Hypothalamic Microinflammation: New Paradigm In Obesity And Metabolic Disease

Anna Meiliana, Nurrani Mustika Dewi, Andi Wijaya


BACKGROUND: Hypothalamus is the master regulator of body’s systemic homeostasis including energy balance, body temperature, sleep, blood pressure, and circadian rhythms. This review article will highlight the shifting of the old paradigm of obesityinflammation-metabolic syndrome, which was focused on visceral organs and systemic inflammation, into a new model involving microinflammation in the master regulator of endocrine system, i.e., hypothalamus.

CONTENT: Since the early stage of over-nutritional conditions and aging process, microinflammation in hypothalamus has started to emerge, due to the activation of several proinflammatory signaling pathways, especially the nuclear factor kappa B (NF-kB) and c-Jun N-terminal kinase (JNK)-mediated nuclear transcriptional programs. Together with intracellular organelle stress signals, these pathways develop a chronic microinflammatory environment in the hypothalamus leading to obesity and metabolic disorders.

SUMMARY: Hypothalamic inflammation has been noted not only as an important driver of impaired energy balance, but also contribute in altered neurocircuit functions and promote obesity-associated metabolic impairment.

KEYWORDS: hypothalamus, inflammation, metabolism, obesity, metabolic syndrome

Full Text:



Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010; 140: 900-17, CrossRef.

Cai D, Liu T. Hypothalamic inflammation: a double-edged sword to nutritional diseases. Ann NY Acad Sci. 2011; 1243: E1-39, CrossRef.

Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002; 110: 1389-98, CrossRef.

Gao F, Yokoyama S, Fujimoto M, Tsuneyama K, Saiki I, Shimada Y, et al. Effect of keishibukuryogan on genetic and dietary obesity models. Evid Based Complementary Altern Med. 2015; 2015: e801291, CrossRef.

Tang Y, Purkayastha S, Cai D. Hypothalamic microinflammation: a common basis of metabolic syndrome and aging. Trends Neurosci. 2015; 38: 36-44, CrossRef.

Cakir L, Nillni EA. Brain inflammation and endoplasmic reticulum stress. In: Nillni EA, editor. Textbook of Energy Balance, Neuropeptide Hormones, and Neuroendocrine Function. 1st ed. New York: Springer International Publishing; 2018. p. 75-108, CrossRef.

Vercruysse P, Vieau D, Blum D, Petersén Å, Dupuis L. Hypothalamic alterations in neurodegenerative diseases and their relation to abnormal energy metabolism. Front Mol Neurosci. 2018; 11: 2, CrossRef.

Berthoud HR. Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev. 2002; 26: 393-428, CrossRef.

Timper K, Brüning JC. Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity. Dis Model Mech. 2017; 10: 679-89, CrossRef.

Morton GJ, Meek TH, Schwartz MW. Neurobiology of food intake in health and disease. Nat Rev Neurosci. 2014; 15: 367-78, CrossRef.

Yi C, Zeltser L, Tschöp M. Metabolic Syndrome ePoster—Brain & Neuron. EPoster presented at: Nature Medicine; 2011.

Yi CX, Tschöp MH. Brain-gut-adipose-tissue communication pathways at a glance. Dis Model Mech. 2012; 5: 583-7, CrossRef.

Yi CX, Scherer T, Tschöp MH. Cajal revisited: does the VMH make us fat? Nat Neurosci. 2011; 14: 806-8, CrossRef.

Kim KW, Li S, Zhao H, Peng B, Tobet SA, Elmquist JK, et al. CNS-specific ablation of steroidogenic factor 1 results in impaired female reproductive function. Mol Endocrinol Baltim Md. 2010; 24: 1240-50, CrossRef.

Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci. 2003; 6: 736-42, CrossRef.

Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med. 2002; 8: 1376-82, CrossRef.

Bruinstroop E, la Fleur SE, Ackermans MT, Foppen E, Wortel J, Kooijman S, et al. The autonomic nervous system regulates postprandial hepatic lipid metabolism. Am J Physiol Endocrinol Metab. 2013; 304: E1089-96, CrossRef.

