Hypothalamic innate immune reaction in obesity

Journal name:
Nature Reviews Endocrinology
Volume:
11,
Pages:
339–351
Year published:
DOI:
doi:10.1038/nrendo.2015.48
Published online

Abstract

Findings from rodent and human studies show that the presence of inflammatory factors is positively correlated with obesity and the metabolic syndrome. Obesity-associated inflammatory responses take place not only in the periphery but also in the brain. The hypothalamus contains a range of resident glial cells including microglia, macrophages and astrocytes, which are embedded in highly heterogenic groups of neurons that control metabolic homeostasis. This complex neural–glia network can receive information directly from blood-borne factors, positioning it as a metabolic sensor. Following hypercaloric challenge, mediobasal hypothalamic microglia and astrocytes enter a reactive state, which persists during diet-induced obesity. In established mouse models of diet-induced obesity, the hypothalamic vasculature displays angiogenic alterations. Moreover, proopiomelanocortin neurons, which regulate food intake and energy expenditure, are impaired in the arcuate nucleus, where there is an increase in local inflammatory signals. The sum total of these events is a hypothalamic innate immune reactivity, which includes temporal and spatial changes to each cell population. Although the exact role of each participant of the neural–glial–vascular network is still under exploration, therapeutic targets for treating obesity should probably be linked to individual cell types and their specific signalling pathways to address each dysfunction with cell-selective compounds.

At a glance

Figures

  1. The cytoarchitecture of hypothalamic NPY and POMC neurons, microglia, astrocytes and vasculature.
    Figure 1: The cytoarchitecture of hypothalamic NPY and POMC neurons, microglia, astrocytes and vasculature.

    a | A 3D reconstruction of NPY neurons (green), AIF-1-ir microglia (pink) and GFAP-ir astrocytes (white) in the arcuate nucleus. b | A 3D reconstruction of POMC neuron (green) and microglia (AIF-1-ir, in red) in the arcuate nucleus. c | Blood vessel (red) with microglia/perivascular macrophages (from CX3Cr1-GFP, green) and GFAP-ir astrocytes (blue) in the mediobasal hypothalamus. Asterisks denote location of the third ventricle. Scale bar: 35 µm in a, 50 µm in b and 70 µm in c. Abbreviations: AIF-1, allograft inflammatory factor 1; GFP, green fluorescent protein; GFAP-ir, immunofluorescent staining of glial fibrillary acidic protein; NPY, neuropeptide Y; POMC, proopiomelanocortin.

  2. The diversity of hypothalamic microglia and macrophages visualized in CX3Cr1-GFP mice.
    Figure 2: The diversity of hypothalamic microglia and macrophages visualized in CX3Cr1-GFP mice.

    a | Microglia and macrophages in different locations of the mediobasal hypothalamus. b | NPY neurons (from NPY-GFP mice, in green) extend into the internal zone of the ME, while microglia (by AIF-1-ir in red) are densely distributed throughout the entire ME. c | The cytoarchitecture of microglia and macrophages (in green), astrocytes and tanycytes (GFAP-ir, in red) in the IZ and EZ of the ME (indicated by DAPI in blue). The white arrows point to macrophage-like cells in the EZ of the ME. d | GFP+ (green) or AIF-1-ir+ (red) microglia and macrophages in the ME, white arrow points to a CX3CR1+ cell without AIF-1-ir in the EZ of the ME. e | Two perivascular GFP+CX3CR1+ cells (indicated by white arrows) tightly apposed to blood vessels (in blue) in the mediobasal hypothalamus. 'Merge', shown in yellow, indicates microglia and macrophages that are positive for GFP and AIF-ir. Asterisks denote location of the third ventricle. Scale bar: 70 µm in b, 50 µm in c and d and 20 µm in e. Abbreviations: AIF-1, allograft inflammatory factor 1; EZ, external zone; GFP, green fluorescent protein; GFAP-ir, immunofluorescent staining of glial fibrillary acidic protein; IZ, internal zone; ME, median eminence; NPY, neuropeptide Y.

  3. Morphological comparison of microglial reactivity in diet-induced obesity as visualized by AIF-1-ir.
    Figure 3: Morphological comparison of microglial reactivity in diet-induced obesity as visualized by AIF-1-ir.

    a | Reactivity in chow-fed mice. b | Reactivity in 8-month old mice fed a high-fat diet. Peripheral nerve injury in c | control mice and d | injured mice. e | Mediobasal hypothalamus injected with lentivirus carrying an empty vector at a concentration of 108/ml, and 1 µl was injected in the mediobasal hypothalamus of wild-type C57BL/6 mice. f | Mediobasal hypothalamus mechanically injured with a 32 gauge needle used for virus injection. The high-fat diet induced microglial reactivity, visualized by ramification and soma size, is comparable to those by peripheral nerve injury or mechanical injury, but much less than those activated by infectious lentivirus. Scale bar: 20 µm. Abbreviation: AIF-1, allograft inflammatory factor 1.

