Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 2/2017

01-02-2017 | Review

Glia: silent partners in energy homeostasis and obesity pathogenesis

Authors: John D. Douglass, Mauricio D. Dorfman, Joshua P. Thaler

Published in: Diabetologia | Issue 2/2017

Login to get access

Abstract

Body weight stability requires homeostatic regulation to balance energy intake and energy expenditure. Research on this system and how it is affected by obesity has largely focused on the role of hypothalamic neurons as integrators of information about long-term fuel storage, short-term nutrient availability and metabolic demand. Recent studies have uncovered glial cells as additional contributors to energy balance regulation and obesity pathogenesis. Beginning with early work on leptin signalling in astrocytes, this area of research rapidly emerged after the discovery of hypothalamic inflammation and gliosis in obese rodents and humans. Current studies have revealed the involvement of a wide variety of glial cell types in the modulation of neuronal activity, regulation of hormone and nutrient availability, and participation in the physiological regulation of feeding behaviour. In addition, one glial type, microglia, has recently been implicated in susceptibility to diet-induced obesity. Together, these exciting new findings deepen our understanding of energy homeostasis regulation and raise the possibility of identifying novel mechanisms that contribute to the pathogenesis of obesity.
Appendix
Available only for authorised users
Literature
1.
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671PubMed
2.
Barsh GS, Farooqi IS, O’Rahilly S (2000) Genetics of body-weight regulation. Nature 404:644–651PubMed
3.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432PubMedCrossRef
4.
5.
Thaler JP, Yi CX, Schur EA et al (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122:153–162PubMedCrossRef
6.
Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK (2014) Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 9:2124–2138PubMedPubMedCentralCrossRef
7.
Valdearcos M, Xu AW, Koliwad SK (2015) Hypothalamic inflammation in the control of metabolic function. Annu Rev Physiol 77:131–160PubMedCrossRef
8.
Thaler JP, Guyenet SJ, Dorfman MD, Wisse BE, Schwartz MW (2013) Hypothalamic inflammation: marker or mechanism of obesity pathogenesis? Diabetes 62:2629–2634PubMedPubMedCentralCrossRef
9.
Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW (2006) Central nervous system control of food intake and body weight. Nature 443:289–295PubMedCrossRef
10.
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. Endocrinology 146:4192–4199PubMedCrossRef
11.
12.
13.
14.
Li JM, Ge CX, Xu MX et al (2015) Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats. Mol Nutr Food Res 59:189–202PubMedCrossRef
15.
Grayson BE, Levasseur PR, Williams SM, Smith MS, Marks DL, Grove KL (2010) Changes in melanocortin expression and inflammatory pathways in fetal offspring of nonhuman primates fed a high-fat diet. Endocrinology 151:1622–1632PubMedPubMedCentralCrossRef
16.
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 Endocrinol Metab 296:E1003–E1012PubMedCrossRef
17.
Milanski M, Degasperi G, Coope A et al (2009) 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
18.
Morselli E, Fuente-Martin E, Finan B et al (2014) Hypothalamic PGC-1alpha protects against high-fat diet exposure by regulating ERalpha. Cell Rep 9:633–645PubMedPubMedCentralCrossRef
19.
Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D (2008) Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135:61–73PubMedPubMedCentralCrossRef
20.
Munzberg H, Flier JS, Bjorbaek C (2004) Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 145:4880–4889PubMedCrossRef
21.
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 10:249–259PubMedPubMedCentralCrossRef
22.
Hong J, Stubbins RE, Smith RR, Harvey AE, Nunez NP (2009) Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutr J 8:11PubMedPubMedCentralCrossRef
23.
Gao Y, Ottaway N, Schriever SC et al (2014) Hormones and diet, but not body weight, control hypothalamic microglial activity. Glia 62:17–25PubMedCrossRef
24.