Lam TKT, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med. 2005; 11: 320-7, CrossRef.

Henry FE, Sugino K, Tozer A, Branco T, Sternson SM. Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss. eLife. 2015; 4: e09800, CrossRef.

Williams KW, Liu T, Kong X, Fukuda M, Deng Y, Berglund ED, et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab. 2014; 20: 471-82, CrossRef.

Cakir I, Nillni EA. Endoplasmic reticulum stress, the hypothalamus, and energy balance. Trends Endocrinol Metab TEM. 2019; 30: 163-76, CrossRef.

Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372: 425-32, CrossRef.

Williams KW, Elmquist JK. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat Neurosci. 2012; 15: 1350-5, CrossRef.

Begg DP, Woods SC. The endocrinology of food intake. Nat Rev Endocrinol. 2013; 9: 584-97, CrossRef.

Furuhashi M, Fucho R, Görgün CZ, Tuncman G, Cao H, Hotamisligil GS. Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice. J Clin Invest. 2008; 118: 2640-50, CrossRef.

Mathis D. Immunological goings-on in visceral adipose tissue. Cell Metab. 2013; 17: 851-9, CrossRef.

Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008; 135: 61-73, CrossRef.

De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, et al. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology. 2005; 146: 4192-9, CrossRef.

Kälin S, Heppner FL, Bechmann I, Prinz M, Tschöp MH, Yi CX. Hypothalamic innate immune reaction in obesity. Nat Rev Endocrinol. 2015; 11: 339-51, CrossRef.

Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011; 29: 415-45, CrossRef.

Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018; 14: 576-90, CrossRef.

van Beek AA, Van den Bossche J, Mastroberardino PG, de Winther MPJ, Leenen PJM. Metabolic Alterations in aging macrophages: ingredients for inflammaging? Trends Immunol. 2019; 40: 113-27, CrossRef.

Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and “garb-aging.” Trends Endocrinol Metab TEM. 2017; 28: 199-212, CrossRef.

Darwin CR. On the Origin of Species by Means of Natural Selection, or The Preservation of Favoured Races in the Struggle for Life. 1st ed. London: John Murray; 1859.

Fumagalli M, Sironi M, Pozzoli U, Ferrer-Admettla A, Pattini L, Nielsen R. Signatures of environmental genetic adaptation pinpoint pathogens as the main selective pressure through human evolution. PLOS Genet. 2011; 7: e1002355, CrossRef.

Vasseur E, Quintana-Murci L. The impact of natural selection on health and disease: uses of the population genetics approach in humans. Evol Appl. 2013; 6: 596-607, CrossRef.

Ottaviani E, Franceschi C. The invertebrate phagocytic immunocyte: clues to a common evolution of immune and neuroendocrine systems. Immunol Today. 1997; 18: 169-74, CrossRef.

Chung S, Lapoint K, Martinez K, Kennedy A, Boysen Sandberg M, McIntosh MK. Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. Endocrinology. 2006; 147: 5340-51, CrossRef.

Charrière G, Cousin B, Arnaud E, André M, Bacou F, Pénicaud L, et al. Preadipocyte conversion to macrophage: evidence of plasticity. J Biol Chem. 2003; 278: 9850-5, CrossRef.

Hotamisligil GS, Erbay E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol. 2008; 8: 923-34, CrossRef.

Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006; 444: 860-7, CrossRef.

Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017; 542: 177-85, CrossRef.

Ye J, Keller JN. Regulation of energy metabolism by inflammation: a feedback response in obesity and calorie restriction. Aging. 2010; 2: 361-8, CrossRef.

Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2001; 21: 1133-45, CrossRef.

Alle H, Roth A, Geiger JRP. Energy-efficient action potentials in hippocampal mossy fibers. Science. 2009; 325: 1405-8, CrossRef.

Bélanger M, Allaman I, Magistretti PJ. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 2011; 14: 724-38, CrossRef.

Yi CX, Habegger KM, Chowen JA, Stern J, Tschöp MH. A role for astrocytes in the central control of metabolism. Neuroendocrinology. 2011; 93: 143-9, CrossRef.