  4. The distribution pattern of the GFP+ astrocytes (green) and GFAP-ir astrocytes (red) in hGFAP-GFP transgenic mouse hypothalamus.
    Figure 4: The distribution pattern of the GFP+ astrocytes (green) and GFAP-ir astrocytes (red) in hGFAP-GFP transgenic mouse hypothalamus.

    Abbreviations: GFAP-ir, immunofluorescent staining of glial fibrillary acidic protein; GFP, green fluorescent protein.

  5. The diverse cell populations in the local microenvironment of the mediobasal hypothalamus and their respective transitions from basal conditions to reactive stages in the metabolic syndrome.
    Figure 5: The diverse cell populations in the local microenvironment of the mediobasal hypothalamus and their respective transitions from basal conditions to reactive stages in the metabolic syndrome.

    With exposure to a hypercaloric environment, microglia and astrocytes rapidly enter reactive states. Peripheral monocytes might also infiltrate this area as part of the local microenvironment immune response. In the long term, the communication between neurons and the general circulation is hampered by astrocytosis and angiogenic factors derived from the local microenvironment, which drive angiogenesis. The cell-specific antiobesity therapeutic strategy of targeting cells expressing the glucagon-like peptide 1 receptor with metabolically beneficial estradiol is effective, depending on the specific intercellular and intracellular mechanisms. This strategy confers the benefits of estrogen without the unwanted adverse effects. To specifically target reactive microglia, a conjugate in which fractalkine can carry anti-inflammatory steroids (such as dexamethasone) into the microglia is proposed.

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Author information

Affiliations

  1. Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment & Technische Universität München, 85748, Munich, Germany.

    • Stefanie Kälin &
    • Matthias H. Tschöp
  2. Department of Neuropathology, Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany.

    • Frank L. Heppner
  3. Institute of Anatomy, University of Leipzig, Liebigstr. 13, 04103 Leipzig, Germany.

    • Ingo Bechmann
  4. Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106 Freiburg, Germany.

    • Marco Prinz
  5. Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands.

    • Chun-Xia Yi

Contributions

M.H.T. and C.-X.Y. provided substantial contribution to discussion of the content. S.K. and C.-X.Y. wrote the article. F.L.H., I.B., M.P., M.H.T. and C.-X.Y. reviewed and edited the manuscript before submission.

Competing interests statement

The authors declare no competing interests.

Corresponding author

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Author details

  • Stefanie Kälin

    Dr Stefanie Kälin is a Postdoc in the neuroendocrinology group at the Institute for Diabetes and Obesity, affiliated to the Helmholtz Diabetes Center Munich, Germany. She received her PhD from the Humboldt University Berlin (2010–2014) working at the Charité Hospital as a member of the international Max Planck Research School. Her principal research interest is the pathophysiology of the metabolic syndrome in rodent models, with particular reference to immune regulatory circuits in the central nervous system.

  • Frank L. Heppner

    Frank L. Heppner, MD, is Professor of Neuropathology and Director of the Department of Neuropathology at the Charité–Universitätsmedizin Berlin, Germany. His research group aims to understand microglia biology in health and disease and studies the impact of the immune system on the pathogenesis of neurological disorders such as neurodegenerative diseases, ultimately aimed at recognizing novel therapeutic strategies and targets to treat these central nervous system diseases.

  • Ingo Bechmann

    Dr Ingo Bechmann is the Director of the Institute of Anatomy, Universität Leipzig, Germany. His group has been working in the field of neuroimmunology with a particular focus on immune tolerance in the brain ('immune privilege'), microglial and the blood–brain barrier.

  • Marco Prinz

    Marco Prinz is Professor of Neuropathology and Director of the Institute of Neuropathology at the University of Freiburg, Germany. His laboratory focuses on the development and molecular pathogenesis of disease. He co-chairs the Research Unit 1336 'From monocytes to brain macrophages: conditions influencing the fate of myeloid cells in the brain', which is funded by the German Research Foundation.

  • Matthias H. Tschöp

    Dr Matthias H. Tschöp is the Director of the Institute for Diabetes and Obesity at Helmholtz Center Munich, the Research Director of the Helmholtz Diabetes Center, and the Chair of the Division of Metabolic Diseases at the Technical University Munich, Germany. The aim of his Institute is the discovery, validation and targeting of novel pathomechanisms and molecular signals in metabolic disease. To this end, his research is focused on identifying molecular signals for the development of personalized preventative and therapeutic strategies for diabetes mellitus and obesity, as well as related comorbidities.

  • Chun-Xia Yi

    Dr Chun-Xia Yi received an MD from Tongji Medical College of Huazhong University of Science and Technology, China, and a PhD from the Netherlands Institute for Neuroscience. She is a group leader in the Institute for Diabetes and Obesity, Helmholtz Zentrum München, Germany, and an Assistant Professor in the Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Netherlands. Her research focuses on deconstructing neuron–microglia circuits in the brain regions that sense energy states and regulate metabolism, in animal models and humans. She aims to identify targets for normalizing dysfunctional microglia in metabolic diseases.

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