Garcia-Caceres C, Fuente-Martin E, Diaz F et al (2014) The opposing effects of ghrelin on hypothalamic and systemic inflammatory processes are modulated by its acylation status and food intake in male rats. Endocrinology 155:2868–2880PubMedCrossRef
25.
Wang X, Ge A, Cheng M et al (2012) Increased hypothalamic inflammation associated with the susceptibility to obesity in rats exposed to high-fat diet. Exp Diabetes Res 2012:847246PubMedPubMedCentral
26.
Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60:430–440PubMedCrossRef
27.
Pfrieger FW, Slezak M (2012) Genetic approaches to study glial cells in the rodent brain. Glia 60:681–701PubMedCrossRef
28.
Wieghofer P, Prinz M (2016) Genetic manipulation of microglia during brain development and disease. Biochim Biophys Acta 1862:299–309PubMedCrossRef
29.
Goodman T, Hajihosseini MK (2015) Hypothalamic tanycytes-masters and servants of metabolic, neuroendocrine, and neurogenic functions. Front Neurosci 9:387PubMedPubMedCentralCrossRef
30.
Fenno L, Yizhar O, Deisseroth K (2011) The development and application of optogenetics. Annu Rev Neurosci 34:389–412PubMedCrossRef
31.
Sternson SM, Roth BL (2014) Chemogenetic tools to interrogate brain functions. Annu Rev Neurosci 37:387–407PubMedCrossRef
32.
Yang L, Qi Y, Yang Y (2015) Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Rep 11:798–807PubMedCrossRef
33.
Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468:253–262PubMedCrossRef
34.
Ginhoux F, Greter M, Leboeuf M et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845PubMedPubMedCentralCrossRef
35.
Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM (2011) Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14:1142–1149PubMedCrossRef
36.
37.
38.
Baufeld C, Osterloh A, Prokop S, Miller KR, Heppner FL (2016) High-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia. Acta Neuropathol 132:361–375PubMedPubMedCentralCrossRef
39.
Djogo T, Robins SC, Schneider S et al (2016) Adult NG2-Glia are required for median eminence-mediated leptin sensing and body weight control. Cell Metab 23:797–810PubMedCrossRef
40.
Reis WL, Yi CX, Gao Y, Tschop MH, Stern JE (2015) Brain innate immunity regulates hypothalamic arcuate neuronal activity and feeding behavior. Endocrinology 156:1303–1315PubMedPubMedCentralCrossRef
41.
42.
43.
Cardona AE, Pioro EP, Sasse ME et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924PubMedCrossRef
44.
Morris DL, Oatmen KE, Wang T, DelProposto JL, Lumeng CN (2012) CX3CR1 deficiency does not influence trafficking of adipose tissue macrophages in mice with diet-induced obesity. Obesity 20:1189–1199PubMedPubMedCentralCrossRef
45.
Polyak A, Ferenczi S, Denes A et al (2014) The fractalkine/Cx3CR1 system is implicated in the development of metabolic visceral adipose tissue inflammation in obesity. Brain Behav Immun 38:25–35PubMedCrossRef
46.
Morari J, Anhe GF, Nascimento LF et al (2014) Fractalkine (CX3CL1) is involved in the early activation of hypothalamic inflammation in experimental obesity. Diabetes 63:3770–3784PubMedCrossRef
47.
48.
49.
Imai T, Hieshima K, Haskell C et al (1997) Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91:521–530PubMedCrossRef
50.
Jung S, Aliberti J, Graemmel P et al (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20:4106–4114PubMedPubMedCentralCrossRef
51.
Butovsky O, Jedrychowski MP, Moore CS et al (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143PubMedCrossRef
52.
Zhang Y, Chen K, Sloan SA et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947
53.
54.
Garcia-Caceres C, Quarta C, Varela L et al (2016) Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166:867–880PubMedCrossRef
55.
Rothstein JD, Dykes-Hoberg M, Pardo CA et al (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686PubMedCrossRef
56.
Cataldo AM, Broadwell RD (1986) Cytochemical identification of cerebral glycogen and glucose-6-phosphatase activity under normal and experimental conditions. II. Choroid plexus and ependymal epithelia, endothelia and pericytes. J Neurocytol 15:511–524PubMedCrossRef
57.
Leloup C, Arluison M, Lepetit N et al (1994) Glucose transporter 2 (GLUT 2): expression in specific brain nuclei. Brain Res 638:221–226PubMedCrossRef
58.