Banks WA. Blood-brain barrier as a regulatory interface. Forum Nutr. 2010; 63: 102-10, CrossRef.

Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev. 2006; 86: 1009-31, CrossRef.

Filosa JA, Blanco VM. Neurovascular coupling in the mammalian brain. Exp Physiol. 2007; 92: 641-6, CrossRef.

Frago LM, Chowen JA. Involvement of astrocytes in mediating the central effects of ghrelin. Int J Mol Sci. 2017; 18: 536, CrossRef.

Colombo E, Farina C. Astrocytes: key regulators of neuroinflammation. Trends Immunol. 2016; 37: 608-20, CrossRef.

Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 2009; 32: 638-47, CrossRef.

Cordiglieri C, Farina C. Astrocytes exert and control immune responses in the brain. Curr Immunol Rev. 2010; 6: 150-9, CrossRef.

Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007; 28: 138-45, CrossRef.

Melø TM, Nehlig A, Sonnewald U. Neuronal-glial interactions in rats fed a ketogenic diet. Neurochem Int. 2006; 48: 498-507, CrossRef.

Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. 1999; 343: 281-99, CrossRef.

Bröer S, Rahman B, Pellegri G, Pellerin L, Martin JL, Verleysdonk S, et al. Comparison of lactate transport in astroglial cells and monocarboxylate transporter 1 (MCT 1) expressing Xenopus laevis oocytes. Expression of two different monocarboxylate transporters in astroglial cells and neurons. J Biol Chem. 1997; 272: 30096-102, CrossRef.

Lin T, Koustova E, Chen H, Rhee PM, Kirkpatrick J, Alam HB. Energy substrate-supplemented resuscitation affects brain monocarboxylate transporter levels and gliosis in a rat model of hemorrhagic shock. J Trauma. 2005; 59: 1191–202, CrossRef.

Leino RL, Gerhart DZ, Duelli R, Enerson BE, Drewes LR. Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain. Neurochem Int. 2001; 38: 519-27, CrossRef.

Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Sotonyi P, Shanabrough M, et al. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci USA. 2010; 107: 14875-80, CrossRef.

Baquedano E, Chowen JA, Argente J, Frago LM. Differential effects of GH and GH-releasing peptide-6 on astrocytes. J Endocrinol. 2013; 218: 263-74, CrossRef.

Fuente-Martín E, García-Cáceres C, Argente-Arizón P, Díaz F, Granado M, Freire-Regatillo A, et al. Ghrelin regulates glucose and glutamate transporters in hypothalamic astrocytes. Sci Rep. 2016; 6: 23673, CrossRef.

García-Cáceres C, Fuente-Martín E, Díaz F, Granado M, Argente-Arizón P, Frago LM, et al. The opposing effects of ghrelin on hypothalamic and systemic inflammatory processes are modulated by its acylation status and food intake in male rats. Endocrinology. 2014; 155: 2868-80, CrossRef.

Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 2003; 37: 649-61, CrossRef.

Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. Ghrelin. Mol Metab. 2015; 4: 437-60, CrossRef.

Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001; 409: 194-8, CrossRef.

Schmid SM, Hallschmid M, Jauch-Chara K, Born J, Schultes B. A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men. J Sleep Res. 2008; 17: 331-4, CrossRef.

Dickson SL, Luckman SM. Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6. Endocrinology. 1997; 138: 771-7, CrossRef.

Jerlhag E, Egecioglu E, Landgren S, Salomé N, Heilig M, Moechars D, et al. Requirement of central ghrelin signaling for alcohol reward. Proc Natl Acad Sci. 2009; 106: 11318-23, CrossRef.

Ahima RS, Antwi DA. Brain regulation of appetite and satiety. Endocrinol Metab Clin North Am. 2008; 37: 811-23, CrossRef.

Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E. The role of the central ghrelin system in reward from food and chemical drugs. Mol Cell Endocrinol. 2011; 340: 80-7, CrossRef.

Skibicka KP, Hansson C, Egecioglu E, Dickson SL. Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression. Addict Biol. 2012; 17: 95-107, CrossRef.

Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci. 2006; 9: 381-8, CrossRef.

Kanoski SE, Fortin SM, Ricks KM, Grill HJ. Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling. Biol Psychiatry. 2013; 73: 915-23, CrossRef.

Andrews ZB, Erion D, Beiler R, Liu ZW, Abizaid A, Zigman J, et al. Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. J Neurosci. 2009; 29: 14057-65, CrossRef.

Moon M, Kim HG, Hwang L, Seo JH, Kim S, Hwang S, et al. Neuroprotective effect of ghrelin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease by blocking microglial activation. Neurotox Res. 2009; 15: 332-47, CrossRef.

Molofsky AV, Krencik R, Krenick R, Ullian EM, Ullian E, Tsai H, et al. Astrocytes and disease: a neurodevelopmental perspective. Genes Dev. 2012; 26: 891-907, CrossRef.

Bélanger M, Magistretti PJ. The role of astroglia in neuroprotection. Dialogues Clin Neurosci. 2009; 11: 281-95, PMID.

Fuente-Martin E, Garcia-Caceres C, Morselli E, Clegg DJ, Chowen JA, Finan B, et al. Estrogen, astrocytes and the neuroendocrine control of metabolism. Rev Endocr Metab Disord. 2013; 14: 331-8, CrossRef.

García-Cáceres C, Fuente-Martín E, Argente J, Chowen JA. Emerging role of glial cells in the control of body weight. Mol Metab. 2012; 1: 37-46, CrossRef.

Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest. 2001; 107: 7-11, CrossRef.

Brambilla R, Bracchi-Ricard V, Hu W-H, Frydel B, Bramwell A, Karmally S, et al. Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med. 2005; 202: 145-56, CrossRef.

Brambilla R, Persaud T, Hu X, Karmally S, Shestopalov VI, Dvoriantchikova G, et al. Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J Immunol Baltim Md 1950. 2009; 182: 2628-40, CrossRef.

Brambilla R, Morton PD, Ashbaugh JJ, Karmally S, Lambertsen KL, Bethea JR. Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. Glia. 2014; 62: 452-67, CrossRef.

Fu ES, Zhang YP, Sagen J, Candiotti KA, Morton PD, Liebl DJ, et al. Transgenic inhibition of glial NF-kappa B reduces pain behavior and inflammation after peripheral nerve injury. PAIN. 2010; 148: 509-18, CrossRef.

Füchtbauer L, Groth-Rasmussen M, Holm TH, Løbner M, Toft-Hansen H, Khorooshi R, et al. Angiotensin II Type 1 receptor (AT1) signaling in astrocytes regulates synaptic degeneration-induced leukocyte entry to the central nervous system. Brain Behav Immun. 2011; 25: 897-904, CrossRef.

Khorooshi R, Babcock AA, Owens T. NF-κB-driven STAT2 and CCL2 expression in astrocytes in response to brain injury. J Immunol. 2008; 181: 7284-91, CrossRef.

Dvoriantchikova G, Barakat D, Brambilla R, Agudelo C, Hernandez E, Bethea JR, et al. Inactivation of astroglial NF-κB promotes survival of retinal neurons following ischemic injury. Eur J Neurosci. 2009; 30: 175-85, CrossRef.

Barakat DJ, Dvoriantchikova G, Ivanov D, Shestopalov VI. Astroglial NF-κB mediates oxidative stress by regulation of NADPH oxidase in a model of retinal ischemia reperfusion injury. J Neurochem. 2012; 120: 586-97, CrossRef.

Colombo E, Di Dario M, Capitolo E, Chaabane L, Newcombe J, Martino G, et al. Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann Neurol. 2014; 76: 325-37, CrossRef.

Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-Wit D, et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol. 2007; 8: 247-56, CrossRef.

Spiegel S, Milstien S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011; 11: 403-15, CrossRef.

Fischer I, Alliod C, Martinier N, Newcombe J, Brana C, Pouly S. Sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 are functionally upregulated on astrocytes under pro-inflammatory conditions. PLOS ONE. 2011; 6: e23905, CrossRef.

Choi JW, Gardell SE, Herr DR, Rivera R, Lee CW, Noguchi K, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci. 2011; 108: 751-6, CrossRef.

Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002; 53: 409-35, CrossRef.

Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004; 306: 457-61, CrossRef.

Huang C, Lin C, Haataja L, Gurlo T, Butler AE, Rizza RA, et al. High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated beta-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes. 2007; 56: 2016-27, CrossRef.

Sachdeva MM, Claiborn KC, Khoo C, Yang J, Groff DN, Mirmira RG, et al. Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. Proc Natl Acad Sci USA. 2009; 106: 19090-5, CrossRef.

Schneeberger M, Dietrich MO, Sebastián D, Imbernón M, Castaño C, Garcia A, et al. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell. 2013; 155: 172-87, CrossRef.

Contreras C, González-García I, Martínez-Sánchez N, Seoane-Collazo P, Jacas J, Morgan DA, et al. Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Rep. 2014; 9: 366-77, CrossRef.

Yang L, Calay ES, Fan J, Arduini A, Kunz RC, Gygi SP, et al. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science. 2015; 349: 500-6, CrossRef.

Ma X, Xu L, Alberobello AT, Gavrilova O, Bagattin A, Skarulis M, et al. Celastrol protects against obesity and metabolic dysfunction through activation of a HSF1-PGC1α transcriptional axis. Cell Metab. 2015; 22: 695-708, CrossRef.

Hosoi T, Sasaki M, Miyahara T, Hashimoto C, Matsuo S, Yoshii M, et al. Endoplasmic reticulum stress induces leptin resistance. Mol Pharmacol. 2008; 74: 1610-9, CrossRef.

Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009; 9: 35-51, CrossRef.

Turpin SM, Nicholls HT, Willmes DM, Mourier A, Brodesser S, Wunderlich CM, et al. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 2014; 20: 678-86, CrossRef.

Contreras C, González-García I, Seoane-Collazo P, Martínez-Sánchez N, Liñares-Pose L, Rial-Pensado E, et al. Reduction of hypothalamic endoplasmic reticulum stress activates browning of white fat and ameliorates obesity. Diabetes. 2017; 66: 87-99, CrossRef.

Borg ML, Omran SF, Weir J, Meikle PJ, Watt MJ. Consumption of a high-fat diet, but not regular endurance exercise training, regulates hypothalamic lipid accumulation in mice. J Physiol. 2012; 590: 4377-89, CrossRef.

Ramírez S, Martins L, Jacas J, Carrasco P, Pozo M, Clotet J, et al. Hypothalamic ceramide levels regulated by CPT1C mediate the orexigenic effect of ghrelin. Diabetes. 2013; 62: 2329-37, CrossRef.

Kooijman S, van den Heuvel JK, Rensen PCN. Neuronal control of brown fat activity. Trends Endocrinol Metab TEM. 2015; 26: 657-68, CrossRef.

López M, Nogueiras R, Tena-Sempere M, Diéguez C. Hypothalamic AMPK: a canonical regulator of whole-body energy balance. Nat Rev Endocrinol. 2016; 12: 421-32, CrossRef.

Tseng YH, Cypess AM, Kahn CR. Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov. 2010; 9: 465-82, CrossRef.

Villarroya F, Vidal-Puig A. Beyond the sympathetic tone: the new brown fat activators. Cell Metab. 2013; 17: 638-43, CrossRef.

Nedergaard J, Cannon B. The browning of white adipose tissue: some burning issues. Cell Metab. 2014; 20: 396-407, CrossRef.

López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med. 2010; 16: 1001-8, CrossRef.

Martínez de Morentin PB, González-García I, Martins L, Lage R, Fernández-Mallo D, Martínez-Sánchez N, et al. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab. 2014; 20: 41-53, CrossRef.

Morrison SF, Madden CJ. Central nervous system regulation of brown adipose tissue. Compr Physiol. 2014; 4: 1677-713, CrossRef.

