothalamus. Brain 132, 889-902.   DOI
95 Karmi, A., Iozzo, P., Viljanen, A., Hirvonen, J., Fielding, B.A., Virtanen, K., Oikonen, V., Kemppainen, J., Viljanen, T., Guiducci, L., et al. (2010). Increased brain fatty acid uptake in metabolic syndrome. Diabetes 59, 2171-2177.   DOI
96 Sa, M., Yoo, E.S., Koh, W., Park, M.G., Jang, H.J., Yang, Y.R., Lim, J., Won, W., Kwon, J., Bhalla, M., et al. (2022). Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA. BioRxiv, https://doi.org/10.1101/2021.11.07.467613   DOI
97 Waterson, M.J. and Horvath, T.L. (2015). Neuronal regulation of energy homeostasis: beyond the hypothalamus and feeding. Cell Metab. 22, 962-970.   DOI
98 Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., Gu, W., Kesterson, R.A., Boston, B.A., Cone, R.D., et al. (1997). Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131-141.   DOI
99 Jeong, J.H., Lee, D.K., and Jo, Y.H. (2017). Cholinergic neurons in the dorsomedial hypothalamus regulate food intake. Mol. Metab. 6, 306-312.   DOI
100 Jin, S., Kim, K.K., Park, B.S., Kim, D.H., Jeong, B., Kang, D., Lee, T.H., Park, J.W., Kim, J.G., and Lee, B.J. (2020). Function of astrocyte MyD88 in high-fat-diet-induced hypothalamic inflammation. J. Neuroinflammation 17, 195.   DOI
101 Lee, C.H., Suk, K., Yu, R., and Kim, M.S. (2020). Cellular contributors to hypothalamic inflammation in obesity. Mol. Cells 43, 431-437.   DOI
102 Liu, T., Zhang, L., Joo, D., and Sun, S.C. (2017). NF-kappaB signaling in inflammation. Signal Transduct. Target. Ther. 2, 17023.   DOI
103 Martins, L., Seoane-Collazo, P., Contreras, C., Gonzalez-Garcia, I., Martinez- Sanchez, N., Gonzalez, F., Zalvide, J., Gallego, R., Dieguez, C., Nogueiras, R., et al. (2016). A functional link between AMPK and orexin mediates the effect of BMP8B on energy balance. Cell Rep. 16, 2231-2242.   DOI
104 Lee, S., Yoon, B.E., Berglund, K., Oh, S.J., Park, H., Shin, H.S., Augustine, G.J., and Lee, C.J. (2010). Channel-mediated tonic GABA release from glia. Science 330, 790-796.   DOI
105 Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdan, M.G., Diano, S., Horvath, T.L., Cone, R.D., and Low, M.J. (2001). Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480-484.   DOI
106 Brusilow, S.W., Koehler, R.C., Traystman, R.J., and Cooper, A.J. (2010). Astrocyte glutamine synthetase: importance in hyperammonemic syndromes and potential target for therapy. Neurotherapeutics 7, 452-470.   DOI
107 Bysted, A., Holmer, G., Lund, P., Sandstrom, B., and Tholstrup, T. (2005). Effect of dietary fatty acids on the postprandial fatty acid composition of triacylglycerol-rich lipoproteins in healthy male subjects. Eur. J. Clin. Nutr. 59, 24-34.   DOI
108 Casse, F., Richetin, K., and Toni, N. (2018). Astrocytes' contribution to adult neurogenesis in physiology and Alzheimer's disease. Front. Cell. Neurosci. 12, 432.   DOI
109 Douglass, J.D., Dorfman, M.D., Fasnacht, R., Shaffer, L.D., and Thaler, J.P. (2017). Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation. Mol. Metab. 6, 366-373.   DOI
110 Firl, N., Kienberger, H., Hauser, T., and Rychlik, M. (2013). Determination of the fatty acid profile of neutral lipids, free fatty acids and phospholipids in human plasma. Clin. Chem. Lab. Med. 51, 799-810.   DOI
111 Fuente-Martin, E., Garcia-Caceres, C., Granado, M., de Ceballos, M.L., Sanchez-Garrido, M.A., Sarman, B., Liu, Z.W., Dietrich, M.O., Tena-Sempere, M., Argente-Arizon, P., et al. (2012). Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes. J. Clin. Invest. 122, 3900-3913.   DOI
112 Gao, Y., Layritz, C., Legutko, B., Eichmann, T.O., Laperrousaz, E., Moulle, V.S., Cruciani-Guglielmacci, C., Magnan, C., Luquet, S., Woods, S.C., et al. (2017). Disruption of lipid uptake in astroglia exacerbates diet-induced obesity. Diabetes 66, 2555-2563.   DOI
113 Bouret, S.G., Draper, S.J., and Simerly, R.B. (2004). Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J. Neurosci. 24, 2797-2805.   DOI
114 Thorburn, A.W. and Proietto, J. (1998). Neuropeptides, the hypothalamus and obesity: insights into the central control of body weight. Pathology 30, 229-236.   DOI