Suh SW, Bergher JP, Anderson CM, Treadway JL, Fosgerau K, Swanson RA (2007) Astrocyte glycogen sustains neuronal activity during hypoglycemia: studies with the glycogen phosphorylase inhibitor CP-316,819 ([R-R*, S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)pro pyl]-1H-indole-2-carboxamide). J Pharmacol Exp Ther 321:45–50PubMedCrossRef
59.
Brown AM, Sickmann HM, Fosgerau K et al (2005) Astrocyte glycogen metabolism is required for neural activity during aglycemia or intense stimulation in mouse white matter. J Neurosci Res 79:74–80PubMedCrossRef
60.
61.
62.
63.
Le Foll C, Dunn-Meynell AA, Miziorko HM, Levin BE (2014) Regulation of hypothalamic neuronal sensing and food intake by ketone bodies and fatty acids. Diabetes 63:1259–1269PubMedPubMedCentralCrossRef
64.
Le Foll C, Levin BE (2016) Fatty acid-induced astrocyte ketone production and the control of food intake. Am J Physiol Regul Integr Comp Physiol 310:R1186–R1192PubMedCrossRef
65.
Cheunsuang O, Morris R (2005) Astrocytes in the arcuate nucleus and median eminence that take up a fluorescent dye from the circulation express leptin receptors and neuropeptide Y Y1 receptors. Glia 52:228–233PubMedCrossRef
66.
Fuente-Martin E, Garcia-Caceres C, Granado M et al (2012) Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes. J Clin Invest 122:3900–3913PubMedPubMedCentralCrossRef
67.
Kim JG, Suyama S, Koch M et al (2014) Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat Neurosci 17:908–910PubMedCrossRef
68.
69.
Hsuchou H, He Y, Kastin AJ et al (2009) Obesity induces functional astrocytic leptin receptors in hypothalamus. Brain: J Neurol 132:889–902CrossRef
70.
Jayaram B, Pan W, Wang Y et al (1985) (2013) Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity. J Appl Physiol 114:734–741CrossRef
71.
Fuente-Martin E, Garcia-Caceres C, Argente-Arizon P et al (2016) Ghrelin regulates glucose and glutamate transporters in hypothalamic astrocytes. Sci Rep 6:23673PubMedPubMedCentralCrossRef
72.
Reiner DJ, Mietlicki-Baase EG, McGrath LE et al (2016) Astrocytes regulate GLP-1 receptor-mediated effects on energy balance. J Neurosci 36:3531–3540
73.
Chen N, Sugihara H, Kim J et al (2016) Direct modulation of GFAP-expressing glia in the arcuate nucleus bi-directionally regulates feeding. Elife 5, e18716PubMedPubMedCentral
74.
Guyenet SJ, Nguyen HT, Hwang BH, Schwartz MW, Baskin DG, Thaler JP (2013) High-fat diet feeding causes rapid, non-apoptotic cleavage of caspase-3 in astrocytes. Brain Res 1512:97–105PubMedPubMedCentralCrossRef
75.
Buckman LB, Thompson MM, Lippert RN, Blackwell TS, Yull FE, Ellacott KL (2015) Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice. Mol Metab 4:58–63PubMedCrossRef
76.
Buckman LB, Thompson MM, Moreno HN, Ellacott KL (2013) Regional astrogliosis in the mouse hypothalamus in response to obesity. J Comp Neurol 521:1322–1333PubMedPubMedCentralCrossRef
77.
Berkseth KE, Guyenet SJ, Melhorn SJ et al (2014) Hypothalamic gliosis associated with high-fat diet feeding is reversible in mice: a combined immunohistochemical and magnetic resonance imaging study. Endocrinology 155:2858–2867PubMedPubMedCentralCrossRef
78.
Lee D, Thaler JP, Berkseth KE, Melhorn SJ, Schwartz MW, Schur EA (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–E1250PubMedPubMedCentralCrossRef
79.
Schur EA, Melhorn SJ, Oh SK et al (2015) Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans. Obesity 23:2142–2148PubMedPubMedCentralCrossRef
80.
81.
Bull C, Freitas KC, Zou S et al (2014) Rat nucleus accumbens core astrocytes modulate reward and the motivation to self-administer ethanol after abstinence. Neuropsychopharmacol 39:2835–2845
82.
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 U S A 107:14875–14880PubMedPubMedCentralCrossRef
83.
Elizondo-Vega R, Cortes-Campos C, Barahona MJ, Oyarce KA, Carril CA, Garcia-Robles MA (2015) The role of tanycytes in hypothalamic glucosensing. J Cell Mol Med 19:1471–1482PubMedPubMedCentralCrossRef
84.
Morgello S, Uson RR, Schwartz EJ, Haber RS (1995) The human blood-brain barrier glucose transporter (GLUT1) is a glucose transporter of gray matter astrocytes. Glia 14:43–54PubMedCrossRef
85.
Garcia M, Millan C, Balmaceda-Aguilera C et al (2003) Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing. J Neurochem 86:709–724PubMedCrossRef