Contreras C, Gonzalez F, Fernø J, Diéguez C, Rahmouni K, Nogueiras R, et al. The brain and brown fat. Ann Med. 2015; 47: 150-68, CrossRef.

Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012; 26: 271-81, CrossRef.

Ruan HB, Dietrich MO, Liu ZW, Zimmer MR, Li MD, Singh JP, et al. O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell. 2014; 159: 306-17, CrossRef.

Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP, Svensson KJ, et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell. 2014; 156: 304-16, CrossRef.

Cakir I, Cyr NE, Perello M, Litvinov BP, Romero A, Stuart RC, et al. Obesity induces hypothalamic endoplasmic reticulum stress and impairs proopiomelanocortin (POMC) post-translational processing. J Biol Chem. 2013; 288: 17675-88, CrossRef.

Won JC, Jang PG, Namkoong C, Koh EH, Kim SK, Park JY, et al. Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin. Obes Silver Spring Md. 2009; 17: 1861-5, CrossRef.

Mayer CM, Belsham DD. 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. 2010; 151: 576-85, CrossRef.

Diaz B, Fuentes-Mera L, Tovar A, Montiel T, Massieu L, Martínez-Rodríguez HG, et al. Saturated lipids decrease mitofusin 2 leading to endoplasmic reticulum stress activation and insulin resistance in hypothalamic cells. Brain Res. 2015; 1627: 80-9, CrossRef.

Kleinridders A, Schenten D, Könner AC, Belgardt BF, Mauer J, Okamura T, et al. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab. 2009; 10: 249-59, CrossRef.

Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, 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 Off J Soc Neurosci. 2009; 29: 359-70, CrossRef.

Kanczkowski W, Alexaki VI, Tran N, Großklaus S, Zacharowski K, Martinez A, et al. Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation. Proc Natl Acad Sci. 2013; 110: 14801-6, CrossRef.

Hosoi T, Yokoyama S, Matsuo S, Akira S, Ozawa K. Myeloid differentiation factor 88 (MyD88)-deficiency increases risk of diabetes in mice. PloS One. 2010; 5: e12537, CrossRef.

Giorgi C, Missiroli S, Patergnani S, Duszynski J, Wieckowski MR, Pinton P. Mitochondria-associated membranes: composition, molecular mechanisms, and physiopathological implications. Antioxid Redox Signal. 2015; 22: 995-1019, CrossRef.

van Vliet AR, Verfaillie T, Agostinis P. New functions of mitochondria associated membranes in cellular signaling. Biochim Biophys Acta. 2014; 1843: 2253-62, CrossRef.

Zhang X, Wang C, Song G, Gan K, Kong D, Nie Q, et al. Mitofusion-2-mediated alleviation of insulin resistance in rats through reduction in lipid intermediate accumulation in skeletal muscle. J Biomed Sci. 2013; 20: 45, CrossRef.

Nie Q, Wang C, Song G, Ma H, Kong D, Zhang X, et al. Mitofusin 2 deficiency leads to oxidative stress that contributes to insulin resistance in rat skeletal muscle cells. Mol Biol Rep. 2014; 41: 6975-83, CrossRef.

Könner AC, Brüning JC. Selective insulin and leptin resistance in metabolic disorders. Cell Metab. 2012; 16: 144-52, CrossRef.

Clegg DJ, Gotoh K, Kemp C, Wortman MD, Benoit SC, Brown LM, et al. Consumption of a high-fat diet induces central insulin resistance independent of adiposity. Physiol Behav. 2011; 103: 10-6, CrossRef.

Prada PO, Zecchin HG, Gasparetti AL, Torsoni MA, Ueno M, Hirata AE, et al. Western diet modulates insulin signaling, c-Jun N-terminal kinase activity, and insulin receptor substrate-1ser307 phosphorylation in a tissue-specific fashion. Endocrinology. 2005; 146: 1576-87, CrossRef.

Jais A, Brüning JC. Hypothalamic inflammation in obesity and metabolic disease. J Clin Invest. 2017; 127: 24-32, CrossRef.

Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2012; 122: 153-62, CrossRef.

Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006; 443: 289-95, CrossRef.

Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998; 395: 763-70, CrossRef.

Coll AP, Farooqi IS, O’Rahilly S. The hormonal control of food intake. Cell. 2007; 129: 251-62, CrossRef.

Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005; 8: 571-8, CrossRef.

Sandoval D, Cota D, Seeley RJ. The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annu Rev Physiol. 2008; 70: 513-35, CrossRef.

Marino JS, Xu Y, Hill JW. Central insulin and leptin-mediated autonomic control of glucose homeostasis. Trends Endocrinol Metab TEM. 2011; 22: 275-85, CrossRef.

Lam TKT, Schwartz GJ, Rossetti L. Hypothalamic sensing of fatty acids. Nat Neurosci. 2005; 8: 579-84, CrossRef.

Friedman JM. Obesity: Causes and control of excess body fat. Nature. 2009; 459: 340-2, CrossRef.

Belgardt BF, Brüning JC. CNS leptin and insulin action in the control of energy homeostasis. Ann NY Acad Sci. 2010; 1212: 97-113, CrossRef.

Myers MG, Leibel RL, Seeley RJ, Schwartz MW. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab TEM. 2010; 21: 643-51, CrossRef.

Elmquist JK, Flier JS. Neuroscience. The fat-brain axis enters a new dimension. Science. 2004; 304: 63-4, CrossRef.

Rahmouni K, Correia MLG, Haynes WG, Mark AL. Obesity-associated hypertension: new insights into mechanisms. Hypertens Dallas Tex 1979. 2005; 45: 9-14, CrossRef.

Dietrich MO, Horvath TL. Feeding signals and brain circuitry. Eur J Neurosci. 2009; 30: 1688-96, CrossRef.

Myers MG, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008;70: 537-56, CrossRef.

Cai D. Neuroinflammation and neurodegeneration in overnutrition-induced diseases. Trends Endocrinol Metab TEM. 2013; 24: 40-7, CrossRef.

Meng Q, Cai D. Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IkappaB kinase beta (IKKbeta)/NF-kappaB pathway. J Biol Chem. 2011; 286: 32324-32, CrossRef.

Purkayastha S, Zhang H, Zhang G, Ahmed Z, Wang Y, Cai D. Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress. Proc Natl Acad Sci USA. 2011; 108: 2939-44, CrossRef.

Purkayastha S, Zhang G, Cai D. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat Med. 2011; 17: 883-7, CrossRef.

Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, et al. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature. 2013; 497: 211-6, CrossRef.

Purkayastha S, Cai D. Neuroinflammatory basis of metabolic syndrome. Mol Metab. 2013; 2: 356-63, CrossRef.

Li J, Tang Y, Cai D. IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat Cell Biol. 2012; 14: 999, CrossRef.

Li J, Tang Y, Purkayastha S, Yan J, Cai D. Control of obesity and glucose intolerance via building neural stem cells in the hypothalamus. Mol Metab. 2014; 3: 313-24, CrossRef.

Tang Y, Cai D. Hypothalamic inflammation and GnRH in aging development. Cell Cycle Georget Tex. 2013; 12: 2711-2, CrossRef.

Smith K. Neuroscience: Settling the great glia debate. Nature. 2010; 468: 160-2, CrossRef.

Allen NJ, Barres BA. Neuroscience: Glia - more than just brain glue. Nature. 2009; 457: 675-7, CrossRef.

Kohman RA, Rhodes JS. Neurogenesis, inflammation and behavior. Brain Behav Immun. 2013; 27: 22-32, CrossRef.

Yan J, Zhang H, Yin Y, Li J, Tang Y, Purkayastha S, et al. Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response. Nat Med. 2014; 20: 1001-8, CrossRef.

Valdearcos M, Xu AW, Koliwad SK. Hypothalamic inflammation in the control of metabolic function. Annu Rev Physiol. 2015; 77: 131-60, CrossRef.

DOI: https://doi.org/10.18585/inabj.v12i3.1235

Copyright (c) 2020 The Prodia Education and Research Institute

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.


Indexed by:






The Prodia Education and Research Institute