86.
Millan C, Martinez F, Cortes-Campos C et al (2010) Glial glucokinase expression in adult and post-natal development of the hypothalamic region. ASN Neuro 2:e00035PubMedPubMedCentralCrossRef
87.
Cortes-Campos C, Elizondo R, Llanos P, Uranga RM, Nualart F, Garcia MA (2011) MCT expression and lactate influx/efflux in tanycytes involved in glia-neuron metabolic interaction. PLoS One 6:e16411PubMedPubMedCentralCrossRef
88.
Langlet F, Levin BE, Luquet S et al (2013) Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab 17:607–617PubMedPubMedCentralCrossRef
89.
90.
91.
Robins SC, Stewart I, McNay DE et al (2013) Alpha-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors. Nat Commun 4:2049PubMedCrossRef
92.
93.
Levine JM, Stallcup WB (1987) Plasticity of developing cerebellar cells in vitro studied with antibodies against the NG2 antigen. J Neurosci 7:2721–2731
94.
95.
Rhee W, Ray S, Yokoo H et al (2009) Quantitative analysis of mitotic Olig2 cells in adult human brain and gliomas: implications for glioma histogenesis and biology. Glia 57:510–523PubMedPubMedCentralCrossRef
96.
Geha S, Pallud J, Junier MP et al (2010) NG2+/Olig2+ cells are the major cycle-related cell population of the adult human normal brain. Brain Pathol 20:399–411PubMedCrossRef
97.
Nishiyama A, Komitova M, Suzuki R, Zhu X (2009) Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat Rev Neurosci 10:9–22PubMedCrossRef
98.
99.
Mueller K, Anwander A, Moller HE et al (2011) Sex-dependent influences of obesity on cerebral white matter investigated by diffusion-tensor imaging. PLoS One 6:e18544PubMedPubMedCentralCrossRef
100.
Stanek KM, Grieve SM, Brickman AM et al (2011) Obesity is associated with reduced white matter integrity in otherwise healthy adults. Obesity 19:500–504PubMedCrossRef
101.
Karlsson HK, Tuulari JJ, Hirvonen J et al (2013) Obesity is associated with white matter atrophy: a combined diffusion tensor imaging and voxel-based morphometric study. Obesity 21:2530–2537PubMedCrossRef
102.
Yokum S, Ng J, Stice E (2012) Relation of regional gray and white matter volumes to current BMI and future increases in BMI: a prospective MRI study. Int J Obes 36:656–664CrossRef
103.
Shott ME, Cornier MA, Mittal VA et al (2015) Orbitofrontal cortex volume and brain reward response in obesity. Int J Obes 39:214–221CrossRef
104.
Puig J, Blasco G, Daunis IEJ et al (2015) Hypothalamic damage is associated with inflammatory markers and worse cognitive performance in obese subjects. J Clin Endocrinol Metab 100:E276–E281PubMedCrossRef
105.
Cazettes F, Cohen JI, Yau PL, Talbot H, Convit A (2011) Obesity-mediated inflammation may damage the brain circuit that regulates food intake. Brain Res 1373:101–109PubMedCrossRef
106.
107.
Zhang Y, Sloan SA, Clarke LE et al (2016) Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89:37–53PubMedCrossRef
108.
Han X, Chen M, Wang F et al (2013) Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12:342–353PubMedPubMedCentralCrossRef
Metadata
Title
Glia: silent partners in energy homeostasis and obesity pathogenesis
Authors
John D. Douglass
Mauricio D. Dorfman
Joshua P. Thaler
Publication date
01-02-2017
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 2/2017
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-4181-3

Other articles of this Issue 2/2017

Diabetologia 2/2017 Go to the issue

Article

Salt-inducible kinase 2 and -3 are downregulated in adipose tissue from obese or insulin-resistant individuals: implications for insulin signalling and glucose uptake in human adipocytes

Article

Nonlinear association of BMI with all-cause and cardiovascular mortality in type 2 diabetes mellitus: a systematic review and meta-analysis of 414,587 participants in prospective studies

Article

The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE −/− mice fed a western diet

Erratum

Erratum to: Glucose concentrations of less than 3.0 mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes

Article

Insulitis in human diabetes: a histological evaluation of donor pancreases

Short Communication

Type 1 diabetes mellitus and risk of incident epilepsy: a population-based, open-cohort study

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits